Chronic impairment of neurovascular coupling and cognitive decline in young survivors of severe traumatic brain injury - Zsofia Dina Magyar-Sumegi; Mark Csendes; Dominika Lendvai-Emmert; Gabriella Sebestyen; Viktoria Tamas; Szabolcs Bandi; Andras Czigler; Andriy Yabluchanskiy; Stefano Tarantini; Zoltan Ungvari; Endre Czeiter; Krisztina Amrein; et al. (GeroScience, 2025)
Severe traumatic brain injury (TBI) leads to chronic cognitive decline, imposing a significant societal burden. The regulation of cerebral blood flow (CBF) is critical for cognitive function, and acute disruptions in CBF regulation predict poor TBI outcomes. However, the long-term effects of TBI on CBF regulation and their association with cognitive function remain poorly understood. This study aimed to investigate whether severe TBI results in chronic CBF dysregulation and whether this contributes to long-term cognitive deficits. Additionally, we examined the role of TBI-induced insulin-like growth factor 1 (IGF-1) deficiency in cerebrovascular dysfunction. We assessed cognitive function, basal CBF (via phase contrast MRI), CBF autoregulation (via transcranial Doppler), and neurovascular coupling (NVC) in 33 TBI survivors (mean age 37.6 years, ~ 10 years post-injury) and 21 age-matched healthy controls. Serum IGF-1 levels were also measured. TBI survivors exhibited significant impairments in memory and executive function compared to controls. While basal CBF and autoregulation remained intact, NVC responses were chronically impaired and correlated with cognitive deficits. However, IGF-1 levels did not differ between groups and were not associated with NVC impairment or cognitive function. Our findings indicate that severe TBI results in chronic impairment of neurovascular coupling, which likely contributes to long-term cognitive deficits. These results highlight the need for further research to identify underlying neurovascular mechanisms and develop interventions to restore NVC and cognitive function in TBI survivors.

Regionally specific picture naming benefits of focal tDCS are dependent on baseline performance in older adults - A. Yucel; F. Niemann; M. Meinzer; A. K. Martin (GeroScience, 2025)
Word-finding difficulty is a common challenge in older age and is linked to various neuropathological conditions associated with ageing. Transcranial direct current stimulation (tDCS) has shown promise as a cognitive enhancement tool for both healthy aging and age- related cognitive disorders. However, its effectiveness in enhancing word-finding ability remains inconsistent, especially among healthy adults. Variability across studies is likely due to factors such as task selection, stimulation parameters, and small and variable sample sizes. Additionally, many studies have overlooked within-study variability of potentially relevant participant characteristics, including the role of baseline performance in evaluating tDCS efficacy. In this preregistered study, we examined 72 older and 72 younger adults using a double-blind, sham-controlled design, delivering anodal focal tDCS to either the left inferior frontal gyrus or the left temporoparietal junction. Baseline naming performance and fluid intelligence were measured before stimulation. Anodal stimulation of the left inferior frontal gyrus significantly increased response speed for object and action naming in older adults, but crucially only in older adults who performed poorly during the baseline naming session, p = .02, η 2 ₚ = 0.17. Findings demonstrate regionally specific effects of focal tDCS in healthy older individuals in greater need for naming facilitation. Notably, performance on a broad measure of fluid intelligence was unrelated to stimulation response, suggesting task specificity of this effect.

The associations between biological markers of aging and appetite loss across adulthood: retrospective case–control data from the INSPIRE-T study - Annelie Turesson; Afsaneh Koochek; Margaretha Nydahl; Jean-Marc Lemaitre; Paul Bensadoun; Laurent O. Martinez; Sophie Guyonnet; Yves Rolland; Bruno Vellas; Philipe De Souto Barreto; Lauréane Brigitte; Agathe Milhet; et al. (GeroScience, 2025)
Appetite loss is a common clinical condition in older adulthood, but how this condition associates with biological aging remains unknown. The present study aims to examine the associations of biological aging markers with appetite loss in community-dwelling people aged 21 to 102 years. This retrospective case–control study used baseline data from the INSPIRE-T cohort in Toulouse, France. Each of the 49 cases with appetite loss was sex- and age-matched to two controls without appetite loss ( n = 147; median age of 79 years, interquartile range: 19.5; 67% women). Appetite loss was assessed using a single yes–no question from the World Health Organization´s Integrated Care for Older People screening tool. Biomarkers (first- and second-generation DNA methylation-based epigenetic clocks [Horvath, Hannum, PhenoAge, and GrimAge], the inflammatory aging clock iAge, and Adenosine triphosphatase inhibitory factor 1—IF1) were derived from blood samples. Logistic regression analyzed the associations of these markers with appetite loss. In fully adjusted models, accelerated aging using GrimAge was the only biomarker associated with appetite loss (Odds Ratio = 1.21, 95% Confidence Interval: 1.03, 1.43). When stratified by age (≤ 65 years vs. > 65 years) and sex, this association remained significant only in individuals over 65 years and men. Future research is needed to explore the potential mechanisms involved, as well as how other biological drivers of aging (e.g., cell senescence, deregulated nutrient sensing) relate to appetite loss.

Spontaneous intracerebral hemorrhage during computed tomography scanning—assessment of hyperacute hematoma growth - Bence Gunda; Péter Böjti; Tímea Takács; Esra Zhubi; Dániel Bereczki; Andrea Varga; Lajos R. Kozák (GeroScience, 2025)
Pathophysiological mechanisms underlying hematoma expansion in spontaneous intracerebral hemorrhage (ICH) remain poorly understood, and most data are derived from postmortem studies or serial neuroimaging studies performed over hours to days from onset. Our unique case report of a hypertensive ICH serendipitously captured by serial CT provides valuable in vivo data from the very onset of hematoma formation in an aging individual. A 76-year-old hypertensive man underwent elective carotid CT angiography to evaluate a previously known asymptomatic right carotid stenosis. During scanning, he developed severe right hemispheric neurological deficit signs. Immediate rescanning and subsequent follow-up imaging revealed the hyperacute evolution of a right putaminal ICH. We co-registered four scans (from 00 h:00 min, 00 h:06 min, 00 h:21 min, and 24 h:58 min) to a common template in 3D and made volumetric measurements of the growing hematoma also assessing the spatial relationship of expansion with the sources of bleed seen as contrast extravasation (“spot signs”). We found that spot signs appeared on the periphery of the initial hematoma, and further expansion was seen in the directions determined by these spot signs. Most of the final ICH volume developed in the first 20 min post-onset, highlighting the hyperacute nature of hematoma growth. Our findings support the hypothesis that hematoma expansion in hypertensive ICH, particularly in aging individuals, results from multiple sources of bleeding due to a cascade of secondary vessel ruptures with eccentric expansion rather than a single source and continuous bleeding with concentric expansion reflecting the global fragility of the cerebral vasculature. The therapeutic time window for hematoma expansion prevention is very narrow.

Predictors of graft patency following coronary artery bypass graft surgery: the role of nebivolol therapy - Tímea Balla; Tamás Maros; Gábor Csató; Nóra Erdei; Beatrix Ványai; Noel Johny Nellamkuzhi; Riko Shima; Dániel Czuriga; Zoltán Csanádi; Andrea Molnár; Nóra Homoródi; Zsolt Kőszegi; et al. (GeroScience, 2025)
The long-term postoperative occlusion of venous or arterial grafts following coronary artery bypass graft surgery (CABG) is a constant and unresolved problem, with a negative impact on clinical outcome. In our study, we aimed to find predictors that influence graft patency. The data of 202 patients who underwent CABG and had control coronary angiography on an average of 8.55 ± 4.56 years were analyzed retrospectively. Based on the presence of graft occlusion ascertained at control coronary angiography, patients were divided into two groups: 81 in the graft occlusion group (with 89 grafts degeneration: 64 saphenous vein [SVG] and 25 arterial graft) and 121 in the control group with patent grafts. The two groups were considerably well-matched regarding patient characteristics. Among medical conditions, peripheral artery disease has been found to be an independent predictor of increased graft occlusion, but only in SVG patients (OR 3.64, CI 1.21–11.03, p = 0.021). When evaluating medical therapy, significantly more patients were on nebivolol in the control group, compared to the graft occlusion group ( p = 0.032). Moreover, nebivolol has been found to be an independent predictor of a lower degree of graft occlusion development (OR 0.36, CI 0.14–0.94, p = 0.036). Nebivolol has been found especially effective in preventing SVG graft occlusion (OR 0.24, CI 0.07–0.76, p = 0.015). Nebivolol has been found to reduce the frequency of graft occlusion following CABG, especially in case of SVG grafts. The vasodilatory properties of nebivolol may, at least in part, be responsible for the favorable effects of the drug to prevent graft occlusion.

Neuroprotective mechanism of hydrogen sulfide in okadaic acid-induced alzheimer-like pathology - Pradip K. Kamat; Anuradha Kalani; Nabendu Debnath; Zayd Mushtaq; Suresh C. Tyagi; Neetu Tyagi (GeroScience, 2025)

Age-associated methionine sulfoxide reductase A protects against valvular interstitial cell senescence and valvular calcification - Qing Li; Chengxiang Song; Zisong Wei; Hao Zhou; Shuoding Wang; Hongde Li; Haoran Yang; Qiang Luo; Junli Li; Mao Chen (GeroScience, 2025)
Calcific aortic valve disease (CAVD) is a cardiovascular disease prevalent in the aging population, resulting in high morbidity and mortality rates. However, the molecular mechanisms underlying CAVD remain unclear. We initially conducted an RNA sequencing analysis of aortic valve leaflets from rats of different ages to identify key genes involved in valvular aging and calcification. Bioinformatics analysis demonstrated that methionine sulfoxide reductase A (MSRA) was crucial to valvular calcification and senescence. To further investigate whether and how MSRA influences CAVD pathogenesis, we utilized two in vitro models: a human valvular interstitial cell (VIC) calcification model induced by osteogenic medium, and a VIC senescence model induced by hydrogen peroxide. Western blotting, immunofluorescence, flow cytometry, and alkaline phosphatase staining were conducted to evaluate the changes in calcific nodule formation and senescent markers. In vivo, ApoE −/− mice were treated either a normal chow or a high-cholesterol chow to determine the effects of MSRA overexpression on aortic valve calcification and senescence. MSRA silencing increased the osteogenic differentiation and senescence of VIC, whereas its overexpression produced the opposite effects. Similarly, we found that MSRA overexpression reduced calcium deposition and decreased the levels of senescent markers in ApoE −/− mice. Further mechanism experiments showed that MSRA suppressed osteoblastic differentiation via inhibiting the toll-like receptor (TLR2)/nuclear factor-κB (NF-κB) pathway. Our findings demonstrate that MSRA ameliorates valvular calcification and senescence by inhibiting TLR2/NF-κB pathway, highlighting MSRA as a promising target for treating age-associated CAVD.

Kynurenine pathway dysregulation in cognitive impairment and dementia: a systematic review and meta-analysis - Kyonghwan Choe; Lieke Bakker; Daniel L. A. van den Hove; Simone J. P. M. Eussen; Gunter Kenis; Inez H. G. B. Ramakers; Frans R. J. Verhey; Bart P. F. Rutten; Sebastian Köhler (GeroScience, 2025)
The kynurenine pathway (KP) might be involved in pathophysiological processes associated with dementia, but clinical studies reported contradictory results. This systematic review and meta-analysis summarized the available evidence for (i) differences in KP metabolites in patients with cognitive impairment compared to cognitively healthy individuals and (ii) associations between KP metabolites and cognitive functioning. English, full-length articles with prospective, cross-sectional, or case–control study designs, published in Pubmed, Embase, PsychINFO, or the Cochrane Database of Systematic Reviews up to October 2023, were included. Random-effects meta-analyses of standardized mean differences (SMD) were performed. Heterogeneity, meta-regression, small study bias, and study quality assessments were carried out. Of 8797 retrieved studies, 98 were eligible for the systematic review. Meta-analyses comparing Alzheimer’s disease (AD) dementia patients to controls (n = 27 studies) indicated lower CSF levels of tryptophan (SMD = − 0.26 [95% CI − 0.41, − 0.12]), 3-hydroxykynurenine (− 0.21 [− 0.39, − 0.04]), anthranilic acid (− 0.28 [− 0.48, − 0.08]), and quinolinic acid (− 0.38 [− 0.56, − 0.21]) in AD dementia, while CSF levels of kynurenic acid were higher (0.18 [0.01, 0.35]). Blood levels of tryptophan (− 0.39 [− 0.51, − 0.28]), kynurenic acid (− 0.31 [− 0.47, − 0.15]), xanthurenic acid (− 0.34 [− 0.54, − 0.15]), and 3-hydroxyanthranilic acid (− 0.42 [− 0.61, − 0.22]) were lower in AD dementia. For some of these metabolites, similar directions were observed in meta-analyses comparing individuals with mild cognitive impairment with controls, although the number of included studies in these analyses was relatively small (n = 11). Associations with cognitive test scores were inconclusive and generally non-significant. These results suggest that AD dementia is associated with lower blood levels of several KP metabolites. Findings challenge current assumptions of neurotoxic quinolinic acid levels being associated with dementia.

Bilateral neuromuscular adaptation to acute unilateral resistance exercise in healthy older adults - Nishadi N. Gamage; Abdulmajeed Altheyab; Yuxiao Guo; Bethan E. Phillips; George M. Opie; John G. Semmler; Philip Atherton; Mathew Piasecki (GeroScience, 2025)
Resistance exercise (RE) enhances functionality in older adults and has proven effective as a means of cross-education in scenarios of unilateral disuse. However, the extent to which older adults demonstrate cross-limb transfer at the motor unit (MU) level following a single bout of unilateral RE is unclear. Thirteen healthy older adults (74.9 ± 4.8 years; 5 females) underwent bilateral neuromuscular assessments pre- and post- a single bout of unilateral RE consisting of sets of 12 repetitions of leg extension of the dominant (exercise) leg, at 75% of 1 repetition maximum, performed to failure. Maximum voluntary contraction (MVC) and force steadiness (FS) were measured. Central and peripheral features of individual MU were recorded using high-density surface electromyography and intramuscular electromyography (HDs/iEMG), during contractions normalised to 25% MVC. Following unilateral RE, MVC reduced in exercise (-14.8%, p < 0.001) and control (-6.9%, p = 0.003) legs, with reduced FS performance in the exercise leg compared to the control (p = 0.002). MU firing rate increased during contractions normalised to 25% baseline MVC in the exercised leg ( p < 0.05), with no adaptation in the control leg ( p > 0.05). All iEMG recorded measures of MU potentials remained unchanged in both legs (all p > 0.05). Acute unilateral RE leads to bilateral MVC reduction in older males and females, demonstrating the cross-limb transfer effect. However, adaptation of MU features was only apparent in the exercised limb, and mechanisms underlying the force decline in the non-exercised limb remain uncertain.

Stepping and tapping: combining motor tasks improves cognitive classification - Kaylee D. Rudd; Michele L. Callisaya; Katherine Lawler; Alastair J. Noyce; James C. Vickers; Jane Alty (GeroScience, 2025)
Gait and key-tapping are individually associated with mild cognitive impairment (MCI) and dementia. However, it is unclear if these motor functions are correlated, or whether combining them improves classification of objective (dementia, MCI) and subjective cognitive impairment (SCI). We recruited 73 participants with dementia, 106 MCI, 57 SCI, and 83 cognitively healthy controls (HC). Consensus diagnosis was made after gold-standard interdisciplinary assessment. Fast-paced gait was assessed on an electronic walkway and fast-paced key-tapping on a computer keyboard. Correlations between gait and key-tapping measures (speed, frequency, variability and contact) were tested using Pearson’s correlation. Classification accuracy was calculated using area under receiver-operating-characteristic curves (AUC) and compared to the null model comprising age, sex and education. Gait and key-tapping measures correlated moderately. Combined gait and key-tapping speed improved classification accuracy of dementia (.97), and MCI (.91), from HC, but not SCI, compared to gait (dementia: .94, MCI: .87) or the null model (dementia: .89, MCI: .79). Gait and key-tapping measures were associated with Alzheimer’s disease and vascular dementia, but the effect size for key-tapping variability was larger in vascular dementia ( β : 225.71) compared to Alzheimer’s disease ( β : 38.30). Gait and key-tapping variability was associated with non-amnestic MCI. Measures of gait were correlated with corresponding key-tapping measures, but their association with cognitive impairment was not the same. Combining gait and key-tapping motor measures improved classification accuracy of MCI and dementia. This suggests gait and key-tapping measures provide information about different aspects of motor-cognitive association worth further investigation.

Towards Precision Geromedicine in Singapore - Jonas John Posko Amalaraj; Louis Island; Jane Yu Ying Ong; Laureen Wang; Jose Hans M. Valderas; Michael Dunn; Yap Seng Chong; Johannes Meij; Andrea B. Maier (GeroScience, 2025)
Since the discovery that ageing is a modifiable process in animal models, significant advancements in geroscience have led to the emergence of the field of Precision Geromedicine, which aims to optimise health and healthspan by targeting ageing-related processes. Ageing-related diseases (ARDs), accounting for 80% of Singapore’s disease burden in 2019, are on the rise as the nation approaches the “super-aged” status by 2030. In response, Singapore is reshaping its healthcare system to focus on healthy ageing, as seen in the launch of the Healthier SG initiative in 2023, which empowers citizens to manage their health proactively with support from over 1800 private general practices. Additionally, Singapore is investing in geroscience to build the foundations of Precision Geromedicine, aiming to integrate gerodiagnostics and gerotherapeutics into clinical practice. Leveraging its robust healthcare system, digital infrastructure, and socio-political stability, Singapore is well-positioned to become a model for addressing ARDs amidst global demographic shifts.

No detectable impact of short-term treatment delays on lung cancer survival - Zoltan Ungvari; Mónika Fekete; Annamaria Buda; Andrea Lehoczki; János Tibor Fekete; Gyöngyi Munkácsy; Péter Varga; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Timely initiation of treatment is a core principle of oncologic care, especially for aggressive cancers such as lung cancer. However, the real-world impact of short-term delays in treatment initiation on survival outcomes in lung cancer remains unclear. This meta-analysis evaluates the association between treatment delays of 4, 8, and 12 weeks and all-cause mortality in lung cancer patients. A systematic search was conducted in PubMed, Scopus, and Web of Science for studies published between 2000 and 2025. Of 5360 screened records, 15 studies were included, comprising 16 cohorts for overall survival of lung cancer patients. Hazard ratios (HRs) for 4-, 8-, and 12-week treatment delays were estimated using random-effects meta-analyses. Heterogeneity was measured with the I 2 statistic, and publication bias was assessed using funnel plots and Egger’s test. No significant association was found between treatment delay and survival at any of the time points. Pooled HRs were 1.00 (95% CI, 0.99–1.02) for a 4-week delay, 1.01 (95% CI, 0.99–1.03) for an 8-week delay, and 1.01 (95% CI, 0.98–1.05) for a 12-week delay. Despite high heterogeneity ( I 2 = 97%), no evidence of publication bias was detected. This meta-analysis found no significant impact of short-term treatment delays (up to 12 weeks) on mortality in lung cancer patients. These findings challenge the assumption that brief delays universally worsen outcomes and underscore the importance of individualized treatment planning and prioritization.

The association between statins and gait speed reserve in older adults: effects of concomitant medication - Anton De Spiegeleer; Antoon Bronselaer; Ine Mahieu; Dorien Vreys; Aaron Haslbauer; Jan-Philipp Leibfarth; Lara Van Schoote; Aster Wakjira; Mirko Petrovic; Evelien Wynendaele; Bart De Spiegeleer; Nele Van Den Noortgate; et al. (GeroScience, 2025)
Statins are frequently prescribed to older adults, yet their effects on ageing phenotypes such as frailty or physiological reserves remain poorly understood. Gait Speed Reserve (GSR), defined as the difference between maximal and usual gait speeds, serves as an indicator of physiological reserve, reflecting the body’s ability to perform beyond baseline functional levels. Polypharmacy, prevalent in this population, may contribute to inconsistent findings through interactions between statins and concomitant medications. We aimed to investigate how concomitant medications moderate the association between statin use and GSR in older adults. To this end, we conducted a cross-sectional observational cohort study using data from the Mobility Center at the University Department of Geriatric Medicine FELIX PLATTER, Basel, Switzerland ( n = 5519 adults aged ≥ 60 years). Moderation regression analyses with propensity score weighting were used to evaluate the effect of concomitant medications on the association between statin use and GSR. Results showed statin use was associated with a lower GSR compared to non-use (− 1.9 cm/s [95% CI, − 3.1 to − 0.72]). However, ACE inhibitors and aspirin significantly influenced this association. The GSR difference for statin users compared to non-users increased by 3.7 cm/s (from − 2.2 to 1.5 cm/s; 95% CI, 0.0 to 7.4) with concomitant ACE inhibitor use and by 5.8 cm/s (from − 3.4 to 2.3 cm/s; 95% CI, 2.5 to 9.1) with aspirin use. We found no statistically significant association between statin use and usual gait speed, the secondary outcome. In conclusion, ACE inhibitors and aspirin interacted with statins, reversing the negative association with GSR into a positive one when co-used. Future clinical trials are needed to determine causality and further investigate the impact of concomitant medication use on statin effects in aging populations. Meanwhile, our findings underscore the importance of considering concomitant medication use when assessing the effects of statins in older adults.

The PARP inhibitor olaparib promotes senescence in murine macrophages - Anna Kieronska-Rudek; Karim Zuhra; Kelly Ascenção; Stefan Chlopicki; Csaba Szabo (GeroScience, 2025)
Cellular senescence is a multifaceted process involving cell cycle arrest, telomere shortening, and the accumulation of DNA damage associated with aging and cellular stress. It is marked by persistent cell cycle arrest and DNA damage accumulation, and plays an increasingly recognized role in age-related diseases and cancer therapy. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for use in ovarian cancer treatment. We hypothesized that olaparib may influence senescence by inhibiting DNA damage repair, and investigated its effects on non-senescent and replicatively senescent murine macrophages (RAW 264.7 cells). Senescent cells exhibited elevated baseline levels of PARP1 expression, PARylation, and DNA damage relative to non-senescent control cells. Olaparib amplified these differences by upregulating senescence markers (SA-β-gal and p21), inhibiting proliferation, and exacerbating DNA damage. Many of its effects were more pronounced in senescent cells. At higher concentrations (10–30 µM), olaparib induced significant cytotoxicity through mixed apoptotic and necrotic mechanisms, with senescent cells exhibiting a predominantly necrotic response. Interestingly, both mitochondrial activity and cellular bioenergetics were elevated in senescent cells at baseline, and were more severely impaired by olaparib compared to non-senescent control cells. These findings underscore olaparib’s enhanced cytotoxic and pro-senescent effects in senescent immune cells and suggest potential implications for its use in elderly cancer patients with an increased burden of senescent cells.

Dietary vitamin D intake and 2-year changes in cognitive function in older adults with overweight or obesity and metabolic syndrome - Héctor Vázquez-Lorente; Jiaqi Ni; Indira Paz-Graniel; Estefanía Toledo; Dolores Corella; Olga Castañer; J. Alfredo Martínez; Ángel M. Alonso-Gómez; Julia Wärnberg; Jesús Vioque; Dora Romaguera; José López-Miranda; et al. (GeroScience, 2025)
The protective role of dietary vitamin D intake on cognitive function is of interest, but evidence remains inconsistent. We aimed to evaluate the association between dietary vitamin D intake and 2-year cognitive changes in older adults at risk of cognitive decline. This longitudinal study comprised 5454 individuals (aged 55–75 years in men and 60–75 years in women) who exhibited overweight/obesity and metabolic syndrome. Data on dietary vitamin D intake was assessed using a validated 143-item food frequency questionnaire. Cognitive function was assessed through five composite scores derived from a comprehensive battery of eight neuropsychological tests, encompassing global cognitive function, general cognitive function, attention, executive function, and language domains. Multivariable-adjusted linear regression models were fitted to examine the association between energy-adjusted cumulative average dietary vitamin D intake over time and 2-year changes in cognitive function. After adjusting for multiple covariates, energy-adjusted cumulative average dietary vitamin D intake as a continuous variable was associated with greater 2-year improvements in global cognitive function ( β 1.18 × 10 −2 ; 95% CI 0.19 × 10 −2 to 2.17 × 10 −2 ), executive function ( β 1.12 × 10 −2 ; 95% CI 0.03 × 10 −2 to 2.21 × 10 −2 ), and language ( β 1.61 × 10 −2 ; 95% CI 0.43 × 10 −2 to 2.78 × 10 −2 ). Additionally, the higher cumulative average dietary vitamin D intake quartile was associated with an increase in global cognitive function ( β 7.10 × 10 −2 ; 95% CI 0.59 × 10 −2 to 13.6 × 10 −2 ), language ( β 7.07 × 10 −2 ; 95% CI − 0.52 × 10 −2 to 14.7 × 10 −2 ), and a lower decline in attention ( β 9.58 × 10 −2 ; 95% CI 1.60 × 10 −2 to 17.5 × 10 −2 ). A higher dietary vitamin D intake was associated with modest favorable changes in cognitive function and a reduced cognitive decline over a 2-year period. These findings highlight the need for further research to explore the potential benefits of boosting dietary vitamin D intake for cognitive health in older adults.

Effects of tetrahydroindenoindole supplementation on metabolism: A systematic review with meta-analysis of rodent-based studies - Miguel Pérez-Rodríguez; Rafael A. Casuso; Sandra Rodríguez-López; José A. González-Reyes; José M. Villalba (GeroScience, 2025)
Identifying novel compounds with therapeutic potential is a main area of interest in biomedical research. Tetrahydroindenoindole (THII) has emerged as a compound of interest due to both its antioxidant properties and its action as a pharmacological activator of the enzyme cytochrome b 5 reductase 3. However, there is a lack of comprehensive synthesis of findings, particularly concerning the effects of THII on metabolism in mice under non-disease conditions. This systematic review with meta-analysis aims to bridge this gap by analyzing existing studies. Our findings demonstrated that THII supplementation reduced body weight gain, while fat mass remained unchanged. Fasting blood glucose and plasma insulin levels, as well as insulin levels during the glucose tolerance test, showed no changes. However, glucose tolerance improved with THII supplementation during the glucose tolerance test, particularly in animals under a high-fat diet. THII supplementation also increased O 2 consumption and CO 2 production, with a tendency to lower respiratory quotient. In mitochondria, THII supplementation did not affect state 3 respiration, while increased state 4, and decreased the respiratory exchange ratio. Notably, mitochondrial H 2 O 2 production during state 4 respiration and ATP levels also remained unchanged. Furthermore, THII supplementation reduced NADPH-dependent O 2 uptake, NADPH-dependent H 2 O 2 production, and lipid peroxidation. Despite the limitations and potential sources of bias identified, we observed valuable outcomes linked to THII supplementation. The significant impact on energy metabolism, mitochondrial function, and oxidative stress underscores THII as a promising intervention with translational relevance for aging-related alterations, enhancing healthspan, and targeting metabolic-associated diseases such as obesity or diabetes.

Depression increases cancer mortality by 23–83%: a meta-analysis of 65 studies across five major cancer types - Zoltan Ungvari; Mónika Fekete; Annamaria Buda; Andrea Lehoczki; János Tibor Fekete; Péter Varga; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Depression is a prevalent but often underrecognized comorbidity among cancer patients. Emerging evidence suggests that psychological distress may adversely impact cancer outcomes, but the magnitude of its effect on survival remains unclear. This meta-analysis evaluates the association between depression diagnosed after cancer diagnosis and cancer-specific and all-cause mortality across major cancer types. A systematic search of PubMed, Web of Science, Google Scholar, and the Cochrane Library was conducted to identify cohort studies examining the impact of depression on cancer mortality. Studies were included if they assessed clinically diagnosed depression or depressive symptoms using validated scales and reported hazard ratios (HRs) for mortality outcomes. A random-effects meta-analysis was performed to pool HR estimates, with heterogeneity assessed via Cochran’s Q and I 2 statistics. Funnel plots and Egger’s test were used to evaluate publication bias. A total of 65 cohort studies were included. Depression was associated with significantly increased cancer-specific mortality in colorectal cancer (HR 1.83, 95% CI 1.47–2.28), breast cancer (HR 1.23, 95% CI 1.13–1.34), lung cancer (HR 1.59, 95% CI 1.36–1.86), and prostate cancer (HR 1.74, 95% CI 1.36–2.23). When considering mixed cancer types, depression was linked to a 38% increased risk of cancer mortality (HR 1.38, 95% CI 1.20–1.60). Significant heterogeneity was observed across studies ( I 2 range 56–98%), suggesting variations in study populations and methodologies. Sensitivity analyses confirmed the robustness of the findings, and trial sequential analysis indicated sufficient evidence for a conclusive association. Depression after cancer diagnosis is associated with a significantly increased risk of cancer-specific mortality across multiple cancer types. These findings highlight the urgent need for integrating routine mental health screening and interventions into oncology care. Future research should focus on mechanistic pathways and targeted interventions to mitigate the negative impact of depression on cancer survival.

Anthocyanin supplementation in adults at risk for dementia: a randomized controlled trial on its cardiometabolic and anti-inflammatory biomarker effects - Miguel German Borda; Robinson Ramírez-Vélez; Felipe Botero-Rodriguez; Jonathan Patricio-Baldera; Chiara de Lucia; Ilaria Pola; George E. Barreto; Khadija Khalifa; Anne Katrine Bergland; Miia Kivipelto; Tommy Cederholm; Henrik Zetterberg; et al. (GeroScience, 2025)
Anthocyanins are dietary flavonoids shown to have a therapeutic capacity to mitigate inflammation and oxidative stress. The present secondary analyses from the “Anthocyanins in People at Risk for Dementia Study” were aimed at (I) determining the intervention’s effect on blood-based markers of cardiovascular disease and inflammation and (II) evaluating whether baseline factors such as age, sex, inflammation, or cardiometabolic score may moderate the intervention’s effect on inflammatory status. This study was an ancillary, 24-week randomized, double-blind, placebo-controlled Phase II trial. Sub-sample participants ( n = 99), aged 60–80 years with mild cognitive impairment or cardiometabolic disorders, were randomized to receive either 320 mg/day of anthocyanins or placebo. The biomarkers analyzed included inflammatory biomarker assessment (IL − 6, IL − 8, IL − 10, IL − 1b, TNF − α, IFN − γ), and C-reactive protein (CRP), as well as albumin, thrombocytes, cholesterol, LDL, HDL, and triglycerides, which were longitudinally compared between both groups. Baseline characteristics were balanced between the groups. ANCOVA analyses reveal 24-week differences favoring the anthocyanin treatment in LDL cholesterol levels (ƞp 2 = 0.078; p = 0.015), cardiometabolic score (ƞp 2 = 0.073; p = 0.021), CRP levels (ƞp 2 = 0.417; p = 0.0001), IL − 6 (ƞp2 = 0.085; p = 0.015), IL − 1b (ƞp 2 = 0.058; p = 0.037), and Inflam z-score 5 (ƞp 2 = 0.059, p = 0.004). Moderation analysis demonstrated that the inflammatory score at baseline was a significant predictor of the effect of the intervention on the CRP levels. Anthocyanin supplementation reduces CRP and cardiovascular disease biomarkers in individuals at risk of dementia, especially when there is increased inflammation at baseline. ClinicalTrials.gov study identifier: NCT03419039.

