Age-adjusted neurofilament light chain cutoffs for diagnosing neurodegenerative dementia: a two-threshold machine learning approach - Chiara Gallingani; Riccardo Maramotti; Chiara Carbone; Giulia Vinceti; Silvia Cossutti; Najara Iacovino; Daniela Ballotta; Simone Salemme; Teresa Urbano; Roberta Bedin; Annalisa Chiari; Giovanna Zamboni; et al. (GeroScience, 2026)
Clinical implementation of neurofilament light chain (NfL), a biomarker of neurodegeneration, remains challenging due to absence of reliable cutoffs and influence of confounding factors, particularly age. We aimed to develop an age-adjusted, two-threshold classification framework to support clinical interpretation of NfL in the neurodegenerative dementia diagnosis. We retrospectively enrolled subjects with cognitive/behavioral disturbances and cognitively unimpaired controls (CTR). Participants underwent a baseline diagnostic workup, including at least a neuropsychological assessment, blood test, CSF and serum NfL measurement, and MRI, and were followed up for 2 years. At follow-up, they were diagnosed with either a neurodegenerative dementia [Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), or Lewy Body Dementia (LBD)] or a non-neurodegenerative condition [Other Etiology (OE)]. AD, FTD, and LBD were grouped as Neurodegenerative (NDG), while OE and CTR were grouped as Non-Neurodegenerative (non-NDG). Bayesian regression models assessed the effects of age, disease duration, renal function, and gender on NfL. A weighted support vector machine (SVM) with leave-one-out cross-validation defined age-adjusted cutoffs using a two-threshold strategy constraining sensitivity ≥ 85% and limiting the intermediate zone. We included 217 subjects (158 NDG, 59 non-NDG). Serum and CSF NfL levels were significantly higher in NDG. Age strongly increased NfL levels, particularly in serum where diagnostic separation declined beyond age 70. The SVM-based model applied to CSF NfL defined continuous, age-adjusted, two-threshold cutoffs, identifying low-risk, high-risk, and intermediate zones. The proposed framework for CSF NfL provides a clinically oriented decision-support tool to stratify the likelihood of underlying neurodegeneration and guide diagnostic workup in cognitive neurology settings, pending external validation. Graphical abstract

Construct validation of the vitality capacity domains ‘energy and metabolism’ and ‘neuromuscular function’ in relation to locomotor capacity and quality of life in community-dwelling middle-aged and older adults - Francis Louter; Veerle Knoop; Jeroen Demarteau; Liza De Dobbeleer; David Beckwee; Siddhartha Lieten; Aziz Debain; Ellen Gorus; Sabrina Chettouf; Dax Houtkamp; Bart C. Bongers; Albert Van De Wiel; et al. (GeroScience, 2026)

Elevated levels of circulating plasma sPDGFRβ in cognitively impaired APOE4 carriers - Abhay P. Sagare; Trevor Lohman; Ivan Ramirez; Elizabeth B. Joe; Michael G. Harrington; Helena C. Chui; Lon S. Schneider; Hussein N. Yassine; John M. Ringman; Arthur W. Toga; Daniel A. Nation; Berislav V. Zlokovic (GeroScience, 2026)
Increased levels of cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor-β (sPDGFRβ), a marker of blood–brain barrier (BBB)-associated pericyte cell injury, have been shown to correlate with increased BBB permeability and severity of Alzheimer’s disease (AD) pathology. It has been also shown that increased CSF sPDGFRβ levels can predict cognitive dysfunction in APOE4 carriers bearing the main susceptibility gene for AD. Whether plasma sPDGFRβ levels are also elevated in APOE4 carriers has not been explored. Here, we analyzed plasma samples for sPDGFRβ levels, Ab 42/40 ratio, and pTau217 in 115 APOE3 homozygotes and APOE4 carriers with Clinical Dementia Rating (CDR) score of 0 and 0.5. Our data show that plasma sPDGFRβ levels are increased in APOE4 carriers with cognitive impairment compared to APOE4 carriers that are cognitively unimpaired as well as relative to cognitively impaired APOE3 carriers even after controlling for plasma Aβ 42/40 ratio and pTau217. Thus, our data suggest that plasma sPDGFRβ is a useful biomarker of brain pericytes/BBB damage in APOE4 carriers.

Galectin-3 binding protein is upregulated in heart failure with preserved ejection fraction and associated with endothelial nitric oxide synthase deficiency - Rosalinda Madonna; Maria Concetta Cufaro; Samuele Gagliardi; Riccardo Morganti; Fabio Di Ferdinando; Sandra Ghelardoni; Alessandra Marzoppi; Ashot Avagimyan; Vincenzo Lionetti; Giuseppe Ambrosio; Francesco Fedele; Piero Del Boccio (GeroScience, 2026)

Is morbidity compressing or expanding? Cross-national trends in midlife multimorbidity across cohorts - Toshiaki Komura; Soohyeon Ko; Koryu Sato; Rockli Kim; S. V. Subramanian (GeroScience, 2026)

High-resolution glutamate-weighted mapping of in vivo mouse brain across age with chemical exchange saturation transfer MRI - R. Gaudin; T. Delebarre; M. Glatigny; E. Selingue; C. Debacker; L. Ciobanu; D. Boido (GeroScience, 2026)
Aging in the mammalian brain involves significant structural, functional, and metabolic changes, including a decrease in glutamate concentration. Glutamate-weighted chemical exchange saturation transfer (gluCEST) MRI provides a non-invasive method for mapping glutamate distribution with high spatial resolution. Collecting data from a large cohort of healthy mice aged 2 to 23 months, scanned in vivo at 17.2 T, we demonstrate that gluCEST can differentiate multiple brain regions, and introduce a gluCEST template for the mouse mid-rostrocaudal brain from Bregma −0.5 to −4 mm approximately. Our findings reveal significant age-related decreases in gluCEST values in the hippocampus, thalamus, and hypothalamus. These decreases did not correlate with volume reductions of these regions, except in the hippocampus, indicating gluCEST as a complementary neuroimaging approach to overall anatomical changes. Our study also demonstrates gluCEST’s potential to monitor age-related changes in smaller brain subregions, such as cortical and hippocampal layers, providing a valuable tool for longitudinal investigations into aging and neurodegenerative diseases. The high spatial resolution and sensitivity offered by ultra-high magnetic field MR scanners enhance the precision of these measurements, paving the way for future preclinical and clinical applications.

Senolytic treatment with dasatinib and quercetin selectively improves cardiac autonomic balance in obesity - Mahesh Kumar Sivasubramanian; Raisa Monteiro; Joshua T. Butcher; UdayKiran Venugopal; Yasodha Kesavan; Priya Balasubramanian; Madhan Subramanian (GeroScience, 2026)
Chronic sympathetic nerve activity (SNA) to end organs plays a crucial role in the pathophysiology of obesity-induced hypertension. Oxidative stress and neuroinflammation in the rostral ventrolateral medulla (RVLM), a key brainstem region regulating sympathetic outflow, have been implicated in the sympathetic overactivity in obesity. However, the upstream mechanisms driving RVLM neuroinflammation remain unknown. We hypothesized that obesity induces cellular senescence, a stress response characterized by irreversible cell cycle arrest, in the RVLM and contributes to sympathoexcitation. To test this, C57BL/6 J male mice were fed chow or a high-fat diet (HFD) for 16 weeks, followed by treatment with Dasatinib (5 mg/kg) and Quercetin (50 mg/kg) (D + Q) to selectively eliminate senescent cells. Blood pressure was assessed by radiotelemetry in conscious, freely moving mice. SNA was indirectly measured through heart rate variability (HRV) analysis, depressor response to hexamethonium, and serum norepinephrine levels. The RVLM was microdissected for gene expression and protein analysis of senescence markers and DNA damage. Our results showed that HFD mice had a significant increase in mean arterial pressure and SNA compared to chow-fed controls. Obesity was associated with increased DNA damage and upregulation of cellular senescence markers in the RVLM. Senolytic treatment with D + Q selectively improved cardiac autonomic balance as assessed by HRV, without altering indices of global SNA or blood pressure. Collectively, our findings identify cellular senescence in the RVLM as a novel contributor to obesity-induced sympathoexcitation, and senolytic therapy could be a potential therapeutic avenue for obesity-associated autonomic dysfunction. Graphical Abstract

Comparative effectiveness of SGLT-2 inhibitors and GLP-1 receptor agonists on the risk of incident dementia after acute kidney injury: a target-trial emulation - Ying-Ru Chen; Zheng-Hong Jiang; Jui-Yi Chen; Vin-Cent Wu (GeroScience, 2026)

Plasma pTau181 is associated with subjective cognitive concerns but not objective cognitive decline or structural brain integrity measures in midlife - Ashleigh Barrett-Young; Erin E. Cawston; Brigid Ryan; Wickliffe C. Abraham; Antony Ambler; Tim Anderson; Kirsten Cheyne; Elizabeth Goodin; Sean Hogan; Renate M. Houts; David Ireland; Annchen R. Knodt; et al. (GeroScience, 2026)
Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer’s disease from healthy older adults, there are few studies of plasma biomarkers among middle-aged populations. Given the potential utility of plasma AD biomarkers such as pTau181 in screening for disease risk, examining pTau181 in a middle-aged cohort without AD is important for future implementation. The objectives of this study were to characterise plasma pTau181 in a middle-aged birth cohort aged 45 years and to investigate associations with early indicators of dementia risk. Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972–1973. Plasma pTau181, self-reported cognitive concerns, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. Plasma pTau181 concentrations at age 45 ( n = 854, 49% female) were associated with self-reported cognitive concerns (β = 0.09, p = .008); however, no significant associations were observed with objective cognitive decline, worse structural brain integrity, or biological ageing. Higher plasma pTau181 was associated with self-reported cognitive concerns at age 45, but not objective AD-related measures. The association of plasma pTau181 and self-reported cognitive concerns in this cohort suggests that AD pathology may begin to accumulate by age 45 and may be associated with subtle changes in cognition that are not at objectively measurable levels. Graphical Abstract

Correction to: Differential striatal dopamine binding in Parkinson’s Disease with and without REM sleep behavior disorder: A Tc‑99 m TRODAT‑1 SPECT study - Pei‑Hsuan Wang; Yang‑Pei Chang; Ching‑Fang Chien; Poyin Huang (GeroScience, 2026)

Age- and cognitive load–related variability and entropy of gait: integrating coefficient of variation, median absolute deviation, and permutation entropy of spatiotemporal parameters into the Semmelweis Study gait assessment framework - Peter Mukli; Mihaly Muranyi; Ágnes Lipecz; Zsofia Szarvas; Tamás Csípő; Mónika Fekete; Vince Fazekas-Pongor; Anna Peterfi; Ágnes Fehér; Norbert Dosa; Csilla Kaposvári; Anna Aliquander; et al. (GeroScience, 2026)
Aging profoundly alters the neuromotor and cognitive systems that support gait control, leading to increased variability and instability that predict functional decline and dementia risk. In this pilot study, conducted to inform the design of the Semmelweis Study gait assessment pipeline, we examined how aging and cognitive load influence the magnitude and temporal organization of gait fluctuations. The Semmelweis Study is a large, prospective workplace cohort at Semmelweis University designed to identify the determinants of unhealthy aging and the mechanisms that preserve functional resilience across the life course. One hundred three adults aged 23–87 years completed single- and dual-task walking trials on a 20-foot pressure-sensitive walkway. Gait variability was quantified using the median absolute deviation (MAD) and coefficient of variation (CoV) of key spatiotemporal parameters, while permutation entropy (PE) captured the complexity of stride-to-stride dynamics. Aging was associated with progressive increases in both the variability (MAD, CoV) and changes in orderliness (PE) of gait fluctuations, particularly under dual-task conditions, suggesting a dual contribution of neuromotor degradation and compensatory recruitment of higher-order control processes. The amplification of these effects during cognitive load highlights the vulnerability of cognitive–motor integration with advancing age. By integrating robust, relative, and nonlinear variability metrics within a unified analytical framework, this study provides a multidimensional characterization of gait control and establishes sensitive indicators for detecting early functional decline. Within the translational framework of the Semmelweis Study, these quantitative gait measures—together with vascular, metabolic, and cognitive assessments—are expected to serve as informative components of a comprehensive biomarker system aimed at identifying early determinants of unhealthy brain aging and guiding preventive strategies to promote healthy longevity.

Epigenetic age acceleration measures and chemotoxicity in older adults with early breast cancer - Jingran Ji; Can-Lan Sun; William Dale; Heeyoung Kim; Vani Katheria; Catherine Lee; Claire Smith; Nala Sun; Yuan Chun Ding; Susan L. Neuhausen; Harvey J. Cohen; Alexandra Binder; et al. (GeroScience, 2026)
Among older adults with early breast cancer, the risk of chemotoxicity can vary widely despite similar chronological age. Here, we evaluated whether epigenetic indicators of biological age can stratify the risk of chemotoxicity in this population. In a prospective study of 394 women age > 65 with stage I–III breast cancer treated with neo/adjuvant chemotherapy, we analyzed peripheral blood DNA methylation patterns to estimate epigenetic age acceleration (EAA) before chemotherapy. We tested five epigenetic clocks. The primary endpoint was grade 2+ chemotoxicity (yes/no, yes defined as any grade 2+ toxicity attributed to chemotherapy). Using multivariable logistic regression, we examined the association between EAA and grade 2+ chemotoxicity, adjusting for demographic, clinical, and geriatric covariates. We also evaluated the relationship between EAA and individual grade 2+ toxicities. The median (range) pre-treatment chronological age was 70 years (65–85); 65% had stage II/III disease; 38% received anthracycline; and 75% received G-CSF prophylaxis. A total of 334 (84.8%) participants experienced a grade 2+ toxicity. After multivariable adjustment, there was no significant association between measures of EAA and grade 2+ chemotoxicity. For individual toxicities, EAA by GrimAge was associated with increased risk for infection without neutropenia, and EAA by DunedinPACE was associated with increased risk for diarrhea. In this cohort of older adults with early breast cancer, there was no significant association between pre-treatment EAA and overall grade 2+ chemotoxicity. Further research is needed to examine whether blood-based biomarkers of aging may identify older adults at high risk of chemotoxicity. NCT01472094, Hurria Older PatiEnts (HOPE) with Breast Cancer Study.

A conserved regulatory architecture stabilizes cellular senescence across distinct triggers in human fibroblasts - Mohd Shahzaib; Domenico Aprile; Tiziana Squillaro; Nicola Alessio; Gianfranco Peluso; Giovanni Di Bernardo; Umberto Galderisi (GeroScience, 2026)
Cellular senescence arises through replicative exhaustion or acute stress, yet whether these distinct triggers share a reproducible transcriptional organization has remained unresolved. Seven public human fibroblast RNA-seq datasets were integrated across both trigger types, moving from differential expression through Gene Ontology and Reactome enrichment to protein–protein interaction network embedding within a single harmonized framework. Both triggers converged on concordant repression of replication and chromatin programs alongside induction of inflammatory and extracellular matrix outputs. Cross-trigger combination identified 263 commonly repressed and 112 commonly induced GO terms, with consistently higher enrichment scores in the repressed set, and 145 versus 13 shared Reactome pathways. Conserved induction of calcium ion homeostasis and membrane potential regulation, and conserved repression of RHO GTPase-Formin signaling, extended the shared program beyond canonical SASP biology into dimensions not previously described in human fibroblasts. Interactome embedding, applied here for the first time in a cross-trigger senescence framework, identified ten genes occupying both induced and repressed neighborhoods simultaneously, a structural layer invisible to enrichment analysis alone. ELAVL1 coordinates SASP output and growth arrest post-transcriptionally, while suppressed PARP1 alongside active ATM defines a self-reinforcing damage configuration. These results provide a quantitative cross-study reference and a structured basis for senotherapeutic candidate prioritization. Graphical abstract Distinct senescence triggers, including replicative exhaustion and acute stress, converge on a shared senescent state in human fibroblasts. This state is defined by a conserved regulatory architecture comprising interconnected modules of checkpoint enforcement, inflammatory/SASP signaling, and repression of replication and chromatin programs. A small set of bridging nodes links these modules, supporting a stable and self-maintaining network organization of cellular senescence.

The association between ultra-processed food exposure and cognition in older adults - Sarah Gauci; Belayneh Mengist; Mojtaba Lotfaliany; Malcolm Forbes; Farzaneh Asoudeh; Deb Junyi Zhang; Suzanne G. Orchard; Alice J. Owen; Daniel Clayton-Chubb; Robyn L. Woods; John J. McNeil; Joanne Ryan; et al. (GeroScience, 2026)
With an ageing population comes a growing burden of age-related cognitive decline. While evidence supports a relationship between higher diet quality and better cognitive outcomes, the association between ultra-processed foods (UPFs) and cognitive function remains underexplored. We examined this association using prospective data from the ASPirin in Reducing Events in the Elderly (ASPREE) study, a cohort of Australian adults aged 70 years and older. Dietary intake was assessed via a mail-based diet screening questionnaire and categorised according to the Nova classification. Cognitive performance was assessed using the Controlled Oral Word Association Test (COWAT), Symbol Digit Modalities Test (SDMT), Hopkins Verbal Learning Test–Revised (HVLT-R), Modified Mini-Mental State Examination (3MS), and a composite cognitive Z score. Participants were stratified into high UPF (≥ 4 servings/day) and low UPF (< 4 servings/day). Marginal structural models with inverse probability of treatment weighting estimated associations, adjusting for demographic, lifestyle, and clinical confounders. Among 11,502 participants (3505 high UPF; 7997 low UPF), over a median follow-up of 5.6 (± 2.4) years, higher UPF consumption was associated with poorer performance on the 3MS (mean difference –0.28, 95% CI –0.52 to –0.04), COWAT (–0.23, 95% CI –0.44 to –0.03), SDMT (–0.51, 95% CI –0.94 to –0.08), and the composite Z score (–0.04, 95% CI –0.07 to –0.01), but not HVLT-R (–0.12, 95% CI –0.26 to 0.02). Higher UPF intake was associated with poorer cognitive performance across multiple domains. These findings support initiatives to reduce UPF exposure as a potential strategy to promote healthy cognitive ageing.

Loss of sirtuin 3 disrupts cellular senescence signaling pathways - Niharika Kura; Bronwyn A. Mogck; Samantha T. Jezak; Michael C. Velarde; Christopher D. Wiley (GeroScience, 2026)

Correlations between white matter hyperintensities, magnetic resonance imaging findings, and cognition in the oldest old: a multimodal cross-sectional study - Ryo Ueda; Ryo Shikimoto; Jinichi Hirano; Takashi Sasaki; Yukiko Abe; Masaru Mimura; Yasumichi Arai (GeroScience, 2026)

Frequency-specific photobiomodulation at theta and gamma enhances cognitive networks and mitigates age-related decline - Natalia Arias; Lucía Rodríguez-Fernández; Candela Zorzo; Verónica Peña León; Laura Mañas Cordero; Alba Gutiérrez-Menéndez; Juan A. Martínez; Jorge L. Arias (GeroScience, 2026)

Association between dietary patterns and CAIDE-predicted dementia risk: A 20-year cohort of the Korean Genome and Epidemiology study - Ji-Eun Youn; Seok-Jae Heo; Yae-Ji Lee; Tae-hwa Han; Yu-Jin Kwon; Ji-Won Lee (GeroScience, 2026)

Associations of psychosocial factors with cardiovascular health in aging: insights from the Inlife-Aging Project - Iván H. Martín-Costa; Laura Martínez-Sánchez; Verónica Mihaiescu-Ion; Sonia Ortega-Gómez; Javier S. Morales; José L. Andrey-Guerrero; María J. Pedrosa-Martínez; Eulalio Valmisa; José D. Santotoribio; David Jiménez-Pavón; Ana Carbonell-Baeza (GeroScience, 2026)
Life’s Essential 8 (LE8) provides a multidimensional framework to assess cardiovascular health (CVH) in aging populations. The objective of this study was to describe LE8 component scores and their variation by age, sex, and psychosocial factors in middle-aged and older adults from Cádiz, Spain. Cross-sectional data were analyzed from 495 adults aged 50–79 years (59.4% women; 34.7% ≥ 65 years). LE8 scores were calculated following American Heart Association guidelines. Group comparisons used t-tests, ANOVA, and chi-square tests to explore differences across demographic and psychosocial variables. Age- and sex-adjusted linear regressions were fitted for CVH, health behaviors (HB), and health factors (HF). Most participants showed moderate CVH, HB, and HF scores (76.6%; 53.1%; 62.2%). Diet quality had the lowest mean (40.8 ± 31.7), while physical activity and sleep health were the highest (88.3 ± 30.6 and 85.0 ± 22.2). Middle-aged adults presented higher CVH and HF scores (mean differences [MD]: 2.5 ± 0.3; 7.8 ± 1.5), whereas older adults scored better in HB (MD: 2.8 ± 1.4). Women exhibited higher CVH, HB, and HF scores than men (MD: 3.6 ± 0.3; 2.8 ± 0.4; 4.4 ± 0.4), with middle-aged women showing the most favorable CVH profile (73.0 ± 10.5) and older men the least favorable (66.4 ± 11.0). Higher self-rated health (β = 0.240; R2 = 0.096) and educational attainment (β = 0.235; R2 = 0.090) were the strongest correlates of CVH (both P < 0.001). LE8 scoring revealed an intermediate CVH profile, with disparities by age, sex, and psychosocial context. Middle-aged women showed the most favorable profiles, while self-rated health and educational attainment emerged as key psychosocial markers for CVH assessment. Graphical Abstract

Associations of gait speed, grip strength, depressive symptoms, and their combinations with fracture risk in older adults - Temam Beshir Raru; Julie A. Pasco; Mojtaba Lotfaliany; Shiva Ganjali; Robyn L. Woods; Anna Barker; Suzanne G. Orchard; Joanne Ryan; Alice J. Owen; Michael Berk; Mohammadreza Mohebbi (GeroScience, 2026)
Gait speed, grip strength, and depression are common and often coexist in older adults, and their interaction may provide a comprehensive understanding of fracture risk. This study examined the individual and combined associations of slow gait, weak grip, and depressive symptoms with the risk of fractures in older adults. Sixteen thousand three hundred fifty-seven Australian participants aged ≥ 70 years from the ASPirin in Reducing Events in the Elderly (ASPREE) trial were included. Sub-distribution hazard ratios (sHR) and 95% confidence intervals (CI) were estimated using a multivariable-adjusted Fine–Gray model, accounting for death as a competing risk. The sHR for any fractures was 17% higher among participants with slow gait and 23% higher among those with depressive symptoms, while weak grip was not significantly associated. The co-occurrence of slow gait and weak grip was associated with a 23% higher risk of any fracture (sHR = 1.23; 95% CI 1.04–1.46). Slow gait combined with depressive symptoms was associated with a 46% higher risk of any fracture and a 64% higher risk of MOF (sHR = 1.46; 95% CI 1.06–2.01; sHR = 1.64; 95% CI 1.03–2.61, respectively). Weak grip combined with depressive symptoms was associated with a 47% higher risk of any fracture and a 57% higher risk of MOF (sHR = 1.47; 95% CI 1.08–2.00; sHR = 1.57; 95% CI 1.01–2.47, respectively). These associations were stronger among males and those with diabetes. The combination of slow gait with either weak grip or depressive symptoms was more strongly associated with fracture risk than each factor individually. These findings underscore the importance of incorporating physical function and mental health assessments in clinical evaluations of older adults. Graphical Abstract

ZNRF2-mediated CD-M6PR degradation and lysosomal dysfunction aggravate cellular senescence and aging - Tingting Zhao; Weitong Xu; Fangfang Wang; Honghan Chen; Hui Gong; Yu Yang; Ning Huang; Ming Yang; Jian Zhang; Chuhui Gong; Xiaoli Huang; Ying Li; et al. (GeroScience, 2026)

Low genetic risk for coronary artery disease underlies multigenerational longevity and healthy aging - Pedro Sant’ Anna Barbosa Ferreira; Stella Trompet; Eline Slagboom; Joris Deelen; Marian Beekman; Niels van den Berg (GeroScience, 2026)
Aging is a major risk factor for chronic diseases. Unlike the general population, members of long-lived families maintain exceptional health as they age, with over 10 years delayed onset of their first chronic disease. We therefore hypothesize that one of the key features explaining healthy survival up to high ages (longevity) is the absence of chronic disease risk alleles. We investigated this hypothesis in the Leiden Longevity Study, a cohort with data from more than 420 long-lived families in three generations and the Leiden 85-plus study. To analyze our data, we constructed a set of polygenic scores (PGS) covering the top diseases causing most deaths in the Netherlands. We showed that having an increasing number of long-lived ancestors is additively associated with lower genetic risk for coronary artery disease (CAD). Using accelerated failure time modelling, we further showed that a lower PGS for CAD explains up to 20% of the delay in cardiovascular disease incidence in descendants of long-lived families. Finally, we constructed a novel cholesterol-metabolism-PGS, based on gene-annotation enrichment analysis, that predicted time to all-cause mortality in two independent 90 + study populations. Our findings demonstrate that the absence of chronic disease risk alleles is one key feature linked to longevity and that alleles linked to cholesterol metabolism are a key component in healthy aging trajectories. Graphical abstract

Autophagy revealed as a targetable vulnerability in senescent cells by cell painting phenotypic profiling: a mechanistic study of MCOPPB and related compounds - Matthew Lacey; Lucie Beresova; Alzbeta Srovnalova; Pavlo Polishchuk; Michal Sala; Zdenek Skrott; Marian Hajduch; Petr Dzubak; Jiri Bartek; Anna Siskova; Martin Loffelmann; Radim Nencka; et al. (GeroScience, 2026)
Senescent cells accumulate with age and contribute to tissue dysfunction and chronic inflammation. Senolytic agents that selectively eliminate senescent cells hold therapeutic promise; however, few mechanistic classes have been established. Using Cell Painting–based morphological profiling, we identified a distinct cluster of senolytic compounds comprised of both known and novel autophagy inhibitors, including AZ191, bafilomycin A1, chloroquine, daurisoline, dauricine, MCOPPB, and its derivative MS1108. These compounds selectively eliminated senescent cells by disrupting autophagic flux. Our findings reveal senescent cell dependence on autophagy as an essential survival mechanism, define the existence of a mechanistically distinct class of senolytics acting through autophagy inhibition, and demonstrate the predictive value of Cell Painting in aging-related drug discovery. Our results provide new insights into senescent cell vulnerability and expand the therapeutic landscape for aging-related pathologies by highlighting autophagy as a targetable dependency.