The effect of enhanced glycolysis on cardiac aging - Anna Faakye; Kylene M. Harold; Satoshi Matsuzaki; Atul Pranay; Maria F. Mendez Garcia; Brooke L. Loveland; Sandra N. Rigsby; Frederick F. Peelor; Craig Eyster; Benjamin F. Miller; Timothy M. Griffin; Michael Kinter; et al. (GeroScience, 2025)
Cardiac aging is associated with metabolic changes, including an increased reliance on glycolysis, and an increased susceptibility to cardiovascular diseases. This study explores the relationship between enhanced cardiac glycolysis and aging using the Glyco Hi mouse model, characterized by constitutively elevated glycolysis. We compared cardiac function, metabolism, mitochondrial performance, and hallmarks of aging between aged (21 and 24 months) Glyco Hi and wild-type (WT) mice across sexes. Our findings reveal modest reductions in cardiac function in aged Glyco Hi mice compared to WT mice, with sex-specific differences in heart size and collagen concentration. Female Glyco Hi hearts exhibited hypertrophy without fibrosis, while males showed elevated collagen levels. Whole-body metabolic assessments revealed similar energy expenditure and respiratory patterns across genotypes, with females displaying less circadian-associated variation in metabolism. Mitochondrial analyses showed that aged Glyco Hi hearts maintained metabolic adaptations favoring glycolysis but did not exhibit significant bioenergetic dysfunction or oxidative stress. Pyruvate dehydrogenase activity, initially elevated in younger Glyco Hi hearts, normalized to WT levels with age. Proteomic and metabolomic analyses highlighted distinct profiles between genotypes, with Glyco Hi hearts exhibiting increased glycolytic enzyme levels and reduced abundance of fatty acid oxidation proteins. Despite these differences, indicators of oxidative stress, proteostasis, and cellular senescence were comparable between genotypes, suggesting no acceleration of aging-related dysfunction. This study demonstrates that increased cardiac glycolysis alone does not suffice to drive accelerated cardiac aging. Instead, metabolic and functional changes in aged Glyco Hi hearts reflect adaptations rather than pathological declines, providing insights into potential metabolic targets for interventions against cardiac aging.

Association of longitudinal body mass index trajectories with phenotypic age acceleration: a cross-sectional study based on growth mixture modeling - Yalan Liu; Li Zhang; Zhaofeng Jin; Lin Zhang; Yan Song; Li He (GeroScience, 2025)

The road to a long lifespan in the Persian squirrel, a natural model for extended longevity: resisting free radical stress and healthy phospholipids - Fahimeh Salehi; Gholamreza Kavoosi; Paul. J. Jacobs; Nigel C. Bennett; Shahin Ahmadian; Babak Bastani; Mahdi Gholami (GeroScience, 2025)

Beyond genes and environment: mapping biological stochasticity in aging - Adam J. Hruby; Gilberto Garcia; Max A. Thorwald; Caleb E. Finch; Joshua Johnson; Ryo Higuchi-Sanabria (GeroScience, 2025)
Aging is characterized by extensive variability in the onset of morbidity and mortality, even in genetically identical populations with carefully controlled environments. This points to the important role stochasticity plays in shaping the divergent aging process between individual organisms. Here, we survey how stochastic factors at the level of molecules, cells, tissues, and organisms manifest in and impact the aging process, with a focus on the nematode Caenorhabditis elegans . Findings of stochasticity in C. elegans give additional insights for aspects of aging in the more complex settings of mammals with parallels drawn between organisms when appropriate. The emerging understanding of the stochastic contributors to longevity will enhance research strategies and medical interventions for personalized medicine.

Epigenetic clocks and inflammaging: pitfalls caused by ignoring cell-type heterogeneity - Xiaolong Guo; Andrew E. Teschendorff (GeroScience, 2025)

Biological age acceleration and interaction with genetic predisposition in the risk of type 2 diabetes and coronary artery disease - Guangrui Yang; Xihao Du; Xuanwei Jiang; Jingxuan Wang; Shuxiao Shi; Victor W. Zhong (GeroScience, 2025)

Associations of cardiorespiratory fitness with brain white matter microstructural integrity and white matter hyperintensity volume across the adult lifespan - Junyeon Won; Takashi Tarumi; Tsubasa Tomoto; Kevin Shan; Karen M. Rodrigue; Kristen M. Kennedy; Denise C. Park; Rong Zhang (GeroScience, 2025)

Global and tissue-specific transcriptomic dysregulation in human aging: Pathways and predictive biomarkers - Muhammad Arif; Andrea Lehoczki; György Haskó; Falk W. Lohoff; Zoltan Ungvari; Pal Pacher (GeroScience, 2025)
Aging is a universal biological process that impacts all tissues, leading to functional decline and increased susceptibility to age-related diseases, particularly cardiometabolic disorders. While aging is characterized by hallmarks such as mitochondrial dysfunction, chronic inflammation, and dysregulated metabolism, the molecular mechanisms driving these processes remain incompletely understood, particularly in a tissue-specific context. To address this gap, we conducted a comprehensive transcriptomic analysis across 40 human tissues using data from the Genotype-Tissue Expression (GTEx) project, comparing individuals younger than 40 years with those older than 65 years. We identified over 17,000 differentially expressed genes (DEGs) across tissues, with distinct patterns of up- and down-regulation. Enrichment analyses revealed that up-regulated DEGs were associated with inflammation, immune responses, and apoptosis, while down-regulated DEGs were linked to mitochondrial function, oxidative phosphorylation, and metabolic processes. Using gene co-expression network (GCN) analyses, we identified 1,099 genes as dysregulated nodes (DNs) shared across tissues, reflecting global aging-associated transcriptional shifts. Integrating machine learning approaches, we pinpointed key aging biomarkers, including GDF15 and EDA2R, which demonstrated strong predictive power for aging and were particularly relevant in cardiometabolic tissues such as the heart, liver, skeletal muscle, and adipose tissue. These genes were also validated in plasma proteomics studies and exhibited significant correlations with clinical cardiometabolic health indicators. This study provides a multi-tissue, integrative perspective on aging, uncovering both systemic and tissue-specific molecular signatures. Our findings advance understanding of the molecular underpinnings of aging and identify novel biomarkers that may serve as therapeutic targets for promoting healthy aging and mitigating age-related diseases.

Comment on article: Acquired hemophilia A as a disease of the elderly by Lehoczki A. et al - Antonella Mameli; Francesco Marongiu; Doris Barcellona (GeroScience, 2025)

Correction to: Functional and vascular neuroimaging in maritime pilots with long‑term sleep disruption - Lara J. Mentink; Matthias J. P. van Osch; Leanne J. Bakker; Marcel G. M. Olde Rikkert; Christian F. Beckmann; Jurgen A. H. R. Claassen; Koen V. Haak (GeroScience, 2025)

Predicting the progression of MCI and Alzheimer’s disease on structural brain integrity and other features with machine learning - Marthe Mieling; Mushfa Yousuf; Nico Bunzeck; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; Susan Landau; Monica Rivera-Mindt; Leslie M. Shaw; Edward B. Lee; et al. (GeroScience, 2025)
Machine learning (ML) on structural MRI data shows high potential for classifying Alzheimer’s disease (AD) progression, but the specific contribution of brain regions, demographics, and proteinopathy remains unclear. Using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, we applied an extreme gradient-boosting algorithm and SHAP (SHapley Additive exPlanations) values to classify cognitively normal (CN) older adults, those with mild cognitive impairment (MCI) and AD dementia patients. Features included structural MRI, CSF status, demographics, and genetic data. Analyses comprised one cross-sectional multi-class classification (CN vs. MCI vs. AD dementia, n = 568) and two longitudinal binary-class classifications (CN-to-MCI converters vs. CN stable, n = 92; MCI-to-AD converters vs. MCI stable, n = 378). All classifications achieved 70–77% accuracy and 61–83% precision. Key features were CSF status, hippocampal volume, entorhinal thickness, and amygdala volume, with a clear dissociation: hippocampal properties contributed to the conversion to MCI, while the entorhinal cortex characterized the conversion to AD dementia. The findings highlight explainable, trajectory-specific insights into AD progression.

Self-report and actigraphy measures of sleep and domain-specific cognitive performance in older adults - Kelsey R. Sewell; Audrey M. Collins; Miranda G. Chappel-Farley; Shivangi Jain; Haiqing Huang; George Grove; Arthur F. Kramer; Edward McAuley; Jeffrey Burns; Charles Hillman; Eric Vidoni; Anna Marsland; et al. (GeroScience, 2025)

Normal cerebral oxygen consumption and lactate levels in patients with Alzheimer’s disease and Lewy body dementia - Christian Sandøe Musaeus; Gunhild Waldemar; Troels Wesenberg Kjær; Birgitte Bo Andersen; Peter Høgh; Steen Gregers Hasselbalch; Ulrich Lindberg; Kristian Steen Frederiksen; Henrik Bo Wiberg Larsson; Mark B. Vestergaard (GeroScience, 2025)
Brain metabolism is reduced in patients with dementia disorders, as demonstrated by hypometabolism on 2-deoxy-2-[ 18 F]fluoroglucose ([ 18 F]FDG) positron emissions tomography. A contributing factor to the hypometabolism could be decreased cerebral blood flow (CBF) leading to a state of subtle hypoperfusion‐induced tissue hypoxia causing a reduced brain oxygen metabolism and consequently elevated brain lactate. In the current exploratory study, we investigated brain lactate, global and regional CBF, and global cerebral metabolic rate of oxygen (CMRO 2 ) in patients with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLBs). We hypothesized that the patients demonstrate a state of tissue hypoxia with reduced CMRO 2 and elevated brain lactate concentration. Participants included 24 AD patients, 10 DLB patients, and 15 healthy controls. MR spectroscopy measured lactate in the precuneus and occipital lobe. Global CBF and venous oxygen saturation (for CMRO2 calculation) were assessed using phase-contrast and susceptibility-based oximetry MRI, respectively. Regional CBF was measured with ASL-MRI. We observed no significant difference in either brain lactate or CMRO 2 between groups. The regional CBF in precuneus was significantly lower in AD compared to HC; however, this hypoperfusion was not associated with a higher lactate concentration. The lack of a difference in CMRO 2 or lactate concentration between patients and controls suggests that the hypometabolism observed in patients with AD and DLB may reflect structural neurodegeneration and not a state of tissue hypoxia. The local decrease of CBF in precuneus in patients with AD may be due to a lower CBF demand due to neurodegeneration.

Longitudinal changes in blood-borne geroscience biomarkers: results from a population-based study - Anna Picca; Ngoc Viet Nguyen; Riccardo Calvani; Matilda Dale; Claudia Fredolini; Emanuele Marzetti; Amaia Calderón-Larrañaga; Davide Liborio Vetrano (GeroScience, 2025)
Multi-marker approaches are well suited for untangling the intrinsic complexity of aging and related conditions. Herein, we quantified (1) baseline concentrations of a panel of geroscience biomarkers pertaining to four biological domains (i.e., metabolism, inflammation, vascular/organ dysfunction and cellular senescence, and neurodegeneration) in individuals aged ≥60 years; (2) investigated linear and non-linear changes in biomarker levels over a 6-year period according to age and sex; and (3) described the relationships among geroscience biomarkers at baseline and follow-up. We found that repeated measures of age-dependent changes of 47 blood-borne biomarkers over 6 years had differential associations depending on the biological domains. The most relevant biomolecules in the associations between age and repeated assessments were (1) adiponectin, C-peptide, renin (metabolism), (2) CXCL10, IL-1α, IL-1β, IL-6, IL-10, IL-12p70, MPO (inflammation), (3) cystatin C, MMP7, MMP12, VCAM-1 (vascular/organ dysfunction and cellular senescence), and (4) S100B and Tau protein (neurodegeneration). Among these molecules, a negative association with increasing age was found for IL-1α, IL-1β, IL-12p70, S100B, and Tau protein. Non-linear relationships were also identified with age for IGFBP-1, leptin, β2M, TNFRSF1B, fibrinogen, GDF-15, N-cadherin, and BDNF. Our results indicate that inflammatory and metabolic biomolecules are strongly associated with aging over 6 years of follow-up. Whether the biological pathways reflected by these biomarkers contribute to the aging process or are associated with negative health-related events needs to be explored through comprehensive multi-omics longitudinal analysis in larger cohorts.

Correction to: Whole‑body networks: a holistic approach for studying aging - Orestis Stylianou; Johannes M. Meixner; Tilman Schlick; Colin M. Krüger (GeroScience, 2025)

Alcohol and the aging cardiovascular system: a dangerous synergy uncovered - Csaba Szabo (GeroScience, 2025)

“Doctored: fraud, arrogance, and tragedy in the quest to cure Alzheimer’s”: an important new book with direct relevance to GeroScience - Csaba Szabo (GeroScience, 2025)

Sex differences in body mass index and waist circumference trajectories and dementia risk: the HUNT4 70+ study - Ekaterina Zotcheva; Bjørn Heine Strand; Vegard Skirbekk; Kay Deckers; Steinar Krokstad; Gill Livingston; Archana Singh-Manoux; Geir Selbæk (GeroScience, 2025)
We examined associations between body mass index (BMI), waist circumference (WC), and dementia risk, and differences in BMI and WC trajectories before dementia diagnosis. We included 9,739 participants (54% women) aged 70+ from the Trøndelag Health Study (HUNT4 70+). BMI was measured four times (1984–2019) and WC three times (1995–2019). Dementia diagnoses were clinically assessed at HUNT4 70+ . Women and men with dementia had higher midlife BMI and WC than those without dementia. These differences diminished closer to diagnosis, especially in women. Midlife obesity in both sexes and midlife overweight, high WC, and overweight/obesity with high WC in men were linked to higher dementia risk. Lower dementia risk was observed with late-life overweight for both sexes, late-life high WC in women, late-life overweight/obesity with normal WC in men or high WC in women. Adiposity measures and their changes influence dementia risk differently in women and men.

Effects of aerobic exercise of different intensities on the social, emotional, and financial functioning of healthy older adults: results from a 16-week exercise randomized control trial - Charleen J. Gust; Renée Martin-Willett; Laurel P. Gibson; Gregory Giordano; Douglas R. Seals; Angela D. Bryan (GeroScience, 2025)
Better social, emotional, and financial functioning are associated with improved health outcomes in older adults. While the literature supports a positive relationship between physical activity and increased functional ability in older adulthood, the intensity of physical activity necessary to achieve these gains remains uncertain. To address this gap, the current analysis uses data collected as part of a larger randomized controlled trial to examine the effects of a supervised exercise intervention on measures of social, emotional, and financial functioning. Healthy older adults ( n = 211) completed baseline assessments including cardiovascular fitness and health and functioning measures and were randomly assigned to 16 weeks of either: (1) low intensity continuous training (LICT); or (2) moderate intensity continuous training + interval training (MICT + IT). Participants across exercise conditions reported a significant decrease from baseline to post-intervention in depression [ F (1, 158) = 22.17, p < .001] and instrumental risk taking [ F (1, 157) = 6.72, p < .05]. Further, participants assigned to the MICT + IT condition showed significantly greater improvements in loneliness relative to those in the LICT condition [ F (1, 157) = 5.99, p < .05]. By and large, healthy older adults experienced some improvements in functional ability after 16 weeks of exercise. Though most changes were not related to the intensity of exercise condition, associations between increased cardiovascular fitness and both depression and anxiety suggest that exercising at an intensity that improves fitness may confer greater benefits in some domains. Trial registration: ClinicalTrials.gov, NCT02068612.

Glycation metabolites predict incident age-related comorbidities and mortality in older people with HIV - Xi Qiao; Liangliang Zhang; Emely A. Hoffman; Grace E. Mastin; Corrilynn O. Hileman; Asha R. Kallianpur; Ming Wang; Ronald J. Ellis; Susan L. Koletar; Frank J. Palella; Katherine K. Tassiopoulos; Alan L. Landay; et al. (GeroScience, 2025)
Glycation is a class of modifications arising from non-enzymatic reactions of reducing sugars with proteins, lipids, and/or DNA, generating advanced glycation end-products (AGEs). AGEs are linked to many age-related comorbidities. In response to HIV-1 infection, activated T-cells and macrophages shift their predominate metabolism from oxidative phosphorylation to glycolysis. Increased glycolytic flux enhances AGE formation, which may increase age-related comorbidities. In this prospective, multicenter cohort study of antiretroviral therapy treated people with HIV, we explored predictive associations by baseline plasma AGE concentrations and their corresponding detoxification metabolites, with incident comorbidities and mortality. AGEs included dicarbonyl sugars: 3-deoxyglucosone, glyoxal, and methylglyoxal. Methylglyoxal-derived metabolites included carboxyethyl-arginine, carboxyethyl-lysine, and methylglyoxal hydroimidazolone-1. Detoxification metabolites included reduced and oxidized glutathione, and the glyoxalase cycle products lactoyl-glutathione and lactoyl-Lysine modified proteins. Plasma was collected at study entry, in the fasting state, and assayed by liquid chromatography-mass spectroscopy. Incident clinical outcomes included diabetes, chronic kidney disease, hypertension, neurocognitive impairment, peripheral neuropathy, frailty, fractures, recurrent falls, and all-cause mortality. Among 376 participants, higher baseline plasma concentrations of methylglyoxal derived AGEs predicted increased risks of diabetes, chronic kidney disease, and recurrent falls, while higher 3-deoxyglucosone predicted an increased risk of peripheral neuropathy. By contrast, higher baseline concentrations of reduced or oxidized glutathione, lactoyl-glutathione, and/or lactoyl-Lysine modified proteins predicted lower risks of diabetes, neurocognitive impairment, frailty, fractures, recurrent falls, and all-cause mortality. These findings support growing experimental evidence of the potential to mitigate age-related declines by interventions that reduce glycation or increase glutathione.

Effects of life-long hyperlipidaemia on age-dependent development of endothelial dysfunction in humanised dyslipidaemic mice - Anna Bar; Piotr Berkowicz; Anna Kurpinska; Tasnim Mohaissen; Agnieszka Karaś; Patrycja Kaczara; Joanna Suraj-Prażmowska; Magdalena Sternak; Brygida Marczyk; Agata Malinowska; Agnieszka Kij; Agnieszka Jasztal; et al. (GeroScience, 2025)
Little is known, how life-long hyperlipidaemia affects vascular ageing, before atherosclerosis. Here, we characterise effects of mild, life-long hyperlipidaemia on age-dependent endothelial dysfunction (ED) in humanised dyslipidaemia model of E3L.CETP mice. Vascular function was characterised using magnetic resonance imaging in vivo and wire myograph ex vivo. Plasma endothelial biomarkers and non-targeted proteomics in plasma and aorta were analysed. Early atherosclerosis lesions were occasionally present only in 40-week-old or older E3L.CETP mice. However, age-dependent ED developed earlier, in 14-week-old male and 22-week-old female E3L.CETP mice as compared with 40-week-old female and male C57BL/6J mice. Acetylcholine-induced vasodilation in 8-week-old E3L.CETP, especially female mice, was blocked by catalase and attributed to H 2 O 2 . In 8-week-old female E3L.CETP mice, changes in plasma proteome in response to hyperlipidaemia were modest, while in male mice a number of differentially expressed proteins were identified that were involved in oxidative stress response, inflammation and regulation of metabolic pathways. In contrast, in older E3L.CETP and C57BL/6J mice, either plasma or aortic proteome displayed similar pattern of vascular ageing, dominating over hyperlipidaemia-induced changes. Interestingly, in 48-week-old male but not female E3L.CETP mice, vascular mitochondrial functional response was impaired. Early resilience of hyperlipidaemia-induced detrimental effects in young female E3L.CETP mice on a functional level was associated with a switch in vasodilation mechanism, blunted systemic proteomic response in plasma and slower ED development as compared to male E3L.CETP mice. The results indicate that profile of early vascular response to risk factors in young age may determine level of ED in older age before atherosclerosis development.

Prospective association of depression symptoms with exceptional longevity among older women - Carlos E. Rosas; Steve Nguyen; Aladdin H. Shadyab; Ariana M. Stickel; Shawnita Sealy-Jefferson; Michelle J. Naughton; Lorena Garcia; Linda C. Gallo; Andrea Z. LaCroix (GeroScience, 2025)

German longevity study reveals novel rare pro-longevity alleles clustering in mTOR signaling pathway - Daniel Kolbe; Janina Dose; Pasquale Putter; Malte Ziemann; Matthias Laudes; P. Eline Slagboom; Andre Franke; Joris Deelen; Almut Nebel (GeroScience, 2025)
In this study, we investigated the contribution of rare coding variants to human longevity by analyzing whole exome sequencing data from 1245 German long-lived individuals (LLI) and 4105 geographically matched younger controls. We identified novel exome-wide significant associations at both the single-variant and gene level, with a significant over-representation of genes involved in mechanistic target of rapamycin (mTOR) signaling. As such, three rare single variants in the mTOR-pathway genes RPS6 , FLCN , and SIK3 were enriched in LLI. Additionally, RWDD1 emerged as a strong candidate gene for longevity, with LLI exhibiting a statistically significant burden of rare missense variants in this gene. Other associations involved PRAC2 , SLC16 A6 , FOCAD , IHH , MESD , HOXA4 , and DNAJB13 . Furthermore, we observed an enrichment of protein-truncating variants in the genes ASXL1 and TET2 amongst LLI, likely as a result of clonal haematopoiesis. The study emphasizes the role of rare variants in human longevity, particularly through mTOR signaling.

Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development - Silvia Vicenzi; Fangyuan Gao; Parker Côté; Joshua D. Hartman; Lara C. Avsharian; Ashni A. Vora; R. Grant Rowe; Hojun Li; Dorota Skowronska-Krawczyk; Leslie A. Crews (GeroScience, 2025)
Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. Human aging has also been associated with diverse lipid alterations across tissues, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, comprehensive multi-omics analyses uncovered a role for a key PUFA biosynthesis gene, ELOVL2 , in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies and complementary flow cytometric analyses of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global downregulation in lymphoid cell markers and expression of genes involved specifically in B cell development. These studies unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker whose loss is associated with accelerated immune aging. The lipidome of mutant versus wild-type mice also displayed significant changes in the biophysical properties of cellular membranes. To investigate the relevance of these finding to human bone marrow aging, analyses of a single cell RNA-seq dataset of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (< 7%) of CD34 + HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B -expressing lymphoid-committed cells, were almost completely absent in CD34 + cells isolated from elderly bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in downregulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.

Reliability and validity of a full-body function Get-Up test in older adults - Nathan F. Meier; Brandon S. Klinedinst; Duck-chul Lee (GeroScience, 2025)

HDAC11 deficiency regulates age-related muscle decline and sarcopenia - Renato Odria; Aina Cardús; Clara Gomis-Coloma; Marta Balanyà-Segura; Alexandra Mercado-Amarilla; Pau Maestre-Mora; Andrea Poveda-Sabuco; Joan Carles Domingo; Gisela Nogales-Gadea; Jose A. Gomez-Sanchez; Erica Hurtado; Mònica Suelves (GeroScience, 2025)
Sarcopenia, defined as the progressive loss of skeletal muscle mass and function associated with ageing, has devastating effects in terms of reducing the quality of life of older people. Muscle ageing is characterised by muscle atrophy and decreased capacity for muscle repair, including a reduction in the muscle stem cell pool that impedes recovery after injury. Histone deacetylase 11 (HDAC11) is the newest member of the HDAC family and it is highly expressed in skeletal muscle. Our group recently showed that genetic deficiency in HDAC11 increases skeletal muscle regeneration, mitochondrial function and globally improves muscle performance in young mice. Here, we explore for the first time the functional consequences of HDAC11 deficiency in old mice, in homeostasis and during muscle regeneration. Aged mice lacking HDAC11 show attenuated muscle atrophy and postsynaptic fragmentation of the neuromuscular junction, but no significant differences in the number or diameter of myelinated axons of peripheral nerves. Maintenance of the muscle stem cell reservoir and advanced skeletal muscle regeneration after injury are also observed. HDAC11 depletion enhances mitochondrial fatty acid oxidation and attenuates age-associated alterations in skeletal muscle fatty acid composition, reducing drastically the omega-6/omega-3 fatty acid ratio and improving significantly the omega-3 index, providing an explanation for improved muscle strength and fatigue resistance and decreased mortality. Taken together, our results point to HDAC11 as a new target for the treatment of sarcopenia. Importantly, selective HDAC11 inhibitors have recently been developed that could offer a new therapeutic approach to slow the ageing process.

Bryostatin-1 improves function in arteries with suppressed endothelial cell autophagy - Jae Min Cho; Seul-Ki Park; Sohom Mookherjee; Emily Carolyn Peters; Paulo W. Pires; J. David Symons (GeroScience, 2025)
We have previously reported that when autophagy is suppressed in endothelial cells (ECs), a glycolytic defect limits shear-stress -induced ATP production to an extent that purinergic 2Y1 receptor (P2Y1R)-mediated activation of EC nitric oxide (NO) synthase (eNOS) is compromised. Subsequently we demonstrated the functional relevance of this finding in arteries from mice with genetic, pharmacological, and age-associated EC autophagy impairment. Using gain and loss of function approaches in vitro, we further revealed that p-PKCδ T505 serves as a signaling link between P2Y1R activation and NO generation. Here we sought to discern the functional relevance of this observation. First, shear-stress- induced activating phosphorylation of eNOS (p-eNOS S1177 ) that is otherwise prevented by knockdown of autophagy-related gene 3 ( Atg3 ) in ECs was restored by the PKC agonist bryostatin-1. Next, in murine models of genetic and age-associated EC autophagy compromise, depressed vasodilation displayed by femoral and cerebral arteries was reversed by bryostatin-1 in a manner that could be prevented by concurrent NO synthase inhibition. Finally, the bryostatin-1-mediated normalization of intraluminal flow-induced vasodilation observed in femoral arteries from both models of EC autophagy disruption was mitigated by inhibiting downstream targets of p-PKCδ T505 i.e., p-PKD S744/S748 and p-PKD S916 . These findings provide evidence that stimulating PKC/PKD has strategic potential to restore compromised endothelial function in pathologies associated with suppressed EC autophagy e.g., aging. Graphical Abstract

Cerebral hypoperfusion, brain structural integrity, and cognitive impairment in older APOE4 carriers - Ioannis Pappas; Trevor Lohman; Shubir Dutt; Arunima Kapoor; Allison C. Engstrom; John Paul M. Alitin; Samuel Barnes; Ararat Chakhoyan; Lucas Saca; Raghav Gaggar; Elnaz Nourollahimoghadam; Danny J. J. Wang; et al. (GeroScience, 2025)
Cerebral blood flow (CBF) deficits, cognitive decline, and brain structural changes have been reported in older adults with and without apolipoprotein E-e4 ( APOE4 )-related risk for dementia. However, it remains unclear whether brain structural changes mediate the effects of hypoperfusion on cognitive impairment in APOE4 carriers and non-carriers. We studied 166 (60–89 years) APOE4 carriers (ε3/ε4 or ε4/ε4) and APOE3 homozygotes (e3/e3) with and without cognitive impairment by clinical dementia rating (CDR) and neuropsychological testing. Pseudocontinuous arterial spin-labeling-MRI assessed regional CBF, and T1-anatomical and diffusion-MRI assessed structural integrity. Mediation analyses examined relationships among grey matter CBF, grey matter volume, and white matter integrity in regions underlying impairment in distinct cognitive ability domains. APOE4 carriers with global/memory impairment (CDR 0.5) exhibited decreased CBF in the posterior cingulate, decreased grey matter volume in the hippocampus, parahippocampal gyrus, and posterior cingulate, and decreased white matter integrity in the cingulum relative to APOE4 carriers with no impairment (CDR 0). Mediation analysis in APOE4 carriers indicated decreased posterior cingulate CBF effects on global/memory impairment were mediated by decreased cingulum integrity. In the combined APOE4 and APOE3 carriers sample, there were direct effects of frontal and inferior parietal CBF and superior longitudinal fasciculus integrity on attention/executive impairment. There were also direct effects of left inferior frontal CBF on language impairment. Findings suggest links between hypoperfusion and brain structural integrity underlying global/memory impairment in APOE4 carriers. Independent CBF relationships with structural integrity are also identified across genotypes and impairment domains.

Exercise and survival benefit in cancer patients: evidence from a comprehensive meta-analysis - Zoltan Ungvari; Mónika Fekete; Péter Varga; Gyöngyi Munkácsy; János Tibor Fekete; Andrea Lehoczki; Annamaria Buda; Csaba Kiss; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Cancer remains a major global health challenge, and growing evidence suggests that physical activity is a key modifiable factor that may improve survival outcomes in cancer patients. However, a comprehensive, large-scale synthesis of the effects of post-diagnosis physical activity across multiple cancer types remains lacking. This meta-analysis aims to systematically evaluate the association between physical activity and survival in patients diagnosed with breast, lung, prostate, colorectal, and skin cancers. We conducted a comprehensive search in PubMed, Web of Science, Scopus, and Cochrane Library for studies on physical activity and cancer survival. Eligible studies (January 2000–November 2024) included adults (≥ 18 years) with breast, lung, prostate, colorectal, or skin cancer. Only prospective cohort and case–control studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall or cancer-specific mortality were included, with a minimum sample size of 100 and at least six months of follow-up. Meta-analysis was performed using metaanalysisonline.com, applying random-effects models and assessing heterogeneity via the I 2 statistic. Sensitivity analyses and publication bias (Egger’s test, funnel plots) were evaluated. The meta-analysis included 151 cohorts with almost 1.5 million cancer patients. Post-diagnosis physical activity was associated with significantly lower cancer-specific mortality across all five cancer types. The greatest benefit was observed in breast cancer, with a pooled hazard ratio (HR) of 0.69 (95% CI: 0.63–0.75), followed by prostate cancer (HR: 0.73, 95% CI: 0.62–0.87). Lung cancer patients who engaged in physical activity had a 24% lower risk of cancer-specific death (HR: 0.76, 95% CI: 0.69–0.84), while colorectal cancer patients experienced a similar benefit (HR: 0.71, 95% CI: 0.63–0.80). In skin cancer, physical activity was associated with a non-significant reduction in mortality (HR: 0.86, 95% CI: 0.71–1.05). These findings provide robust evidence supporting the survival benefits of post-diagnosis physical activity in cancer patients, particularly for breast, prostate, lung, and colorectal cancers. The results underscore the potential for incorporating structured physical activity interventions into oncological care to improve long-term patient outcomes.