Long-term cerebrovascular effects of cyclophosphamide and vincristine: endothelial senescence, impaired DNA repair signaling, and blood–brain barrier dysfunction - Dorina Nagy; Kiana Vali Kordestan; Roland Patai; Rafal Gulej; Siva Sai Chandragiri; Raghavendra Y. Nagaraja; Santny Shanmugarama; Shoba Ekambaram; Evelyn Brunner; Rebeka Kristof; Mark Nagykaldi; Parikshat Sirpal; et al. (GeroScience, 2026)
Chemotherapy-related cognitive impairment is increasingly recognized as a long-term consequence of cancer treatment, yet the contribution of the cerebrovascular system remains poorly defined. In this study, we investigated the long-term effects of clinically relevant treatment regimens with cyclophosphamide (CP) and vincristine (VIN) on cerebrovascular cellular senescence, associated molecular signatures, and downstream functional outcomes, including disruption of blood–brain barrier (BBB) integrity in a mouse model. Our results showed that CP induces a persistent cerebrovascular endothelial phenotype characterized by increased cellular senescence, upregulation of mRNA expression of DNA damage checkpoint regulators, and concomitant downregulation of key DNA repair genes. BBB integrity was preserved after CP treatment for larger molecular tracers (40 kDa and 3 kDa) but exhibited increased permeability to small tracers (0.3 kDa), measured by in vivo two-photon microscopy, indicating a subtle yet persistent disruption of barrier function. In contrast, VIN elicited a markedly attenuated and heterogeneous transcriptional response and did not produce detectable BBB impairment, underscoring agent-specific cerebrovascular effects of chemotherapy. Collectively, these findings suggest that chemotherapy induces a persistent cerebrovascular injury phenotype with features resembling vascular aging and reduced vascular resilience, providing a potential mechanistic link between systemic cancer therapy and long-term adverse effects on brain health.

Inflammatory protein epigenetic scores (EpiScores) and cognitive function in the longitudinal Swedish adoption/twin study of aging (SATSA) - Kazuyuki Ishihara; Sara Hägg; Thaís Lopes De Oliveira (GeroScience, 2026)
Protein epigenetic scores (EpiScores) are DNA methylation (DNAm)-based proxies for circulating protein levels and may provide insights into inflammation-cognition relationships. Although some EpiScores have been linked to cognitive decline, it remains unclear whether these proxies show similar associations in other cohorts, and whether their effects vary across distinct cognitive domains. We aimed to evaluate the associations between inflammatory proteins EpiScores and cognitive functions including specific domains in the Swedish Adoption/Twin Study of Aging (SATSA) cohort. We analyzed 1332 repeated measurements from 520 SATSA participants across up to six testing waves (1992–2014). Inflammatory protein EpiScores ( N = 27) were generated using previously published CpG site-specific weights. Outcomes were a global cognitive function (GCF) score and four specific cognitive domains (verbal ability, spatial ability, memory, and perceptual speed). We applied marginal linear models within the generalized estimating equations (GEE) framework to estimate population-averaged longitudinal associations, controlling the false discovery rate (FDR) using the Benjamini–Hochberg (BH) procedure ( q < 0.05 considered significant). Two EpiScores—C-X-C motif chemokine ligand 9 (CXCL9) and vascular cell adhesion molecule 1 (VCAM1)—showed significant positive associations with GCF. In domain-specific outcomes, VCAM1 demonstrated a positive association with spatial ability, whereas C-X-C motif chemokine ligand 11 (CXCL11) had a negative association with verbal ability. These associations were broadly consistent across multiple sensitivity analyses. Inflammation-related DNAm signatures of certain proteins were associated with cognitive performance in SATSA samples. Moreover, the associations differ by cognitive domain. Future longitudinal studies are warranted to clarify the causal implications of these EpiScore-cognition associations and to explore population differences in DNAm patterns.

Correction to: Searching for shared epigenetic clocks: evaluating ultra‑conserved markers in a de novo genome assembly of the albacore tuna - Thomas Chevrier; Sylvain Bonhommeau; Michael Thompson; Jessica Farley; Giorgia Del Vecchio; Anne‑Elise Nieblas; Dominique A. Cowart; Jérémie Chanut; Julie Imbert Nguyễn; Serge Bernard; Yann Guiguen; Cedric Cabau; et al. (GeroScience, 2026)

Age-related changes in performance in memory athletes - Riya Pradhan; Brian M. Mills; Hirofumi Tanaka (GeroScience, 2026)
Memory athletes demonstrate remarkable cognitive performance. However, limited research has examined how memory performance changes with advancing age in these athletes. The present study investigated age-associated changes in memory performance in athletes competing in memory championship events. We evaluated performance trends in five-min number, fifteen-min number, five-min word, and ten-min card events, in which participants memorize and recall random digits, words, or cards within a specified time. Participants were categorized into four age groups: junior (≤ 17 years), young (18–39), middle-age (40–59), and senior (≥ 60). The top 30 performers in each category were included in the analysis. Polynomial and non-parametric regressions revealed an inverted U-shaped association between age and performance. Performance increased from junior to young categories, peaking at 28–29 years and then gradually declined. Performance declined by 16–22% at age 40, 46–56% at age 50, and 74–76% at age 60 compared with peak values. Violin plots indicated that middle-aged adults exhibited consistent performance, whereas seniors showed wider variability. In conclusion, memory performance improves from junior to young, peaking around the late 20 s, and declines gradually and markedly with advancing age, even among individuals with highly trained memory systems. Graphical Abstract

A telomere–lipid–immunity axis linking viral integration to autoimmune disease risk - May A. Beydoun; Minkyo Song; Choa Yun; Hind A. Beydoun; Nigus G. Asefa; Jordan Weiss; Nicole Noren Hooten; Michele K. Evans; Alan B. Zonderman (GeroScience, 2026)

Unequal healthy ageing trajectories across Europe: socioeconomic development and age-related disease burden in the European Union and South-Eastern European countries - Nora Kovacs; Peter Piko; David Major; Vince Fazekas-Pongor; Zoltan Ungvari; Roza Adany (GeroScience, 2026)
Although life expectancy has increased, many of the added years are lived in poor health, highlighting growing inequalities in ageing trajectories. Despite the increasing need for ageing-related health strategies, non-EU European countries remain underrepresented in comparative research, leaving limited evidence on healthy ageing disparities between EU and South-Eastern European (SEE) nations. This study explored variations in key health and socioeconomic indicators of societal ageing and age-related disease burden among individuals aged 70 and older across European countries, with a focus on EU and non-EU SEE nations. Data for 33 European countries were extracted from Global Burden of Disease 2021 study. Indicators included mortality, years lived with disability (YLD), healthy life expectancy (HALE), current health expenditure (HE), and Human Development Index (HDI). Hierarchical cluster analysis was used to classify EU countries, and SEE countries were analysed separately. Trends in mortality, YLD rates, and HALE were analysed using Joinpoint regression. Spearman’s rank correlation was used to assess relationships between health, socioeconomic factors, and disease burden. Western and Northern European countries showed the most favourable values for indicators, while SEE countries exhibited the highest all-cause and cardiovascular mortality and the lowest HALE and HDI values. Across all countries, strong negative correlations were observed between HE, HDI, HALE, and total mortality (r = -0.81, -0.82, and -0.92, p < 0.001; respectively). Regionally adjusted and coordinated policies are needed to reduce inequalities and promote healthy ageing across Europe. Such strategic integration is essential to narrowing the gaps in ageing trajectories and socioeconomic development between EU and SEE countries.

Greater recalled pain and movement-evoked pain are associated with longer 400-m walk and repeat stair climb timein older adults: the study of muscle, mobility, and aging - Theresa Mau; Corey B. Simon; Haley N. Barnes; Megan Hetherington-Rauth; Scott R. Bauer; Elsa S. Strotmeyer; Nancy E. Lane; Michael C. Rowbotham; Ashley A. Weaver; Terri L. Blackwell; Yurun Cai; Nancy W. Glynn; et al. (GeroScience, 2026)

The association between height-indexed skeletal muscle mass and cardiometabolic multimorbidity is largely accounted for by body mass index: findings from an older UK cohort - Setor K. Kunutsor; Ashish H. Shah; Sae Young Jae; Jari A. Laukkanen (GeroScience, 2026)

Twenty-four-hour blood pressure and CSF biomarkers of Alzheimer’s disease and related dementias in a community cohort - Madeline Gibson; William T. O’Brien; Ella Rowsthorn; Katherine H. Franks; Lachlan Cribb; Marina Cavuoto; Beaudan Campbell-Brown; Ian Harding; Meng Law; Trevor T.-J. Chong; Stuart J. McDonald; Terence J. O’Brien; et al. (GeroScience, 2026)
Hypertension in midlife is associated with increased dementia risk, yet its relationship with early pathological changes of Alzheimer’s disease and related dementias (ADRD) remains unclear. Unlike office blood pressure (BP), 24-h ambulatory BP (ABPM) may better reflect cardiovascular risk, but associations between 24-h BP measures with ADRD biomarkers are unknown. This cross-sectional study examined associations between BP and cerebrospinal fluid biomarkers of ADRD in mid-to-late life. Dementia-free participants ( n = 77; mean age = 67 [SD, 6]; 39% women) from the community-based Brain and Cognitive Health (BACH) cohort underwent office and 24-h ABPM assessments to calculate mean BP, nocturnal dipping, blood pressure variability (BPV, coefficient of variation) across 24-h, awake and asleep periods. Participants also completed a lumbar puncture to assess ADRD biomarkers: Aβ42/Aβ40 ratio, phosphorylated tau at threonine 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Linear regression models examined associations between BP and ADRD biomarkers, adjusting for age, sex, BMI, smoking, anti-hypertensive medication use, and APOE ε4 status. Higher 24-h and awake mean BP were associated with higher GFAP (24-h: per 1-SD unit increase, β = 1606.6 pg/mL, p = .03; awake: β = 1668.pg/mL, p = .03) and NfL (24-h: β = 172.3 pg/mL, p = .03; awake: β = 162.3 pg/mL, p = .04) levels. Elevated asleep BPV was associated with higher Aβ42/Aβ40 ratio ( β = 0.01, p = .01). No, other clear associations were identified for the other BP metrics ( p > .05 for all). Findings indicate that elevated BP is associated with neuronal injury and astrocytic reactivity, suggesting possible pathways through which BP may relate to neurodegenerative processes, independent of overt amyloid or tau.

Correction to: Dementia risk across distinct metabolic profiles in the UK Biobank - Amanda L. Lumsden; Anwar Mulugeta; Elina Hyppönen (GeroScience, 2026)

Immune activation from M. tuberculosis screening tests predicts mortality - Benjamin Seligman; David A. Ganz; Matthew Bidwell Goetz; David O. Beenhouwer (GeroScience, 2026)
Impaired immune responses are a key feature of aging; however, there are few laboratory tests that link these responses to clinical outcomes. Interferon-gamma release assays (IGRAs) for tuberculosis screening quantify release of interferon-gamma by T-cells, and the difference between unstimulated and mitogen-stimulated T-cells is assessed for test validity. We assess this measure’s relationship with all-cause mortality. We obtained the most recent negative and indeterminate outpatient IGRAs from a large health system along with demographics, frailty, lymphocyte count, and inflammatory markers. We removed individuals on hemodialysis or immunosuppressive medications. We assessed the association of mitogen-nil with mortality at 6 months, 1 year, and 5 years by Kaplan-Meier analysis and Cox regression. Among 16,104 individuals, reported mitogen-nil ranged from < 0.01 to ≥ 10 IU/mL, and median (IQR) age was 64 (57, 72). Cumulative mortality (95% CI) at 5 years was estimated at 28% (23%–33%) for values 0–1 versus 19% (18%–19%) ≥ 10. In Cox regression, relative to values ≥ 10, values from 0–1 had hazard ratios for mortality at 6 months, 1 year, and 5 years of 2.77 (1.47–5.22), 2.22 (1.41–3.50), and 1.76 (1.31–2.36). Among those with data, adding lymphocyte count did not alter associations. Lower T-cell response to mitogen stimulation in IGRAs is associated with greater mortality. This common test may provide additional information to risk-stratify patients and as a phenotype of impaired immune response.

Correction to: Socio‑economic position and healthy ageing across the life course: a systematic review of longitudinal studies - Yisheng Ye; Chengxu Long; Kia‑Chong Chua; Darío Moreno‑Agostino; Matthew Prina (GeroScience, 2026)

Class I histone deacetylases and their inhibitors as targets to modulate cellular senescence in osteoarthritis - Kavya Gupta; Hannah Swahn; Martin K. Lotz (GeroScience, 2026)
Cellular senescence plays a significant role in age-related conditions like osteoarthritis (OA) and intervertebral disc degeneration, in part due to the accumulation of senescent cells (SCs) in musculoskeletal tissues. Identifying novel therapeutics that can clear SCs is crucial for improving musculoskeletal health in the elderly. The present study aimed to elucidate the changes in Class I histone deacetylases (HDACs) and their role during senescence. All Class I HDACs except HDAC1 were downregulated during senescence in the human TC28a2 immortalized human chondrocyte cell line. Knockdown experiments showed that HDAC1 is essential for maintaining the viability of both non-senescent cells (NSCs) and SCs, while HDAC2 plays a key role in modulating inflammation in part by targeting the NF-κB signaling pathway. Mocetinostat, an HDAC inhibitor, selectively kills senescent TC28a2 cells and primary human knee chondrocytes via apoptosis while not affecting the viability of NSCs. Mocetinostat also affected both inflammation-associated and chondrogenesis-associated genes. Overall, our findings demonstrate a key role of Class I HDACs in regulating chondrocyte survival and ECM gene expression. Mocetinostat holds promise as a senolytic therapeutic for OA and potentially other aging-related musculoskeletal disorders.

Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice - Abigail R. Williamson; Angad Yadav; Wenxia Ma; Susan Schmitt; Shelby Rorrer; Lauren E. Odom; Luisa F. Castillo; Chloe T. Purello; Olga V. Malysheva; James Mobley; Martha Field; Anna E. Thalacker-Mercer (GeroScience, 2026)
Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced age, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

Cross-species characterisation of microglial morphology and proliferation during ageing - Laura M. Carr; Angus McNamara; Shannon M. Stuckey; Isabella M. Bilecki; Sanam Mustafa; Renée J. Turner; Lyndsey E. Collins-Praino (GeroScience, 2026)
By 2050, one-fifth of the world is expected to be over 60, and the prevalence of age-related neurological conditions is predicted to increase dramatically. Aged animals are currently underutilised in neurological research, leading to a gap in knowledge about the contribution of biological age to the pathophysiology of age-related neurological conditions. Additionally, it is unclear whether age-related changes differ across species used in preclinical models, and how these differences may compare to the aged human brain. Understanding these points is critical for successful translation of findings from preclinical studies to the human context. The current study presents a cross-species characterisation of microglia, the key regulator of the brain’s immune response, during ageing. Microglial number, proliferation and morphology were assessed in archival tissue from Sprague Dawley rats (males; 3 to 18 months old) and Merino sheep (males and females; 1 to 6 years old), with these two species selected for their relevance to preclinical modelling of neurological disease. Increased numbers of proliferating microglia were observed in the cortex, hippocampus and portions of the striatum in both species. This proliferation declined at the oldest timepoint assessed (i.e. 18 months old) in rats, a pattern not seen in the sheep. Total microglial number was largely unchanged with age in the rat brain; however, in sheep, the number of microglia decreased significantly in the dentate gyrus in older animals. Notably, microglia in 18-month-old rats were larger in all regions, but changes in branching were observed exclusively the striatum. Similarly, in sheep, morphological changes were localised to the striatum, with increased cell and soma size in the caudate nucleus, and increased cell size and process length in the putamen. These changes suggest a shift away from homeostasis in the cortex and hippocampus and towards a semi-ramified morphology in the striatum in late middle adulthood that is largely conserved across these two species. Nevertheless, the age of the oldest animals here equates to only ~ 60 years old in humans, rather than reflecting an aged human population. Thus, future work is needed to understand how species-specific differences continue to evolve in older age.

ChREBP-mediated regulation of lipid metabolism in liver and brown adipose tissue of long-lived mice - Mary Hager; Christopher Adam; Leanne Mercier; Alexander Voorhees; Michael Lee; Lucas Ball; Jackson Yang; Andrzej Bartke; Richard A. Miller; Xinna Li (GeroScience, 2026)
De novo lipogenesis (DNL) is a metabolic process by which carbohydrates are converted into fatty acids and used for immediate energy or stored as triglycerides for later use. Increased DNL in brown adipose tissue (BAT) is believed to be a marker of metabolic health, but indicates poor metabolism if upregulated in hepatic tissue. ChREBP is a primary regulator of whole-body DNL and promotes production of key enzymes including fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. ChREBP is highly expressed in primary sites of lipogenesis such as the liver, intestines, and adipose tissue. In the liver, ChREBP is associated with aging-related symptoms such as increased insulin resistance and gluconeogenesis. In BAT, ChREBP plays an important role as a regulator of uncoupling protein 1 (UCP1) and DNL. Previous research has linked increased metabolic activity in BAT to increased longevity, but the effects of ChREBP-regulated DNL on aging have not been studied yet. To elucidate this relationship, we analyzed the expression of key enzymes and regulators associated with DNL in the liver and BAT of long-lived mutant mice (Ames, Snell, GHR-KO, Pappa-KO, and PTENOE). We observed a decrease in lipogenic enzymes (FASN and ACC1) and their regulator, ChREBP in the liver of the slow-aging mouse models and a contrasting increase in these same markers in BAT. Tissue-specific modulation of DNL is a shared trait among at least these five varieties of slow-aging mice, and may contribute to the extended longevity of these strains.

Key factors of the deranged antiviral response in elderly patients with COVID-19: a machine-learning analysis - Tamara Postigo-Casado; Alicia Ortega; Alejandro Álvaro-Meca; Daniel Vélez-Serrano; Nadia García-Mateo; Ana P. Tedim; Raquel Almansa; Jose María Eiros; David de Gonzalo-Calvo; Anna Moncusí-Moix; Clara Gort-Paniello; Manel Perez-Pons; et al. (GeroScience, 2026)
Age is a well-known risk factor to develop severe viral respiratory infections, including severe COVID-19. This study aimed to identify the biological alterations linked to severe disease in elderly patients with COVID-19. For this purpose, we employed a derivation cohort with 450 SARS-CoV-2 infected and unvaccinated patients admitted to hospital wards and a validation cohort with 244 SARS-CoV-2 infected and unvaccinated patients admitted to hospital Intensive Care Unit (ICU). Twenty-one biomarkers were measured in plasma samples from patients upon admission, including SARS-CoV-2 RNA, IgG antibodies, and protein biomarkers. Patient cohorts were divided into two groups based on age: adult (≤ 70 years old) and elderly (> 70 years old) patients. In the derivation cohort, 90-day mortality rate observed in the adult group was 6.0% whereas in the elderly group it rises to 31.6%, same trend was noticed regarding the validation cohort, with 11.2% versus 40.3% 90-day mortality rates for adult and elderly groups, respectively. The machine-learning framework XGBoost-SHAP, fed with the plasma biomarkers information, was used to profile an age-related host response to SARS-CoV-2 infection. Based on SHAP plot, elderly patients had a strong thrombo-inflammatory response profile (significantly elevated plasma levels of: lipocalin-2, endothelin-1, D-dimer) combined with deficient adaptive and cytotoxic antiviral responses. Model performance evaluated with the validation cohort confirmed the robustness and generalizability of the model developed (AUC = 0.710). In conclusion, the machine learning approach we built allowed us to identify the presence of a deranged host response in elderly patients with COVID-19 linked to poor viral control and increased mortality. Graphical Abstract

Prediction of cognitive test scores: a comparison of brain structure, health, demographic, and cognitive data across adulthood - Camilla Mendl-Heinisch; Nora Bittner; Tatiana Miller; Paulo Dellani; Fabian Bamberg; Klaus Berger; Patricia Bohmann; Josua A. Decker; Agnes Flöel; Karin Halina Greiser; Manuela Harries; Jan Kapar; et al. (GeroScience, 2026)
Cognitive performance prediction may help identify early cognitive decline. However, the heterogeneity of research findings impedes the identification of key predictors. This study used 21,877 participants (25–74 years) from the German National Cohort (NAKO Gesundheitsstudie, NAKO) to systematically predict cognitive test scores based on brain structure, demographic, health-related, and cognitive data. Importantly, validation analyses were performed across study sites and external samples (1000BRAINS). Higher predictability was observed in the total sample compared to age-specific subgroups (10% difference in explained variance). Demographic (e.g. age) and cognitive data (e.g. memory) outperformed brain structure (e.g. grey matter volume) and health-related data (e.g. hypertension). Cognitive tests were differentially predictable, most evident between episodic memory and motor speed (R 2 ≤ 0.32 versus R 2 ≤ 0.18). Differences in predictability between age groups finally highlight the importance of comparing prediction outcomes between adult lifespan and age-specific groups to elucidate general and age-sensitive predictors of cognitive test scores.

Decline in cardiorespiratory fitness and its association with vascular aging and subclinical atherosclerosis in healthy older adults: a 3-year longitudinal study - Vincent Groesser; Christopher Weyh; Torsten Frech; Natascha Sommer; Klaus Eder; Astrid Most; Samuel Sossalla; Karsten Krüger; Pascal Bauer (GeroScience, 2026)
Aging is associated with progressive deterioration of vascular function and cardiovascular risk. Cardiorespiratory fitness (CRF) is closely associated with cardiovascular health, yet longitudinal data in healthy older adults remain limited. This study examined 3-year changes in vascular and echocardiographic parameters in older adults and their associations with CRF and muscle strength. Forty-nine participants (mean age 63.8 ± 3.8 years) underwent vascular assessments (brachial/central blood pressure (BP), pulse wave velocity (PWV), augmentation index), echocardiography, CRF testing via spiroergometry to determine VO 2 peak, muscle strength testing, and carotid sonography at baseline and after 3 years. Participants were grouped by carotid plaque status: no atherosclerosis, existing atherosclerosis, or newly developed atherosclerosis. Over 3 years, CRF and muscle strength (grip strength, leg flexion) declined significantly (all p < 0.005), while systolic BP ( p = 0.042), brachial-ankle PWV ( p = 0.006), and echocardiographic parameters including aortic root diameter and ventricular dimensions increased (all p < 0.001). Participants with newly developed atherosclerosis showed the greatest CRF decline ( p = 0.012). Changes in CRF were inversely associated with changes in systolic, diastolic, and central BP (all p < 0.01). Declines in leg flexion strength were also linked to larger BP increases. Participants maintaining > 90% of baseline VO 2 peak had significantly smaller BP increases. These results indicate that vascular aging progresses measurably within a few years in clinically healthy older adults and is associated with declines in CRF and muscle strength. Preservation of CRF is linked to more favorable vascular aging profiles and a lower prevalence of newly developed atherosclerosis. Graphical Abstract

Brain, benefit, or burden? Revisiting statins and cognitive function in older adults - Yiwen Liu; Setor K. Kunutsor (GeroScience, 2026)

Do subjective cognitive complaints and slow gait speed increase the probability of progression to objective cognitive impairment? A systematic review and meta-analysis on motoric cognitive risk syndrome - Fátima Fernández-Feijoo; Lucía Pérez-Blanco; Scott B. Patten; Ana Nieto-Vieites; Cristina Lojo-Seoane; David Facal; Arturo X. Pereiro-Rozas (GeroScience, 2026)
Motoric cognitive risk (MCR) syndrome, characterized by the coexistence of subjective cognitive complaints (SCCs) and slow gait speed, has been identified as a potential risk factor for objective cognitive impairment and dementia. This research article performs a systematic review and meta-analysis to analyze cross-sectional and longitudinal associations between MCR syndrome and objective cognitive impairment. Cross-sectional and longitudinal studies in cognitively unimpaired adults with SCCs were included. The risk associated with progression to mild cognitive impairment (MCI) or dementia was estimated, also for longitudinal studies specifically. An additional meta-analysis was conducted to explore the association with SCCs and gait speed independently. Random-effects meta-analyses were conducted to estimate pooled effects with 95% confidence intervals and assess heterogeneity. Egger’s test and Trim and Fill procedure were used to detect publication bias. The findings show a significant association between MCR syndrome in preclinical stages and objective cognitive impairment. Longitudinally, the risk of progression to MCI or dementia increased from 1.99 (95% CI, 1.61 to 2.45, p < .001) to 2.49 (95% CI, 1.85 to 3.34, p < .001). Additional meta-analyses conducted to separately analyze the effect of MCR components did not reveal any significant associations. Individuals with MCR showed an almost twofold higher risk of cognitive impairment compared with non-MCR participants, and this risk increases when based solely on longitudinal predictions. Individually, components of the MCR syndrome showed no significant associations. Our results supported that MCR syndrome at preclinical stages was associated with objective cognitive decline.

Higher plasma serine levels are associated with favorable values of metabolic health markers among middle-aged and older adults in The Maastricht Study - Thomas Olsen; Amany Elshorbagy; Elena C. Tore; Nasser E. Bastani; Emma Stolt; Gabriëlla A. M. Blokland; Coen D. A. Stehouwer; M. Eline Kooi; Jacobus F. A. Jansen; Simone J. P. M. Eussen; Pol Grootswagers; Helga Refsum; et al. (GeroScience, 2026)

Map-based spatial perspective taking reveals frontal late negativity loss and posterior delta gain in mild cognitive impairment - Tsu-Jen Ding; Hui-Yu Hsu; Jui-Cheng Chen; Chen-Yu Yao; Zai-Fu Yao; Tzuhui Angie Tseng (GeroScience, 2026)

Interactions between rare variants in DNA repair genes and cardiometabolic risk explain more variability in cognitive function - Nicolas Cherbuin; Leticia Camargo Tavares; Mark A. Fraser; Yuan Li; Claudia Navarro; Erin I. Walsh; Shea J. Andrews; Richard A. Burns; Anne Brüstle; Lene Juel Rasmussen (GeroScience, 2026)

A systematic review of the association between phase angle and cognitive function among older adults - Lizhen Wang; Mu-Hsing Ho; Maya Minamizaki; Yuka Kanoya; Derong Zeng (GeroScience, 2026)

Interpretable deep learning reveals spatiotemporal MRI features of brain aging that align with neurodegeneration - Nikhil N. Chaudhari; Owen M. Vega; Phoebe Imms; Jaron M. Kawamura; Nahian F. Chowdhury; Tamara Jafar; Andrei Irimia; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; et al. (GeroScience, 2026)
Cortical thinning and atrophy are hallmarks of brain aging that have been characterized using magnetic resonance imaging (MRI). Brain aging involves many neuroanatomic features whose effects on brain structure remain unexplored. To address this challenge, we trained interpretable deep neural networks (DNNs) to estimate brain age (BA) from T 1 -weighted ( T 1 w) MRI. By identifying MRI features unapparent to humans, DNNs can find aging-related structural alterations above and beyond cortical thickness and atrophy. Using a novel approach to DNN interpretability, we mapped brain aging progression in 25,539 cognitively normal UK Biobank adults aged 45–83 years. Cortical aging is found to involve anatomic features becoming prominent during the 50s within frontolateral, mesolimbic, cuneal, and occipitotemporal regions. From these foci, aging-related features propagate to adjacent areas at rates peaking in the 60s. Cortical thinning and atrophy do not trend closely with neurodegeneration, but important DNN-identifiable anatomic features have spatiotemporal dynamics that match those of amyloid or tau. Our results challenge the assumption that MRI cannot map anatomic features trending with neurodegeneration. Interpretable DNNs can empower MRI to quantify anatomic aging as a process of spatial feature expansion from focal regions into nearby structures in the sequence of neurodegenerative pathology. Traditional morphometrics explain only ∼1% of variance in DNN-identifiable features, which clarifies why the former are insensitive to anatomic changes involving neurodegeneration. Our results conceptualize brain aging in the context of spatial and temporal parallels between anatomic senescence and neuropathology. These findings may help to map cognitively normal adults’ neurodegenerative anatomy even without PET measurements. Graphical Abstract

Wobble-board dynamics as a scalable assay of long-latency reflex function in aging - Theodoros Deligiannis; Mahsa Barfi; Jessica Fabianiak; Brian Schlattmann; Ken Kiyono; Damian G. Kelty-Stephen; Madhur Mangalam (GeroScience, 2026)
Understanding how aging reshapes balance is essential for targeted assessment and rehabilitation. Because wobble boards impose continuous instability, their kinematics may provide a noninvasive readout of long-latency (transcortical) reflex function in ecologically valid conditions. We analyzed wobble-board dynamics in healthy younger adults ( $$19\text {--}35$$ 19 -- 35 y, $$n\!=\!29$$ n = 29 ) and community-dwelling older adults ( $$56\text {--}70$$ 56 -- 70 y, $$n\!=\!29$$ n = 29 ) performing with and without a concurrent cognitive load (Trail Making Task). Spatial behavior was indexed by peak angular excursion magnitudes and their RMS; temporal behavior by cycle durations. For each series, we estimated Hurst exponents ( $$H$$ H ) using detrended moving-average analysis. Across ages and task conditions, cycle-duration series clustered near $$H_{\mathrm {cycle\;duration}}\!≈ \!0.5$$ H cycle duration ≈ 0.5 , indicating emergent timing, and peak-angular-excursion series exhibited persistence ( $$H_{\mathrm {peak\;angular\;excursion}}\!≈ \!0.7$$ H peak angular excursion ≈ 0.7 ). Age did not affect $$H$$ H for either measure, nor the number of cycles per trial. By contrast, older adults showed substantially larger peak angular excursions and higher root mean square (RMS) peak angular excursions than younger adults. Multivariate analyses (principal components and canonical correlations) revealed that wobble-board metrics capture variance not explained by center-of-pressure and center-of-mass measures, yielding distinct signatures differentiating individuals, conditions, and—via amplitude metrics—age groups. These results indicate that wobble-board dynamics in aging primarily differ in amplitude rather than in temporal organization or cadence of corrections. This pattern suggests that the timing of corrective responses remains intact with aging, while their effectiveness is reduced. These findings support wobble-board dynamics as a promising paradigm for assessing age-related changes in balance control. Direct validation using electromyography (EMG) and controlled perturbations is warranted to confirm that wobble-board metrics reflect long-latency reflex function.

Infratentorial cerebral microbleeds and brain age gap in stroke patients: a cross-sectional neuroimaging study - Raghav Pallapothu; Santosh Kudaravalli; Roger D. Newman-Norlund; Sriya Pallapothu; Pranesh Rajesh Kannan; Sai Kanha Kummari; John Absher; Chris Rorden (GeroScience, 2026)
Stroke survivors often face long-term cognitive and motor deficits. Brain age gap (BAG), the difference between chronological age and age estimated based on MRI data, has emerged as a biomarker for neurodegeneration. While prior work links BAG to stroke outcomes, the relationship between BAG and cerebral microbleeds (CMBs), particularly infratentorial CMBs common in hypertensive arteriopathy, remains unclear. The sensorimotor network (SMN) is highly susceptible to both direct and remote injury after stroke and is structurally and functionally interconnected with infratentorial regions via pathways such as the corticospinal tract. Vascular disruption in the cerebellum or brainstem may therefore have downstream effects on supratentorial SMN regions, making this network a biologically relevant target for investigating BAG–CMB relationships. We analyzed data from 1725 stroke patients in the Stroke Outcomes Optimization Projects. Two trained raters manually counted infratentorial CMBs on susceptibility-weighted MRI images (SWI), while BAG was computed using the automated volBrain BrainStructureAges pipeline on T1-weighted images. Spearman correlations tested associations between CMB count and regional BAG in 14 a priori brain regions of interest (ROI) and results were conditioned for age, sex, race, white matter hyperintensities, hypertension, type of scanner, and total ischemic lesion volume. Infratentorial CMB count was positively correlated with BAG in 9/14 sensorimotor regions: right precentral gyrus medial segment ( r (213) = 0.186, p = 0.007), left precentral gyrus medial segment ( r (213) = 0.186, p = 0.007), right postcentral gyrus medial segment ( r (213) = 0.202, p = 0.004), right postcentral gyrus ( r (213) = 0.202, p = 0.004), left postcentral gyrus ( r (213) = 0.161, p = 0.021), right parietal operculum (r (213) = 0.198, p = 0.004), right central operculum ( r (213) = 0.195, p = 0.005), right precentral gyrus ( r (213) = 0.184, p = 0.008), and left postcentral gyrus medial segment ( r (213) = 0.192, p = 0.006). Our findings suggest that infratentorial microvascular injury is associated with accelerated aging in functionally connected motor cortices. This supports a network-level model of stroke-related brain aging, with implications for predicting sensorimotor outcomes. BAG may serve as a sensitive marker for cerebrovascular injury and guide targeted rehabilitation efforts.

Overweight and obesity increase breast cancer risk in postmenopausal women: a meta-analysis of 38 observational studies - Piercarlo Del Console; Stefania Catalano; Balázs Győrffy (GeroScience, 2026)
Obesity is a recognized host-related factor associated with increased breast cancer (BC) risk—the most common malignancy and leading cause of cancer-related death among women. Menopausal status plays a critical role in this association due to hormonal and metabolic differences that may influence the impact of excess weight on carcinogenesis. This meta-analysis investigates the relationship between overweight, obesity, and BC risk, stratified by menopausal status. A systematic search of PubMed, Web of Science, and Cochrane Central Register of Controlled Trials databases (1987–2025) was conducted to identify observational studies examining the association between overweight, obesity, and BC risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were extracted and pooled using a random-effects model. Subgroup analyses were performed for premenopausal and postmenopausal women. Publication bias was assessed through funnel plots and Egger’s test. Thirty-eight independent studies were included, totaling 115,870 women. In postmenopausal women, both overweight (OR = 1.31; 95% CI 1.13–1.53) and obesity (OR = 1.43; 95% CI 1.25–1.63) were significantly associated with increased BC risk. Among premenopausal women, the associations were weaker and not statistically significant for either overweight (OR = 1.04; 95% CI 0.83–1.3) or obesity (OR = 1.11; 95% CI 0.89–1.38). Funnel plots showed no publication bias. Overweight and obesity significantly increase BC risk in postmenopausal women, but not in premenopausal women. These findings highlight the role of menopausal status and support the need for weight management strategies, particularly in postmenopausal women, to reduce obesity-related breast cancer risk.

Biological age acceleration, longitudinal change and mortality risk in the Dutch Lifelines cohort - Shanshan Zuo; Juan Carlos Rivillas; Tim van Zutphen; Judith M. Vonk (GeroScience, 2026)
Accelerated biological aging has been associated with mortality, but it remains unclear whether longitudinal changes in age acceleration predict long-term mortality risk. In the population-based Dutch Lifelines cohort, we estimated biological age using the Klemera–Doubal method (KDM-BA) and derived KDM-BA acceleration at baseline and follow-up. We examined baseline acceleration (continuous and categorical: < − 1, − 1 to 1 [reference], > 1 year), annual change in acceleration and four aging trajectory groups. Associations with all-cause mortality were assessed using Cox models adjusted for age, sex, socioeconomic status and lifestyle factors. Among 90,632 participants (3,976 deaths; median follow-up 13.8 years), higher baseline KDM-BA acceleration was associated with higher mortality (HR per 1-year increase = 1.07; 95% CI: 1.06–1.08); acceleration > 1 year predicted higher mortality risk (HR = 1.31; 95% CI: 1.21–1.42) compared with − 1 to 1 years. Among 25,752 participants with repeated assessments (879 deaths; median baseline-to-follow-up 4.3 years), a greater annual increase in acceleration was associated with higher mortality (HR per 1-year/year increase = 1.21; 95% CI: 1.07–1.37), and persistent accelerated aging showed the highest risk (HR = 1.39; 95% CI: 1.19–1.62) compared with stable non-accelerated aging. Higher baseline KDM-BA acceleration and worsening acceleration over time were associated with higher long-term all-cause mortality, supporting repeated clinical assessment to monitor biological aging in population settings. Graphical Abstract

Aging effects on nigrostriatal structure, hemodynamics, and connectivity: implications for Parkinson’s disease - Jiaqi Wen; Chenyang Li; Huize Pang; Li Jiang; Toby Nguyen; Xiaojun Guan; Xiaojun Xu; Yulin Ge (GeroScience, 2026)

Bidirectional associations between biological aging, cardiovascular health, and cardiovascular risk: findings from the INSPIRE-T lifespan cohort - Mathilde Strumia; Vanina Bongard; Samuel Thuriot; Philippe Cestac; Brigitte Sallerin; Jean-Marc Lemaitre; David Furman; Sophie Guyonnet; Bruno Vellas; Sandrine Andrieu; Laure Rouch; Sophie Guyonnet; et al. (GeroScience, 2026)
Chronological age is a common and non-modifiable factor for chronic disease, but does not fully explain age-related changes. Biological clocks have been developed to explore biological aging mechanisms. They could help identify protective factors against accelerated aging and associated diseases. We aim to assess the association between reduced epigenetic or inflammatory aging and ideal cardiovascular health or cardiovascular risk. We conducted a cross-sectional analysis of participants from the INSPIRE-T cohort. Cardiovascular health (CVH) was assessed using the Life’s Essential 8 score. Cardiovascular risk was assessed using the American Framingham risk score (FRS) and the European Systematic Coronary Risk Evaluation (SCORE2) score. Epigenetic and inflammatory aging was calculated from the residuals from linear regression of biological age (based on five epigenetic clocks and one inflammatory clock) and chronological age. Linear and logistic regression models were used. Better CVH has been associated with slower epigenetic aging, particularly in younger subjects and men. Accelerated epigenetic aging measured by GrimAge was associated with an increase cardiovascular risk (for SCORE2: OR = 1.10 95%CI [1.04; 1.16]). No persistent association was found with the inflammatory clock. Our study reported an association between ideal global CVH with reduced epigenetic aging after adjustment for chronological age and gender. This suggests that epigenetic aging may be modifiable through healthy lifestyle and cardiovascular risk management, although a potential underlying causal relationship remains to be established. Moreover, accelerated epigenetic aging is linked to worsening cardiovascular risk, and could be a new risk factor alongside chronological age. Graphical Abstract

The aging epigenome: integrative analyses reveal intersection with Alzheimer’s disease - Wei Zhang; David Lukacsovich; Juan I. Young; Lissette Gomez; Michael A. Schmidt; Brian W. Kunkle; Xi Chen; Eden R. Martin; Lily Wang (GeroScience, 2026)
Aging is the strongest risk factor for Alzheimer’s disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. We performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We adjusted for sex and immune cell-type proportions and corrected batch effects and genomic inflation. Integrative analyses included pathway enrichment, mQTL analysis, colocalization with Alzheimer’s disease and related dementia (ADRD) GWAS summary statistics, brain-blood DNAm correlations, and comparison to independent AD methylation studies. We identified 3758 CpGs and 556 differentially methylated regions (DMRs) consistently associated with chronological age in both cohorts at a 5% false discovery rate. Our pathway enrichment analyses highlighted metabolic regulation and synaptic signaling, processes previously implicated in Alzheimer’s disease. Colocalization with ADRD GWAS summary statistics identified 32 genomic regions consistent with shared genetic signals for DNAm and ADRD risk. Roughly one-third of aging-associated CpGs overlapped CpGs associated with AD or AD neuropathology in external studies. Finally, we prioritized nine promoter CpGs (including those located in PDE1B , ELOVL2 , and PODXL2 ) showing strong positive blood-to-brain methylation concordance and external AD associations, nominating them as candidate blood-based biomarkers. Our study demonstrated that late-life aging signatures in blood DNAm converge on processes implicated in AD and intersect with dementia genetics. A small set of CpGs with blood-brain concordance and external AD support offers promising candidate blood-based biomarkers for future validation.