Sleep disorders increase the risk of dementia, Alzheimer’s disease, and cognitive decline: a meta-analysis - Zoltan Ungvari; Mónika Fekete; Andrea Lehoczki; Gyöngyi Munkácsy; János Tibor Fekete; Virág Zábó; György Purebl; Péter Varga; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Sleep disorders, particularly insomnia and obstructive sleep apnea, are increasingly implicated as significant contributors to cognitive decline, dementia, and neurodegenerative diseases such as Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID). However, the extent and specificity of these associations remain uncertain. This meta-analysis evaluates the impact of common sleep disorders on the risk of developing dementia and cognitive decline. A comprehensive search of the literature was conducted to identify prospective cohort studies assessing sleep disorders and dementia risk. Studies reporting risk estimates for dementia, AD, or cognitive decline associated with obstructive sleep apnea, insomnia, and other sleep disorders (e.g., restless legs syndrome, circadian rhythm sleep disorders, excessive daytime sleepiness) were included. Meta-analyses were performed using a random-effects model to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Thirty-nine cohort studies were included, with subgroup analyses showing significant associations between all-cause dementia and obstructive sleep apnea (HR 1.33, 95% CI 1.09–1.61), insomnia (HR 1.36, 95% CI 1.19–1.55), and other sleep disorders (HR 1.33, 95% CI 1.24–1.43). Obstructive sleep apnea increased the risk for AD (HR 1.45, 95% CI 1.24–1.69), though its association with vascular dementia did not reach statistical significance (HR 1.35, 95% CI 0.99–1.84). Insomnia was significantly associated with increased risk for both vascular dementia (HR 1.59, 95% CI 1.01–2.51) and AD (HR 1.49, 95% CI 1.27–1.74). This meta-analysis highlights the critical role of sleep disorders in dementia risk, emphasizing the need for early detection and management of sleep disturbances. Targeted interventions could play a pivotal role in reducing dementia risk, particularly among high-risk populations.

Clonal hematopoiesis of indeterminate potential (CHIP) in cerebromicrovascular aging: implications for vascular contributions to cognitive impairment and dementia (VCID) - Attila Kallai; Anna Ungvari; Dora Csaban; Zoltan Orfi; Andrea Lehoczki; Jozsef Harasztdombi; Andriy Yabluchanskiy; Zoltán Benyó; Ágnes Szappanos; Stefano Tarantini; Farzaneh Sorond; Péter Sótonyi; et al. (GeroScience, 2025)
Vascular contributions to cognitive impairment and dementia (VCID) represent a major public health challenge in the aging population, with age-related cerebromicrovascular dysfunction playing a critical role in its development. Understanding the mechanisms underlying cerebromicrovascular aging is crucial for devising strategies to mitigate this burden. Among the key hallmarks of aging, genomic instability and genetic heterogeneity have emerged as significant drivers of age-related diseases. Clonal hematopoiesis of indeterminate potential (CHIP) is a prominent manifestation of this instability, characterized by the non-malignant expansion of hematopoietic stem cell clones that harbor somatic mutations. CHIP is well-established as a contributor to atherosclerosis and cardiovascular disease through its promotion of chronic inflammation. Given that aging is also a major risk factor for cerebral small vessel disease (CSVD) and VCID, it is likely that the same aging processes driving large artery atherosclerosis in CHIP carriers also impair small vessels, including the cerebral microvasculature. While the role of CHIP in large vessel disease is well-documented, its specific contributions to cerebrovascular aging and microvascular dysfunction remain poorly understood. This review explores the potential role of CHIP in age-related cerebrovascular pathologies, with a particular focus on its contribution to CSVD. We discuss how CHIP-related mutations can promote inflammation and oxidative stress, potentially leading to endothelial dysfunction, dysregulation of cerebral blood flow (CBF), blood–brain barrier (BBB) disruption, microvascular inflammation, and cerebral microhemorrhages. Given the potential implications for VCID, elucidating these mechanisms is critical for developing targeted therapies aimed at reducing the burden of cognitive decline in aging populations. This review aims to highlight the current knowledge gaps and encourage further research into the intersection of CHIP, CSVD, and cognitive aging.

Associations of epigenetic aging and COVID- 19: A 3-year longitudinal study - Gabor Farkas; Zahira El Mahdaouy; Gergely Babszky; Matyas Jokai; Ferenc Torma; Yaodong Gu; Ricardo Pinho; Ildiko Miklossy; Juozas Gordevicius; András Benczúr; Csaba Kerepesi; Zsolt Radak (GeroScience, 2025)
Aging and COVID- 19 are known to influence DNA methylation, potentially affecting the rate of aging and the risk of disease. The physiological functions of 54 volunteers—including maximal oxygen uptake (VO₂ max), grip strength, and vertical jump—were assessed just before the COVID- 19 pandemic and again 3 years later. Of these volunteers, 27 had contracted COVID- 19. Eight epigenetic clocks were used to assess the rate of aging during the 3-year period: DNAmAge showed accelerated aging, and five clocks showed slowed aging (DNAmAgeSkinBlood, DNAmAgeHannum, DNAmFitAge, PhenoAge, and DNAmTL). When we considered only females, we observed a stronger effect in the increase of DNAmAge acceleration, while we observed slowed aging in the case of SkinBloodClock, and DNAmTL. The methylation of the promoter region of the H1 FNT genes, which encodes testis-specific histone H1 family member N (H1fnt) and plays a crucial role in spermatogenesis decreased the most significantly. In contrast, the promoter of CSTL1, which encodes Cystatin-like 1, showed the most significant increase. We found that having COVID- 19 during the 3-year study period significantly increased the progress of aging assessed by DNAmGrimAge, DNAmGrimAge2, and DNAmFitAge ( p = 0.024, 0.047, 0.032, respectively, after we adjusted the analysis for baseline variables). The data suggest that COVID- 19 may have a mild long-term effect on epigenetic aging.

Association between red and processed meat consumption and colorectal cancer risk: a comprehensive meta-analysis of prospective studies - Zoltan Ungvari; Mónika Fekete; Péter Varga; Andrea Lehoczki; Gyöngyi Munkácsy; János Tibor Fekete; Giampaolo Bianchini; Alberto Ocana; Annamaria Buda; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Increasing evidence suggests that red and processed meat consumption may elevate the risk of colorectal cancer (CRC), yet the magnitude and consistency of this association remain debated. This meta-analysis aims to quantify the relationship between red and processed meat intake and the risk of CRC, colon cancer, and rectal cancer using the most comprehensive set of prospective studies to date. We conducted a comprehensive search in PubMed, Web of Science, Cochrane Library, Embase, and Google Scholar databases from 1990 to November 2024, to identify relevant prospective studies examining red, processed, and total meat consumption in relation to colorectal, colon, and rectal cancer risk. Hazard ratios (HR) and 95% confidence intervals (CI) were extracted for each study and pooled using a random-effects model to account for variability among studies. Statistical evaluation was executed using the online platform MetaAnalysisOnline.com. A total of 60 prospective studies were included. Red meat consumption was associated with a significantly increased risk of colon cancer (HR = 1.22, 95% CI 1.15–1.30), colorectal cancer (HR = 1.15, 95% CI 1.10–1.21), and rectal cancer (HR = 1.22, 95% CI 1.07–1.39). Processed meat consumption showed similar associations with increased risk for colon cancer (HR = 1.13, 95% CI 1.07–1.20), colorectal cancer (HR = 1.21, 95% CI 1.14–1.28), and rectal cancer (HR = 1.17, 95% CI 1.05–1.30). Total meat consumption also correlated with an elevated risk of colon cancer (HR = 1.22, 95% CI 1.11–1.35), colorectal cancer (HR = 1.17, 95% CI 1.12–1.22), and rectal cancer (HR = 1.28, 95% CI 1.10–1.48). This meta-analysis provides robust evidence that high consumption of red and processed meats is significantly associated with an increased risk of colorectal, colon, and rectal cancers. These findings reinforce current dietary recommendations advocating for the limitation of red and processed meat intake as part of cancer prevention strategies.

Hemisphere- and condition-specific alpha oscillations support semantic and spatial cognition in aging - Maggie P. Rempe; Danae S. Manta; Kayle Cohen; Ryan J. Glesinger; Hannah J. Okelberry; Jason A. John; Anna T. Coutant; Lucy K. Horne; Grant M. Garrison; Kennedy A. Kress; Lucas Weyrich; Chloe C. Casagrande; et al. (GeroScience, 2025)

Association of Klotho and FGF23 with cardiovascular outcomes in diabetic older adults with chronic limb-threatening ischemia: a prospective study - Federico Biscetti; Silvia Giovannini; Roberto Iezzi; Claudia Loreti; Pietro Caliandro; Lorenzo Biscotti; Dario Pitocco; Andrea Flex (GeroScience, 2025)

Cognitive decline limits compensatory resource allocation within the aged swallowing network - Sonja Suntrup-Krueger; Paul Muhle; Janna Slavik; Jonas von Itter; Andreas Wollbrink; Rainer Wirth; Tobias Warnecke; Rainer Dziewas; Joachim Gross; Sven G. Meuth; Bendix Labeit (GeroScience, 2025)
Cognitive decline has been postulated to predispose to presbyphagia but the neurophysiological basis of this interaction is unclear. To investigate the role of cognition for compensatory resource allocation within the swallowing network and behavioral swallowing performance in dual-task cognitive and motor interference in ageing, volunteers ≥ 70 years of age without preexisting diseases causing dysphagia were investigated using Flexible Endoscopic Evaluation of Swallowing (FEES) including a cognitive and motor dual-task paradigm and a Montreal Cognitive Assessment. The neural correlates of swallowing during dual-task were characterized using magnetoencephalography. Results were related to cognitive function. Sixty-three participants (77.7 ± 6.1 years) underwent FEES, of which 40 additionally underwent MEG. Both cognitive and motor dual-tasks interfered with swallowing function resulting in an increase in pharyngeal residue and premature bolus spillage. The extent of swallowing deterioration (“dual-task cost”) was associated with cognitive decline (cognitive dual-task: Spearman’s rho = − 0.39, p = 0.002; motor dual-task: Spearman’s rho = − 0.25, p = 0.046). When challenged with dual-tasking participants with regular cognition showed compensatory stronger and broader brain activation in cortical pre- and supplementary motor planning areas as well as in frontal executive regions within the cortical swallowing network ( p = 0.004) compared to participants with cognitive deficits. They also performed better in the competing cognitive and motor dual-task and showed fewer incorrect responses ( p = 0.028). Oropharyngeal swallowing involves cognitive cortical processing. Cognitive decline seems to limit the capacity for compensatory resource allocation within the swallowing network. This may lead to deterioration in both swallowing function and concurrent cognitive-motor performance in challenging dual-task situations.

Bilingualism and “brain reserve” in subregions of the hippocampal formation - Katharina Peitz; Nora Bittner; Stefan Heim; Svenja Caspers (GeroScience, 2025)
With aging, the hippocampal formation shows variable structural atrophy, which is associated with a decline in cognitive performance. Bilingualism is related to higher hippocampal gray matter volume (GMV), potentially representing a form of brain reserve in aging. However, the differential influence of bilingualism on hippocampal subregions remains unclear. Thus, we investigated GMV differences and differences in age-GMV relationships between mono- and bilinguals in the hippocampal formation and its subregions, hippocampus proper and subicular complex. We included 661 adults aged 19 to 85 years (257 monolinguals, 404 sequential bilinguals, predominantly native German speakers with variable second language background) from the population-based 1000BRAINS cohort. GMV differences in mono- vs. bilinguals were assessed for six regions of interest (hippocampal formation, hippocampus proper, and subicular complex; each left and right) using analyses of covariance. Effects of bilingualism on age-GMV relationships were investigated via moderation analyses. We found higher GMV in bilinguals in the bilateral subicular complex, while only a trend towards this effect existed for the hippocampal formation. Moderation analyses revealed similar age-GMV relationships between mono- and bilinguals for all regions of interest. Higher GMV in bilinguals’ hippocampal formation seems specifically attributable to the subicular complex rather than the hippocampus proper. With similar age-GMV relationships for mono- and bilinguals, bilingual brain reserve in the subicular complex may persist over time. This may be particularly beneficial since subicular atrophy has previously been associated with higher risk for dementia. Altogether, a differential impact of bilingualism on hippocampal subregions has been demonstrated.

Exploring the power of MRI and clinical measures in predicting AD neuropathology - Farooq Kamal; Cassandra Morrison; Michael D. Oliver; Mahsa Dadar (GeroScience, 2025)

Endothelial IGF- 1R deficiency disrupts microvascular homeostasis, impairing skeletal muscle perfusion and endurance: implications for age-related sarcopenia - Adam Nyul-Toth; Santny Shanmugarama; Roland Patai; Rafal Gulej; Janet Faakye; Dorina Nagy; Mark Nagykaldi; Tamas Kiss; Tamas Csipo; Madison Milan; Shoba Ekambaram; Sharon Negri; et al. (GeroScience, 2025)
Aging is associated with a progressive decline in circulating insulin-like growth factor- 1 (IGF- 1) levels in humans, which has been implicated in the pathogenesis of sarcopenia. IGF- 1 is an anabolic hormone that plays a dual role in maintaining skeletal muscle health, acting both directly on muscle fibers to promote growth and indirectly by supporting the vascular network that sustains muscle perfusion. However, the microvascular consequences of IGF- 1 deficiency in aging muscle remain poorly understood. To elucidate how impaired IGF- 1 input affects skeletal muscle vasculature, we examined the effects of endothelial-specific IGF- 1 receptor (IGF- 1R) deficiency using a mouse model of endothelial IGF- 1R knockdown (VE-Cadherin-CreER T2 /Igf1r f/f mice). These mice exhibited significantly reduced skeletal muscle endurance and attenuated hyperemic response to acetylcholine, an endothelium-dependent vasodilator. Additionally, they displayed microvascular rarefaction and impaired nitric oxide-dependent vasorelaxation, indicating a significant decline in microvascular health in skeletal muscle. These findings suggest that endothelial IGF- 1R signaling is critical for maintaining microvascular integrity, muscle perfusion, and function. Impaired IGF- 1 input to the microvascular endothelium may contribute to reduced muscle blood flow and exacerbate age-related sarcopenia. Enhancing vascular health by modulating IGF- 1 signaling could represent a potential therapeutic strategy to counteract age-related muscle decline.

Associations between plasma proteomic signatures and secondary sleep in older adults - Kaushalya Madhawa; Thomas Svensson; Hoang Nt; Ung-il Chung; Akiko Kishi Svensson (GeroScience, 2025)
Sleep disturbances are prevalent among elderly populations and are linked to various health complications. Understanding the underlying biological mechanisms contributing to sleep disorders is crucial for developing targeted interventions. In this study, we measured 355 plasma proteins in an elderly Japanese cohort ( n =77) using a high-throughput proteomic platform. Additionally, we collected over 25,000 person-days of physical activity and sleep behavior data from wrist-worn wearable devices, focusing on total sleep time (TST) across 24 h and daytime sleep. Fragmented sleep was observed as one of the most prevalent sleep disturbances in this population. In protein expression analysis, we identified 9 protein biomarkers associated with increased secondary sleep TST, defined as additional sleep episodes outside of the main sleep episode within 24 h. These findings may suggest disruptions in circadian rhythms or underlying health conditions. Functional analysis revealed that biological processes related to inflammation play a significant role in regulating sleep behavior. Further analysis showed an association of 12 proteins with daytime sleep and 5 proteins with afternoon sleep. Overall, this study identified inflammatory biomarkers and biological processes associated with sleep behavior in the elderly, presenting promising opportunities for developing diagnostic tools and targeted clinical interventions.

Treatment delay significantly increases mortality in colorectal cancer: a meta-analysis - Zoltan Ungvari; Mónika Fekete; János Tibor Fekete; Andrea Lehoczki; Annamaria Buda; Gyöngyi Munkácsy; Péter Varga; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Delaying the initiation of cancer treatment increases the risk of mortality, particularly in colorectal cancer (CRC), which is among the most common and deadliest malignancies. This study aims to explore the impact of treatment delays on mortality in CRC. A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between 2000 and 2025. Meta-analyses were performed using random-effects models with inverse variance method to calculate hazard ratios (HRs) for both overall and cancer-specific survival at 4-, 8-, and 12-week treatment delay intervals, with heterogeneity assessed through I 2 -statistics and publication bias evaluated using funnel plots and Egger’s test. A total of 20 relevant studies were included in the meta-analysis. The analyses of all patients demonstrated a progressively increasing risk of 12–39% with longer treatment delays (4 weeks, HR = 1.12; 95% CI, 1.08–1.16; 8 weeks, HR = 1.24; 95% CI, 1.16–1.34; 12 weeks, HR = 1.39; 95% CI, 1.25–1.55). In particular, incrementally higher hazard ratios were observed for all–cause mortality at 4 weeks (HR = 1.14; 95% CI, 1.09–1.18), 8 weeks (HR = 1.29; 95% CI, 1.20–1.39), and 12 weeks (HR = 1.47; 95% CI, 1.31–1.64). In contrast, cancer-specific survival analysis showed a similar trend but did not reach statistical significance (4 weeks, HR = 1.07; 95% CI, 0.98–1.18; 8 weeks, HR = 1.15; 95% CI, 0.95–1.39; 12 weeks, HR = 1.23; 95% CI, 0.93–1.63). Treatment delays in colorectal cancer patients were associated with progressively worsening overall survival, with each 4-week delay increment leading to a substantially higher mortality risk. This study suggests that timely treatment initiation should be prioritized in clinical practice, as these efforts can lead to substantial improvements in survival rates.

The selection of participants for interventional microbiota trials involving cognitively impaired older adults - Adam Golden; Cynthia Williams; Hariom Yadav; Michal M. Masternak; Corinne Labyak; Peter J. Holland; Andrea Y. Arikawa; Shalini Jain (GeroScience, 2025)

Comparative effects of angiotensin II stimulating and inhibiting antihypertensives on dementia risk: a systematic review and meta-analysis - Eyayaw Ashete Belachew; Gregory M. Peterson; Woldesellassie M. Bezabhe (GeroScience, 2025)
Studies comparing the effects of Angiotensin II (Ang-II) stimulating and inhibiting antihypertensive medications (AHMs) on dementia risk have reported inconsistent findings. Based on the PRISMA guidelines, this study was performed to pool these findings. We searched PubMed, Scopus, Embase Ovid, PsycINFO, and CINAHL from inception to 22 May 2024 for randomised controlled trials (RCTs) and observational studies that compared the use of Ang-II stimulating (thiazides, Ang-II receptor blockers, and dihydropyridine calcium channel blockers) and inhibiting AHMs (β-blockers, angiotensin-converting enzyme inhibitors, and non-dihydropyridine calcium channel blockers) and the subsequent risk of developing dementia. Two reviewers independently performed study selection, data extraction, and quality assessment. Random effects meta-analysis models were used to calculate hazard ratios (HRs) or risk ratios (RRs) with their confidence intervals (CIs). All-cause dementia was the primary outcome. Alzheimer’s disease (AD), vascular dementia (VD), and mild cognitive impairment (MCI) were secondary outcomes. We included 18 studies with 1,883,283 participants. Observational studies showed that the use of Ang-II stimulating AHMs reduced the risk of all-cause dementia by 13% (HR = 0.87; 95% CI = 0.82–0.93) compared with Ang-II inhibiting AHMs. The risk of AD was reduced by 12% (HR = 0.88; 95% CI = 0.86–0.90), VD by 19% (HR = 0.81; 95% CI = 0.72–0.91), and MCI by 24% (HR = 0.76; 95% CI = 0.68–0.85) in these studies. A meta-analysis of four RCTs revealed a non-significant 8% reduction in dementia risk with Ang-II stimulating AHMs versus control (RR = 0.92; 95% CI = 0.79–1.08). Observational evidence suggests that Ang-II stimulating AHMs may offer neuroprotective benefits relative to Ang-II inhibiting AHMs.

NIA Caenorhabditis Intervention Testing Program: identification of robust and reproducible pharmacological interventions that promote longevity across experimentally accessible, genetically diverse populations - Monica Driscoll; Christine A. Sedore; Brian Onken; Anna L. Coleman-Hulbert; Erik Johnson; Patrick C. Phillips; Gordon Lithgow (GeroScience, 2025)
A core facet of the National Institute on Aging’s mission is to identify pharmacological interventions that can promote human healthy aging and long life. As part of the comprehensive effort toward that goal, the NIA Division of Biology of Aging established the Caenorhabditis Intervention Testing Program (CITP) in 2013. The C. elegans model (with an ~ 21 day lifespan) has led the field in dissection of longevity genetics and offers features that allow for relatively rapid testing and for the potential elaboration of biological mechanisms engaged by candidate geroprotectants. CITP builds on this foundation by utilizing a genetically diverse set of intervention test strains so that “subjects” represent genetic diversity akin to that that between mouse and humans. Another distinctive aspect of the CITP is a dedicated focus on reproducibility of longevity outcomes as labs at three independent test sites confirm positive outcomes. The overall goal of the Caenorhabditis Intervention Testing Program (CITP) is to identify robust and reproducible pro-longevity interventions affecting genetically diverse cohorts in the Caenorhabditis genus. A strong Data Collection Center supports data collection and dissemination. Pharmacological interventions tested by CITP can be nominated by the general public, directed by in-house screens, or supported by published scientific literature. As of December 2024, CITP tested > 75 compounds and conducted > 725,000 animal assays over 891 trials. We identified 12 compounds that confer a ≥ 20% increase in median lifespan to reproducibly and robustly extend lifespan across multiple strains and labs. Five of these interventions have pro-longevity impact reported in the mouse literature (most CITP positive interventions are not tested yet in mouse). As part of the celebration of the 50th Anniversary of the NIA, we review the development history and accomplishments of the CITP program, and we comment on translation and the promise of advancing understanding of fundamental aging biology that includes the pharmacological intervention/health interface.

Preoperative physical resilience indicators and their associations with postoperative outcomes - Marjolein Klop; René J. F. Melis; G. M. E. E. Geeske Peeters; Guillaume S. C. Geuzebroek; Robin H. Heijmen; Richard J. A. van Wezel; Jurgen A. H. R. Claassen (GeroScience, 2025)
The health benefit of surgery in older adults may be outweighed by negative effects on cognitive or physical function. Physical resilience is defined as the potential for recovery after a stressor such as surgery. We assessed associations between physical resilience measured by orthostatic blood pressure (BP) and cerebral oxygenation recovery or grip work (sustained hand grip strength; GW) and postoperative outcome in two cohorts of (older) surgical patients. The first cohort (CTC) consisted of patients undergoing complex cardiothoracic surgery. The second cohort (GRR) held geriatric outpatients undergoing various surgical procedures. Outcome measures were length of stay (LoS) and postoperative complications. Negative binomial (LoS) and ordinal (complications) regression models were used to determine associations. 261 patients (113 CTC and 148 GRR) underwent surgery. Median LoS was 10 (CTC) and 5 days (GRR). Postoperative complications occurred in 80% (CTC) and 45% (GRR) of patients. In CTC, 10 mmHg higher systolic BP recovery was associated with a 12% shorter LoS (incidence rate ratio (IRR) 0.88 (95% CI 0.78–0.98)). 10 s longer sustained hand grip was associated with a 5% shorter LoS in GRR (IRR 0.95 (0.90–1.00)), but a 7% longer LoS in CTC (IRR 1.07 (1.03–1.11)). No significant associations were found with postoperative complications. Orthostatic cerebral oxygenation recovery in CTC was not significantly associated with any postoperative outcome. Our results imply that resilience indicators might be associated with LoS after surgery. Future research should seek to replicate our findings and investigate whether adding resilience parameters to preoperative assessment can support postoperative outcome prediction.

Aging, mitochondrial dysfunction, and cerebral microhemorrhages: a preclinical evaluation of SS-31 (elamipretide) and development of a high-throughput machine learning-driven imaging pipeline for cerebromicrovascular protection therapeutic screening - Roland Patai; Krish Patel; Boglarka Csik; Rafal Gulej; Raghavendra Y. Nagaraja; Dorina Nagy; Siva Sai Chandragiri; Santny Shanmugarama; Kiana Vali Kordestan; Mark Nagykaldi; Shoba Ekambaram; Anna Ungvari; et al. (GeroScience, 2025)
Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) contribute to vascular cognitive impairment and dementia (VCID), with aging and hypertension being key risk factors. Mitochondrial oxidative stress is a hallmark of cerebrovascular aging, leading to endothelial dysfunction. This study tests the hypothesis that increased mitochondrial oxidative stress contributes to age-related CMH susceptibility and evaluates the mitochondrial-targeted antioxidative peptide SS-31 (elamipretide) as a potential protective agent in an aged, hypertensive mouse model. Concurrently, we developed a high-throughput, machine learning–driven imaging pipeline to enhance CMH quantification and facilitate the screening of anti-aging vasoprotective interventions. To detect CMHs, brain sections were labeled with diaminobenzidine (DAB) and digitized using a slide scanner-based imaging platform. We developed multiple quantification tools, including color space transformation for enhanced contrast separation and a supervised machine-learning approach utilizing a random forest algorithm to generate whole-brain 3D reconstructions and precisely localize CMHs. We optimized a semi-automated detection method integrating color space transformation and machine learning, benchmarking it against traditional manual counting and color deconvolution-based approaches. While SS-31 treatment did not significantly mitigate hypertension-induced CMH burden in aged mice, our high-throughput imaging pipeline provided a reliable, scalable, and unbiased approach to CMH detection, reducing processing time while improving accuracy. This methodological advancement paves the way for future preclinical studies evaluating therapeutic strategies for cerebrovascular protection in aging. Our findings underscore the need for multi-targeted interventions to mitigate CMH-related neurovascular impairments and prevent VCID.

Voxel-wise insights into early Alzheimer’s disease pathology progression: the association with APOE and memory decline - Maha Wybitul; Nicolas Langer; Christoph Hock; Anton Gietl; Valerie Treyer; Michael Weiner; Paul Aisen; Ronald-Petersen; Clifford R. Jack; William Jagust; John Q. Trojanowski; Arthur W. Toga; et al. (GeroScience, 2025)
Longitudinal investigation of the Apolipoprotein E (APOE) genotype’s impact on Alzheimer’s disease (AD) biomarker progression, focusing on amyloid beta (Aβ) accumulation and gray matter (GM) atrophy, integrating cognitive decline and baseline levels. Longitudinal florbetapir-PET and T1-weighted MRI data from 100 cognitively normal (CN) and mild cognitive impaired (MCI) participants both with considerable global Aβ accumulation (“high Aβ accumulators”) were analyzed using a voxel-wise approach. Associations of APOE genotype and memory decline with Aβ accumulation and GM atrophy were examined separately for each neuroimaging modality, controlling for baseline Aβ levels and diagnosis. Alternatively, the effect of baseline diagnosis, while controlling for memory decline, was investigated. A multimodal analysis evaluated interactions between genotype, memory decline, and GM atrophy on Aβ accumulation. High Aβ accumulators displayed extensive Aβ pathology predominantly in the medial orbito-frontal cortex, cingulate cortex, and precuneus, along with GM atrophy in temporal, occipital, orbito-frontal, and parietal areas. ɛ4 carriers with memory decline exhibited greater Aβ accumulation and GM atrophy in selective regions compared to non-carriers with memory decline, while no genotype difference was observed in individuals without decline. No interaction effect was observed for MCI diagnosis. Regional associations between the two biomarkers were similarly dependent on genotype and memory decline. ɛ4 carriers exhibiting memory decline present an accelerated neurobiological pattern at predementia stages, supporting early ɛ4 carrier monitoring and interventions in this at-risk group. Importantly, memory decline might be more informative than MCI regarding AD pathology progression emphasizing the importance of repeated cognitive assessments.

Cardiac-specific overexpression of serum response factor regulates age-associated decline in mitochondrial function - Pankaj Patyal; Gohar Azhar; Xiaomin Zhang; Ambika Verma; Jeanne Y. Wei (GeroScience, 2025)
Cardiac aging is an intrinsic process that leads to impaired heart function, along with cellular and molecular changes. Recent research highlights the important role of mitochondria in cardiac function, due to the heart's high energy demands. Serum response factor (SRF), a transcription factor involved in regulating actin and smooth muscle gene expression, is well known as a regulator of various aspects of cardiac function. However, its role in mitochondrial regulation and cardiac aging is poorly understood. Our laboratory generated a transgenic mouse model with cardiac-specific overexpression of SRF, which exhibits characteristics of diastolic dysfunction and accelerated cardiac aging in young adult transgenic mice. In this study, we tested how cardiac-specific overexpression of SRF affects age associated mitochondrial dysfunction in the heart. Our results showed that cardiac specific SRF overexpression reduced the lifespan of mice and induced cardiomyopathy. Histological analysis revealed cardiac hypertrophy and fibrosis in transgenic mice hearts. SRF overexpression led to significant alterations in mitochondrial structure and function, including reduced mitochondrial biogenesis and dysregulation of oxidative phosphorylation. These changes were accompanied by increased oxidative stress, a decline in antioxidant enzyme activity, and disrupted calcium handling. Moreover, cardiac-specific SRF overexpression activated the MAPK signaling pathway. Our findings were further corroborated by similar mitochondrial dysfunction observed in a human cardiomyocyte cells transfected with SRF plasmid. Taken together, these findings suggest that SRF plays a novel role in cardiac aging, thus establishing SRF as a potential therapeutic target for mitigating age-associated decline in mitochondrial function and preserving cardiac health in older adults.

Uncovering somatic genetic drivers in prostate cancer through comprehensive genome-wide analysis - Lede Lin; Zhen Li; Kai Chen; Yanxiang Shao; Xiang Li (GeroScience, 2025)

The role of purpose in life in healthy aging: implications for the Semmelweis Study and the Semmelweis-EUniWell Workplace Health Promotion Model Program - Virág Zábó; Andrea Lehoczki; Monika Fekete; Ágnes Szappanos; Péter Varga; Marianna Moizs; Giorgia Giovannetti; Yura Loscalzo; Marco Giannini; M. Cristina Polidori; Beatrix Busse; Miklos Kellermayer; et al. (GeroScience, 2025)
The global aging population presents significant challenges to public health systems, particularly in countries like Hungary, which faces some of the least favorable health indicators in the European Union. To address these challenges, Purpose in Life (PIL) has emerged as a critical determinant of healthy aging, influencing physical, mental, and social health. Defined as a sense of meaning, direction, and intentionality, PIL promotes resilience, mitigates age-related decline, and fosters well-being. This review explores the theoretical frameworks, mechanisms, and practical implications of PIL in the context of aging. Biologically, PIL regulates stress responses, contributing to reduced disease risk and improved longevity. Psychologically, PIL fosters resilience, self-regulation, and positive emotions, which buffer against mental health challenges and support cognitive health. Socially, PIL strengthens meaningful relationships, promotes prosocial behaviors, and fosters collective purpose, reducing isolation and enhancing social cohesion. These mechanisms interact to create a synergistic effect that supports healthy aging trajectories. The Semmelweis Study, Hungary’s most extensive workplace cohort study, offers a unique opportunity to integrate PIL assessment into its longitudinal design, providing novel insights into how PIL influences aging outcomes. Complementing this research, the Semmelweis-EUniWell Workplace Health Promotion Program translates these insights into actionable interventions, designed to enhance employee well-being and productivity. Drawing from global best practices, including insights from Blue Zones and Mediterranean-inspired interventions, Hungary can position PIL as a cornerstone of its healthy aging agenda. Incorporating PIL-focused strategies into workplace health programs and national public health policies holds the potential to extend healthspan, reduce healthcare costs, and foster a resilient and purposeful aging population. This review highlights the transformative potential of PIL in addressing the multifaceted challenges of aging and advancing public health goals.

Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats - Sarah Ding; Anisha Banerjee; Sara N. Burke; Abbi R. Hernandez (GeroScience, 2025)
Many of the “hallmarks of aging” involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation, and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver, and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8 to 25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. Within the brain, SIRT1 and MAPK8 were reduced in CA3 of kTRF-fed rats. Additionally, IGF1 expression was significantly upregulated in the CA1 of cTRF-fed rats, but this effect was ameliorated in the kTRF fed group. AKT and FOXO1 expression were significantly reduced in kTRF-fed rats within liver. Interestingly, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance, and FOXO1 expression was higher in the CA3 of AL-fed rats correlated with the poorest cognitive performance. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.

Biological age construction for prediction of mortality in the Chinese population - Kaiyue Wang; Jingli Gao; Ying Liu; Zuyun Liu; Yaqi Li; Shuohua Chen; Liang Sun; Shouling Wu; Xiang Gao (GeroScience, 2025)

Correction to: Cognitive frailty and functional disability in older adults: A 10‑year prospective cohort study in Japan - Sanmei Chen; Tao Chen; Takanori Honda; Hiro Kishimoto; Yu Nofuji; Kenji Narazaki (GeroScience, 2025)

Association between night shift work and markers of metabolism, cardiovascular and immune system in a population-based German cohort - Nora Bittner; Horst-Werner Korf; Susanne Moebus; Börge Schmidt; Svenja Caspers (GeroScience, 2025)
In humans, night shift work is a major reason for chronodisruption, may affect health and increase the risk of a metabolic syndrome, but results obtained so far are ambiguous. In this population-based, cross-sectional study, PRESENT and FORMER shift workers were compared to age- and sex-matched controls, who never worked in shift with regard to body mass index, waist-hip-ratio total, high-density lipoprotein and low-density lipoprotein, cholesterol and C-reactive protein. Moreover, association with sex, length of shift work and medication were investigated. The present results do not support the hypothesis that night shift work per se is associated to an increased risk of metabolic syndrome, and cardiovascular and immune malfunctions: no differences were found in mean anthropomteric and blood values between present or former shift workers and respective matched controls. When analyzing the proportion of participants showing values beyond the clinically relevant cut-offs, no general effect of shift work was observed, but the data may suggest an interaction between shift work and sex. These divergent results may be due to differences in the socio-economic status, the health care system and the shift schedule. All these parameters need to be considered in future studies addressing the impact of night shiftwork on human health.

WormRACER: Robust Analysis by Computer-Enhanced Recording - Bennett T. Van Camp; Quinn N. Zapata; Sean P. Curran (GeroScience, 2025)
The pace of scientific high-throughput screening for age-related phenotypes requires the need for developing streamlined and efficacious methods of measuring and quantifying physiological outcomes and at a scale that enables adequate statistical power to measure the variation in populations. Here, we introduce Worm Robust Analysis by Computer-Enhanced Recording (WormRACER), a computationally efficient computer vision software capable of extracting six different crawling and swimming metrics from many animals simultaneously, including worm area, worm length, crawling speed, swimming speed, dynamic amplitude, and wave initiation rate (thrashing). Additionally, we developed a web-based portal that provides metric averages and metric vs time graphs that allow for simple data analysis and quality assurance. WormRACER will facilitate the rapid and quantitative characterization of movement as a facile measurement of healthspan enabling power for high-throughput screening of genetic, environmental, and pharmacological interventions.

Growth hormone–deficient Ames dwarf mice resist sarcopenia and exhibit enhanced endurance running performance at 24 months - Matthew J. Johnston; Sharlene G. Rakoczy; LaDora V. Thompson; Holly M. Brown-Borg (GeroScience, 2025)
Ames dwarf mice ( df/df ) live 50% longer than normal littermates due to a genetic defect in growth hormone (GH) signaling. The enhanced longevity of Ames dwarfs has been studied extensively in an endocrinological context of cellular metabolism and increased resistance to oxidative stress (Bartke. World J Mens Health 37(1):19, 8; Bartke 2; BartkeJ Am Aging Assoc 23(4):219, 10; Bartke. World J Mens Health 39(3):454-465, 11; Brown-Borg et al. Nature 384(6604):33-33, 1; Masternak et al. 2018). However, the skeletal muscle system is relatively unexplored, the quality of which dictates metabolic homeostasis, permits movement and exercise, and exerts paracrine effects on other organs (Delmonico and Beck Am J Lifestyle Med 11(2):167-181, 25; Evans et al. GeroScience 46(1):183, 26; Kim and Kim. Endocrinol Metab (Seoul) 35(1):1-6, 15; Masternak et al. 2018). Here, we characterize the fitness capacity and skeletal muscle morphology of Ames mice to determine if previously established longevous effects of GH deficiency extend to skeletal muscle tissue. Mutually exclusive, age-matched cohorts of male Ames mice and wildtype controls performed grip strength, rotarod, and endurance running experiments over 6 months. The largest difference in physical performance was observed in endurance running capacity, where dwarf mice outperformed wildtype controls increasingly with age. Tibialis anterior (TA) muscles were evaluated for myofiber size, quality, and environment. Ames mice show reduced myofiber cross-sectional area (CSA) paired with increased myofibers per muscle. Dwarf myofiber populations are less heterogenous in size and seemingly resist sarcopenia, as skeletal muscle from aged individuals shows youthful morphological resemblance in mean myofiber CSA, size frequency distribution, and presence of fibrotic tissue. Declines in fitness performance and myofiber integrity were observable in age-matched wildtype controls. Utilizing an established longevity model to investigate skeletal muscle function and morphology is a novel approach to gaining insight into the seemingly inverse relationship between GH signaling and mammalian longevity.

Paying attention to proprioception: age affects ankle proprioception and the attentional demand of proprioceptive processing in sedentary adults - Marie Julie Vermette; Emmeline Paré; François Prince; Julie Messier (GeroScience, 2025)

Dietary mixed-oxysterols and 27-Hydroxycholesterol induce cognitive impairment by regulating gut microbiota and miR-144-3p in vivo - Tao Wang; Mengwei Ju; Xiaona Zhang; Wenjing Feng; Lijing Wang; Ling Hao; Huiyan Yu; Rong Xiao (GeroScience, 2025)

Correction to: Biomarkers of cellular senescence and major health outcomes in older adults - Steven R. Cummings; Li‑Yung Lui; Zaira Aversa; Theresa Mau; Roger A. Fielding; Elizabeth J. Atkinson; Sheena Patel; Nathan LeBrasseur (GeroScience, 2025)

Prognostic impact of a senescence gene signature in multiple myeloma - Andrea Lehoczki; Otilia Menyhart; Hajnalka Andrikovics; Monika Fekete; Csaba Kiss; Gabor Mikala; Zoltan Ungvari; Balázs Győrffy (GeroScience, 2025)
Multiple myeloma (MM), an incurable malignancy of plasma cells, is predominantly an age-related disease, with the majority of cases occurring in patients over the age of 60. Cellular senescence, a fundamental biological process underlying aging, has been increasingly recognized for its critical role in developing age-related malignancies. In this study, we aimed to investigate the prognostic significance of genes implicated in the molecular mechanisms of senescence within a large cohort of MM patients. Gene expression and clinical data from 1416 MM patients were obtained from four GEO datasets (GSE24080, GSE4204, GSE57317, and GSE9782) and integrated into a unified database. The raw data were processed using MAS5 normalization, scaling adjustments, and JetSet probe selection to ensure cross-platform comparability. A curated set of senescence-associated genes, the SenMayo gene signature, was employed for subsequent analyses. The final gene signature was computed as a weighted mean expression of 122 senescence-associated genes, with weights derived from univariate hazard ratios. Prognostic significance was evaluated using Cox regression, Kaplan–Meier survival analysis, and multivariate models incorporating clinical parameters such as gender, isotype, and molecular subtypes. False discovery rate (FDR) correction was applied to ensure the statistical robustness of findings. The weighted SenMayo gene signature strongly correlated with overall survival in MM patients (HR = 0.6, 95% CI = 0.47–0.76, p = 1.7e-05). The 75th percent probability of survival was reached at 36.1 months in the low-expression patient group, compared to 57 months in the high-expression group. Independent validation in datasets with sufficient patient numbers confirmed the prognostic value of the SenMayo signature (GSE4204: HR = 0.58, 95% CI = 0.39–0.88, p = 0.0089; GSE24080: HR = 0.61, 95% CI = 0.45–0.83, p = 0.0012; GSE57317: HR = 0.25, 95% CI = 0.08–0.77, p = 0.0095). Multivariate analyses further established the SenMayo signature as an independent prognostic factor, even when accounting for established clinical parameters such as sex and isotype. These findings underscore the robustness and independence of the SenMayo gene signature as a predictor of overall survival in multiple myeloma. This signature provides clinically valuable insights into the role of cellular senescence in disease progression.

Innovative approaches in the treatment-resistant depression: exploring different therapeutic pathways - Anna Łysik; Katarzyna Logoń; Aleksandra Szczygieł; Julia Wołoszczak; Martyna Wrześniewska; Jerzy Leszek (GeroScience, 2025)
Treatment-resistant depression (TRD) remains a vital challenge in psychiatry, affecting a significant number of patients with major depressive disorder. Current pharmacological approaches often do not provide sufficient therapeutic results, prompting the need for innovative treatments. This review summarizes recent advances in TRD management, including non-pharmacological therapies such as transcranial magnetic stimulation, deep brain stimulation, electroconvulsive therapy, and vagus nerve stimulation, and describes their mechanisms of action. Novel pharmacotherapies, particularly glutamatergic modulators like ketamine and esketamine, have shown promising results with esketamine being available to eligible patients in Poland since 2023 within a drug program. Electroconvulsive therapy remains an effective treatment for TRD, usually with small side effects mainly including transient memory impairment, headache, or cardiovascular changes. Transcranial magnetic stimulation is a non-invasive procedure with proven efficacy; therefore several psychiatric organizations recommend it as a treatment option for major depressive disorder in their clinical guidelines. Deep brain stimulation is a relatively new treatment modality for TRD, with its primary risk being associated with the required neurosurgical procedure. Vagus nerve stimulation seems to be a promising adjunctive treatment for TRD, showing significant improvements in depressive symptoms, especially at higher electrical doses but with no side effects. While these treatments appear to have potential, personalized approaches are crucial for optimizing outcomes. Future research should focus on refining the techniques, improving safety profiles, and validating the long-term efficacy.

Functional ultrasound imaging reveals microvascular rarefaction, decreased cerebral blood flow, and impaired neurovascular coupling in a mouse model of paclitaxel-induced chemobrain - Siva Sai Chandragiri; Adam Nyul-Toth; Sharon Negri; Roland Patai; Rafal Gulej; Boglarka Csik; Santny Shanmugarama; Kiana Vali Kordestan; Mark Nagykaldi; Peter Mukli; Anna Ungvari; Andriy Yabluchanskiy; et al. (GeroScience, 2025)
Chemotherapy-induced cognitive impairment (CICI), often referred to as “chemobrain,” significantly affects the quality of life in cancer survivors. Although traditionally attributed to neuronal toxicity, emerging evidence suggests a key role of cerebrovascular dysfunction in its pathogenesis. We hypothesized that paclitaxel (PTX, Taxol) treatment induces long-term cerebrovascular dysfunction, including microvascular rarefaction, impaired neurovascular coupling (NVC), and altered cerebral blood flow (CBF), which contribute to CICI. Using a clinically relevant PTX treatment regimen in non-tumor-bearing mice, we evaluated the long-term effects of PTX on cerebrovascular health. Ultrasound localization microscopy (ULM) and functional ultrasound imaging (fUS) were employed to assess microvascular density, CBF, and NVC. PTX treatment resulted in a significant reduction in microvascular density in the cerebral cortex and hippocampus, key regions involved in cognitive function. PTX significantly reduced blood velocity in the middle cerebral artery. Moreover, PTX impaired NVC responses, as evidenced by a diminished CBF increase in response to whisker stimulation, indicative of impaired reactive hyperemia. In conclusion, these findings demonstrate that PTX induces long-lasting cerebrovascular dysfunction, including microvascular rarefaction, impaired NVC, and altered CBF dynamics, which likely contribute to CICI. This study underscores the critical role of cerebrovascular health in cognitive function and highlights the potential of targeting cerebrovascular pathways as a therapeutic approach for mitigating chemotherapy-induced cognitive deficits.

Correction to: White matter lipid alterations during aging in the rhesus monkey brain - Christina Dimovasili; Ana T. Vitantonio; Bryce Conner; Kelli L. Vaughan; Julie A. Mattison; Douglas L. Rosene (GeroScience, 2025)

Cortical adaptations in regional activity and backbone network following short-term postural training with visual feedback for older adults - Yi-Ching Chen; Yi-Ying Tsai; Wei-Min Huang; Chen-Guang Zhao; Ing-Shiou Hwang (GeroScience, 2025)

Cerebromicrovascular senescence in vascular cognitive impairment: does accelerated microvascular aging accompany atherosclerosis? - Anna Ungvari; Ádám Nyúl-Tóth; Roland Patai; Boglarka Csik; Rafal Gulej; Dorina Nagy; Santny Shanmugarama; Zoltán Benyó; Tamas Kiss; Zoltan Ungvari; Anna Csiszar (GeroScience, 2025)
Vascular cognitive impairment (VCI) is a leading cause of age-related cognitive decline, driven by cerebrovascular dysfunction and cerebral small vessel disease (CSVD). Emerging evidence suggests that cerebromicrovascular endothelial senescence plays an important role in the pathogenesis of VCI by promoting cerebral blood flow dysregulation, neurovascular uncoupling, blood–brain barrier (BBB) disruption, and the development of cerebral microhemorrhages (CMHs). This review explores the concept of cerebromicrovascular senescence as a continuum of vascular aging, linking macrovascular atherosclerosis with microvascular dysfunction. It examines the mechanisms by which endothelial senescence drives neurovascular pathology and highlights the impact of cardiovascular risk factors in accelerating these processes. We examine preclinical and clinical studies that provide compelling evidence that atherosclerosis-induced microvascular senescence exacerbates cognitive impairment. In particular, findings suggest that targeting senescent endothelial cells through senolytic therapy can restore cerebrovascular function and improve cognitive outcomes in experimental models of atherosclerosis. Given the growing recognition of microvascular senescence as a therapeutic target, further research is warranted to explore novel interventions such as senolytics, anti-inflammatory agents, and metabolic modulators. The development of circulating biomarkers of vascular senescence (e.g., senescence-associated secretory phenotype [SASP] components and endothelial-derived extracellular vesicles) could enable early detection and risk stratification in individuals at high risk for VCI. Additionally, lifestyle modifications, including the Mediterranean diet, hold promise for delaying endothelial senescence and mitigating cognitive decline. In conclusion, cerebromicrovascular senescence is a key mechanistic link between atherosclerosis and cognitive impairment. Addressing microvascular aging as a modifiable risk factor through targeted interventions offers a promising strategy for reducing the burden of VCI and preserving cognitive function in aging populations.

Chronic alcohol consumption accelerates cardiovascular aging and decreases cardiovascular reserve capacity - Partha Mukhopadhyay; Burhan Yokus; Bruno Paes-Leme; Sándor Bátkai; Zoltán Ungvári; György Haskó; Pal Pacher (GeroScience, 2025)
The pathology of cardiovascular aging is complex, involving mitochondrial dysfunction, oxidative and nitrative stress, oxidative DNA injury, impaired lipid metabolism, cell death, senescence, and chronic inflammation. These processes lead to remodeling and structural changes in the cardiovascular system, resulting in a progressive decline in cardiovascular reserve capacity and health, and an increased risk of diseases and mortality. Excessive alcohol consumption exacerbates these risks by promoting hypertension, stroke, arrhythmias, coronary artery disease, cardiomyopathy, and sudden cardiac death, yet the effects of chronic alcohol consumption on cardiovascular aging remain unclear. Herein, we explored the impact of a 6-month 5% Lieber-DeCarli alcohol diet in young (3 months old) and aging (24–26 months old) Fisher F344BNF1 rats. We assessed detailed hemodynamics, mitochondrial function, oxidative/nitrative stress, lipid metabolism, inflammation, cell death, senescence, and myocardial fibrosis using the pressure–volume system, isolated vascular rings, and various histological, biochemical, and molecular biology methods. Alcohol consumption in both young and aging rats impaired mitochondrial function, disrupted cholesterol and triglyceride metabolism, and increased oxidative/nitrative stress, inflammation, cell death, and senescence, leading to a decline in systolic contractile function. In aging rats, alcohol further exacerbated diastolic dysfunction and myocardial fibrosis. Alcohol also increased oxidative/nitrative stress, apoptosis, and senescence in the vasculature, contributing to endothelial dysfunction and increased total peripheral resistance. Additionally, alcohol exacerbated the aging-related ventriculo-arterial uncoupling and diminished cardiac efficiency, further reducing cardiovascular reserve capacity. In conclusion, chronic alcohol consumption promotes cardiovascular aging and further diminishes the already impaired cardiac and vascular reserve capacity associated with aging.

Age-related alterations of angiogenesis, inflammation and bone microarchitecture during fracture healing in mice - Maximilian M. Menger; Ruben Manuschewski; Sandra Hans; Benedikt J. Braun; Moses K. D. El Kayali; Sabrina Ehnert; Emmanuel Ampofo; Selina Wrublewsky; Michael D. Menger; Tina Histing; Matthias W. Laschke (GeroScience, 2025)
The surgical treatment of geriatric patients represents a major challenge in traumatology. It is well known that aging affects fracture healing. However, the exact pathophysiology of age-related changes in angiogenesis, inflammation and bone remodeling remains still elusive. Therefore, we herein studied the differences of femoral fracture healing in young adult (3–4 months) and aged (16–18 months) CD-1 mice by using a stable closed femoral fracture model with intramedullary screw fixation. The callus tissue was analyzed by means of X-ray, micro-computed tomography (µCT), histology and immunohistochemistry. We found a deteriorated trabecular architecture and a reduced bone formation within the callus tissue of aged mice. Moreover, aged animals showed an increased number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts at an early healing time point, whereas the fraction of mature α-smooth muscle actin (SMA)-positive microvessels was significantly reduced. Furthermore, the numbers of macrophages and granulocytes were higher in the callus tissue of aged animals at the end of the healing process. Taken together, these results demonstrate a delayed femoral fracture healing in aged CD-1 mice. This is most likely caused by an early overshooting osteoclast response, a decelerated maturation of the callus microvasculature and a late increased recruitment of pro-inflammatory cells. Targeting these alterations may contribute to the development of novel treatment approaches for the stimulation of bone regeneration in geriatric patients.

Insomnia accelerates the epigenetic clocks in older adults - Nadia Alejandra Rivero-Segura; Julian Daniel Rodriguez Cuartas; Paola Garcia-delaTorre; Sergio Sanchez-Garcia; Ricardo Ramirez-Aldana; Juan Carlos Gomez-Verjan (GeroScience, 2025)

An incidental finding during a brain plasticity study: substantial telomere length shortening after COVID-19 lockdown in the older population - Kirsten Jahn; Shambhabi Chatterjee; Christopher Sinke; Jonas Janik Ralf Koberschinski; Kristin Jünemann; Clara Eline James; Florian Worschech; Damien Marie; Eckart Altenmüller; Christian Bär; Tillmann Horst Christoph Krüger (GeroScience, 2025)
The detrimental effects of lockdowns have already been proven by numerous studies, mainly using psychometric measurements. Since telomere shortening is a driver of aging and aging-associated disorders, including cognitive decline, the telomere length in the older population has been investigated in the current study. Measurements were taken over a 6-month period just before and during the 6 months that included the first lockdown. The cohort of 55 persons aged 64 to 70 years was investigated in the context of a study focusing on neuroplasticity. Participants were recruited in Germany and Switzerland and characterized by psychometric measurements concerning neurocognition and neuroplasticity. Telomere lengths were measured by real-time PCR-based LTL measurement. We found an impressive and significant decline in telomere lengths in the period that included the lockdown (2.33 (± 0.1) at T1 vs. 1.35 (± 0.1) at T2), whereas it was stable in the phase before the lockdown in the same individuals (T0 was 2.25 (± 0.1 S.E.M.) vs. T1, 2.33 (± 0.1)). Correlation of the sudden decrease revealed no linkage to health issues or general physical activity but was in trend related to a decline in the WHOQOL-BREF Social Score referring to the social interaction of the study participants. Our data support, at a biological level, the results of clinical and psychosocial studies showing the detrimental effects of lockdowns.

Effect of acipimox on skeletal muscle biochemistry, structure and function in older people with probable sarcopenia: an experimental medicine study - Claire McDonald; Craig Alderson; Matthew G. Birkbeck; Silvia Del Din; Gráinne S. Gorman; Kieren G. Hollingsworth; Cameron Kirk; Clare Massarella; Lynn Rochester; Helen A. L. Tuppen; Charlotte Warren; Avan A. Sayer; et al. (GeroScience, 2025)
Background Skeletal muscle nicotinamide adenine dinucleotide (NAD) concentrations are low in people with sarcopenia. Increasing NAD concentrations may offer a novel therapy. This study tested if acipimox (a NAD precursor) improves skeletal muscle NAD concentration and function in people with probable sarcopenia. Participants aged 65 and over with low walk speed (< 0.8 m/s) and low muscle strength (by 2019 European Working Group criteria) were recruited to this before and after, proof-of-concept study. Participants received acipimox 250 mg orally (twice or thrice daily according to creatinine clearance) + aspirin 75 mg daily (to prevent facial flushing) for 4 weeks. Muscle biopsy of the vastus lateralis, 31 P magnetic resonance spectroscopy and a 7-digital mobility assessment were performed before starting acipimox and after 3 weeks of treatment. The primary outcome was change in skeletal muscle NAD concentration. Secondary outcomes included change in phosphocreatine recovery rate and measures of physical performance. Eleven participants (8 women), mean age 78.9 years (SD 4.3), were recruited. Mean walk speed at baseline was 0.69 m/s (SD 0.07). All completed baseline and follow-up visits. Median medication adherence was 95% (range 91–104%). There was no statistically significant difference in the primary outcome of change in NAD concentrations in skeletal muscle between baseline and follow-up [median difference: − 0.003 umol/g (IQR − 0.058 to 0.210); P = 0.26] or secondary outcomes. Nineteen none-serious adverse events were reported. Although the study protocol was feasible and well tolerated, acipimox did not improve skeletal muscle NAD concentration, biochemical markers or physical function in people with probable sarcopenia. ClinicalTrials.gov Identifier: ISRCTN (ISRCTN87404878).

Frailty incidence by diabetes treatment regimens in older adults with diabetes mellitus in the ASPirin in Reducing Events in the Elderly Study - Sara E. Espinoza; Jonathan C. Broder; Rory Wolfe; Michael E. Ernst; Raj C. Shah; Suzanne G. Orchard; Robyn L. Woods; Joanne Ryan; Anne Murray (GeroScience, 2025)
Diabetes mellitus is a major risk factor for frailty in older adults, and studies suggest that frailty risk may differ by diabetes treatment regimen. To investigate the association between diabetes medication use and frailty, we conducted an observational cohort analysis of older adults with diabetes enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Diabetes at baseline ( N = 2045) was defined as self-reported diabetes, fasting blood glucose levels > 125 mg/dL, or use of diabetes medication. Diabetes medication exposure at baseline was categorized as use of metformin only (monotherapy) ( N = 545), metformin combined with other diabetes medications ( N = 420), other diabetes medications only ( N = 200), or no diabetes medications ( N = 880). Frailty was defined using a modified Fried frailty phenotype (presence of ≥ 3 of 5 criteria) and a deficit accumulation frailty index (FI, score > 0.21/1.00). Mixed effects ordinal logistic regression models revealed the odds of frailty at baseline were highest for the other diabetes medications only group, but this difference remained consistent over follow-up. After adjustment for covariates, including baseline pre-frailty, no differences in the rates of Fried or FI frailty were observed among the diabetes medication exposure groups. These findings suggest that diabetes medication exposure in older adults with diabetes does not directly impact frailty risk. Graphical abstract

Sex differences in cognitive performance persist into your 80s - Ross Julian; Stephanie Fröhlich; Katrin Müller; Melanie Dammhahn; Claudia Voelcker-Rehage (GeroScience, 2025)
Background Sex differences in cognitive performance have been extensively documented. Understanding the underlying factors contributing to sex differences in older adults is imperative to promote healthy cognitive aging. Sex hormones, estrogens, and testosterone have been suggested to be associated with cognition. Nevertheless, there is a scarcity of studies investigating the sex difference in cognitive performance and the contribution of gonadal hormones in older adults. Hence, the current study aimed to investigate sex differences in cognitive performance and elucidate the association between gonadal hormones and cognitive performance in 80+ -year-olds. Methods Using confirmatory factor analysis in a sample of 131 older adults (aged 80 to 92 years), 17 cognitive performance measures were divided into two cognitive components: executive functioning and memory. Subsequently, mediation analyses were conducted to determine the direct effect of sex and the indirect effect mediated by gonadal hormones on executive functioning and memory. Results Females outperformed males in executive functioning and memory. However, gonadal hormones did not mediate the sex effect on cognitive performance. Estrogen levels significantly predicted executive functioning but not memory. Testosterone levels did neither predict executive functioning nor memory. Conclusion Our study confirms enduring sex differences in memory and executive function, even among individuals aged 80 and above. Current gonadal hormone levels do not mediate these differences. While estrogen may predict executive function, its influence does not explain the sex differences. These findings underscore the complex nature of cognitive disparities between sexes in older age, warranting further investigation into underlying mechanisms.

Assessing the gut microbiota composition in older adults: connections to physical activity and healthy ageing - Catarina Ramos; Daniele Magistro; Gemma E. Walton; Anya Whitham; Nicola Camp; Carlos Poveda; Glenn R. Gibson; John Hough; Will Kinnear; Kirsty Hunter (GeroScience, 2025)
The composition and functionality of the gut microbiota (GM) changes throughout the life course. As we move into older age, it starts to shift towards a less healthy one, which may lead to an imbalance in the GM community. Strategies that can reverse age-related dysbiosis are an important part of healthy aging. Little is known about the GM composition of older adults with different physical activity (PA) levels and whether it might contribute to healthy ageing. The aim of this study was to compare the GM composition of older adults with different PA levels and assess if it is associated with healthy ageing. 101 participants aged between 65–85 years undertook anthropometric measures, a 6-min walking test, wore an accelerometer for 7 days and provided a faecal sample. Faecal GM composition was analysed using 16S rRNA sequencing. We found that those who fulfilled the WHO/UK PA recommendations had higher relative abundance of several health-related bacteria such as Lactobacillus, F. prausnitzii and Roseburia intestinalis and lower abundance of disease-associated bacteria such as D.piger or Enterobacterales when compared to those who did not reach PA recommendations. These findings suggest that PA might improve the GM composition and has the potential to, at least partially, revert age-associated dysbiosis and promote healthy ageing.

3-Monothiopomalidomide, a new immunomodulatory imide drug (IMiD), blunts inflammation and mitigates ischemic stroke in the rat - Kai-Yun Chen; Shih-Chang Hsueh; Pathik Parekh; Buyandelger Batsaikhan; David Tweedie; Weiming Luo; Chirag Patel; Yung-Hsiao Chiang; Nicholas Bambakidis; Barry J. Hoffer; Chi-Zong Huang; Seong-Jin Yu; et al. (GeroScience, 2025)
An overactive neuroinflammatory response is often evident in the elderly and is a significant contributor to brain tissue damage following acute ischemic stroke. Such an inflammatory response is largely mediated by microglial cells and peripheral blood mononuclear cells (PBMCs). Classical anti-inflammatory agents have not proved clinically effective in mitigating the impact of ischemic stroke but have highlighted targets for new drug development, in particular excessive proinflammatory cytokine release. The immunomodulatory imide drug (IMiD) class has shown potential in reducing neuroinflammation and switching microglial phenotypic expression away from a proinflammatory to a regenerative anti-inflammatory one. 3-Monothiopomalidomide (3-MP), a new IMiD, has a brain/plasma concentration ratio of 0.5 to 0.6, an oral bioavailability of 38.5%, and a monophasic disappearance of half-life 3.2 h following oral administration. 3-MP pretreatment mitigates lipopolysaccharide (LPS)-induced inflammation in cellular human PBMCs and, in rat studies, 3-MP pretreatment lowers proinflammatory cytokine levels in the conditioned media and in plasma and the brain, respectively. Administered systemically to rats challenged with middle cerebral artery occlusion (MCAo) and reperfusion, 3-MP post-MCAo treatment reduced infarction volume; improved body asymmetry, a behavioral measure of stroke impact; and lowered inflammation. In summary, 3-MP exerted neuroprotective effects via anti-inflammatory actions against MCAo-induced ischemic injury and represents a therapeutic that warrants further investigation as a treatment for brain damage and related disorders associated with excessive inflammation.

Machine vision-based frailty assessment for genetically diverse mice - Gautam S. Sabnis; Gary A. Churchill; Vivek Kumar (GeroScience, 2025)

Epigenetic age acceleration and mortality risk prediction in US adults - Angelico Mendy; Tesfaye B. Mersha (GeroScience, 2025)
Epigenetic clocks have emerged as novel measures of biological aging and potential predictors of mortality. We examined all-cause, cardiovascular, and cancer mortality prediction by epigenetic age acceleration (EAA) estimated using different epigenetic clocks. Among 2105 participants to the 1999–2002 National Health and Nutrition Examination Survey aged ≥ 50 years old and followed for mortality through 2019, we calculated EAAs from the residuals of nine epigenetic clocks regressed on chronological age. We assessed the association of EAAs and pace of aging with mortality adjusting for covariates. During 17.5 years of median follow-up, 998 deaths occurred, including 272 from cardiovascular disease and 209 from cancer. Overall mortality was most significantly predicted by Grim EAA ( P < 0.0001) followed by Hannum ( P = 0.005), Pheno ( P = 0.004), Horvath ( P = 0.03), and Vidal-Bralo ( P = 0.04) EAAs. Grim EAA predicted cardiovascular mortality ( P < 0.0001), whereas Hannum ( P = 0.006), Horvath ( P = 0.009), and Grim ( P = 0.01) EAAs predicted cancer mortality. Overall mortality prediction differed by race/ethnicity between non-Hispanic White and White participants for Horvath ( P interaction = 0.048), Hannum ( P interaction = 0.01), and Grim ( P interaction = 0.04) EAAs. Hannum prediction of cancer mortality also differed between the two races/ethnicities ( P interaction = 0.007). Despite being predictive in non-Hispanic White participants, Horvath ( P = 0.75), Hannum ( P = 0.84), and Grim ( P = 0.10) EAAs failed to predict overall mortality in Hispanic participants, and Hannum EAA was not associated with cancer mortality in Hispanic participants ( P = 0.18). In a US representative sample, Horvath, Hannum, SkinBlood, Pheno, Vidal-Bralo, and Grim EAAs as well as pace of aging predict mortality. Howbeit, Horvath, Hannum, and Grim EAAs were less predictive in Hispanic participants.