Breaking the nap habit: one-year nap restriction mitigates memory decline in older adults - Marine Dourte; Gregory Hammad; Stella de Haan; Mathilde Reyt; Michele Deantoni; Marion Baillet; Alexia Lesoinne; Gilles Vandewalle; Fabienne Collette; Vincenzo Muto; Philippe Peigneux; Christina Schmidt (GeroScience, 2026)

Age-related cognitive decline in house crickets reveals conserved patterns of sensory and learning deficits across the lifespan - Gerald Yu Liao; Jenna Klug; Warren Ladiges (GeroScience, 2026)

Conserved trajectories of age-related thigmotaxis across insects and mammals reveal the house cricket as a scalable model for behavioral aging - Gerald Yu Liao; Jenna Klug; Swastik Singh; Christina Pettan-Brewer; Warren Ladiges (GeroScience, 2026)

Correction to: Effects of electrical muscle stimulation on cognitive function and neuropathology in senescence‑accelerated mouse (SAMP8) model of aging‑associated cognitive decline - Hanlin Jiang; Tingrui Zhao; Chunxiao He; Bin Liu; Wanlin Ai; Yuxin Chen; Hideki Moriyama (GeroScience, 2026)

Genome-wide association study and pathway analysis of healthy aging in Super Seniors - Rawnak Hoque; Stephen Leach; Angela Brooks-Wilson (GeroScience, 2026)

Grip strength modifies the association between blood-based alzheimer’s biomarkers and cognitive function - Semere Bekena; Ramkrishna K. Singh; Yiqi Zhu; Jean-Francois Trani; Beau M. Ances; Ganesh M. Babulal (GeroScience, 2026)
Blood-based biomarkers are increasingly used to characterize Alzheimer’s disease (AD)–related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau 217 ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and total tau (tTau). Multiple linear regression models tested biomarker × grip strength interactions, adjusting for demographic factors, APOE ε4 status, cardiometabolic risk factors, body mass index, and creatinine. Sensitivity analyses included age-based propensity score matching and age-stratified models. Participants with low PACC were older, had lower grip strength, and higher plasma biomarker levels than those with normal cognition (all p < 0.001). In adjusted models, significant interactions between low grip strength and biomarkers were observed for pTau 217 (β = − 0.046, p < 0.01), NfL (β = − 0.002, p < 0.001), and GFAP (β = − 0.005, p < 0.05). Age-matched showed attenuation of some interaction effects except for low grip strength and NfL. Age-stratified analyses showed a significant interaction for NfL among adults ≥ 65 years and for GFAP among those < 65 years. Grip strength moderated the association between plasma AD-related biomarkers and cognitive performance, supporting physical strength as an indicator of vulnerability. Integrating simple strength measures with blood biomarkers may improve cognitive risk stratification in community-dwelling adults.

Peripheral microRNA signature in genetic frontotemporal dementia—findings from the GENFI initiative - Chiara Fenoglio; Maria Serpente; Marina Arcaro; Tiziana Carandini; Luca Sacchi; Manuela Pintus; Vittoria Borracci; Giulia Giudici; Marta Rigoni; Paola Muti; Laura Ghezzi; Arabella Bouzigues; et al. (GeroScience, 2026)
Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by significant clinical and genetic heterogeneity, with approximately 40% of cases linked to hereditary genetic mutations, including MAPT , GRN , and C9ORF72 . Recently, microRNAs (miRNAs) have emerged as key regulators of cellular processes related to neurodegeneration and as potential biomarkers for FTD. However, their relevance in presymptomatic stages remains poorly understood. We conducted a miRNA expression analysis using TaqMan OpenArray® panels on blood samples collected from 171 individuals, including symptomatic mutation carriers (SMC), presymptomatic carriers (PMC), and healthy non-carriers (NC). Dysregulated miRNAs were validated and bioinformatic tools were used to identify potential associated molecular pathways. In C9ORF72 , miR-20b-5p and miR-223-5p were significantly upregulated in SMC (fold regulation over NC: 2.418 p = 0.0336 and 7.829 p < 0.0264 respectively) and PMC (5.518, p < 0.0001 and 3.941, p < 0.0001 respectively). In GRN mutation carriers, miR-28-3p was altered in both SMC and PMC (fold regulation over NC: 1.484 p < 0.050 and 3.287, p < 0.050). In MAPT mutation carriers, miR-28-5p, miR-192-3p, miR-25-3p, and miR-532-3p were altered only in SMC (fold regulation over NC: 1.496 p < 0.050, 1.911 p = 0.006, 1.468 p < 0.05, and 0.728 p < 0.05). Bioinformatic analysis revealed enrichment of pathways related to neurodegeneration and synapse impairment. These results suggest that miRNA expression levels are deregulated in mutated SMC, in C9ORF72 and GRN PMC. Notably, miR-20b-5p, miR-223-5p, and miR-28-3p were increased in preclinical stages of the disease, supporting their role as early biomarkers for C9ORF72 -FTD and GRN -FTD. Conversely, alterations in MAPT carriers appeared only in symptomatic stages, suggesting a different involvement in disease progression.

What emergency department length of stay reveals about aging-related vulnerability and declining resilience - Szabolcs Gaal-Marschal; Dora Melicher; Kornel Adam; Dora Gaal; Bence Sipos; Brigitta Szilagyi; Csaba Varga (GeroScience, 2026)

Molecular and histological characterizations reveal two distinct senescent microglia populations in Niemann–Pick disease type C mouse model - Ki-Seok Lee; Tadahiro Numakawa; Chisato Horita; Yoichi Ishitsuka; Keiichi Motoyama; Toru Takeo; Takumi Era (GeroScience, 2026)

Lifestyle enrichment through social and cognitive engagement in later life: its associations with frailty trajectories and risk over 11 years - Claire McCubbin; Joanne Ryan; Zimu Wu; Swarna Vishwanath; Alice J. Owen; Sara E. Espinoza; Robyn L. Woods; Aung Zaw Zaw Phyo (GeroScience, 2026)
Frailty is a common geriatric syndrome associated with higher risks of hospitalisation and falls. The extent to which social and cognitive engagement activities (lifestyle enrichment) influence frailty is still largely unexplored. This study investigates the association between such enrichment and changes in frailty and frailty risk; 12,862 community-dwelling Australians aged ≥70 (54.4% female) enrolled in the ASPREE study were followed for 11 years. Nineteen baseline measures of social and cognitive activity (lifestyle enrichment) were grouped into seven domains using exploratory-factor analysis. Frailty was assessed annually over 11 years using a 67-item Frailty Index (FI) and modified Fried phenotype. Linear mixed models and Cox regression were used. Frequent passive mental activities (e.g., reading, watching TV) or adult literacy (e.g., writing letters, computer use) were associated with a 0.04-unit slower increase in FI-defined frailty burden. External outings had a 0.03-unit reduction annually; interpersonal networks or social activities, 0.02; and creative artistic engagement, 0.01. Active mental engagement showed no significant change. Over a median of 7.38-year follow-up, 3630 participants had an incident frailty. Passive mental engagement, interpersonal networks, social activities, external outings, adult literacy, and active mental engagement were associated with 2% to 5% lower risk of frailty. These associations were more evident among women and individuals with middle-/high-socioeconomic status. Similar findings were observed when using Fried phenotype. Frequent social and cognitive activities were associated with slower frailty progression and reduced frailty risk, informing clinical and public health strategies to maintain older adults’ independence and resilience. Graphical abstract

Restoration of gamma center frequency via personalized entrainment marks cognitive preservation in early Alzheimer’s disease - Yeseung Park; Hyeonwook Chae; Euisuk Yoon; Yejung Kim; Ji Won Han; Se Joon Woo; Seunghyup Yoo; Ki Woong Kim (GeroScience, 2026)
Gamma entrainment shows promise for Alzheimer’s disease (AD) treatment in preclinical models, but human trials have yielded heterogeneous results. We hypothesized that the clinical efficacy of gamma entrainment depends on individual neurophysiological receptivity, specifically the capacity for neural circuit plasticity. In this open-label pilot study, we screened 37 individuals and enrolled 16 participants with early AD (CDR 0.5–1.0, amyloid-positive) who completed 12 weeks of home-based flickering light stimulation at individually optimized gamma frequencies (32–40 Hz). Pre- and post-intervention assessments included 64-channel EEG recordings and MMSE. Participants demonstrated dichotomous neurophysiological responses: 43.8% showed center frequency (CF) increase (increased CF [ICF+]) while 56.3% showed no change/decrease (non-increased CF [ICF−]). CF restoration was significantly associated with cognitive preservation ( r = 0.52, p = 0.039). Notably, future responders exhibited distinct baseline signatures of “neural reserve,” characterized by higher temporal gamma power (Cohen’s d = 0.70–0.92) and stronger frontotemporal connectivity (Cohen’s d = 1.11–1.47). Almost 30% of screened candidates failed to show baseline entrainment, highlighting a distinct “non-responsive” biological subtype. CF restoration following personalized gamma entrainment identifies a neurophysiological subtype capable of meaningful plasticity. Rather than a universal remedy, gamma entrainment appears to act on specific neural substrates preserved in a subset of patients. These findings suggest that baseline electrophysiological profiling could unlock gamma entrainment’s therapeutic potential by stratifying likely responders for precision neuromodulation.

Global executive function advantages in older adults with long-term habitual exercise are associated with resting-state functional reorganization - Weikun Zhang; Geng Li; Gesi Teng; Mingzhu Ye; Zijin Liu; Yumin Liu; Antao Chen (GeroScience, 2026)

The influence of age and captivity on cardiac structure and function in rhesus macaques - T. G. Dawkins; B. A. Curry; A. Drane; V. N. Rivas; Y. Ueda; J. A. Stern; D. Philips; J. Negron-Del Valle; Lauren Brent; James Higham; Angelina Ruiz-Lambides; Noah Snyder-Mackler; et al. (GeroScience, 2026)

Oocyte aging in focus: Environmental and endogenous stressors driving reproductive potential decline - Katarzyna Ratajewska; Pawel Kordowitzki (GeroScience, 2026)
Oocyte quality, a critical determinant of female reproductive potential, experiences a progressive decline with age, largely driven by the cumulative effects of oxidative stress and mitochondrial dysfunction. This review thoroughly synthesizes the latest evidence concerning the molecular, cellular, and environmental factors that disrupt redox homeostasis within oocytes. It particularly highlights the pivotal roles of reactive oxygen species, impaired mitochondrial metabolism, epigenetic dysregulation, and alterations in the ovarian microenvironment. We further elucidate how aging, environmental toxicants, lifestyle choices, and pathological conditions such as cystic ovaries and endometriosis exacerbate oxidative damage, thereby severely compromising meiotic competence and embryonic development. Compelling evidence from both human and animal models has shed light on the intricate mechanisms underlying ROS-induced oocyte deterioration, which will be discussed herein. Moreover, we evaluate promising emerging interventions, including antioxidant, dietary, lifestyle, and mitochondria-targeted strategies, all aimed at preserving reproductive longevity. Collectively, these insights firmly establish oxidative stress as a central and undeniable driver of oocyte aging, underscoring the urgent need for integrated biomedical and environmental strategies to safeguard female fertility.

Sex-specific associations of low-level urinary albumin-creatinine ratio with mortality and adverse cardiac events in older adults - Cammie Tran; Rowan G. Walker; Hans G. Schneider; Que T. Lam; Chenglong Yu; Zhen Zhou; Flavia Cicuttini; Sultana Monira Hussain; Paul Lacaze; John J. McNeil (GeroScience, 2026)
Albuminuria is traditionally defined using fixed urinary albumin–creatinine ratio (UACR) thresholds, although cardiovascular disease (CVD) risk has been reported to increase continuously across the UACR spectrum. Whether these associations are present in healthy older adults and differ by sex remains unclear. We examined sex-specific associations between low-level UACR, mortality, and cardiovascular outcomes in older adults with preserved kidney function. From the ASPirin in Reducing Events in the Elderly (ASPREE) study, we included 5396 males and 6305 females aged ≥ 70 years with baseline UACR and eGFR ≥ 60 mL/min/1.73 m 2 ). Sex-stratified Cox models examined associations between UACR quintiles (Q) and mortality, CVD, major adverse cardiovascular events (MACE), and stroke, using Q1 as reference. Over a median follow-up of 8.3–8.6 years, increasing UACR was associated with progressively higher risk of all-cause mortality in both sexes, despite most values being below the guideline thresholds. Mortality risk reached statistical significance for males from Q4 (HR 1.45; 95% CI 1.18–1.77) and females from Q2 (HR 1.33; 95% CI 1.04–1.71). Males also had a statistically significant increase in CVD from Q4 (HR 1.32; 95% CI 1.03–1.70) and MACE and stroke in Q5 (HR 1.61; 95% CI 1.25–2.07 and HR 1.96; 95%CI 1.38–1.78). Despite an increasing trend in females, adverse cardiovascular outcomes did not reach significance. UACR levels below guideline thresholds were associated with all-cause mortality in both sexes, with increased cardiovascular disease predominately observed in men. These findings support a continuous relationship between UACR and risk and suggest that even low-level albuminuria may have prognostic significance in healthy older adults.

Impact of miR-181a-5p and miR-1249-3p treatment on the visceral adipose tissue transcriptome of female mice - Driele N. Garcia; Bianka M. Zanini; Sarah A. Ashiqueali; Miguel Brieño-Enriquez; Jeffrey B. Mason; Augusto Schneider; Michal M. Masternak (GeroScience, 2026)

Age-stratified genomic analyses reveal population-specific genetic determinants of exceptional longevity in Taiwan - Ming-Shun Hsieh; Shu-Min Yang; Shu-Hui Liao; Chayanika Goswami; Pei-Hsuan Wu; Tzu-Hung Hsiao; Yi-Ming Chen; Sung-Yuan Hu; Chorng-Kuang How; Tzu-Pin Lu; Amrita Chattopadhyay (GeroScience, 2026)

Longitudinal course of depressive symptoms and the risk of all-cause mortality in a nationally representative cohort of middle-aged and older adults in South Korea: exploring the mediating role of social frailty - Seong-Uk Baek; Jin-Ha Yoon (GeroScience, 2026)

Accelerated biological aging is associated with faster multimorbidity progression: a UK biobank study - Zhaoyu Wang; Jiaojiao Liao; Dongwei Fan; Minyue Pei; Zhaoji Li; Qianqian Dai; Hui Wang; Nan Li; Liyuan Tao (GeroScience, 2026)

Gait speed and domain-specific cognitive performance in a diverse cohort of the oldest-old: the LifeAfter90 Study - Rifat B. Alam; Hilary L. Colbeth; Alexander Ivan B. Posis; Maria M. Corrada; Kristen M. George; Paola Gilsanz; Cathy Liu; Katherine Colcord; Nancy X. Chen; Rachel A. Whitmer (GeroScience, 2026)
Gait speed is a robust marker of health in older adults and is associated with cognition, yet few studies have examined this in the oldest-old and if there are differences by cognitive domain. We examined the association between gait speed and cognition across three domains in individuals aged 90 + , considering differences by gender and device use. Then, 502 participants were included from the LifeAfter90 Study. Baseline gait speed (meters/second) was measured using the 4-meter walk test. The Spanish and English Neuropsychological Assessment Scale assessed executive function (EF), verbal episodic memory (VEM), and semantic memory (SM). We tested cross-sectional and longitudinal associations of gait speed with cognition using linear mixed-effects models adjusted for age, gender, race/ethnicity, education, device, interview mode, and practice effects. Models were stratified by gender and device. Participants’ mean age was 92.9 ± 2.4 years, 62.6% female, 22.3% African American/Black, 20.9% Asian, 12.3% Hispanic/Latino, 35.9% White, and 8.6% multiracial/other. Faster gait speed was associated with better EF ( β (95%CI) = 1.3 (0.9, 1.8)), VEM (0.7 (0.1, 1.2)), and SM (0.8 (0.4, 1.3)). Gender-stratified models showed better EF and SM in both sexes and better VEM in women. Device-stratified models showed better EF and SM in both groups and better VEM in nondevice users. Longitudinally, faster gait speed was associated with slower SM decline (0.1 (0.0003, 0.2)). No other longitudinal associations were significant in pooled or stratified analyses. Faster baseline gait speed was linked to better cognitive performance and slower SM decline. Findings varied by domain, gender, and device use, highlighting gait speed’s utility in reflecting cognitive variability among those with exceptional longevity.

The MetaboHealth score is 40% heritable and is influenced by frailty status, BMI, and smoking in Swedish twins - Larissa Smulders; Jonathan K. L. Mak; Sara Hägg; Joris Deelen (GeroScience, 2026)
The MetaboHealth score, a metabolomics-based biomarker trained on mortality, is associated with ageing-related phenotypes and morbidity, but its heritable component is still uncertain. Understanding genetic versus environmental contributions is essential for its utility as an intervention-responsive biomarker. Hence, the aim of this study was to estimate heritability of the MetaboHealth score in the large Swedish TwinGene cohort and evaluate interactions with modifiable lifestyle factors and health outcomes. We analysed 12,256 twins (55% female; mean age 64.8 years at blood draw) with Nightingale Health-based metabolomics data, followed until February 2024 (median follow-up time of 16.2 years). We subsequently estimated the heritability of the score using additive genetic (A), shared environmental (C), and unique environmental (E) (ACE) modelling via Cholesky decomposition in 1,370 monozygotic and 3,381 dizygotic twin pairs. Cox regression was used to assess mortality associations, with sensitivity analyses stratified by age, smoking, body mass index (BMI), and frailty. The MetaboHealth score was significantly associated with all-cause mortality (Hazard ratio (HR) = 1.91, 95% confidence interval (CI): 1.73–2.11; P = 1.32 × 10⁻ 38 ) in Swedish twins and its heritable component was estimated to be 40% (95% CI: 37–43%), with 57.5% of the variance attributable to unique environment and 2.5% to shared environment. Lifestyle factors and health outcomes, including BMI (P = 8.36 × 10⁻⁶), smoking (P = 0.009), and frailty (P = 6.55 × 10⁻ 4 ), were associated with the score. Notably, mortality associations were strongest in younger adults (HR = 2.76 in individuals ≤ 65 years of age versus HR = 1.77 in individuals > 65 years of age) and smokers (HR = 2.16 in smokers versus HR = 1.59 in non-smokers). Moreover, analyses of monozygotic twins showed reduced score correlations in discordant pairs, where one twin was non-frail and the other pre-frail or frail (r 2 concordant = 0.184 versus r 2 discordant = 0.119; P = 0.042). In conclusion, with only 40% of its variance fixed by genetics, the MetaboHealth score is predominantly environmentally modifiable. Its heightened sensitivity to mortality risk in younger adults and smokers, and association with frailty status and BMI, supports its use as a biomarker for precision interventions in healthy ageing. Graphical Abstract

Age-related neural inefficiency: fNIRS evidence of prefrontal hyperactivation during emotional response inhibition - Gong-Hong Lin; Dorothy Bai; Mai Thi Thuy Vu; Yi-Jing Huang (GeroScience, 2026)

Inflammaging-associated mitochondrial degeneration occurs in hypoglossal motor neurons prior to tongue muscle - Matthew J. Fogarty; Debanjali Dasgupta; Trace A. Christensen; Genesis A. Hernandez-Vizcarrondo; Sanjana Mahadev Bhat; Kathryn D. Rooker; Gary C. Sieck (GeroScience, 2026)

Deciphering the molecular landscape of aortic aging: a meta-analysis of bulk RNA sequencing studies in mice - Baptiste Pialot; Guillaume Courbon; Stéphane Avril (GeroScience, 2026)

Task difficulty and limb dominance modulate the effects of ageing on neuromuscular function - Yuxiao Guo; Eleanor J. Jones; Abdulmajeed Altheyab; Nishadi N. Gamage; Bethan E. Phillips; Philip J. Atherton; Mathew Piasecki (GeroScience, 2026)
Neuromuscular function is critical for independence in ageing, yet asymmetries between dominant and non-dominant limbs, arising from central or peripheral mechanisms, are not well understood. This study examined age- and limb-related differences and motor unit (MU) firing behaviour of the vastus lateralis under tasks of varying difficulty. Twenty-one young (22 ± 4 years; 15 M, 6F) and seventeen older adults (74 ± 5 years; 12 M, 5F) performed constant and variable force unilateral isometric knee extensions. In both limbs, high-density surface electromyography signals were decomposed into MU spike trains. Force control and MU firing properties were analysed using multilevel mixed-effects regression models. Older adults showed reduced maximal muscle strength ( p < 0.001) and increased force tracking error ( p = 0.008). Force outcomes, including muscle strength and force control, showed no significant limb-specific differences in either age group. MU firing rate (MUFR) was significantly lower in older adults during constant contractions ( p = 0.001) and trended toward lower during variable contractions ( p = 0.061). MUFR variability showed a significant Leg × AgeGroup interaction ( p < 0.001); older adults had greater variability in non-dominant legs, while younger adults showed the opposite. With variable force contractions in both age groups, MUFR was higher during ascending segments with greater variability during descending segments. Neuromuscular ageing involves asymmetric adaptations rather than a uniform decline, with leg dominance effects being more pronounced under variable force modulation. Task difficulty amplifies these asymmetries, underscoring the need to consider limb-specific neural control in age-related motor assessments.

Prevalence and determinants of ageism experiences in the Singapore population: insights from the HEalthy LOngevity (HELO) survey - Lara M. A. Bruschinski; E. J. Horberg; Paul A. O’Keefe; Belinda Wang; Anna Szücs; Johannes J. Meij; Aja L. Murray; Andrea B. Maier (GeroScience, 2026)
Ageism refers to stereotypes, prejudice, and discrimination based on age. Ageism negatively impacts physical and mental health across the lifespan, yet knowledge about the experience of ageism in Singapore is limited. This study evaluated the prevalence of experienced ageism in Singapore and identified its key determinants within a nationally representative cohort. In the cross-sectional HEalthy LOngevity (HELO) survey ( N = 3034), ageism was measured using the newly launched World Health Organization (WHO) Ageism Experiences Scale. Associations with chronological age, perceived age, gender, socioeconomic, and health-related factors were examined using nonparametric tests and multivariable linear regression. Respondents’ median chronological age was 46 [interquartile range (IQR): 34–59] years, and 54.1% were female. Experiences of ageism were reported by 49.4% of respondents. Total ageism scores were on average 1.5 points higher among the youngest (21–30 years) and oldest (71+ years) age groups and approximately 1 point higher among respondents with lower socioeconomic status, particularly those with lower education levels. Respondents who felt older than their chronological age reported significantly higher ageism scores. This first large-scale study on ageism in Singapore reveals high experienced ageism, consistent with global estimates, particularly among older and younger adults. Feeling older was one of the strongest ageism predictors. Addressing ageism by targeting social determinants and subjective ageing perceptions is essential to promote healthy ageing and to inform public health policy and interventions in Singapore. Graphical Abstract

Lower-limb physical function is associated with executive function in frail older adults - Myles W. OBrien; Shirko Ahmadi; Pierre Faivre; Isadora Quirion; Vicky Bouffard-Levasseur; Tina Emond; Anik Lang; Emily MacDonald; Olivier Dupuy; Anne Sophie Champod; Mathieu Bélanger; Said Mekari (GeroScience, 2026)

Systemic inflammatory response following hip fracture in older people: postoperative CRP and PCT dynamics and their association with coagulation and renal function - Anna Franziska Pries; Valerie Lotzgeselle; Christian Macke; Emmanouil Liodakis; Claudia Neunaber; Manfred Gogol (GeroScience, 2026)

Dorsolateral prefrontal cortex hemispheric asymmetry and chronic low back pain at 8-year follow-up in community-dwelling older adults - Soichiro Matsuda; Takehiko Doi; Kenji Harada; Sho Nakakubo; Fumio Sakimoto; Shinnosuke Nosaka; Kanon Abe; Hiroyuki Shimada (GeroScience, 2026)

Effects of daily multivitamin-multimineral supplementation on metabolomic profiles: 2-year findings from the COSMOS randomized clinical trial - Sidong Li; Rikuta Hamaya; Zareen Farukhi; Jun Li; Pamela M. Rist; JoAnn E. Manson; Howard D. Sesso (GeroScience, 2026)

Genetic deletion of adenosine A2A receptors attenuates memory deterioration and alterations of synaptic plasticity and metabolic controllers in the hippocampus and prefrontal cortex of aged mice - Cátia R. Lopes; Daniela Madeira; Madalena Piteira; Pedro Valada; Joana Santos; Henrique B. Silva; Francisco Q. Gonçalves; Ângelo R. Tomé; Paula M. Canas; João Pedro Lopes; Samira G. Ferreira; Paula Agostinho; et al. (GeroScience, 2026)
The incidence of brain diseases increases with aging, but the biological basis of brain aging is still poorly explored. Synaptic dysfunction occurs at the onset of brain diseases and synaptic neuromodulation systems, such as adenosine A 2A receptors (A 2A R), are necessary and sufficient to trigger brain dysfunction. Since A 2A R are upregulated upon aging, we compared wild-type and A 2A R global knockout mice to test if brain aging involves synaptic senescence linked to A 2A R overfunction, leading to synaptic and cognitive deterioration. Aging impacted different behavioral outputs, namely spatial learning and memory, coupled to aberrant synaptic plasticity in the hippocampus and prefrontal cortex. Moreover, aging led to an imbalance between excitation and inhibition markers and dysregulated key metabolic coordinators, including sirtuin-1, sirtuin-3, AMPK and p38MAPK. These cognitive impairments and synaptic and metabolic signaling alterations were not observed in aged mice with A 2A R genetic elimination. These findings suggest that A 2A R overfunction can be a key driver of age-associated memory deterioration and A 2A R blockade might promote healthy brain aging. Graphical abstract Aging affected memory and synaptic plasticity, disrupted the balance between excitation and inhibition markers and deregulated key metabolic regulators, namely SIRT1, SIRT3, AMPK and p38MAPK, in the hippocampus and prefrontal cortex of aged mice. A 2A R elimination prevented memory deterioration and most synaptic and metabolic-related alterations in both cortical regions were no longer present. Thus, A 2A R upregulation might be a driver of synaptic senescence-like metabolic and A 2A R blockade may help prevent synaptic dysfunction and, consequently, promote healthy aging.