Micro-gyms as a catalyst for healthy aging in university and healthcare settings: applications for the Semmelweis-EUniWell Workplace Health Promotion Model Program - Noémi Mózes; Dorottya Árva; David Major; Mónika Fekete; Norbert Dósa; Andrea Lehoczki; Péter Varga; Kata Pártos; Wei Yi Hung; Giorgia Giovannetti; Daniele Vignoli; Beatrix Busse; et al. (GeroScience, 2025)
Europe is experiencing a significant demographic shift, with aging populations posing economic and social challenges due to increased healthcare costs and a higher prevalence of age-related diseases. Hungary, in particular, faces these challenges acutely due to higher morbidity and mortality rates from a range of chronic age-related diseases and behavioral risk factors. Addressing these issues requires innovative approaches to promote healthy aging. Semmelweis University, the largest healthcare provider and leading health sciences university in the region, is developing a comprehensive healthy aging program. A critical pillar of this program is the Semmelweis-EUniWell Workplace Health Promotion Model Program, a pioneering initiative aimed at tackling unhealthy aging within Hungary’s workforce by leveraging the workplace as a platform for health promotion. Central to this program’s goal of combating sedentary lifestyles—a significant contributor to age-related health issues—is the innovative use of micro-gyms and motivational interviewing. Micro-gyms, with their compact size and accessibility, provide convenient exercise opportunities, while motivational interviewing fosters intrinsic motivation and personalized counseling to encourage sustained physical activity. Through concerted efforts and innovative approaches, including the implementation of micro-gyms, the Semmelweis-EUniWell Workplace Health Promotion Model Program aims to set a benchmark for workplace health promotion, fostering a healthier and more resilient aging population in Hungary. This program not only enhances the well-being of employees at Semmelweis University and its EUniWell partner institutions but also catalyzes broader transformations in workplace health promotion and healthy aging nationwide.

Salutary effects of transdermal curcumin on multiple indices of health span in rodent models of normal aging and hypertension - Kai Mao; Ruixuan Wang; Kateryna Karpoff; Daniel Kerr; Probal Banerjee; Joel M. Friedman; Derek M. Huffman (GeroScience, 2025)
Geroscience has helped to usher in a new and exciting era of aging drug development and evaluation of novel and repurposed agents, as well as natural compounds purported to target one or more aging hallmarks. Among the latter, curcumin has long been pursued as a promising strategy but has failed to provide convincing evidence in human trials. Oral intake is the typical route of administration tested for the vast majority of gerotherapeutic candidates, including curcumin, but efficacy is dependent upon good oral bioavailability and pharmacokinetics. However, unlike FDA-approved oral medications, many natural compounds, such as curcumin, have poor oral bioavailability, which may explain their limited success in translation. To overcome these inherent limitations, we tested a novel solvent-based formulation of concentrated curcumin (VASCEPTOR®), developed for effective skin penetration and delivery of high amounts of bioactive curcuminoids directly to the circulation on aging and age-related conditions. We demonstrate that short-term topical treatment (7.5 mg per dose) with VASCEPTOR® twice per week can improve both vascular health in a rat model of hypertension, while a late-life intervention in aged mice improves multiple indices of health span, including improved exercise tolerance, motor coordination, diastolic function ( p < 0.05), a reduction in frailty status ( p < 0.05) and expression of some age-related markers in tissues, particular heart and kidney. Thus, these data suggest that the therapeutic potential of curcumin can potentially be dramatically enhanced by topical delivery and, along with other promising candidates, should be prioritized for further development, testing and deployment to potentially target some manifestations of aging in humans.

Proteomic and phosphoproteomic signatures of aging mouse liver - Rodrigo Mohallem; Allison J. Schaser; Uma K. Aryal (GeroScience, 2025)

Topoisomerase inhibitor amonafide enhances defense responses to promote longevity in C. elegans - Iman Man Hu; Ana Serna; Stacia Everts; Lale Güngördü; Bauke V. Schomakers; Ellen A. A. Nollen; Arwen W. Gao; Riekelt H. Houtkooper; Georges E. Janssens (GeroScience, 2025)
Aging is a major risk factor for disease, and developing effective pharmaceutical interventions to improve healthspan and promote longevity has become a high priority for society. One of the molecular pathways related to longevity in various model organisms revolves around lowering AKT1 levels. This prompted our in silico drug screen for small molecules capable of mimicking the transcriptional effects of AKT1 knockdown. We found topoisomerase inhibitors as a top candidate longevity-drug class. Evaluating multiple compounds from this class in C. elegans revealed that the topoisomerase inhibitor amonafide has the greatest benefit on healthspan and lifespan. Intriguingly, the longevity effect of amonafide was not solely dependent on DAF-16/FOXO , the canonical pathway for lifespan extension via AKT1 inhibition. We performed RNA-seq on amonafide-treated worms and revealed a more youthful transcriptional signature, including the activation of diverse molecular and cellular defense pathways. We found the mitochondrial unfolded protein response (UPR mt ) regulator afts-1 to be crucial for both improved healthspan and extended lifespan upon amonafide treatment. Moreover, healthspan was partially dependent on the immune response transcription factor zip-2 and the integrated stress response transcription factor atf-4 . We further examined the potential of amonafide in age-related disease. Treating a C. elegans model for Parkinson’s disease with amonafide improved mobility. In conclusion, we identified amonafide as a novel geroprotector, which activates mitochondrial-, pathogen-, and xenobiotic-associated defense responses that—though more studies are needed—may serve as a candidate for Parkinson’s disease therapy.

Polypharmacy and its association with dementia, Parkinson’s disease, and mortality risk in UK adults: a multistate modeling approach - Jordan Weiss; May A. Beydoun; Michael F. Georgescu; Ana I. Maldonado; Hind A. Beydoun; Nicole Noren Hooten; Jack Tsai; Minkyo Song; Allen Nieva; Michele K. Evans; Alan B. Zonderman (GeroScience, 2025)
Polypharmacy is common among older adults and has been linked to adverse outcomes such as dementia, Parkinson’s disease (PD), and mortality. However, its influence on transitions between these health states remains understudied in large, population-based cohorts. Using data from 361,970 UK Biobank participants aged 50 and older with up to 15 years of follow-up, we examined the association between polypharmacy, defined as the use of five or more medications, and transitions between health states: healthy, dementia, PD, and mortality. Multistate parametric models, including Weibull regression, were employed to estimate these associations, adjusting for demographics, socioeconomic status, cardiovascular health, and comorbidities. Latent class analysis was used to identify specific medication combinations associated with health transitions. Polypharmacy was significantly associated with higher risks of transitioning from healthy to dementia (hazard ratio [HR], 1.15; 95% CI, 1.07–1.23) and from healthy to death (HR, 1.11; 95% CI, 1.08–1.09). Women exhibited better cardiovascular health but higher polypharmacy prevalence compared to men. Latent class analysis revealed that certain medication combinations, such as omega-3 fatty acids and multivitamins, were inversely associated with dementia and mortality, independent of polypharmacy status. These findings highlight the complex relationship between polypharmacy and health transitions in older adults. Careful medication management may mitigate risks associated with polypharmacy, particularly among individuals at risk for neurodegenerative diseases. Further research is warranted to investigate the potential protective effects of specific medication combinations on health outcomes.

Automated abdominal aortic calcification scoring from vertebral fracture assessment images and fall-associated hospitalisations: the Manitoba Bone Mineral Density Registry - Marc Sim; Abadi K. Gebre; Jack Dalla Via; Siobhan Reid; Mohammad Jafari Jozani; Douglas Kimelman; Barret A. Monchka; Syed Zulqarnain Gilani; Zaid Ilyas; Cassandra Smith; David Suter; John T. Schousboe; et al. (GeroScience, 2025)
Abdominal aortic calcification (AAC), a subclinical measure of cardiovascular disease (CVD) that can be assessed on vertebral fracture assessment (VFA) images during osteoporosis screening, is reported to be a falls risk factor. A limitation to incorporating AAC clinically is that its scoring requires trained experts and is time-consuming. We examined if our machine learning (ML) algorithm for AAC (ML-AAC24) is associated with a higher fall-associated hospitalisation risk in the Manitoba Bone Mineral Density (BMD) Registry. A total of 8565 individuals (94.0% female, age 75.7 ± 6.8 years) who had a BMD and VFA image from DXA between February 2010 and December 2017 were included. ML-AAC24 was categorised based on established categories (ML-AAC24 = low < 2; moderate 2 to < 6; high ≥ 6). Cox proportional hazards models assessed the relationship between ML-AAC24 categories and incident fall-associated hospitalisations obtained from linked health records (mean ± SD follow-up, 3.9 ± 2.2 years). Individuals with moderate (9.6%) and high ML-AAC24 (11.7%) had a greater proportion of fall-associated hospitalisations, compared to those with low ML-AAC24 (6.0%). In age and sex-adjusted models, compared to low ML-AAC24, moderate (HR 1.49, 95% CI 1.24–1.79) and high ML-AAC24 (HR 1.89, 95% CI 1.56–2.28) were associated with greater hazards for a fall-associated hospitalisation. Results were comparable (HR 1.37, 95% CI 1.13–1.65 and HR 1.60, 95% CI 1.31–1.95, respectively) after multivariable adjustment, including prior falls and CVD, as well as medication use. Integrating ML-AAC24 into bone density machine software to identify high risk individuals would opportunistically provide important information on fall and cardiovascular disease risk to clinicians for evaluation and intervention.

Inadequate sleep increases stroke risk: evidence from a comprehensive meta-analysis of incidence and mortality - Zoltan Ungvari; Mónika Fekete; Andrea Lehoczki; Gyöngyi Munkácsy; János Tibor Fekete; Virág Zábó; György Purebl; Péter Varga; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
The link between abnormal sleep duration and stroke outcomes remains contentious. This meta-analysis quantifies how both short and long sleep durations impact stroke incidence and mortality. A comprehensive search was conducted in PubMed, Web of Science, Cochrane Library, Embase, and Google Scholar up to November 1, 2024, to identify cohort studies evaluating sleep duration and stroke outcomes. Meta-analysis was performed using MetaAnalysisOnline.com and a random-effects model to estimate pooled hazard ratios (HRs). Results were visualized through Forest and Funnel plots. Analysis of 43 studies (35 on stroke incidence, 8 on mortality) revealed significant associations between sleep duration and stroke outcomes. Short sleep duration (≤ 5–6 h) was associated with increased stroke incidence (HR 1.29, 95% CI 1.19–1.40, p < 0.01) and modestly elevated mortality (HR 1.12, 95% CI 1.01–1.25, p = 0.03). Long sleep duration (> 8–9 h) demonstrated stronger associations with both increased stroke incidence (HR 1.46, 95% CI 1.33–1.60, p < 0.01) and mortality (HR 1.45, 95% CI 1.31–1.60, p < 0.01). Significant heterogeneity was observed in incidence studies ( I 2 = 74–75%), while mortality analyses showed moderate to low heterogeneity ( I 2 = 35–40%). This meta-analysis highlights a U-shaped association between sleep duration and stroke risk, with both short and long sleep durations linked to higher stroke incidence and mortality. These findings underscore the importance of balanced sleep duration as a modifiable risk factor in stroke prevention strategies and provide a foundation for the Semmelweis Study, a prospective workplace cohort investigating the role of modifiable lifestyle factors in unhealthy cerebrovascular and brain aging.

Imbalanced sleep increases mortality risk by 14–34%: a meta-analysis - Zoltan Ungvari; Mónika Fekete; Péter Varga; János Tibor Fekete; Andrea Lehoczki; Annamaria Buda; Ágnes Szappanos; György Purebl; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Sleep duration is a crucial factor influencing health outcomes, yet its relationship with mortality remains debated. In this meta-analysis, we aimed to investigate the association between short and long sleep duration and all-cause mortality in adults, including sex-specific differences. A systematic search was performed in multiple databases, including PubMed, Cochrane Central, and Web of Science, up to October 2024. Retrospective and prospective cohort studies involving adults with at least 1 year of follow-up and data on sleep duration and all-cause mortality were included. Hazard ratios were pooled using a random-effects model, with subgroup analyses performed based on sex and sleep duration categories. A total of 79 cohort studies were included, with data stratified by sex and categorized into short and long sleep durations. Short sleep duration (< 7 h per night) was associated with a 14% increase in mortality risk compared to the reference of 7–8 h, with a pooled hazard ratio of 1.14 (95% CI 1.10 to 1.18). Conversely, long sleep duration (≥ 9 h per night) was associated with a 34% higher risk of mortality, with a hazard ratio of 1.34 (95% CI 1.26 to 1.42). Sex-specific analyses indicated that both short and long sleep durations significantly elevated mortality risk in men and women, although the effect was more pronounced for long sleep duration in women. Both short and long sleep durations are associated with increased all-cause mortality, though the degree of risk varies by sex. These findings underscore the importance of considering optimal sleep duration in public health strategies aimed at enhancing longevity and highlight the need for sex-specific approaches in sleep health research.

Long-term dietary allyl isothiocyanate, a TRPA1 agonist, ameliorates cardiac fibrosis and diastolic dysfunction in aged mice - Chunqi Qian; Zachary Fernandez; Seyed A. Sadeghi; Arman Fotouhi; Liangliang Sun; Donna H. Wang; Shuangtao Ma (GeroScience, 2025)

Associations between metabolomic scores and clinical outcomes in hospitalized COVID-19 patients - Jens A. Venema; Anna Kuranova; Daniele Bizzarri; Simon P. Mooijaart; Angele P. M. Kerckhoffs; Kitty Slieker; Evertine J. Abbink; Harmke A. Polinder-Bos; Eline Slagboom; Geeske Peeters; Jacobijn Gussekloo; Karel G. M. Moons; et al. (GeroScience, 2025)
The disease course and outcome of COVID-19 greatly varies between individuals. To explore which biological systems may contribute to this variation, we examined how individual metabolites and three metabolic scores relate to COVID-19 outcomes in hospitalized COVID-19 patients. The metabolome of 346 patients was measured using the 1H-NMR Nightingale platform. The association of individual metabolomic features and multi-biomarker scores, i.e. MetaboHealth, MetaboAge, and Infectious Disease Score (IDS) (higher scores reflect poorer health), with in-hospital disease course, long-term recovery, and overall survival were analyzed. Higher values for the metabolites phenylalanine (HR = 1.33, CI = 1.14–1.56), glucose (HR = 1.37, CI = 1.16–1.62) and lactate (HR = 1.38, CI = 1.16–1.63) were associated with mortality. For all three metabolic scores, higher scores were significantly associated with higher odds of a poorer in-hospital disease course (MetaboHealth: OR = 1.61, CI = 1.29–2.02; ΔMetaboAge: OR = 1.42, CI = 1.16–1.74; IDS: OR = 1.55, 1.25–1.93) and with overall survival (MetaboHealth: HR = 1.57, CI = 1.28–1.92; ΔMetaboAge: HR = 1.34, CI = 1.15–1.57; IDS: HR = 1.56, CI = 1.27–1.93). MetaboHealth and ΔMetaboAge showed a stronger association in younger patients (< 70 yrs.) than older patients. No clear patterns were found in associations between the three scores and measures of long-term recovery. In conclusion, the heterogeneity in disease course after SARS-COV2 infection may be explained either by generic biological frailty reflected by the three metabolomics scores or by glycemic control (glucose, lactate) and respiratory distress (phenylalanine).

Examining the test–retest reliability of commonly used neuromuscular, morphological, and functional measures in aging adults - Gustavo Z. Schaun; Peter Raidl; Luana S. Andrade; Gabriela B. David; Eduardo F. Marins; Mariana S. Häfele; Stephanie S. Pinto; Robert Csapo; Cristine L. Alberton (GeroScience, 2025)
The present study aimed at determining the test–retest reliability of commonly used measures in a sample of middle-aged and older participants who presented with a wide range of functional abilities. Participants were middle-aged (40–55 years) and older adults (> 60 years) with- and without mobility limitations, tested both before and after a 4-week period (n = 43). Measures included maximal dynamic (1-RM) and isometric strength, surface EMG (sEMG), peak power, ultrasound-derived muscle size and quality, as well as the performance on the 30-s sit-to-stand, habitual and maximal gait speed, timed up-and-go, stair climb, and 6-min walk tests. Reliability was assessed by means of the intraclass correlation coefficient (ICC), the standard error of measurement (SEM), the minimal detectable change (MDC), and the coefficient of variation (CV). Both dynamic and isometric strength measures displayed excellent reliability (ICCs = 0.96–0.99; CV = 2.2%-7%), whereas muscle size and quality (ICCs = 0.88–0.98; CV = 3.3%-8.7%), functional performance (ICCs = 0.78–0.92; CV = 4.2%-6.8%) and peak power (ICCs = 0.76–0.98; CV = 6.6%-12.8%) results showed good to excellent reliability. Peak power at 80–90% 1‑RM and sEMG measures, on the other hand, showed larger absolute error (CV = 14.4%-18.3% and CV = 14.3%-19.8%, respectively), despite good relative reliability (ICCs = 0.85–0.86). Further results include the comparison between the three subsets of participants included. Our main analysis suggests that most of these measures are sufficiently reliable, even when the two tests are performed a month apart from each other. Our study also supports the notion that, provided that the same equipment and procedures are used, the test–retest reliability of the measures is mostly comparable between the subsets of participants investigated.

Associations between environmental air pollution, greenspace and apparent biological aging: a cross-sectional study - Yijing Zhao; Xuena Yang; Dan He; Wenming Wei; Bolun Cheng; Feng Zhang (GeroScience, 2025)

Unveiling the geroprotective potential of Monarda didyma L.: insights from in vitro studies and a randomized clinical trial on slowing biological aging and improving quality of life - Manuela Campisi; Luana Cannella; Omar Paccagnella; Alessandra R. Brazzale; Alberto Agnolin; Torsten Grothe; Julia Baumann; Sofia Pavanello (GeroScience, 2025)
Aging is driven by fundamental mechanisms like oxidative stress, telomere shortening and changes in DNA methylation, which together prepare the ground for age-related diseases. Botanical extracts, rich in bioactive phytoconstituents, represent a promising resource for developing therapies that target these mechanisms to promote healthy aging. This study explores the geroprotective potential of Monarda didyma L. extract. In vitro analyses revealed the extract’s strong antioxidant activity, ability to reduce telomere shortening, and capacity to protect against DNA damage, thereby decreasing cellular senescence and improving endothelial function. The randomized, double-blind clinical trial demonstrated that daily oral supplementation with the extract significantly improved leukocyte telomere length (LTL) and stabilized DNA methylation age (DNAmAge) in the intervention group, while the placebo group experienced accelerated epigenetic aging and hypermethylation of critical age-related genes (ELOVL2 and FHL2). The intervention group also reported enhanced quality of life, particularly in the physical domain, along with improved movement and quality sleep indices detected by questionnaire and wearable sensors. These compelling findings position Monarda didyma L. extract as a powerful candidate for future geroprotective therapies, with the potential to significantly impact healthy aging.

Aged regulatory T cells fail to control autoimmune lacrimal gland pathogenic CD4+ T cells - Kaitlin K. Scholand; Laura Schaefer; Gowthaman Govindarajan; Zhiyuan Yu; Jeremias G. Galletti; Cintia S. de Paiva (GeroScience, 2025)

Construction and validation of a DNN-based biological age and its influencing factors in the China Kadoorie Biobank - Yushu Huang; Lijuan Da; Yue Dong; Zihan Li; Yuan Liu; Zilin Li; Xifeng Wu; Wenyuan Li (GeroScience, 2025)
Biological age is an important measure of aging that reflects an individual’s physical health and is linked to various diseases. Current prediction models are still limited in precision, and the risk factors for accelerated aging remain underexplored. Therefore, we aimed to develop a precise biological age and assess the impact of socio-demographic and behavioral patterns on the aging process.We utilized Deep Neural Networks (DNN) to construct biological age from participants with physical examinations, blood samples, and questionnaires data from the China Kadoorie Biobank (CKB) between June 2004 and December 2016. △age, calculated as the residuals between biological age and chronological age, was used to investigate the associations of age acceleration with diseases. Socio-demographics (gender, education attainment, marital status, household income) and lifestyle characteristics (body mass index [BMI], smoking, drinking, physical activity, and sleep) were also assessed to explore their impact on age acceleration. 18,261 participants aged 57 ± 10 years were included in this study. The DNN-based biological age model has demonstrated accurate predictive performance, achieving a mean absolute error of 3.655 years. △age was associated with increased risks of various morbidity and mortality, with the highest associations found for circulatory and respiratory diseases, with hazard ratios of 1.033 (95% CI: 1.023, 1.042) and 1.078 (95% CI: 1.027, 1.130), respectively. Socio-demographics, including being female, lower education, widowed or divorced, and low household income, along with behavioral patterns, such as being underweight, insufficient physical activity, and poor sleep, were associated with accelerated aging. Our DNN model is capable of constructing a precise biological age using commonly collected data. Socio-demographics and lifestyle factors were associated with accelerated aging, highlighting that addressing modifiable risk factors can effectively slow age acceleration and reduce disease risk, providing valuable insights for interventions to promote healthy aging.

Various diseases and conditions are strongly associated with the next-generation epigenetic aging clock CheekAge - Maxim N. Shokhirev; Adiv A. Johnson (GeroScience, 2025)
Epigenetic aging clocks represent contemporary aging biomarkers that predict age using methylomic data. These models can be categorized as first-generation clocks that estimate chronological age or next-generation clocks that are designed to associate with health, lifestyle, and/or outcomes. Recently, we created a next-generation buccal clock called CheekAge that associates with all-cause mortality risk in older adults. To better understand our model, we collated 25 Infinium MethylationEPIC datasets in the Gene Expression Omnibus database and analyzed the ability of CheekAge and five other well-known clocks to associate with distinct health and disease signals. CheekAge outcompeted every other clock tested by significantly associating with a total of 33 different disease and health variables, including human immunodeficiency virus, major depressive disorder, psychological trauma, prediabetes, body mass index, non-alcoholic fatty liver disease, pulmonary fibrosis, exposure to the chemical endocrine disruptor PBB-153, and various cancers and tumors. Of the six clocks tested, the next-generation clocks outperformed the first-generation clocks. To better understand the underlying biology of CheekAge, we iteratively removed CpG inputs to identify DNA methylation sites that promoted or antagonized each association. Finally, we performed detailed enrichment analyses on these sites to unveil overrepresented biological processes and transcription factor targets.

Correction to: Anti-aging interventions in geriatric mice: insights into the timing of treatment, benefits, and limitations - Marco Malavolta (GeroScience, 2025)

Correction to: Association between cognitive reserve proxies and frailty phenotype: data from UK Biobank - Laura Lorenzo‑Lopez; Nuria Cibeira; Ali Hemadeh; Rocío Lopez‑Lopez; Carlota Lema‑Arranz; Ana Maseda; Natalia Fernandez‑Bertolez; Solange Costa; Eduardo Pásaro; Vanessa Valdiglesias; José C. Millan‑Calenti; Blanca Laffon (GeroScience, 2025)

Attention-dependent coupling with forebrain and brainstem neuromodulatory nuclei differs across the lifespan - Nicholas G. Cicero; Elizabeth Riley; Khena M. Swallow; Eve De Rosa; Adam Anderson (GeroScience, 2025)
Attentional states reflect the changing behavioral relevance of stimuli in one’s environment, having important consequences for learning and memory. Supporting well-established cortical contributions, attentional states are hypothesized to originate from subcortical neuromodulatory nuclei, such as the basal forebrain (BF) and locus coeruleus (LC), which are among the first to change with aging. Here, we characterized the interplay between BF and LC neuromodulatory nuclei and their relation to two common afferent cortical targets important for attention and memory, the posterior cingulate cortex and hippocampus, across the adult lifespan. Using an auditory target discrimination task during functional MRI, we examined the influence of attentional and behavioral salience on task-dependent functional connectivity in younger (19–45 years) and older adults (66–86 years). In younger adults, BF functional connectivity was largely driven by target processing, while LC connectivity was associated with distractor processing. These patterns are reversed in older adults. This age-dependent connectivity pattern generalized to the nucleus basalis of Meynert and medial septal subnuclei. Preliminary data from middle-aged adults indicates a transitional stage in BF and LC functional connectivity. Overall, these results reveal distinct roles of subcortical neuromodulatory systems in attentional salience related to behavioral relevance and their potential reversed roles with aging, consistent with managing increased salience of behaviorally irrelevant distraction in older adults. Such prominent differences in functional coupling across the lifespan from these subcortical neuromodulatory nuclei suggests they may be drivers of widespread cortical changes in neurocognitive aging, and middle age as an opportune time for intervention.

Rationale and design of the Dog Aging Project precision cohort: a multi-omic resource for longitudinal research in geroscience - Jena Prescott; Amber J. Keyser; Paul Litwin; Matthew D. Dunbar; Robyn McClelland; Audrey Ruple; Holley Ernst; Brianna L. Butler; Mandy Kauffman; Anne Avery; Benjamin R. Harrison; Maria Partida-Aguilar; et al. (GeroScience, 2025)

Accelerated retinal ageing and multimorbidity in middle-aged and older adults - Ruiye Chen; Xiaomin Zeng; Wenyi Hu; Deepak Jeyarajan; Zhen Yu; Wei Wang; Zongyuan Ge; Xianwen Shang; Mingguang He; Zhuoting Zhu (GeroScience, 2025)
The aim of this study is to investigate the association between retinal age gap and multimorbidity. Retinal age gap was calculated based on a previously developed deep learning model for 45,436 participants. The number of age-related conditions reported at baseline was summed and categorized as zero, one, or at least two conditions at baseline (multimorbidity). Incident multimorbidity was defined as having two or more age-related diseases onset during the follow-up period. Linear regressions were fit to examine the associations of disease numbers at baseline with retinal age gaps. Cox proportional hazard regression models were used to examine associations of retinal age gaps with the incidence of multimorbidity. In the fully adjusted model, those with multimorbidity and one disease both showed significant increases in retinal age gaps at baseline compared to participants with zero disease number ( β = 0.254, 95% CI 0.154, 0.354; P < 0.001; β = 0.203, 95% CI 0.116, 0.291; P < 0.001; respectively). After a median follow-up period of 11.38 (IQR, 11.26–11.53; range, 0.02–11.81) years, a total of 3607 (17.29%) participants had incident multimorbidity. Each 5-year increase in retinal age gap at baseline was independently associated with an 8% increase in the risk of multimorbidity (HR = 1.08, 95% CI 1.02, 1.14, P = 0.008). Our study demonstrated that an increase of retinal age gap was independently associated with a greater risk of incident multimorbidity. By recognizing deviations from normal aging, we can identify individuals at higher risk of developing multimorbidity. This early identification facilitates patients’ self-management and personalized interventions before disease onset.

Sex-specific molecular drivers of cardiac fibrosis in aging hearts - Katie Anne Fopiano; Marta B. Balogh; Vijay S. Patel; Daria V. Ilatovskaya; Zsolt Bagi (GeroScience, 2025)

Associations between shift work and biological age acceleration: A population-based study - Jia-Ning Wang; Wei Hu; Bao-Peng Liu; Cun-Xian Jia (GeroScience, 2025)

Resistance exercise training in older men reduces ATF4-activated and senescence-associated mRNAs in skeletal muscle - Zachary D. Von Ruff; Matthew J. Miller; Tatiana Moro; Paul T. Reidy; Scott M. Ebert; Elena Volpi; Christopher M. Adams; Blake B. Rasmussen (GeroScience, 2025)
Sarcopenia increases the risk of frailty, morbidity, and mortality in older adults. Resistance exercise training improves muscle size and function; however, the response to exercise training is variable in older adults. The objective of our study was to determine both the age-independent and age-dependent changes to the transcriptome following progressive resistance exercise training. Skeletal muscle biopsies were obtained before and after 12 weeks of resistance exercise training in 8 young (24 ± 3.3 years) and 10 older (72 ± 4.9 years) men. RNA was extracted from each biopsy and prepared for analysis via RNA sequencing. We performed differential mRNA expression, gene ontology, and gene set enrichment analyses. We report that when comparing post-training vs pre-training 226 mRNAs and 959 mRNAs were differentially expressed in the skeletal muscle of young and older men, respectively. Additionally, 94 mRNAs increased, and 17 mRNAs decreased in both young and old, indicating limited overlap in response to resistance exercise training. Furthermore, the differential gene expression was larger in older skeletal muscle. Finally, we report three novel findings: 1) resistance exercise training decreased the abundance of ATF4-activated and senescence-associated skeletal muscle mRNAs in older men; 2) resistance exercise-induced increases in lean mass correlate with increased mRNAs encoding mitochondrial proteins; and 3) increases in muscle strength following resistance exercise positively correlate with increased mRNAs involved in translation, rRNA processing, and polyamine metabolism. We conclude that resistance exercise training elicits a differential gene expression response in young and old skeletal muscle, including reduced ATF-4 activated and senescence-associated gene expression.

Restoring neuropetide Y levels in the hypothalamus ameliorates premature aging phenotype in mice - Marisa Ferreira-Marques; Sara Carmo-Silva; Joana Pereira; Mariana Botelho; Clévio Nóbrega; Carlos López‐Otín; Luís Pereira de Almeida; Célia A. Aveleira; Cláudia Cavadas (GeroScience, 2025)
The hypothalamus has been recognized as a regulator of whole-body aging. Neuropeptide Y (NPY), highly abundant in the central nervous system and produced by the hypothalamus, enhances autophagy in this brain region and mediates autophagy triggered by caloric restriction, suggesting a potential role as a caloric restriction mimetic and an aging regulator. Considering that hypothalamic NPY levels decline during aging, we investigated if reestablishment of NPY levels mitigate aging phenotype, using a mouse model of premature aging – Zmpste24 −/− mouse. The results show that reestablishing hypothalamic NPY levels delayed aging-associated features, including lipodystrophy, alopecia, and memory. Moreover, these results suggest that strategies that promote maintenance of hypothalamic NPY levels might be relevant to counteract aging progression and age-related deteriorations.

Decoding cognitive aging: how white matter tracts and demographics distinguish potential Super-Agers - Mohammad Fili; Parvin Mohammadiarvejeh; Guiping Hu; Auriel A. Willette (GeroScience, 2025)
Most adults experience age-related cognitive decline. However, “Positive-Agers” exhibit superior cognition compared to their age-matched peers. Distinguishing between those with superior cognitive performance and those with cognitive decline over time could better inform treatment therapies in older adults. We developed an algorithm called Opti mal C ognitive S coring (OptiCS) that accurately differentiates “Positive-Agers” from “Cognitive Decliners.” This study draws on a cohort of 5797 participants longitudinally enrolled in the UK Biobank. Using a predictive pipeline, OptiCS could strongly differentiate Positive-Agers versus Cognitive Decliners (area under the curve, or AUC of 83%). The top diffusion MRI attributes highlighted tracts implicated in pathological aging, including the fornix from the hippocampus, the tapetum from the splenium of the corpus callosum, and other key tracts. This study provides three key insights: (I) The proposed algorithm offers a robust cognitive scoring system for subtle cognitive changes, (II) OptiCS can use diffusion MRI to accurately gauge cognitive performance, and (III) OptiCS provides a predictive framework for early detection of cognitive decline.

Improving care interactions (and training) in nursing homes with artificial intelligence - Marie Lefelle; Mouny Samy Modeliar (GeroScience, 2025)
As the population continues to age, nursing homes will increasingly play a key role in caring for dependent individuals. To enhance the well-being of the elderly, it is crucial to focus on the language skills used during care interactions. However, issues such as the taboo surrounding dependency, scandals involving private nursing home management, the pressure for caregiver efficiency, and the variety of care contexts make monitoring these skills challenging. One way to address this is by collecting in situ data, supervised by language researchers and caregivers specialized in elderly care. This is the approach we have followed: the data collected was then analyzed using machine learning models to provide caregivers with crucial insights for improving care outcomes. Our research highlights the importance of specific factors in language-based interactions, especially in varied care situations. Notably, we emphasize the careful use of humor and the impact of caregiver experience on the success of care sessions. Consequently, we advocate for caregiver training that is grounded in real-life practice, focusing on context adaptation, active listening, and dialogue with residents.

SenSkin™: a human skin-specific cellular senescence gene set - Saranya P. Wyles; Grace T. Yu; Clarisse Ganier; Tamar Tchkonia; Magnus D. Lynch; George A. Kuchel; James L. Kirkland (GeroScience, 2025)
Cellular senescence gene sets have been leveraged to overcome the inadequate sensitivity or specificity of single markers. However, growing evidence of heterogeneity among tissues in senescent cell phenotypes and gene expression profiles has highlighted the need for tissue-specific gene sets. SenSkin™ was curated by an expert review of literature on cellular senescence in the skin and characterized with pathway analysis. To validate SenSkin™, it was evaluated for enrichment with chronological aging in a bulk RNA-sequencing (RNA-seq) dataset and a pseudobulk RNA-seq dataset. Further, changes to SenSkin™ in different skin cell types with photoaging were evaluated in two single-cell RNA-seq datasets. SenSkin™ predominantly included genes related to the senescence-associated secretory phenotype (SASP), which were associated with metabolism and multiple aspects of immune responses. SenSkin™ was more enriched in chronologically aged skin than other commonly used cellular senescence and aging gene sets. In scRNA-seq, SenSkin™ displayed significant upregulation due to photoaging in ten skin cell types. In conclusion, SenSkin™ is a human skin-specific senescence gene set validated in chronological aging and photoaging, which may be more effective at detecting senescent cells in the skin than non-tissue-specific gene sets.

Awareness, knowledge, and motivations about lifespan, healthspan, and Healthy Longevity Medicine in the general population: the HEalthy LOngevity (HELO) conceptual framework - Belinda Wang; Anna Szücs; Elena Sandalova; E. J. Horberg; Paul A. O’Keefe; Louis Island; Hans J. Meij; Sonny Rosenthal; Andrea B. Maier (GeroScience, 2025)
The global population is ageing and the gap between lifespan (total years lived) and healthspan (years lived free of diseases) is increasing. Healthy Longevity Medicine (HLM) is an approach to optimise health and healthspan, and it has substantial public health implications. Despite those implications, the understanding of public perspectives on this field is lacking. The HEalthy LOngevity (HELO) framework was developed through a literature review guided by expert discussions across disciplines to include evidence-based concepts of health-related decision-making, ageing, and HLM. The framework organises concepts into three components. The first two components, awareness and knowledge, explore public perception and understanding of the healthy longevity field, respectively. The third component, motivations, reflects factors underlying motivations towards healthy longevity. These include personality, current behaviours, personal values and beliefs, and health-related perceptions. The framework outlines the theoretical foundation to explore public knowledge and interest in healthy longevity. The framework will be refined based on findings from qualitative focus groups in Singapore and then applied to quantitative population surveys globally. These HELO initiatives aim to inform strategies for integrating HLM into public healthcare, promoting health and healthspan.

ChatGPT-estimated occupational complexity predicts cognitive outcomes and cortical thickness above and beyond socioeconomic status among older adults - Junhong Yu; Ee-Heok Kua; Rathi Mahendran; Ted Kheng Siang Ng (GeroScience, 2025)

The senolytic ABT-263 improves cognitive functions in middle-aged male, but not female, atherosclerotic LDLr−/−;hApoB100+/+ mice - Mélanie Lambert; Géraldine Miquel; Louis Villeneuve; Nathalie Thorin-Trescases; Eric Thorin (GeroScience, 2025)
Accumulation of cerebral senescent cells may compromise the continuum between vascular and neuronal function, leading to damage and cognitive decline. Elimination of senescent cells might therefore preserve vascular and neuronal functions. To test this hypothesis, we used male and female atherosclerotic LDLr −/− ;hApoB 100 +/+ mice (ATX-mice), a model of vascular cognitive impairment (VCI), treated with the senolytic ABT-263 for 3 months (3- to 6-month or 9- to 12-month old). In young male ATX mice, prevention with ABT-263 improved spatial retention memory, in association with a higher endothelial sensitivity to shear stress and a higher hippocampal CD31 + endothelial cell density, lower activation of both astrocytes and glial cells. In young females, ABT-263 tended to improve delayed memory; however, atherosclerotic plaque was magnified by ABT-263, endothelial function was unaffected, hippocampal astrocyte activation increased and expression of CD31 + cells decreased. Hence, unlike in males, ABT-263 appears deleterious in young ATX females. In middle-aged males, the curative treatment improved the learning process and memory. Although no change in endothelial function was observed, the benefits of ABT-263 were associated with a decreased expression of several inflammaging markers, a higher density of CD31 + cells and a lower activation of glial cells. In middle-aged females, ABT-263 induced a surge of inflammaging markers, associated with a slower learning process. Altogether, our data demonstrate that ABT-263 differentially affects VCI, improving cognition in male while being deleterious in female ATX mice. More studies are needed to understand the mechanisms at the basis of the sexual dimorphic effects of the senolytic ABT-263.

International Consortium to Classify Ageing-related Pathologies (ICCARP) senescence definitions: achieving international consensus - Emma Short; Robert T. R. Huckstepp; Kambiz Alavian; Winfried M. K. Amoaku; Thomas M. Barber; Edwin J. R. van Beek; Emyr Benbow; Sunil Bhandari; Phillip Bloom; Carlo Cota; Paul Chazot; Gary Christopher; et al. (GeroScience, 2025)

Persisting blood–brain barrier disruption following cisplatin treatment in a mouse model of chemotherapy-associated cognitive impairment - Roland Patai; Boglarka Csik; Adam Nyul-Toth; Rafal Gulej; Kiana Vali Kordestan; Siva Sai Chandragiri; Santny Shanmugarama; Stefano Tarantini; Peter Mukli; Anna Ungvari; Andriy Yabluchanskiy; Zoltan Ungvari; et al. (GeroScience, 2025)
Chemotherapy-related cognitive impairment, commonly referred to as “chemobrain,” significantly affects cancer survivors’ quality of life, yet its underlying mechanisms remain unclear. Most chemotherapeutic agents cannot cross the blood–brain barrier (BBB), yet they cause central nervous system side effects, suggesting alternative pathways of toxicity. Given that these drugs interact with the cerebrovascular endothelium at their highest concentrations, it is logical to hypothesize that endothelial damage contributes to these effects. Our recent studies demonstrated that paclitaxel-induced cognitive impairment in a mouse model results in a partial BBB disruption and subsequent neuroinflammation, mediated by chemotherapy-induced endothelial senescence. In this pilot study, we used two-photon microscopy to assess BBB permeability in mice receiving a clinically relevant cisplatin regimen, evaluating the leakage of fluorescent dextran tracers of varying molecular weights. Two months post-treatment, cisplatin-treated mice exhibited significantly increased BBB permeability to smaller molecular tracers (40 kDa, 3 kDa, and 0.3 kDa) compared to controls, indicating sustained BBB disruption. These results align with our findings for paclitaxel and suggest that chemotherapy-induced endothelial damage and senescence play a central role in cognitive impairments. Interventions targeting endothelial health could mitigate these long-term effects, improving cognitive outcomes for cancer survivors.

Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment - Boglarka Csik; Kiana Vali Kordestan; Rafal Gulej; Roland Patai; Adam Nyul-Toth; Santny Shanmugarama; Peter Mukli; Anna Ungvari; Karl E. Balsara; Rene Y. McNall; Talayeh Razzaghi; Stefano Tarantini; et al. (GeroScience, 2025)
The increasing number of cancer survivors has brought heightened attention to the side effects of cancer therapies, including chemotherapy-related cognitive impairment (CRCI, commonly referred to as “chemobrain”). Cisplatin and methotrexate, commonly used first-line chemotherapeutics in gynecologic oncology for cancers such as breast, ovarian, and bladder cancer, are clinically associated with long-term cognitive deficits. Building on our previous preclinical studies demonstrating that paclitaxel chemotherapy induces cerebrovascular endothelial and microglial senescence—leading to blood–brain barrier (BBB) disruption, neuroinflammation, and cognitive impairments—we hypothesized that cisplatin and methotrexate might similarly promote senescence in these cells. Senescent endothelial cells and microglia are known to contribute to neuroinflammation, cerebral blood flow dysregulation, and white matter damage, exacerbating cognitive decline. Using the p16-3MR mouse model, which expresses red fluorescent protein (RFP) in p16 + senescent cells, we evaluated the impact of these drugs on brain endothelial and microglial senescence through flow cytometry. Our results show a significant increase in senescent endothelial and microglial cells two months post-treatment with cisplatin or methotrexate compared to controls. These findings offer new insights into the shared mechanisms underlying CRCI associated with cisplatin or methotrexate treatment, extending our understanding of chemotherapy-induced vascular cognitive impairments.

Transcriptomic profiling of senescence effects on blood–brain barrier-related gene expression in brain capillary endothelial cells in a mouse model of paclitaxel-induced chemobrain - Roland Patai; Tamas Kiss; Rafal Gulej; Adam Nyul-Toth; Boglarka Csik; Siva Sai Chandragiri; Santny Shanmugarama; Stefano Tarantini; Anna Ungvari; Pal Pacher; Peter Mukli; Andriy Yabluchanskiy; et al. (GeroScience, 2025)
Chemotherapy-induced cognitive impairment (CICI), commonly referred to as “chemobrain,” is a frequent and debilitating side effect experienced by cancer survivors treated with paclitaxel (PTX). Preclinical models have shown that PTX promotes cerebromicrovascular endothelial cell senescence, leading to chronic blood–brain barrier (BBB) disruption and neuroinflammation. Conversely, the elimination of senescent cells through senolytic therapies has been shown to restore BBB integrity, reduce neuroinflammation, and alleviate PTX-induced cognitive impairment. In this study, we tested the hypothesis that PTX-induced endothelial senescence alters gene expression patterns associated with BBB integrity. To investigate this, we analyzed a scRNA-seq dataset from the brains of mice treated with a clinically relevant PTX regimen alongside vehicle-treated control mice. We identified capillary endothelial cells by their distinct transcriptomic profiles and matched these profiles to known transcriptomic markers of cellular senescence. Our analysis confirmed that PTX induces senescence in capillary endothelial cells and revealed significant transcriptional alterations linked to impaired BBB function. In senescent endothelial cells, gene set enrichment analysis (GSEA) highlighted downregulated pathways associated with cell junction assembly and upregulated pathways involved in extracellular matrix remodeling and inflammatory signaling, including Vitronectin (VTN) and Pleiotrophin (PTN) pathways. Additionally, cell–cell communication analysis revealed reduced Junctional Adhesion Molecule (JAM) signaling, further implicating senescence in BBB disruption. These findings highlight endothelial senescence as a driver of BBB dysfunction through transcriptional changes and altered intercellular signaling. The enrichment of VTN and PTN pathways in the senescent state indicates a shift toward vascular remodeling and inflammation, exacerbating microvascular fragility and BBB disruption. Supported by prior experimental findings, this study suggests that targeting endothelial senescence and its downstream effects could mitigate PTX-induced BBB dysfunction and associated cognitive impairments. These results advance our understanding of CICI pathogenesis and provide a foundation for developing therapeutic strategies aimed at preserving vascular integrity.

Metabolomic insight into the link of intermuscular fat with cognitive performance: the Health ABC Study - Richard Xu; Qu Tian; Megan M. Marron; Luigi Ferrucci; Shanshan Yao; Seyoung Kim; Ravi V. Shah; Venkatesh L. Murthy; Anne B. Newman; Iva Miljkovic; Caterina Rosano (GeroScience, 2025)
There is growing evidence that higher intermuscular fat (IMF) is associated with worse processing speed, measured by the digit symbol substitution test (DSST) in older adults. However, the underlying biological mechanisms are not well understood. Considering that both muscle and the brain are metabolically active organs, we sought to identify metabolites that may explain the IMF-DSST association. We assessed 613 plasma metabolites in 2388 participants from the Health, Aging, and Body Composition Study (mean age ± SD 74.7 ± 2.9 years, 50% men, 63% white), using liquid chromatography-mass spectrometry. We confirmed that higher IMF was associated with worse DSST scores (standardized beta (95% CI) − 0.08 (− 0.12, − 0.03), p < 0.001). Sixty-six metabolites were significantly associated with both IMF and DSST. Four of the 66 metabolites attenuated the association by ≥ 10%: higher levels of adrenic acid (polyunsaturated fatty acid), and lower levels of C20:5 lysophosphatidylcholine (lysophospholipid), 1-methylnicotinamide (vitamin B3-related myokine), and maslinic acid (triterpene) were associated with higher IMF and worse DSST. Together, they explained 41% of the IMF-DSST association. Pathway enrichment analyses identified two significant shared pathways: unsaturated fatty acid metabolism and the citrate (TCA) cycle. This study provides hypothesis-generating evidence that a set of circulating metabolites related to unsaturated fatty acids, energy metabolism, and myokines may partially explain the inverse association of IMF with processing speed. The findings, if further confirmed by independent studies, advance our understanding of molecular pathways underlying muscle-brain crosstalk. Whether the identified metabolites are early predictors of future decline in processing speed should be further investigated.

Plasma homocysteine level and trajectories in association with longitudinal increase in plasma neurofilament light among urban adults - May A. Beydoun; Nicole Noren Hooten; Michael F. Georgescu; Hind A. Beydoun; Marie T. Fanelli-Kuczmarski; Jordan Weiss; Michele K. Evans; Alan B. Zonderman (GeroScience, 2025)
We tested whether homocysteine (Hcy) was linked to longitudinal change in plasma neurofilament light chain (NfL) overall and differentially across sex and race in a sample of middle-aged urban adults. We used data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study [ n = 690, Age at visit 1 (v 1 :2004–2009): 30-66y, 42.1% male, 55.4% African American] to evaluate relationships between NfL levels and both visit 1 Hcy (Hcy v1 ) and time-dependent Hcy concentrations (Hcy td ). Specifically, we examined the relationship between these measures and visit 1 NfL (NfL v1 ) as well as annualized change in NfL (δNfL) over the study period of ~ 8y [2004–2009 (v 1 ), 2009–2013 (v 2 ) and/or 2013–2017 (v 3 )] using mixed effects linear regression models. Hcy v1 was positively associated with NfL v1 , but not with δNfL. However, when Hcy td was considered along with time-dependent covariates on multiple-imputed data, both NfL v1 and δNfL were associated with Hcy td , with some significant sex difference in the longitudinal association, whereby this relationship was stronger among males. The Hcy exposure obtained from group-based trajectory models, indicated that individuals belonging to the "High increasing" group were consistently associated with both higher NfL v1 and faster increase in NfL (overall, fully adjusted, High vs . Low: γ 0gbtm = + 0.226 ± 0.058, P < 0.001; γ 1gbtm = + 0.022 ± 0.007, P < 0.010). Dynamic Hcy exposures (Hcy td and Hcy gbtm ) were associated with faster rate of increase in NfL over time, reflecting potentially faster rate of axonal degeneration. Further studies are needed in comparable populations to replicate our findings.

Intact embodiment during perspective-taking in older adults is not affected by focal tDCS - Mandy Roheger; Anna Mäder; Steffen Riemann; Filip Niemann; Klaus Kessler; Andrew K. Martin; Marcus Meinzer (GeroScience, 2025)
Embodied processing is crucial for visual perspective taking (VPT), with evidence from non-invasive transcranial direct current stimulation (tDCS) suggesting a causal role of the right temporoparietal junction (rTPJ). However, it is not known whether such embodied factors are maintained in older adults or whether rTPJ-tDCS has comparable effects in advanced age. We employed a balanced and sham-tDCS controlled, double-blinded, cross-over design, including two randomized experimental groups of healthy older adults, receiving focal tDCS over either the rTPJ ( n = 30), or a control region in the dorsomedial prefrontal cortex (dmPFC, n = 30). A healthy young control group ( n = 30, not receiving tDCS) was included to investigate potential changes in embodied processing in older adults. All groups completed neuropsychological baseline testing and an experimental VPT paradigm, in which perspective-taking (requiring embodied rotation) and perspective-tracking (line-of-sight judgements) were assessed. Structural magnetic resonance imaging data were acquired to conduct individualized current flow simulations, aimed at identifying potential changes in neurophysiological effects of tDCS in older adults. Older adults responded slower across perspective tracking and perspective taking tasks but showed comparable embodied effects of body posture and angle of rotation during perspective taking. Contrary to previous results in younger adults that demonstrated regionally and task-specific effects of focal rTPJ-tDCS, no stimulation effects on embodied processing were found in older adults. Electrical field simulations suggested focal current delivery in both age-groups but also significantly reduced current strength in the target regions for tDCS in older adults. Older adults are as embodied as young adults during perspective taking. However, tDCS administered to the rTPJ or dmPFC had no effect, which may be explained by reduced current delivery to the target regions due to age-associated changes in skull and brain anatomy and/or functional brain reorganization. Our results are in line with previous studies suggesting that tDCS effects obtained in young participants may not translate directly to advanced age. Future studies could address this by using individualized modelling approaches aimed at adjusting current dose for (older) study participants and pre-stimulation functional imaging involving VPT tasks-of-interest, to identify optimized target regions for tDCS. Registration: ClinicalTrials.gov Identifier: NCT04633499.

Correction to: Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats - Anna Szilágyi; Barbara Takács; Réka Szekeres; Vera Tarjányi; Dávid Nagy; Dániel Priksz; Mariann Bombicz; Rita Kiss; Adrienn Mónika Szabó; Andrea Lehoczki; Rudolf Gesztelyi; Béla Juhász; et al. (GeroScience, 2025)

Center frequency as optimal frequency of visual stimulation for spreading entrained gamma rhythms to other target brain regions in cognitively normal older adults - Euisuk Yoon; Yeseung Park; Hong Jun Kim; Jaehyeok Park; Ji Won Han; Se Joon Woo; Seunghyup Yoo; Ki Woong Kim (GeroScience, 2025)
Gamma entrainment using 40 Hz sensory stimulation has shown promise in AD mouse models, but inconsistent results in AD patients, possibly due to interspecies and interindividual differences in center frequency (CF). This study aimed to investigate whether gamma rhythms entrained by visual stimulation at an individual’s CF can spread better than those at other frequency conditions in older adults. We entrained gamma rhythms in 32 cognitively normal older participants using light flickering at 32 Hz, 34 Hz, 36 Hz, 38 Hz, and 40 Hz. We identified each individual’s CF among these five frequencies and compared the spread, strength, and stability of gamma connectivity induced by light stimulation flickering at an individual’s CF with those at other frequencies using generalized estimating equation and repeated measures ANOVA. In about two-thirds of the participants, 32 Hz (40.6%) and 34 Hz (28.1%) were identified as CF. The mean spread, strength, and stability of gamma connectivity involving the visual cortex (GC V-NV ) were higher than those do not involve the visual cortex (GC NV-NV , p < 0.05). Between the visual cortex and other brain regions, FLS induced with frequencies of high event related spectral perturbation values, including CF and non-center frequency (NCF) 1, generally induced broader, stronger, and more stable gamma connectivity compared to most other NCFs ( p < 0.001 when comparing NCFs with either CF and NCF1 for both strength and spread; p = 0.012 when comparing CF and NCF3 for stability). Gamma rhythms entrained by visual stimulation may better spread to other brain regions when its frequency matched to the individual’s CF.

Test of Rapamycin in Aging Dogs (TRIAD): study design and rationale for a prospective, parallel-group, double-masked, randomized, placebo-controlled, multicenter trial of rapamycin in healthy middle-aged dogs from the Dog Aging Project - Amanda E. Coleman; Kate E. Creevy; Rozalyn Anderson; May J. Reed; Virginia R. Fajt; Kathleen M. Aicher; Genna Atiee; Brian G. Barnett; Ryan D. Baumwart; Beth Boudreau; Suzanne M. Cunningham; Matthew D. Dunbar; et al. (GeroScience, 2025)

Measuring thymic output across the human lifespan: a critical challenge in laboratory medicine - Vera Middelkamp; Eliisa Kekäläinen (GeroScience, 2025)
Age-associated thymic involution leads to a significant decline in thymic T cell output, a major contributor to immunosenescence in the elderly. Accurately measuring thymic output is therefore critical for understanding the mechanisms behind immune aging. Furthermore, robust quantification of thymic output is essential in various other clinical and research settings, including the diagnosis of immunodeficiencies and the monitoring of T cell reconstitution following therapeutic interventions like hematopoietic stem cell transplantation. Current methodologies for measuring thymic output include T cell receptor excision circle (TREC) quantification via quantitative polymerase chain reaction and the enumeration of recent thymic emigrants (RTEs) using flow cytometry. However, TREC-based assays are inherently insensitive to subtle changes in thymic output, limiting their applicability beyond neonatal immunodeficiency screening. Similarly, RTE enumeration presents challenges; while surface markers exist for CD4⁺ RTEs, validated markers for CD8⁺ cytotoxic T lymphocytes are lacking. This represents a significant knowledge gap, particularly as aging has been shown to disproportionally affect the CD8 T cell pool. Moreover, while flow cytometry effectively measures mature naïve T cells, these cells do not accurately represent real-time thymic output, as they can persist in peripheral circulation for extended periods. These limitations highlight the pressing need for more accurate and sensitive methods to assess thymic output. Improved measurement techniques would not only enhance our understanding of thymic involution in the context of aging but also enable large-scale investigations into thymic function and the mechanisms driving its decline in both health and disease. In this review, we examine current methodologies for measuring thymic output in humans, critically evaluate their limitations, and discuss emerging approaches to address these gaps in the field.

Adipose chemokine ligand CX3CL1 contributes to maintaining the hippocampal BDNF level, and the effect is attenuated in advanced age - Yoshinori Takei; Yoko Amagase; Ai Goto; Ryuichi Kambayashi; Hiroko Izumi-Nakaseko; Akira Hirasawa; Atsushi Sugiyama (GeroScience, 2025)

A multi-omic single-cell landscape of the aging mouse ovary - Jian Zhang; Shunze Jia; Zehua Zheng; Lanrui Cao; Jingyi Zhou; Xudong Fu (GeroScience, 2025)

Unraveling the link between frailty and Alzheimer’s disease biomarkers in patients with mild cognitive impairment - Simona Buscarnera; Marco Canevelli; Giuseppe Bruno; Valentina Garibotto; Giovanni Battista Frisoni; Federica Ribaldi (GeroScience, 2025)
Alzheimer’s disease (AD) can be identified through biomarkers of amyloid (A) and tau (T) pathology. Frailty, a measure of biological aging, could impact the association between AD neuropathology and its clinical manifestation. We aimed to investigate the relationship between frailty and AD biomarkers among people with mild cognitive impairment (MCI) attending a university memory clinic. Data were collected from a cohort of patients with MCI at the Memory Center of Geneva University Hospital (Switzerland). Frailty was assessed using a 35-item Frailty Index (FI). A and T positivity were determined through amyloid and tau PET or CSF analysis. Participants were divided into two subgroups: (i) A + T + (both amyloid and tau positive) and (ii) E/N (either A + or T + , neither A + nor T +), including all other combinations of A/T status. We first explored the correlation between FI, age, and education. Demographics, FI scores, and neuropsychological test results were then compared between these two groups. Logistic regression models, adjusted for age, sex, and education were used to examine the association between FI and AT positivity. One hundred twenty patients were included. FI was positively correlated with age and inversely with education. A + T + patients exhibited lower FI scores compared to E/N participants (0.13 ± 0.10 vs. 0.15 ± 0.08, p = 0.01). Logistic regressions found a negative association between FI and A + T + (OR 0.6, 95% CI 0.32–0.90; p = 0.02). Frailty is associated with a lower likelihood of AD biomarker positivity in patients with MCI. Frailty might reflect alternative pathophysiological mechanisms contributing to cognitive impairment.

Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan - Sabira Mohammed; Phoebe Ohene-Marfo; Chao Jiang; Zongkai Peng; Nidheesh Thadathil; Albert Tran; Evan Nicklas; Shylesh Bhaskaran; Dawei Wang; Ramasamy Selvarani; Amit Singh; Zhibo Yang; et al. (GeroScience, 2025)
Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3. The absence of Mlkl or Ripk3 significantly reduced liver inflammation, steatosis, and fibrosis in aged male mice, supporting the role of necroptosis in age-associated MASLD. Additionally, Mlkl or Ripk3 deletion impacted other non-necroptotic cellular processes that drive inflammation and MASLD, such as cellular senescence, apoptosis, and autophagy in aged liver. Levels of plasma TNFα and IL6, key proinflammatory cytokines associated with inflammaging, are reduced in Mlkl −/− or Ripk3 −/− aged mice, supporting a systemic effect of necroptosis inhibition on inflammation. Proteomic analysis of liver tissues emphasizes the critical role of lipid and immune regulatory processes in maintaining liver homeostasis when Mlkl or Ripk3 is absent in aging liver. While Mlkl deletion did not affect the lifespan of mice, Ripk3 deletion shortened it. Additionally, Mlkl deficiency improved insulin sensitivity, whereas Ripk3 deficiency exacerbated glucose intolerance in aged mice. Thus, selective inhibition of Mlkl, not Ripk3, represents a potential therapeutic avenue for mitigating age-related liver disease and enhancing metabolic outcomes in the elderly.

The role of protective genetic variants in modulating epigenetic aging - Yosra Bejaoui; Luma Srour; Abeer Qannan; Junko Oshima; Chadi Saad; Steve Horvath; Hamdi Mbarek; Nady El Hajj (GeroScience, 2025)
Several progeroid syndromes’ causative mutations have been linked to epigenetic age acceleration as measured via several epigenetic clocks. At the same time, several protective variants have also been discovered that can reduce the risk of developing certain age-related disorders. However, the impact of these protective variants on epigenetic aging has not been well elucidated. Our research, which involved screening over 14,669 healthy individuals enrolled in the Qatar BioBank (QBB) and sequenced by the Qatar Genome Project (QGP), identified individuals carrying protective variants against age-related disorders, including Alzheimer’s disease (AD), type 2 diabetes (T2D), and atherosclerosis. In this study, we measured methylation levels in blood DNA using the EPIC v2 arrays. In addition, epigenetic age was calculated using various epigenetic clocks. Our analysis revealed that the APOE*E2 protective variant reduces the rate of GrimAge epigenetic aging when compared to individuals with the APOE4 AD risk allele. Furthermore, our differential DNA methylation analysis discovered the association of the PCSK9 protective variant with specific biological processes related to immune function and the cardiovascular system. In conclusion, APOE*E2 protective variants have a positive impact on epigenetic aging, while PCSK9 protective variants have a significant effect on DNA methylation signatures. Further studies are needed to better understand the underlying mechanisms by which protective variants influence epigenetic aging, particularly the role of APOE*E2 protective variants in biological aging. Furthermore, additional research is required to fully uncover the processes that might enable specific targeted therapies to mimic the effects of beneficial mutations, such as LOF variants in PCSK9 , in reducing the risk of geriatric disorders.

Workload and clinical impact of MRI-based extension of reperfusion therapy time window in acute ischaemic stroke—a prospective single-centre study - Tímea Tünde Takács; Rita Magyar-Stang; Szabolcs Szatmári; Ildikó Sipos; Katalin Saftics; Ádám József Berki; Sándor Évin; Dániel Bereczki; Csaba Varga; Nóra Nyilas; István Bíró; Péter Barsi; et al. (GeroScience, 2025)
Current European Stroke Organisation (ESO) guidelines recommend extended time window reperfusion therapies (4.5–9 h for thrombolysis, 6–24 h for thrombectomy) based on advanced imaging. However, the workload and clinical benefit of this strategy on a population basis are not known. To determine the caseload, treatment rates, and outcomes in the extended as compared to the standard time windows. All consecutive ischaemic stroke patients within 24 h of last known well between 1st March 2021 and 28th February 2022 were included in a prospective single-centre study. Treatment eligibility in the extended time windows or wake-up strokes recognized within 4 h was based on current ESO guideline criteria using MRI DWI-PWI or DWI-FLAIR mismatch. MRI was only available during working hours (8–20 h); otherwise, CT/CTA was used. Clinical outcome in treated patients was assessed at three months. Among the 777 admitted patients, 252 (32.4%) had MRI. The thrombolysis rate was 119/304 (39.1%) in standard and 14/231 (6.1%) in the extended time window. The thrombectomy rate was 34/386 (8.8%) in standard and 15/391 (3.8%) in the extended time window. Independent clinical outcomes (mRS ≤ 2) were not statistically different in early and late-treated patients both for thrombolysis (48% vs. 28.6%, p = 0.25) and thrombectomy (38.4% vs. 33.3%, p = 0.99). Even with a limited availability of advanced imaging extending therapeutic time windows resulted in an 11.7% increase in thrombolysis and a 44% increase in thrombectomy with comparable clinical outcomes in early and late-treated patients at the price of a twofold burden in clinical and advanced imaging screening.

In vivo medical imaging for assessing geroprotective interventions in humans - Jonas E. Svensson; Martin Schain; Pontus Plavén-Sigray (GeroScience, 2025)
There is a growing interest in developing drugs with a general geroprotective effect, aimed at slowing down aging. Several compounds have been shown to increase the lifespan and reduce the incidence of age-related diseases in model organisms. Translating these results is challenging, due to the long lifespan of humans. To address this, we propose using a battery of medical imaging protocols that allow for assessments of age-related processes known to precede disease onset. These protocols, based on magnetic resonance imaging, positron emission-, computed-, and optical coherence tomography, are already in use in drug development and are available at most modern hospitals. Here, we outline how an informed use of these techniques allows for detecting changes in the accumulation of age-related pathologies in a diverse set of physiological systems. This in vivo imaging battery enables efficient screening of candidate geroprotective compounds in early phase clinical trials, within reasonable trial durations.

Correction to: The efficacy of cognitive stimulation, cognitive training, and cognitive rehabilitation for people living with dementia: a systematic review and meta‑analysis - Alice Paggetti; Ylenia Druda; Francesco Sciancalepore; Francesco Della Gatta; Antonio Ancidoni; Nicoletta Locuratolo; Paola Piscopo; Luca Vignatelli; Luciano Sagliocca; Antonio Guaita; Piero Secreto; Andrea Stracciari; et al. (GeroScience, 2025)

Synergistic effects of plasma S100B and MRI measures of cerebrovascular disease on cognition in older adults - Colleen Pappas; Christopher E. Bauer; Valentinos Zachariou; T. J. Libecap; Beatriz Rodolpho; Tiffany L. Sudduth; Peter T. Nelson; Gregory A. Jicha; Anika MS Hartz; Xingfeng Shao; Danny J. J. Wang; Brian T. Gold (GeroScience, 2025)
There is growing interest in studying vascular contributions to cognitive impairment and dementia (VCID) and developing biomarkers to identify at-risk individuals. A combination of biofluid and neuroimaging markers may better profile early stage VCID than individual measures. Here, we tested this possibility focusing on plasma levels of S100 calcium-binding protein B (S100B), which has been linked with blood–brain-barrier (BBB) integrity, and neuroimaging measures assessing BBB function (water exchange rate across the BBB (k w )) and cerebral small vessel disease (white matter hyperintensities (WMHs)). A total of 74 older adults without dementia had plasma samples collected and underwent cognitive assessment. A subsample had neuroimaging data including diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) for assessment of BBB k w and T2-weighted fluid-attenuated inversion recovery (FLAIR) for quantification of WMHs. Results indicated that higher plasma S100B levels were associated with poorer episodic memory performance ( β = − .031, SE = .008, p < .001). Moreover, significant interactions were observed between plasma S100B levels and parietal lobe BBB k w (interaction β = .095, SE = .042, p = .028) and between plasma S100B levels and deep WMH volume (interaction β = − .025, SE = .009, p = .007) for episodic memory. Individuals with the poorest memory performance showed both high plasma S100B and either low BBB k w in the parietal lobe or increased deep WMH burden. Taken together, our results provide support for the combined use of biofluid and neuroimaging markers in the study of VCID.

Fecal microbiota transplant from long-living Ames dwarf mice alters the microbial composition and biomarkers of liver health in normal mice - Sarah A. Ashiqueali; Natalie Hayslip; Diptaraj S. Chaudhari; Augusto Schneider; Xiang Zhu; Blazej Rubis; Corey E. Seavey; Md Tanjim Alam; Ridwan Hussein; Sarah A. Noureddine; Ewelina Golusinska-Kardach; Pawel Pazdrowski; et al. (GeroScience, 2025)

A cohort study reveals shared and distinct serum metabolic biomarkers for major adverse cardiovascular events in middle-aged and older adults - Yi Ren; Bo Chen; Honggang Zhang; Shaoyong Xu (GeroScience, 2025)

Inhibition of soluble epoxide hydrolase ameliorates cerebral blood flow autoregulation and cognition in alzheimer's disease and diabetes-related dementia rat models - Chengyun Tang; Jane J. Border; Huawei Zhang; Andrew Gregory; Shan Bai; Xing Fang; Yedan Liu; Shaoxun Wang; Sung Hee Hwang; Wenjun Gao; Gilbert C. Morgan; Jhania Smith; et al. (GeroScience, 2025)

Intrinsic brain functional connectivity mediates the relationship between psychological resilience and cognitive decline in ageing - Menglu Chen; Mengxia Gao; Junji Ma; Tatia M. C. Lee (GeroScience, 2025)
Ageing individuals often experience cognitive decline and intrinsic functional connectivity (FC) changes. Psychological resilience, a personality trait that reflects the capacity to adapt and cope with age-related challenges, plays a key role in mitigating cognitive decline. In this study involving 101 older adults, we investigated how psychological resilience influences cognitive decline measured by processing speed. Particularly, we obtained resting-state functional magnetic resonance imaging (fMRI) to assess how intrinsic FC, represented by degree centrality, modulates the relationship between resilience and processing speed. Our results indicated while psychological resilience positively predicted processing speed, this relationship was mainly driven by education. Additionally, the degree centrality of both thalamus and caudate negatively correlated with processing speed and resilience. Notably, the degree centrality of both thalamus and caudate significantly mediated the relationship between resilience and processing speed. These findings suggest that psychological resilience could protect against age-related cognitive decline via its influence on FC in the thalamus and caudate, highlighting these areas as potential intervention targets for reducing cognitive decline in ageing people.

Effects of home-based exercise with or without cognitive training on cognition and mobility in cardiac patients: A randomized clinical trial - Florent Besnier; Emma Gabrielle Dupuy; Christine Gagnon; Thomas Vincent; Tudor Vrinceanu; Caroll-Ann Blanchette; Josep Iglesies-Grau; Kathia Saillant; Malorie Chabot-Blanchet; Sylvie Belleville; Martin Juneau; Paolo Vitali; et al. (GeroScience, 2025)

The prognostic and neuroendocrine implications of SLC25A29-mediated biomass signature in prostate cancer - Chia-Chang Wu; Su-Wei Hu; Shao-Wei Dong; Kai-Yi Tzou; Chien Hsiu Li (GeroScience, 2025)

The unity/diversity framework of executive functions: behavioral and neural evidence in older adults - Sheng-Ju Guo; Ping Wang; Li-Zhi Cao; Hui-Jie Li (GeroScience, 2025)

Nocturia as a clinical marker of loss of function and resilience or risk factor for frailty in older adults? Results of the Berlin Aging Study II - Maximilian König; Carolin Malsch; Joany Mariño; Valentin Max Vetter; Yulia Komleva; Ilja Demuth; Elisabeth Steinhagen-Thiessen (GeroScience, 2025)
The current study examined cross-sectional and longitudinal associations between nocturia and frailty in a cohort of men and women aged 60 years and older, as evidence on this topic was lacking. We analyzed baseline and follow-up data ( n = 1671) from the Berlin Aging Study II (BASE-II), a prospective longitudinal cohort study focusing on the factors associated with “healthy” vs. “unhealthy” aging. Self-reported nocturia was dichotomized into < / ≥ 2 micturitions per night, and frailty was assessed using the Fried frailty phenotype. Covariables were identified a priori based on a review of the existing literature. At baseline, 70.2% of the participants were robust, 28.9% were pre-frail, and 0.9% were frail; 254 participants (23.6%) had self-reported nocturia. In longitudinal analyses, the prevalence and incidence of frailty at follow-up significantly increased when nocturia was present at baseline. Over a median follow-up of 7.1 years, there were 41 incident frailty cases (IR 5.6, 95%-CI 3.9–7.2 per 1000 person-years). After adjusting for age, sex, morbidity burden, and baseline frailty status, baseline nocturia was associated with a 2.23-fold increased risk (95%-CI 1.17–4.18) of frailty at follow-up. Nocturia is associated with an increased risk of developing or progressing in frailty in older adults, and may serve as an early clinical marker for the progression of frailty.

Better objective sleep quality is associated with higher gut microbiota richness in older adults - Maria Teresa Wijaya; Ji-Tseng Fang; Geng-Hao Liu; Yuan-Ming Yeh; Ning-Hung Chen; Chih-Ming Lin; Kuain-Yi Wu; Chih-Mao Huang; Shwu-Hua Lee; Tatia M. C. Lee (GeroScience, 2025)
Aging is associated with disrupted sleep patterns, such as fragmented sleep and reduced efficiency, leading to negative health outcomes. There is evidence of a bidirectional relationship between sleep and gut microbiota, which plays a key role in the gut-brain axis and overall health. However, studies on this relationship in older adults have limited generalizability and show conflicting results, highlighting the need for further research. This study aimed to investigate the associations between sleep quality and gut microbiota composition in healthy Chinese older adults using subjective and objective sleep measures to capture various aspects of sleep quality and explore potential impacts on emotional well-being and cognitive performance. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire, while objective sleep quality was measured with actigraphy. Gut microbiota sequencing was performed on stool samples. The results show a robust positive association between gut microbiota richness and objective sleep quality in older adults, independent of subjective sleep quality and demographics, lifestyle, and health covariates. However, no significant link was found between gut microbiota richness and subjective sleep quality. Specific taxa like Bacteroidetes, Ruminococcus , Collinsella , Veillonella , and Holdemania were tentatively linked to sleep quality. These findings emphasize the connection between sleep quality and gut microbiota composition in older adults with potential research and clinical implications, improving our understanding of the mechanisms underlying the sleep-gut microbiota relationship and guiding the development of interventions for improving both sleep quality and gut health in older adults.

Stochasticity in dietary restriction-mediated lifespan outcomes in Drosophila - Olivia L. Mosley; Joel A. Villa; Advaitha Kamalakkannan; Eliyashaib James; Jessica M. Hoffman; Yang Lyu (GeroScience, 2025)
Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ ad libitum , or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.

Combining non-invasive brain stimulation techniques and EEG markers analysis: an innovative approach to cognitive health in aging - Chiara Pappalettera; Anna Fabbrocino; Francesca Miraglia; Paolo Maria Rossini; Fabrizio Vecchio (GeroScience, 2025)

Dynamic proportional loss of functional connectivity revealed change of left superior frontal gyrus in subjective cognitive decline: an explanatory study based on Chinese and Western cohorts - Luyao Wang; Wenjing Hu; Fan Dong; Can Sheng; Jinglong Wu; Ying Han; Jiehui Jiang; Michael W. Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; et al. (GeroScience, 2025)

Comparative phenotyping of C57BL/6J substrains reveals distinctive patterns of cardiac aging - Sophia Walter; Patricia Baumgarten; Niklas Hegemann; Steffen P. Häseli; Stefanie Deubel; Julia Jelleschitz; Annika Höhn; Nikolaus Berndt; Wolfgang M. Kuebler; Jana Grune; Christiane Ott (GeroScience, 2025)
Research in aging often refers to animal models, particularly C57BL/6J (B6J) mice, considered gold standard. However, B6J mice are distributed by different suppliers, which results in divers substrains exhibiting notable phenotypic differences. To ensure a suitable phenotype of cardiac aging, we performed heart analyses of young (5 months) and old B6J mice (24 months) from two substrains: B6JRj (Janvier) and B6JCrl mice (Charles River). In hearts of both substrains, myocardial fibrosis increased with age; however, only in old B6JRj mice cardiac hypertrophy associated with a decreased ejection fraction was observed. Gene set enrichment analysis in heart tissue using proteomic data revealed different age-associated pathway changes between the substrains, especially in oxidative phosphorylation. Functional assessment of isolated cardiomyocytes verified cardiac impairment during aging in B6JRj mice. Overall, results demonstrate that cardiac aging manifests as a moderate systolic dysfunction in B6JRj mice, while B6JCrl mice display no functional changes with age.

An mTOR inhibitor discovery system using drug-sensitized yeast - Anna K. Breen; Sarah Thomas; David Beckett; Matthew Agsalud; Graham Gingras; Judd Williams; Brian M. Wasko (GeroScience, 2025)
Inhibition of the target of rapamycin (TOR/mTOR) protein kinase by the drug rapamycin extends lifespan and health span across diverse species. However, rapamycin has potential off-target and side effects that warrant the discovery of additional TOR inhibitors. TOR was initially discovered in Saccharomyces cerevisiae (yeast) which contains two TOR paralogs, TOR1 and TOR2 . Yeast lacking functional Tor1 are viable but are hypersensitive to growth inhibition by TORC1 inhibitors, which is a property of yeast that can be exploited to identify TOR inhibitors. Additionally, yeast lacking FK506-sensitive proline rotamase ( FPR1 ) or containing a tor1-1 allele (a mutation in the Fpr1-rapamycin binding domain of Tor1) are robustly and selectively resistant to rapamycin and analogs that allosterically inhibit TOR activity via an FPR1 -dependent mechanism. To facilitate the identification of TOR inhibitors, we generated a panel of yeast strains with mutations in TOR pathway genes combined with the removal of 12 additional genes involved in drug efflux. This creates a drug-sensitive strain background that can sensitively and effectively identify TOR inhibitors. In a wild-type yeast strain background, 25 µM of Torin1 and 100 µM of GSK2126458 (omipalisib) are necessary to observe TOR1 -dependent growth inhibition by these known TOR inhibitors. In contrast, 100 nM Torin1 and 500 nM GSK2126458 (omipalisib) are sufficient to identify TOR1- dependent growth inhibition in the drug-sensitized background. This represents a 200-fold and 250-fold increase in detection sensitivity for Torin1 and GSK2126458, respectively. Additionally, for the TOR inhibitor AZD8055, the drug-sensitive system resolves that the compound results in TOR1- dependent growth sensitivity at 100 µM, whereas no growth inhibition is observed in a wild-type yeast strain background. Our platform also identifies the caffeine analog aminophylline as a TOR1 -dependent growth inhibitor via selective tor1 growth sensitivity. We also tested nebivolol, isoliquiritigenin, canagliflozin, withaferin A, ganoderic acid A, and taurine and found no evidence for TOR inhibition using our yeast growth-based model. Our results demonstrate that this system is highly effective at identifying compounds that inhibit the TOR pathway. It offers a rapid, cost-efficient, and sensitive tool for drug discovery, with the potential to expedite the identification of new TOR inhibitors that could serve as geroprotective and/or anti-cancer agents.

Role for neurological and immunological resilience in the pathway of the aging muscle powerpenia: InCHIANTI study longitudinal results - Raffaello Pellegrino; Roberto Paganelli; Angelo Di Iorio; Matteo Candeloro; Stefano Volpato; Stefania Bandinelli; Antimo Moretti; Giovanni Iolascon; Toshiko Tanaka; Luigi Ferrucci (GeroScience, 2025)
The neuromuscular junction shows several degenerative changes with aging, resulting in a reduction of transmission efficacy. These changes, paired with low-grade chronic inflammation, were considered triggers of the aging muscle processes. The main objective of this study is to assess the role of leukocyte count–derived ratios, nerve conduction velocity (NCV), and compound muscle action potential (CMAP) in determining time-dependent reduction in lower limb muscle explosive strength, a condition that has been defined as powerpenia. The InCHIANTI study enrolled a representative sample from the registry lists of two towns in Tuscany, Italy. Baseline data were collected in 1998, with follow-up visits every 3 years. For the purpose of this analysis, we used 1229 subjects and 3814 follow-up assessments. Subjects with lower values of monocyte-to-lymphocyte ratio (ML-ratio) had higher nerve conduction velocity and higher proximal and distal action potential values; moreover, considering the interaction between age for ML-ratio effect, a statistically significant direct association is found with all the electromyography-parameters. Lower limb muscle power shows a gender dimorphism, male subjects having higher values at baseline, but experiencing steeper decline rate during the follow-up, compared to females. Muscle power was inversely associated with ML-ratio, proximal CMAP, distal CMAP, and NCV. Moreover, we found a direct and statistically significant second-order interaction (age for ML-ratio), meaning that at the same age, increasing ML-ratio increases lower limb muscle power. Lastly, also body composition variation across aging is directly associated with lower limb muscle power. Reduced immunological and neurological homeostasis affects the powerpenia phenotype in a large representative sample of Italian men and women.

Cardiovascular disease, bone fracture, and all-cause mortality risks among postmenopausal women by arthritis and veteran status: A multistate Markov transition analysis - Hind A. Beydoun; May A. Beydoun; Jordan Weiss; Robert Brunner; Nishant K. Mishra; Ming Ding; Jean Wactawski-Wende; Philippe Jean-Luc Gradidge; Simin Liu; Jack Tsai (GeroScience, 2025)

Sex-specific transcriptomic profiling reveals key players in bone loss associated with Alzheimer’s disease - Mohini Gharpure; Sagar Vyavahare; Diana M. Asante; Jie Chen; Roger Zhong; Marion A. Cooley; Ferenc Deak; Xin-Yun Lu; Carlos M. Isales; Sadanand Fulzele (GeroScience, 2025)

Whole-body networks: a holistic approach for studying aging - Orestis Stylianou; Johannes M. Meixner; Tilman Schlick; Colin M. Krüger (GeroScience, 2025)

The negative relationship between brain-age gap and psychological resilience defines the age-related neurocognitive status in older people - Yue Gu; Nichol M. L. Wong; Chetwyn C. H. Chan; Jingsong Wu; Tatia M. C. Lee (GeroScience, 2025)
Biological brain age is a brain-predicted age using machine learning to indicate brain health and its associated conditions. The presence of an older predicted brain age relative to the actual chronological age is indicative of accelerated aging processes. Consequently, the disparity between the brain’s chronological age and its predicted age (brain-age gap) and the factors influencing this disparity provide critical insights into cerebral health dynamics during aging. In this study, we employed a Lasso regression model and analyzed multimodal imaging data from 124 participants aged 53 to 76 to formulate and predict brain age. Additionally, we conducted partial correlation analyses to explore the complex relationship between the brain-age gap and network metrics, cognitive assessments, and emotional evaluations, while controlling for chronological age, gender, and education. Our findings highlight psychological resilience as a significant mitigating factor against premature brain aging. It is established that psychological resilience significantly influences the modulation of the brain-age gap. Moreover, psychological resilience and the brain-age gap exhibit a high accuracy (above 0.72) in segregating Montreal Cognitive Assessment score–based cohorts. This observation underscores significant insight into the potential of utilizing the brain-age gap as a diagnostic tool for the early detection of accelerated aging. It advocates for the timely application of interventions, including the development of programs aimed at bolstering psychological resilience.

Attitudes towards healthy eating and its determinants among older adults in a deprived region of Hungary: implications for the National Healthy Aging Program - Nora Kovacs; Eva Biro; Peter Piko; Zoltan Ungvari; Roza Adany (GeroScience, 2025)
A healthy diet is a key determinant of successful aging. However, the psychological, social, and physiological changes associated with ageing often disrupt dietary behaviours. Hungary has one of the highest rates of chronic age-related diseases in the European Union, exacerbated by unhealthy dietary patterns and rapid population aging. This study evaluates attitudes and barriers to healthy eating among older adults in a socioeconomically disadvantaged region of Hungary, identifying determinants of these attitudes across different age groups. A cross-sectional survey sampled 678 adults aged 18 and older from Northeast Hungary, assessing their beliefs on healthy eating through an attitude score (range: 9–45). Multivariate regression analyses were conducted to explore relationships between mental health, self-perceived health, and attitudes toward healthy eating. The mean attitude score was 31.47 (± 5.14), with older adults (≥ 65 years) showing significantly greater uncertainty about dietary choices. The cost of healthy food was the most frequently reported barrier, regardless of age. Regression results revealed that older adults with higher well-being (B = 0.03, p = 0.026), life satisfaction (B = 0.40, p = 0.005), and self-perceived health (fair: B = 2.20, p = 0.003; good/very good: B = 1.96, p = 0.031) were more likely to have positive attitudes toward healthy eating. These results emphasize the importance of addressing both mental and physical health in educational interventions to promote healthier diets. Tailored approaches addressing affordability and accessibility of healthy foods are critical to advancing Hungary’s National Healthy Aging Program and mitigating dietary risk factors among vulnerable populations.

Cognitive variation reflects amyloid, tau, and neurodegenerative biomarkers in Alzheimer’s disease - Kia Ann Sean Phang; Chin Hong Tan (GeroScience, 2025)

The bioavailability and blood levels of low-dose rapamycin for longevity in real-world cohorts of normative aging individuals - Girish Harinath; Virginia Lee; Andy Nyquist; Mauricio Moel; Maartje Wouters; Jesper Hagemeier; Brandon Verkennes; Colleen Tacubao; Sayem Nasher; Krister Kauppi; Stefanie L. Morgan; Anar Isman; et al. (GeroScience, 2025)
Rapamycin, also known as sirolimus, has demonstrated great potential for application in longevity medicine. However, the dynamics of low-dose rapamycin bioavailability, and any differences in bioavailability for different formulations (e.g., compounded or commercial), remain poorly understood. We thus explored rapamycin bioavailability in two real-world cohorts to begin providing a foundational understanding of differences in effects between formulations over time. The small trial study cohort was utilized to explore the blood rapamycin levels of commercial ( n = 44, dosages 2, 3, 6, or 8 mg) or compounded ( n = 23, dosages 5, 10, or 15 mg) rapamycin 24 h after dose self-administration. Results suggested dose-to-blood level relationships were linear for both formulations, though compounded had a lower bioavailability per milligram of rapamycin (estimated to be 31.03% of the same dose of commercial). While substantial inter-individual heterogeneity in blood rapamycin levels was observed for both formulations, repeat tests for individuals over time demonstrated relative consistency. Extending exploration to 316 real-world longevity rapamycin users from the AgelessRx Observational Research Database produced similar findings, and additionally suggested that blood rapamycin levels peak after 2 days with gradual decline thereafter. Taken together, our findings suggest that individualized dosing and routine monitoring of blood rapamycin levels should be utilized to ensure optimal dosing and efficacy for healthy longevity.

Preserved brain youthfulness: longitudinal evidence of slower brain aging in superagers - Chang-hyun Park; Bori R. Kim; Soo Mee Lim; Eun-Hee Kim; Jee Hyang Jeong; Geon Ha Kim (GeroScience, 2025)

Involvement of TGF-β, mTOR, and inflammatory mediators in aging alterations during myxomatous mitral valve disease in a canine model - Arkadiusz Grzeczka; Szymon Graczyk; Pawel Kordowitzki (GeroScience, 2025)

Multiplexed single-cell imaging reveals diverging subpopulations with distinct senescence phenotypes during long-term senescence induction - Garrett A. Sessions; Madeline V. Loops; Brian O. Diekman; Jeremy E. Purvis (GeroScience, 2025)
Cellular senescence is a phenotypic state that contributes to the progression of age-related disease through secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Understanding the process by which healthy cells become senescent and develop SASP factors is critical for improving the identification of senescent cells and, ultimately, understanding tissue dysfunction. Here, we reveal how the duration of cellular stress modulates the SASP in distinct subpopulations of senescent cells. We used multiplex, single-cell imaging to build a proteomic map of senescence induction in human epithelial cells induced to senescence over the course of 31 days. We map how the expression of SASP proteins increases alongside other known senescence markers such as p53, p21, and p16 INK4a . The aggregated population of cells responded to etoposide with an accumulation of stress response factors over the first 11 days, followed by a plateau in most proteins. At the single-cell level, however, we identified two distinct senescence cell populations, one defined primarily by larger nuclear area and the second by higher protein concentrations. Trajectory inference suggested that cells took one of two discrete molecular paths from unperturbed healthy cells, through a common transitional subpopulation, and ending at the discrete terminal senescence phenotypes. Our results underscore the importance of using single-cell proteomics to identify the mechanistic pathways governing the transition from senescence induction to a mature state of senescence characterized by the SASP.

Painful diabetic neuropathy is associated with accelerated epigenetic aging - Katarzyna Malgorzata Kwiatkowska; Paolo Garagnani; Massimiliano Bonafé; Maria Giulia Bacalini; Luciano Calzari; Davide Gentilini; Dan Ziegler; Monique M. Gerrits; Catharina G. Faber; Rayaz A. Malik; Margherita Marchi; Erika Salvi; et al. (GeroScience, 2025)
About one out of two diabetic patients develop diabetic neuropathy (DN), of these 20% experience neuropathic pain (NP) leading to individual, social, and health-economic burden. Risk factors for NP are largely unknown; however, premature aging was recently associated with several chronic pain disorders. DNA methylation-based biological age (DNAm) is associated with disease risk, morbidity, and mortality in different clinical settings. The purpose of this work was to study, for the first time, whether biological age is involved in pain development in a huge cohort of DN patients with neuropathy assessed by anatomopathological assay (99 painful (PDN), 132 painless (PLDN) patients, 84 controls (CTRL)). Six subsets of DNAm biomarkers were calculated to evaluate NP-associated changes in epigenetic aging, telomere shortening, blood cell count estimates, and plasma protein surrogates. We observed pain-related acceleration of epigenetic age (DNAmAgeHannum, DNAmGrimAgeBasedOnPredictedAge, DNAmAgeSkinBloodClock), pace of aging (DunedinPoAm), and shortening of telomeres between PDN and PLDN patients. PDN showed decreased predicted counts of B lymphocytes, naive and absolute CD8 T cells, and increased granulocyte counts. Several surrogates of plasma proteins were significantly different (GHR, MMP1, THBS2, PAPPA, TGF-α, GDF8, EDA, MPL, CCL21) in PDNs compared to PLDNs. These results provide the first evidence of an acceleration of biological aging in patients with painful compared to painless DN. This achievement has been possible thanks to the state of the art clinical phenotyping of the enrolled patients. Our findings indicate that the aging process may be directly involved in the PDN progression and in general health degeneration in the T2DM patients. Therefore, it is possible to hypothesize that the administration of effective antiaging drugs could slow down or even block the disease advancement.

Depressive intensity, duration, and their associations with cognitive decline: a population-based study in Korea - Kai Lu; Wei Wang; Junyu Wang; Qianqian Du; Chen Li; Yuxin Wei; Menghan Yao; Tao Zhang; Fei Yin; Yue Ma (GeroScience, 2025)

Blockade of A2AR improved brain perfusion and cognitive function in a mouse model of Alzheimer’s disease - Mariana Sayuri Berto Udo; Julia Zaccarelli-Magalhães; Garrett Alan Clemons; Cristiane Teresinha Citadin; Julia Langman; Drew James Smith; Luiz Henrique Matuguma; Vesna Tesic; Hung Wen Lin (GeroScience, 2025)

Circulating biomarkers associated with walking performance in elderly subjects: exploring miRNAs, metabolic and inflammatory biomarkers - Martina Faraldi; Mauro Provinciali; Mirko Di Rosa; Raffaella Moresi; Veronica Sansoni; Marta Gomarasca; Laura Gerosa; Amir Mohammad Malvandi; Fabrizia Lattanzio; Giuseppe Banfi; Giovanni Lombardi (GeroScience, 2025)

Serum β-secretase 1 (sBACE1) activity in subjective cognitive decline: an exploratory study - Carlo Cervellati; Alessandro Trentini; Valentina Rosta; Angelina Passaro; Gloria Brombo; Carlo Renzini; Gerhard Multhaup; Giovanni Zuliani (GeroScience, 2025)
β-Secretase-1 (BACE1) plays a key role in the regulation of cerebral amyloid-β homeostasis, being involved in amyloidogenic and, as recently found, amyloidolytic pathways. Growing evidence indicates that increased serum BACE1 (sBACE1) activity might represent an early biomarker for Alzheimer’s disease. Here, we tested the hypothesis that an increase in sBACE1 activity may already occur in individuals with subjective cognitive decline (SCD). We found that sBACE1 activity was significantly higher in individuals with SCD ( n 118) compared to cognitively normal subjects (controls, n 137) ( p < 0.001). Moreover, compared with SCD, sBACE1 activity was even higher in patients affected by amnestic ( n 179) or non-amnestic mild cognitive impairment (MCI) ( n 99) ( p < 0.001 and p 0.02, respectively). In all cases, the respective increase in sBACE1 activity was significant after adjustment for possible confounders including age, sex, and comorbidities. We also found a significant sexual dimorphism, with women affected by either type of MCI, but not by SCD, having higher levels of serum BACE1 activity compared to men. These results provide evidence supporting the potential use of sBACE1 activity as tool for blood-based screening of cognitively healthy individuals at clinical risk of MCI and dementia.

The senolytic cocktail, dasatinib and quercetin, impacts the chromatin structure of both young and senescent vascular smooth muscle cells - Agnieszka Gadecka; Natalia Nowak; Edyta Bulanda; Dorota Janiszewska; Magdalena Dudkowska; Ewa Sikora; Anna Bielak-Zmijewska (GeroScience, 2025)
One promising strategy to alleviate aging symptoms is the treatment with senolytics that is compounds which selectively eliminate senescent cells. Some therapies aim to reduce symptoms of cellular senescence without senescent cell eradication (senomorphic activity). However, senotherapies raise many questions concerning the selectivity, safety and efficiency of senolitic drugs. A vital question is how the senolytic compounds affect young proliferating cells. In our study, we checked the impact of quercetin and dasatinib (D + Q), one of the promising drug mixtures of drugs, on chromatin structure in young and senescent cells. We analyzed the effect of a single and triple drug treatment on vascular smooth muscle cells. We have shown that D + Q impacts the chromatin in both young and senescent cells. In senescent cells, D + Q caused some symptoms of chromatin “rejuvenation” but in young cells some changes characteristic of senescent cells were observed. The alterations in young cells appeared only transiently and chromatin returned to the initial state after 24 h of recovery. The complexity of chromatin staining and nucleus morphology evaluation indicated that a triple treatment makes senescent cells more similar to the young ones than a single treatment. However, the analysis of senescence markers suggested that a single treatment with D + Q caused slightly less pronounced senescence characteristics and was more efficient in alleviating the features of senescence than a triple treatment. It is still an open question whether the alterations caused by D + Q are beneficial or harmful in the long term; however, so far, it can be concluded that the effects depend on cell type and the physiological context.

Enhancing cognitive functions in aged dogs and cats: a systematic review of enriched diets and nutraceuticals - Tiphaine Blanchard; Justine Eppe; Amélie Mugnier; Fabienne Delfour; Annabelle Meynadier (GeroScience, 2025)
With advancements in veterinary care and the growing recognition of pets as integral member of the family, the lifespans of dogs and cats have significantly increased, leading to a higher prevalence of age-related conditions, including cognitive dysfunction syndrome (CDS). CDS adversely impacts pets’ quality of life and presents emotional and practical challenges for owners. Given its similarities to Alzheimer’s disease in humans, CDS has gained attention as a target for nutrition-based interventions aimed at preserving cognitive function. This systematic review evaluates the efficacy of enriched diets and nutraceuticals in improving cognition in aging companion animals. A literature search was conducted using PubMed, CAB Abstracts, Web of Science, and Dimensions to identify clinical trials published in English that investigated the effects of enriched diets or nutraceuticals on cognitive functions in aged cats or dogs. Study quality was assessed using a modified CAMARADES checklist. A total of 30 studies (27 canine and 2 feline trials) published between 2002 and 2023 were reviewed. Studies on enriched diets generally demonstrated higher methodological quality compared to those on supplements. Omega-3 fatty acids showed cognitive benefits in aging pets, especially at higher doses, while antioxidants from plant extracts and products and vitamins E and C alone were less effective but remain essential for stabilizing omega-3 fatty acids. Other supplements, including S-adenosyl methionine, medium-chain triglycerides, homotaurine, and apoaequorin, also showed promise. However, future studies must standardize protocols, include robust control groups, and utilize both objective tasks and subjective questionnaires to strengthen conclusions.

Substrate stiffness dictates unique doxorubicin-induced senescence-associated secretory phenotypes and transcriptomic signatures in human pulmonary fibroblasts - Huixun Du; Jacob P. Rose; Joanna Bons; Li Guo; Taylor R. Valentino; Fei Wu; Jordan B. Burton; Nathan Basisty; Max Manwaring-Mueller; Priya Makhijani; Nan Chen; Veronica Chang; et al. (GeroScience, 2025)

Light buckets and laser beams: mechanisms and applications of photobiomodulation (PBM) therapy - David W. Frankowski; Luigi Ferrucci; Praveen R. Arany; Dawn Bowers; Janis T. Eells; Francisco Gonzalez-Lima; Nicole L. Lohr; Brendan J. Quirk; Harry T. Whelan; Edward G. Lakatta (GeroScience, 2025)
Photobiomodulation (PBM) therapy, a non-thermal light therapy using nonionizing light sources, has shown therapeutic potential across diverse biological processes, including aging and age-associated diseases. In 2023, scientists from the National Institute on Aging (NIA) Intramural and Extramural programs convened a workshop on the topic of PBM to discuss various proposed mechanisms of PBM action, including the stimulation of mitochondrial cytochrome C oxidase, modulation of cell membrane transporters and receptors, and the activation of transforming growth factor-β1. They also reviewed potential therapeutic applications of PBM across a range of conditions, including cardiovascular disease, retinal disease, Parkinson’s disease, and cognitive impairment. Workshop participants largely agreed that PBM holds immense potential as a safe and effective therapeutic approach for a wide range of age-related diseases and cognitive decline. While further research is needed to fully elucidate its mechanisms and optimize treatment protocols, the findings presented at the NIA workshop provide strong evidence for the continued investigation and clinical translation of this promising, inexpensive, safe technology, to aging and age-associated diseases. Here, we review the research presented and discussion held at the meeting. In addition, the text has been updated, where applicable, with recent research findings that have been made since the meeting occurred.

DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging - Colin M. Skinner; Michael J. Conboy; Irina M. Conboy (GeroScience, 2025)
Biological age estimation from DNA methylation and determination of relevant biomarkers is an active research problem which has predominantly been tackled with black-box penalized regression. Machine learning is used to select a small subset of features from hundreds of thousands of CpG probes and to increase generalizability typically lacking with ordinary least-squares regression. Here, we show that such feature selection lacks biological interpretability and relevance in the clocks of the first and next generations and clarify the logic by which these clocks systematically exclude biomarkers of aging and age-related disease. Moreover, in contrast to the assumption that regularized linear regression is needed to prevent overfitting, we demonstrate that hypothesis-driven selection of biologically relevant features in conjunction with ordinary least squares regression yields accurate, well-calibrated, generalizable clocks with high interpretability. We further demonstrate that the interplay of inflammaging-related shifts of predictor values and their corresponding weights, which we term feature shifts, contributes to the lack of resolution between health and inflammaging in conventional linear models. Lastly, we introduce a method of feature rectification, which aligns these shifts to improve the distinction of age predictions for healthy people vs. patients with various chronic inflammation diseases.

Characterizing biomarkers of ageing in Singaporeans: the ABIOS observational study protocol - Jessica K. Lu; Weilan Wang; Janjira Soh; Elena Sandalova; Zhi Meng Lim; Santosh Kumar Seetharaman; Jing-Dong Jackie Han; Desmond B. Teo; Brian K. Kennedy; Jorming Goh; Andrea B. Maier (GeroScience, 2025)
Ageing is the primary driver of age-associated chronic diseases and conditions. Asian populations have traditionally been underrepresented in studies understanding age-related diseases. Thus, the Ageing BIOmarker Study in Singaporeans (ABIOS) aims to characterise biomarkers of ageing in Singaporeans, exploring associations between molecular, physiological, and digital biomarkers of ageing. This is a single-centre, cross-sectional study that recruits healthy community-dwelling adults (≥ 21 years) from three different ethnic groups (Chinese, Malay, and Indian). Molecular biomarkers of ageing include multi-omics approaches, such as DNA methylation analysis and metabolic and inflammatory proteomic profiling in blood, saliva, and stool. Physiological biomarkers of ageing include bone density, body composition, skin autofluorescence, arterial stiffness, physical performance (e.g., muscle strength and flexibility), cognition, and nutritional status. Digital biomarkers of ageing include three-dimensional facial morphology and objectively measured physical activity. Additional measures, such as habitual physical activity, dietary patterns, and medical history, are also examined. The associations between the molecular, physiological, and digital phenotypes will be explored. This study is expected to generate a comprehensive profile of molecular, physiological, and digital biomarkers of ageing in Chinese, Malay, and Indian populations in Singapore. By integrating diverse age-related biomarkers, clinical indicators, and lifestyle factors, ABIOS will offer unique insights into the ageing process specific to Southeast Asian populations. These findings can help identify markers of biological ageing, uncover ethnic-specific patterns, and reveal modifiable lifestyle factors for healthier ageing. The results could inform evidence-based health policies, personalized interventions, and future cross-ethnic comparative studies to enhance understanding of ageing biology across diverse populations.

5-HT2C agonism as a neurotherapeutic for sarcopenia: preclinical proof of concept - Nathan R. Kerr; Anna R. Dashtmian; Fereshteh B. Darvishi; Charles D. Brennan; Sindhuja N. Ayyagari; Peter J. Moore; Jose A. Viteri; Meifang Wang; Mark M. Rich; Brian C. Clark; W. David Arnold (GeroScience, 2025)

Association between inflammatory biomarkers and the cognitive response to a multidomain intervention: secondary longitudinal analyses from the MAPT study - Emmanuel Gonzalez-Bautista; Maria Soto; Gabor Abellan van Kan; Julien Delrieu (GeroScience, 2025)
The aim of this study is to evaluate the association of systemic inflammation measured by plasma biomarkers with the change in cognitive function among participants from the Multidomain Alzheimer Preventive Trial (MAPT) exposed to the multidomain intervention (MI). Secondary analysis of the MAPT longitudinal data. MAPT is a randomized, placebo-controlled trial with 3 interventional groups (omega-3 only, MI only, omega-3 plus MI) and a control group. We tested the association of the change in cognitive function with inflammatory biomarkers (tumoral necrosis factor receptor-1 (TNFR1), monocyte chemoattractant protein-1 (MCP1), Growth Differentiation Factor-15 (GDF15), Interleukin-6 (IL6) and C reactive protein (CRP)) using mixed-effects models. A subgroup analysis was performed in those exposed to the MI. The response to the MI was defined as the change in the composite cognitive score over the 2-year clinical follow-up period. by modeling the response to the intervention and identifying “good responders”, i.e., those in the 5th quintile of response at the end of the intervention period (2 years after the measurement of inflammatory markers). We included 1,527 participants (mean age 75.3, SD = 4.4; 64% female). Higher levels of GDF15 and TNFR1 were associated with a worse trajectory in the cognitive composite score in adjusted models. "Good responders" had an estimated mean change in the composite score of 0.051 (SD 0.062) over two years of intervention, compared to -0.136 (SD = 0.111) for the "not-good responders". Higher IL6 levels were associated with a decreased likelihood of being a "good responder" (OR = 0.22, p = 0.018, 95% CI 0.06; 0.78), with similar results for CRP (OR = 0.48, p = 0.009, 95% CI 0.28; 0.84). Higher inflammation was associated with a worse cognitive trajectory among nondemented participants and a lower likelihood of being classified as a "good responder" in those receiving a MI. Further confirmation of these findings could lead to the use of systemic inflammation as inclusion or stratification criteria in prevention trials.

Healthy aging changes in conventional frequency bands of neuroelectric brain activity reconstructed from resting-state MEG - Mikhail Ustinin; Anna Boyko; Stanislav Rykunov (GeroScience, 2025)

The bright and dark side of blue-enriched light on sleep and activity in older adults - Débora Barroggi Constantino; Katharina A. Lederle; Benita Middleton; Victoria L. Revell; Tracey L. Sletten; Peter Williams; Debra J. Skene; Daan R. van der Veen (GeroScience, 2025)
Low indoor light in urban housing can disrupt health and wellbeing, especially in older adults who experience reduced light sensitivity and sleep/circadian disruptions with natural aging. While controlled studies suggest that enhancing indoor lighting may alleviate the negative effects of reduced light sensitivity, evidence for this to be effective in the real world is lacking. This study investigates the effects of two light conditions on actigraphic rest-activity rhythms and subjective sleep in healthy older adults (≥ 60 years) living at home. Two photon-matched lights were compared; a control white light (4000 K) and a blue-enriched white light (17000 K) at two different intensities (300–450 lx and 1100–1200 lx respectively). Participants ( n = 36, 25 female) completed an 11-week randomized, cross-over study, comprising 1 week of baseline, 3 weeks of self-administered light exposure (2 h in the morning and 2 h in the evening), and 2 weeks of washout for each light condition. Participants completed sleep diaries, wore a wrist actigraph and a light sensor necklace, and collected urine to measure 6-sulphatoxymelatonin. Longer duration of morning blue-enriched light significantly improved rest-activity rhythm stability and decreased sleep fragmentation. More time spent above 2500 lx increased actigraphy amplitude, daytime activity, and advanced bedtime. Evening light exposure, however, increased sleep latency and lowered sleep efficiency. Our findings show morning blue-enriched light is beneficial whereas evening light should be avoided. Optimal timing of self-administered light interventions thus may offer a promising strategy to improve sleep and rest-activity rhythms in older adults in real-world settings.

Aβ42 biomarker linked to insula, striatum, thalamus and claustrum in dementia with Lewy bodies - Vincent Gabriel; Olivier Bousiges; Mary Mondino; Benjamin Cretin; Nathalie Philippi; Candice Muller; Pierre Anthony; Catherine Demuynck; Paulo Loureiro de Sousa; Anne Botzung; Léa Sanna; Eléna Chabran; et al. (GeroScience, 2025)

The anti-senescence effect of D-β-hydroxybutyrate in Hutchinson-Gilford progeria syndrome involves progerin clearance by the activation of the AMPK-mTOR-autophagy pathway - Feliciano Monterrubio-Ledezma; Ashley Salcido-Gómez; Tania Zavaleta-Vásquez; Fernando Navarro-García; Bulmaro Cisneros; Lourdes Massieu (GeroScience, 2025)
D-β-hydroxybutyrate, BHB, has been previously proposed as an anti-senescent agent in vitro and in vivo in several tissues including vascular smooth muscle. Moreover, BHB derivatives as ketone esters alleviate heart failure. Here, we provide evidence of the potential therapeutic effect of BHB on Hutchinson-Gilford progeria syndrome (HGPS), a rare condition characterized by premature aging and heart failure, caused by the presence of progerin, the aberrant protein derived from LMNA/C gene c.1824C > T mutation. We have assessed several hallmarks of HGPS-senescent phenotype in vitro, such as progerin levels, nuclear morphometric aberrations, nucleolar expansion, cellular senescent morphology, SA-βGal-positive cells, H3K9me3 heterochromatin, γH2AX foci, Lamin B1, p21 Waf1/Cip1 and p16 CDKN2A abundance, and autophagy. Strikingly, BHB improved nuclear and nucleolar morphometrics, diminished the senescence-phenotype, and unstuck autophagy in HGPS as observed by an enhanced degradation of the cargo protein receptor SQSTM1/p62, suggesting the stimulation of the autophagic flux. Additionally, we observed a decrease in progerin abundance, the cause of senescence in HGPS. Furthermore, compound C, an inhibitor of AMPK, and SBI-0206965, an inhibitor of ULK1/2 and AMPK, which prevent autophagy activation, reversed BHB-induced progerin decline as well as its anti-senescent effect in an AMPK-mTORC1 dependent manner. Altogether, these results suggest that the anti-senescence effect of BHB involves progerin clearance by autophagy activation supporting the potential of BHB for HGPS therapeutics and further preclinical trials. Graphical Abstract

Accelerated epigenetic ageing after burn injury - Jack Sullivan; Thomas Nicholson; Jon Hazeldine; Naiem Moiemen; Janet M. Lord (GeroScience, 2025)
Individuals who suffer a major burn injury are at higher risk of developing a range of age-associated diseases prematurely leading to an increase in mortality in adult and juvenile burn injury survivors. One possible explanation is that injury is accelerating the biological ageing process. To test this hypothesis, we analysed DNA methylation in peripheral blood mononuclear cells from adult burn-injured patients (> 5%TBSA) upon admission to hospital and 6 months later, to calculate an epigenetic clock value which can be used to determine biological age. Fifty-three burn-injured participants (mean age 45.43 years, 49 male, mean TBSA 37.65%) were recruited at admission and 34 again 6 months post injury (mean age 40.4 years, 34 male, mean TBSA 30.91%). Twenty-nine healthy controls (mean age 43.69 years, 24 male) were also recruited. Epigenetic age acceleration at admission by PhenoAge was + 7.2 years ( P = 8.31e-5) but by month 6 was not significantly different from healthy controls. PCGrimAge acceleration was + 9.23 years at admission ( P = 5.79e-11) and remained 4.18 years higher than in controls by month 6 ( P = 2.64e-6). At admission, the burn-injured participants had a Dunedin PACE of ageing score 31.65% higher than the control group ( P = 2.14e-12), the equivalent of + 115 days per year of biological ageing. Six months post injury the Dunedin PACE of ageing remained significantly higher (+ 11.36%, 41 days/year) than in the control group ( P = 3.99e-5). No differences were seen using the Horvath and Hannum clocks. Enrichment analysis revealed that key pathways enriched with burn injury related to immune function, activation, and inflammation. The results reveal that epigenetic age, specifically the PACE of ageing and PCGrimAge, was accelerated in burn-injured adults at admission, with some return towards control values by 6 months. That these two clocks are built upon morbidity outcomes suggests that the injury is invoking a biological response that increases the risk of disease. Burn injury in adults induces epigenetic changes suggestive of an acceleration of the ageing process, which may contribute to the increased morbidity and mortality in these patients.

Lung endothelial cell senescence impairs barrier function and promotes neutrophil adhesion and migration - Maliheh Najari Beidokhti; Nuria Villalba; Yonggang Ma; Amanda Reynolds; Juan Hernandez Villamil; Sarah Y. Yuan (GeroScience, 2025)
Cellular senescence contributes to inflammation and organ dysfunction during aging. While this process is generally characterized by irreversible cell cycle arrest, its morphological features and functional impacts vary in different cells from various organs. In this study, we examined the expression of multiple senescent markers in the lungs of young and aged humans and mice, as well as in mouse lung endothelial cells cultured with a senescence inducer, suberoylanilide hydroxamic acid (SAHA), or doxorubicin (DOXO). We detected increased levels of p21, γH2AX, and SA-β-Gal and decreased Ki-67 and Lamin B1 in aged lungs and senescent lung endothelial cells. Importantly, the expression of senescent markers was associated with an inflammatory response in aged mouse lungs characterized by neutrophil infiltration, increased expression of intercellular adhesion molecule 1 (ICAM-1), and decreased protein levels of VE-cadherin and ZO-1. As the latter two are critical constituents of endothelial cell–cell junctions, we hypothesized that their decreased expression could lead to compromised junction barrier integrity. Indeed, senescent endothelial cells (ECs) exhibited impaired barrier properties, as measured by increased permeability to solutes of small size (3-kD) and albumin (70-kD). When co-cultured with neutrophils, senescent ECs and their supernatant promoted neutrophil chemotaxis and trans-endothelial migration. Taken together, our results suggest that lung EC senescence weakens cell–cell junctions, impairs barrier function, and promotes neutrophil adhesion and migration, which may contribute to the development of inflammation and related pathologies in the lungs during aging.

Dietary flaxseed: Cardiometabolic benefits and its role in promoting healthy aging - Setor K. Kunutsor; Davinder S. Jassal; Amir Ravandi; Andrea Lehoczki (GeroScience, 2025)
Flaxseed, a rich source of omega-3 polyunsaturated fatty acid alpha-linolenic acid (ALA), lignans, and soluble fiber, has attracted attention for its potential to improve multiple cardiometabolic risk factors. While its benefits are well-recognized, comprehensive evaluations of its direct impact on clinical outcomes, such as the prevention or progression of cardiometabolic diseases, remain limited. Additionally, its potential to support healthy aging and longevity through fundamental biological mechanisms has not been fully elucidated. This review synthesizes existing research on flaxseed supplementation, highlighting its effects on cardiometabolic risk factors and outcomes, the underlying biological mechanisms, and its broader implications for health promotion and aging. Findings demonstrate that flaxseed supplementation significantly improves several cardiometabolic risk factors, including body weight, body mass index, lipid levels, blood pressure, glycemic measures, markers of inflammation (e.g., C-reactive protein and interleukin-6), oxidative stress, and liver enzymes. Blood pressure reductions range from approximately 2 to 15 mmHg for systolic blood pressure and 1 to 7 mmHg for diastolic blood pressure, with the magnitude influenced by dose, duration, and baseline risk profiles. While direct evidence linking flaxseed to the prevention of hypertension, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, chronic kidney disease, and cardiovascular disease is limited, its bioactive components—ALA, lignans, and fiber—are strongly associated with reduced risks of these conditions. The benefits of flaxseed are mediated through multiple pathways, including anti-inflammatory and antioxidant effects, improved lipid levels, improved glucose metabolism and insulin sensitivity, modulation of gut microbiota, and enhanced vascular health. Beyond cardiometabolic outcomes, flaxseed may influence key biological processes relevant to aging, underscoring its potential to promote healthy aging and longevity. Optimal cardiometabolic benefits appear to be achieved with ground whole flaxseed at doses of ≥ 30 g/day for at least 12 weeks, particularly among individuals at high cardiometabolic risk. Future research should focus on elucidating flaxseed’s mechanisms of action, clarifying its role in disease prevention, and refining dietary recommendations to harness its potential for cardiometabolic health and aging interventions.

Deep learning reveals diverging effects of altitude on aging - Amanuel Abraha Teklu; Indra Heckenbach; Michael Angelo Petr; Daniela Bakula; Guido Keijzers; Morten Scheibye-Knudsen (GeroScience, 2025)
Aging is influenced by a complex interplay of multifarious factors, including an individual’s genetics, environment, and lifestyle. Notably, high altitude may impact aging and age-related diseases through exposures such as hypoxia and ultraviolet (UV) radiation. To investigate this, we mined risk exposure data (summary exposure value), disease burden data (disability-adjusted life years (DALYs)), and death rates and life expectancy from the Global Health Data Exchange (GHDx) and National Data Management Center for Health of Ethiopia for each subnational region of Ethiopia, a country with considerable differences in the living altitude. We conducted a cross-sectional clinical trial involving 227 highland and 202 lowland dwellers from the Tigray region in Northern Ethiopia to gain a general insight into the biological aging at high altitudes. Notably, we observed significantly lower risk exposure rates and a reduced disease burden as well as increased life expectancy by lower mortality rates in higher-altitude regions of Ethiopia. When assessing biological aging using facial photographs, we found a faster rate of aging with increasing elevation, likely due to greater UV exposure. Conversely, analysis of nuclear morphologies of peripheral blood mononuclear cells (PBMCs) in blood smears with five different senescence predictors revealed a significant decrease in DNA damage-induced senescence in both monocytes and lymphocytes with increasing elevation. Overall, our findings suggest that disease and DNA damage-induced senescence decreases with altitude in agreement with the idea that oxidative stress may drive aging.

Age-specific effects of a sustained cognitive activity on perceived cognitive fatigue as well as single- and dual-task treadmill walking performance - Martin Schlegel; Matthias Weippert; Frank Feldhege; Franziska Knaack; Thomas Mittlmeier; Sven Bruhn; Martin Behrens (GeroScience, 2025)
During their daily lives humans are often confronted with sustained cognitive activities (SCA) leading to state fatigue, a psychobiological state characterized by a decrease in cognitive and/or motor performance and/or an increase in perception of fatigue. It was recently shown that performing SCA can impair overground dual-task gait performance in older adults, but it is currently unknown whether there is a task- and/or age-specific modulation in gait performance during treadmill walking. Therefore, the effect of a SCA on single- and dual-task treadmill walking performance was investigated in young and old adults. Using a crossover design, spatio-temporal gait parameters of 24 young and 23 older healthy participants were measured using motion capturing during single- and dual-task (including three cognitive interference tasks: word list generation, arithmetic, and Stroop-task) treadmill walking before and after SCA (30 min Stroop-task) and a control task (reading). Moreover, cognitive fatigue, wakefulness, mood, and arousal were assessed. Although the SCA induced age-specific perceptual responses, no difference was found for cognitive performance during the Stroop-task. The cognitive interference task performance (word list generation, arithmetic, and Stroop-task) during walking on the treadmill did not decrease after the SCA. Single- and dual-task gait performance (e. g., step width and step length) specifically changed after the SCA and after the reading control task in both groups. Data indicate that perceived cognitive fatigue has an impact on single- and dual-task treadmill walking performance, with task- and age-specific differences. Although no general age-specific changes in single- and dual task gait performance following SCA were identified, perceived cognitive fatigue should be considered as an intrinsic risk factor for falls.

Analysis of sex-specific disease patterns associated with human lifespan - Sara Cruces-Salguero; Joaquim Sol; Igor Larrañaga; Reinald Pamplona; Javier Mar; Mariona Jove; Ander Matheu (GeroScience, 2025)
Disability and multimorbidity increase with aging and constitute a challenge for the health system. However, different individuals display different aging trajectories, and understanding the underlying relationships between lifespan and disease is fundamental for identifying the different patterns in human lifespan. A previous study explored associations between lifespan and age of onset of diseases of different organ systems, prevalence of escapers, and percentage of life free of disease (health span), comparing them between genders in Catalonian population. In this retrospective study, we analyzed a cohort of 41,063 old individuals (20,722 men, with a mean lifespan of 79 years [50–109], and 20,341 women, with a mean lifespan of 84 years [50–109]) deceased between 2014 and 2019 in Gipuzkoa (Basque Country, Spain) taken from the Basque Health Service electronic health records data lake and analyzed and contrasted the above cited characteristics. Longevity, defined by age above the mean lifespan of the population, showed a protective effect against developing diseases, with higher lifespans delaying the onset of all diseases both at single and multisystemic levels. Furthermore, individuals with the lowest and highest lifespans were the ones presenting the healthier profiles, with fewer systems altered. There were specific differences according to sex, with women exhibiting decreased mortality risk despite having greater multimorbidity and men having less multimorbidity. In addition, men reached the highest lifespans with a smaller number of comorbidities. These results define the aging trajectories of the Basque population, extend the characterization of the human aging, and provide insight into sex-specific differences in multimorbidity and survival risk.

The impact of co-housing on murine aging studies - Alison Luciano; Gary A. Churchill (GeroScience, 2025)
Analysis of preclinical lifespan studies often assume that outcome data from co-housed animals are independent. In practice, treatments, such as controlled feeding or putative life-extending compounds, are applied to whole housing units, and as a result, the outcomes are potentially correlated within housing units. We consider intra-class (here, intra-cage) correlation in three published and two unpublished lifespan studies of aged mice encompassing more than 20,000 observations. We show that the independence assumption underlying common analytic techniques does not hold in these data, particularly for traits associated with frailty. We describe and demonstrate various analytical tools available to accommodate this study design and highlight a limitation of standard variance components models (i.e., linear mixed models) which are the usual statistical tools for handling correlated errors. Through simulations, we examine the statistical biases resulting from intra-cage correlations with similar magnitudes as observed in these case studies and discuss implications for power and reproducibility.

Enhancing emergency care for older persons: the role and impact of the electronic Frailty Index - Dana Shiffer; Antonio Desai; Matteo Cesari; Elena Generali; Massimiliano Greco; Gabriele Savioli; Mauro Giordano; Antonio Voza (GeroScience, 2025)
As the elderly population expands, enhancing emergency department (ED) care by assessing frailty becomes increasingly vital. To address this, we developed a novel electronic Frailty Index (eFI) from ED health records, specifically designed to assess frailty and predict hospitalization, in-hospital mortality, ICU admissions, and 30-day ED readmissions. This retrospective, single-center study included patients 65 years old or older who presented to the ED of IRCCS Humanitas Research Hospital in Milan, Italy, between January 2015 and December 2019. Frailty was assessed using a novel electronic Frailty Index (eFI), based on the cumulative deficit model, incorporating 45 health deficits to quantify frailty. Patients were divided into four quartiles based on eFI scores to explore the association between frailty levels and adverse outcomes, including hospitalization, in-hospital mortality, ICU admission, and 30-day ED readmission. The study included 21,537 patients (mean age 77.4, 50.7% males). The median eFI score was 0.16. Hospitalization rates rose significantly with frailty, from 20% in the least frail quartile to 43% in the most frail. Similarly, in-hospital mortality and ICU admissions increased markedly with higher eFI scores, with mortality rates climbing from 0.44 to 5.0% across quartiles. The 30-day ED readmission rates significantly rose from 9.9 to 19.8%. For every 0.01 increase in eFI score, the odds of hospitalization, in-hospital mortality, ICU admission, and 30-day ED readmission significantly increased ( P < 0.0001). Specifically, the adjusted odds ratios (OR) for hospitalization, in-hospital mortality, ICU admission, and ED readmission rose to 3.55, 14.15, 4.70, and 2.22, respectively ( P < 0.0001), in the most frail compared to the least frail quartile. The integration of the eFI into ED settings can enable more precise risk stratification and resource allocation, significantly improving patient management and healthcare delivery for older persons in these urgent care contexts.

Ethnicity-specific patterns of epigenetic age acceleration in rheumatoid arthritis - Archana Sharma-Oates; Niall Dunne; Karim Raza; Leonid Padyukov; Natalie Rivera; Annette van der Helm-van Mil; Arthur G. Pratt; Niharika A. Duggal; Simon W. Jones; Janet M. Lord (GeroScience, 2025)
Rheumatoid arthritis (RA) is an age-related chronic inflammatory disease which may include accelerated biological ageing processes in its pathogenesis. To determine if increased biological age is associated with risk of RA and/or is present once disease is established. We used DNA methylation to compare biological age (epigenetic age) of immune cells in adults at risk of RA and those with confirmed RA, including twins discordant for RA. The established RA studies were secondary analyses of existing DNA methylation data. Sub-group analysis considered the influence of ethnicity. Four epigenetic clocks were used to determine DNA methylation age. DNA methylation age was no different in adults at risk of RA in the Leiden Clinically Suspect Arthralgia (CSA) cohort ( n = 38 developed RA, n = 24 did not), and there was also no difference in DNA methylation age between 77 UK twins discordant for RA, or adults with established RA from the Swedish EIRA cohort ( n = 342) compared to healthy controls ( n = 328). A sub-group analysis of RA patients of South Asian ethnicity (10 RA patients, 14 healthy controls) showed DNA methylation age acceleration of 3.3 years ( p = 0.00014) using the mean DNA methylation age of four epigenetic clocks. Our study suggests that epigenetic age acceleration may be differentially influenced by South Asian ethnicity, but that RA was not generally associated with accelerated epigenetic age. The higher epigenetic age in the South Asian patients may explain the earlier age of onset in this minority ethnic population.

The role of the Mediterranean diet in reducing the risk of cognitive impairement, dementia, and Alzheimer’s disease: a meta-analysis - Mónika Fekete; Péter Varga; Zoltan Ungvari; János Tibor Fekete; Annamaria Buda; Ágnes Szappanos; Andrea Lehoczki; Noémi Mózes; Giuseppe Grosso; Justyna Godos; Otilia Menyhart; Gyöngyi Munkácsy; et al. (GeroScience, 2025)
Age-related cognitive impairment and dementia pose a significant global health, social, and economic challenge. While Alzheimer’s disease (AD) has historically been viewed as the leading cause of dementia, recent evidence reveals the considerable impact of vascular cognitive impairment and dementia (VCID), which now accounts for nearly half of all dementia cases. The Mediterranean diet—characterized by high consumption of fruits, vegetables, whole grains, fish, and olive oil—has been widely recognized for its cardiovascular benefits and may also reduce the risk of cognitive decline and dementia. To investigate the protective effects of the Mediterranean diet on cognitive health, we conducted a systematic literature review using PubMed, Web of Science, and Google Scholar, focusing on studies published between 2000 and 2024. The studies included in the meta-nalysis examined the adherence to the Mediterranean diet and the incidence of dementia and AD. We applied a random-effects model to calculate pooled hazard ratios (HRs) with 95% confidence intervals (CIs) and assessed heterogeneity through I -square statistics. Forest plots, funnel plots, and Z -score plots were used to visualize study outcomes. Of the 324 full-text records reviewed, 23 studies met the inclusion criteria. The combined HR for cognitive impairment among those adhering to the Mediterranean diet was 0.82 (95% CI 0.75–0.89); for dementia, the HR was 0.89 (95% CI 0.83–0.95); and for AD, the HR was 0.70 (95% CI 0.60–0.82), indicating substantial protective effects. Significant heterogeneity was observed across studies, though Z -score plots suggested sufficient sample sizes to support reliable conclusions for each condition. In conclusion, this meta-analysis confirms that adherence to the Mediterranean diet is associated with an 11–30% reduction in the risk of age-related cognitive disorders, including cognitive impairment, dementia, and AD. These findings underscore the Mediterranean diet’s potential as a central element in neuroprotective public health strategies to mitigate the global impact of cognitive decline and dementia and to promote healthier cognitive aging.

High prevalence of atrial conduction abnormalities in Lewy body disease – a marker of cardiac complications? - Keivan Javanshiri; Alexander Siotis; Isak Heyman; Mattias Haglund (GeroScience, 2025)
Increasing evidence suggests that Lewy body disease (LBD) is associated with clinically important cardiac complications, including sick sinus syndrome, atrial fibrillation and sudden cardiac death. The high prevalence of sick sinus syndrome and atrial fibrillation in LBD suggests the presence of disease-related atrial conduction disorders. To explore whether LBD is associated with atrial conduction disorders, electrocardiographic (ECG) P wave parameters were analyzed in a cohort of LBD patients (n = 74), using age-matched Alzheimer’s disease (AD) patients (n = 25) as controls. P wave terminal force in V1 and P wave duration were found to be significantly greater in the LBD group than in the AD group. In addition, 43 (58%) individuals in the LBD exhibited pathological P wave terminal force (> 4000 µV*ms) vs 3 (12%) in the AD group, and 60 (81%) in the LBD group exhibited pathological P wave duration (≥ 120 ms), vs 13 (52%) in the AD group. The difference could not be explained by atrial fibrillation or atrial enlargement on echocardiogram. The clinical significance of pathological P wave parameters in LBD is unknown, but their presence suggests an atrial cardiomyopathy that could be due to cardiac alpha-synuclein deposition, autonomic dysfunction, or a combination thereof. Future research is warranted to elucidate whether this proposed disease-related atrial cardiomyopathy is related to cardiac alpha-synuclein deposition, whether it is causally related to cardiac complications in LBD, and whether pathological P wave parameters hold potential as a screening tool for cardiac complications in LBD.

Circulating metabolomic biomarkers of 5-year body weight and composition change in a biracial cohort of community-dwelling older adults - Shanshan Yao; Megan M. Marron; Samaneh Farsijani; Iva Miljkovic; George C. Tseng; Ravi V. Shah; Venkatesh L. Murthy; Anne B. Newman (GeroScience, 2025)

Genomic determinants of biological age estimated by deep learning applied to retinal images - Yu Huang; Mohammad Ghouse Syed; Ruiye Chen; Cong Li; Xianwen Shang; Wei Wang; Xueli Zhang; Xiayin Zhang; Shulin Tang; Jing Liu; Shunming Liu; Sundar Srinivasan; et al. (GeroScience, 2025)
With the development of deep learning (DL) techniques, there has been a successful application of this approach to determine biological age from latent information contained in retinal images. Retinal age gap (RAG) defined as the difference between chronological age and predicted retinal age has been established previously to predict the age-related disease. In this study, we performed discovery genome-wide association analysis (GWAS) on the RAG using the 31,271 UK Biobank participants and replicated our findings in 8034 GoDARTS participants. The genetic correlation between RAGs predicted from the two cohorts was 0.67 ( P = 0.021). After meta-analysis, we found 13 RAG loci which might be related to retinal vessel density and other aging processes. The SNP-wide heritability ( h 2 ) of RAG was 0.15. Meanwhile, by performing Mendelian randomization analysis, we found that glycated hemoglobin, inflammation hemocytes, and anemia might be associated with accelerated retinal aging. Our study explored the biological implications and molecular-level mechanism of RAG, which might enable causal inference of the aging process as well as provide potential pharmaceutical intervention targets for further treatment. Graphical Abstract