A chronological age prediction model using clinical biochemistry and hematological data identifies features of biological age in healthy Labrador retrievers - Carina Salt; Phillip Watson; David Allaway (GeroScience, 2026)

Metabolomic signatures of extreme old age: findings from the New England Centenarian Study - Stefano Monti; Michael S. Lustgarten; Ziwei Huang; Zeyuan Song; Mengze Li; Dylan Ellis; Qu Tian; Luigi Ferrucci; Noa Rappaport; Stacy L. Andersen; Thomas P. Perls; Paola Sebastiani (GeroScience, 2026)

Interactive effects of retinal biomarkers and sleep on cognition: longitudinal evidence from community-dwelling older adults - Ting-Wen Chu; Yi-Ting Hsieh; Jeng-Min Chiou; Yao-Lin Liu; Yen-Ching Chen; Jen-Hau Chen (GeroScience, 2026)

Quadriceps mitochondrial DNA quantity, quality, and gene expression after 2 years of calorie restriction: exploratory results from the CALERIE trial - Jayanta K. Das; Yu Zhang; Leanne M. Redman; Corby K. Martin; Sai Krupa Das; Susan B. Racette; Allen Herbst; Nianjun Liu; David B. Allison; Debbie McKenzie; Judd M. Aiken; Steve Horvath; et al. (GeroScience, 2026)
The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)™ trial was a randomized, 2-year controlled trial of caloric restriction (CR) versus an ad libitum (AL) control condition in nonobese humans. We performed exploratory analyses of muscle mitochondrial DNA (mtDNA) integrity, one element of mitochondrial quality. Our aims were to assess the feasibility of this approach, explore associations to inform future hypotheses, estimate effect sizes and statistical power for subsequent studies, and contribute additional data to the CALERIE database. We used droplet digital PCR to quantitate the copy numbers of nuclear DNA, mtDNA, and mtDNA deletion mutations in remnant total DNA samples extracted from quadriceps biopsies at baseline ( n = 93), 12 months ( n = 44), and 24 months ( n = 31). MtDNA copy number and mutation frequency were correlated with existing gene expression data from the same muscle biopsies. MtDNA copy number was lower in females ( p = 0.0005) and declined over time ( p = 0.0001), with no statistically significant differences observed for CR versus AL ( p = 0.2898) or age across both groups ( p = 0.4644). Baseline copy number correlated positively with baseline physiological measures including fat-free mass ( r = 0.43, p = 2e−05), self-reported energy intake ( r = 0.34, p = 0.00077), resting metabolic rate ( r = 0.42, p = 0.00261), total energy expenditure ( r = 0.31, p = 0.00261), and V̇O₂max ( r = 0.41, p = 1e−04), and with gene expression related to mitochondrial function, while showing negative correlations with nuclear genome maintenance, RNA splicing, and ribosomes. MtDNA mutation frequency increased with age ( p = 0.0041) and showed a weak negative correlation with V̇O 2 max ( r = −0.23, p = 3e−05). MtDNA mutation frequency was not statistically different with CR. Mutation frequency was positively correlated with gene expression changes in inflammation and negatively correlated with protein translation. We observed that, as expected, mtDNA copy number declined over time, was lower in females, and correlated with metabolic measures and mitochondrial gene expression, suggesting its potential utility as a marker of metabolic health. These findings contribute to understanding mitochondrial adaptations to CR and highlight potential benefits of CR interventions. Graphical Abstract

Distinct effects of aging and klotho deletion on the choroid plexus - Zahra Fanaei-Kahrani; Tushar Patel; Christina Valkova; Alexander Gloria; Justine Wagner; Heike Heuer; Markus Schwaninger; Steve Hoffmann; Reinhard Bauer; Christoph Kaether (GeroScience, 2026)

Active immunization against myostatin and activin A improves skeletal muscle performance in growth hormone-deficient mice - Mishfak A. M. Mansoor; Sarah A. Ashiqueali; Md Tanjim Alam; Fabrizzio Lijeron-Herrera; Xiang Zhu; Jash Trivedi; Amanda Lasseter; Augusto Schneider; Lisa Flores; Hu Wang; Xianlin Han; Yuji Ikeno; et al. (GeroScience, 2026)

Searching for shared epigenetic clocks: evaluating ultra-conserved markers in a de novo genome assembly of the albacore tuna - Thomas Chevrier; Sylvain Bonhommeau; Michael Thompson; Jessica Farley; Giorgia Del Vecchio; Anne-Elise Nieblas; Dominique A. Cowart; Julie Imbert Nguyễn; Serge Bernard; Yann Guiguen; Cedric Cabau; Christophe Klopp; et al. (GeroScience, 2026)

Revisiting the social frailty index in aging adults: relevance and implications for an emerging construct - Charles W. Collinge; Alessandro Bartolomucci; Monica Luciana (GeroScience, 2026)
Frailty is an established benchmark of aging-related decline, yet most measures of frailty focus on physical decline. Increasing evidence that social environments influence trajectories of aging has led to growing interest in social frailty. Recently, a 10-item Social Frailty Index (SFI-10) was developed using data from the Health and Retirement Study (HRS) that used 8 social items plus chronological age and sex to predict mortality. This study evaluates the validity of the SFI-10, providing considerations for social frailty measurement. Utilizing HRS cohorts ( n = 8264, ages 66 to 101) and cohorts from the Midlife in the United States (MIDUS) study ( n = 5619, ages 40 to 75), the SFI-10 was evaluated alongside an index including only its social-environmental factors (SFI-8). Logistic regressions were used to predict mortality from the SFI-10, SFI-8, and only age and sex. Within MIDUS, the SFI-10, SFI-8, and age were further evaluated against external criteria relevant for social frailty. Findings indicate that chronological age is the most important predictor of mortality risk across both samples. Social-environmental factors predict mortality only marginally in older adults but more strongly in midlife. When associated with external criteria relevant for social frailty, the SFI-8 exhibited stronger criterion validity than the SFI-10. These findings suggest that social frailty may be best reflected by measures focusing exclusively on social behaviors and resources, excluding demographic characteristics. Our work underscores the need for well-designed measures of social frailty.

Three-dimensional trace element profile reflecting aging, disease, and frailty - Catrin Herpich; Tom Heinze; Varvara Moskiou; Magdalena Kalymon; Lea Göger; Lea Faust; Kristina Lossow; Ursula Müller-Werdan; Tanja Schwerdtle; Lutz Schomburg; Anna P. Kipp; Kristina Norman (GeroScience, 2026)
Older age combined with chronic disease increases the risk of malnutrition and frailty, impacting disease recovery and overall clinical outcomes. Serum concentrations of several trace elements and their respective biomarkers have not yet been investigated with regard to frailty in older adults with disease, although these patients most likely have an altered trace element profile owing to both inflammatory conditions and inadequate dietary intake. This cross-sectional study investigated trace element profiles in relation to age, disease, and frailty status in geriatric patients ( n = 198) as well as in old ( n = 80) and young ( n = 60) healthy controls. Serum concentrations of iron, zinc, selenium, iodine, copper, and manganese were quantified via ICP-MS/MS, alongside inflammatory markers and functional biomarkers. Analysis revealed distinct trace element profiles in patients compared to healthy controls, with lower manganese, iron, zinc, and selenium, but higher copper and iodine ( p ≤ 0.001). Trace element concentrations were similar in young and older healthy controls. Principal component (PC) analysis identified two profiles. PC1 was negatively associated with age, number of drugs, sex, and inflammation. Only PC2 was associated with anorexia (β = 0.053 ± 0.020; 95% CI 0.015, 0.092; p = 0.007). Furthermore, intake of drugs that affect intestinal trace element absorption was associated with PC2. Our analyses suggest that PC1 might reflect disease/inflammation, and PC2 inadequate trace element supply. These cross-sectional findings suggest that inflammation and inadequate trace element intake, rather than age, significantly influence trace element profiles and contribute to frailty. Trail registration number: DRKS00017090, registered 12.04.2019; DRKS00028105, registered 03.03.2022.

Correction to: The effect of anthocyanins and anthocyanin‑rich foods on cognitive function: a meta‑analysis of randomized controlled trials - Agnieszka Micek; Justyna Godos; Francesca Giampieri; Maurizio Battino; José L. Quiles; Daniele Del Rio; Pedro Mena; Giuseppe Caruso; Evelyn Frias‑Toral; Irma Domínguez Azpíroz; Jianbo Xiao; Nicola Veronese; et al. (GeroScience, 2026)

Wobble-board instability re-orthogonalizes postural geometry in older adults through exogenous constraint - Brian Schlattmann; Damian G. Kelty-Stephen; Theodoros Deligiannis; Ken Kiyono; Madhur Mangalam (GeroScience, 2026)
Postural control is expressed as intermittent organization of center-of-pressure (CoP) motion on a saddle-shaped manifold typically aligned with the anteroposterior (AP) and mediolateral (ML) axes. When task demands reorient postural focus, this saddle rotates away from the AP–ML alignment yet preserves orthogonal axes that indicate directions of greatest and least fractal temporal correlations in sway. Preserved orthogonality appears to reflect a balance between endogenous fractal fluctuations and exogenous task demands. Perturbation, however, seems to erode older adults’ endogenous fractal support, prompting heavier, less nuanced reliance on exogenous constraints. We recruited older and younger adults to coordinate with tasks in orthogonal directions—performing the Trail Making Test (TMT) with forward (AP) focus while standing quietly or on a wobble board that induced ML perturbations. The wobble board weakened endogenous fractal support for inter-axial orthogonality in both groups while expanding the range of fractality. A forward focus during TMT reinstated endogenous fractal support in younger adults—except on the wobble board—and narrowed the fractality range. In older adults, TMT increased orthogonality only via exogenous influence, without reinstating endogenous fractal support. Thus, deviations of the saddle topology from the classical AP–ML orientation under competing task alignments reveal that aging entails greater reliance on exogenous supports as endogenous fractality weakens, even as perturbations can increase the range or magnitude of fractal temporal correlations. Neither aging nor perturbed posture so much loses fractal complexity as loses the capacity to exploit endogenous fractality to maintain stable topologies.

Baseline cognition and stimulation site shape the effects of tdcs on verbal fluency in older and younger adults - A. Yucel; A. K. Martin (GeroScience, 2026)
Verbal fluency is a core measure of language and executive function often used in cognitive research. Transcranial direct current stimulation (tDCS) has been investigated for its potential to enhance verbal fluency; however, the results are variable. Discrepancies may indicate variations in electrode montage, stimulation site, measured fluency type, and individual cognitive profiles. In this preregistered, double-blind, sham-controlled study, 72 younger and 72 older adults received anodal tDCS to either the left inferior frontal gyrus (left IFG) or the left temporoparietal junction (left TPJ) while completing phonemic and semantic fluency tasks. Anodal stimulation of the left TPJ significantly improved phonemic fluency compared to sham ( F (1,71) = 4.49, p = .038), with no effects observed for semantic fluency or left IFG stimulation. Additionally, stimulation response in the TPJ group was predicted by fluid intelligence, with lower scores associated with greater benefit (F(1,70) = 7.80, p = .007). Finally, stimulation to the left IFG improved response initiation but impaired sustained energization over the entire minute. These results suggest that the efficacy of focal tDCS for enhancing verbal fluency depends on both stimulation site and task demands, with the left TPJ showing selective benefits for phonemic fluency. Importantly, individual differences in fluid intelligence, but not age, moderated stimulation response, highlighting the role of cognitive capacity in neuromodulation outcomes. Together, these findings demonstrate a nuanced relationship between targeted excitation of the language network and verbal fluency, emphasizing the need for individualized approaches in cognitive enhancement interventions.

Unlocking the role of microbiome through gut-skin axis to alleviate aging: current perspectives and future scope - Arun Kumar Mishra; Shristy Verma; Amrita Mishra; Gyas Khan; Harpreet Singh (GeroScience, 2026)

Modeling and evaluating longitudinal brain maintenance and cognitive reserve using episodic memory, brain structure, and functional connectivity in older adults - Rachel M. Morse; Lídia Vaqué-Alcázar; María Cabello-Toscano; Cristina Solé-Padullés; Lídia Mulet-Pons; Juan Pablo Martin Trias; Micael Andersson; Dídac Vidal-Piñeiro; Alvaro Pascual-Leone; Kristine Walhovd; Lars Nyberg; David Bartres-Faz (GeroScience, 2026)
Cognitive reserve (CR) and brain maintenance (BM) reflect better than expected cognition despite brain pathology and minimal age-related brain changes that explain stable cognition, respectively. Despite being commonly used, joint quantification of these concepts has been limited; our aim is to derive longitudinal CR and BM measures and investigate CR’s relationship with education and functional connectivity. We analyzed longitudinal data from 451 participants (241 female, age mean = 68.5 years, follow-up mean = 4.2 years). From a hippocampus change-memory change regression, we modeled BM as memory stability relative to hippocampal stability and CR as better-than-expected memory stability relative to hippocampal atrophy. We examined whether education and resting-state functional connectivity (Default Mode, Executive Control and anterior Salience Network) (1) moderated the hippocampal-memory relationship using linear mixed effects models (LMEs), (2) moderated the hippocampus change-memory change relationship using linear regressions, and (3) were associated with our CR measure using LMEs. Analyses adjusted for demographics and MRI scanner/cohort, using false discovery rate (FDR) for multiple comparisons. From a significant hippocampus change-memory change relationship ( β = 0.130, p FDR = 0.016, r 2 = 0.282), we derived continuous CR and BM measures, providing subject-level estimates. Salience Network connectivity moderated the hippocampal-memory relationship ( β = − 0.070, p FDR = 0.046, marginal r 2 = 0.179). No variable moderated the hippocampus change-memory change relationship or correlated with our CR measure, consistent with the measure’s longitudinal definition. Our CR and BM measures refine phenotyping of aging trajectories. CR may be expressed through increased Salience Network connectivity, preserving memory level in the presence of hippocampal atrophy. Future work should delineate longitudinal CR mechanisms that decouple memory change from hippocampal atrophy.

Biological evidence of the life expectancy limit in human aging - Yasuhiro Kitazoe; Hiroshi Toki (GeroScience, 2026)

A parsimonious six-predictor model for memory decline: cross-population validation in Chinese and Japanese aging cohorts - Lihui Tu; Qinge Zhang; Yoshinori Nanjo; Dongmei Gu; Yasuo Kuniyoshi (GeroScience, 2026)
To develop and validate a parsimonious risk model for short-term memory decline in older adults and to evaluate its cross-population transportability between Chinese and Japanese cohorts. The model was developed in 5985 cognitively normal older adults from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2015). Seven machine learning algorithms were compared, and a Cox proportional hazards (CoxPH) model was selected for its optimal balance between performance and parsimony. The final model was validated in a temporal CHARLS cohort (2015–2018; n = 1333) and an external Japanese cohort from the Japanese Study of Aging and Retirement (JSTAR, 2007–2009; n = 2798). Performance was assessed using discrimination, calibration, decision curve analysis, and bootstrap-derived confidence intervals. In temporal validation, the model demonstrated good discrimination (C-index = 0.72) with acceptable calibration (slope = 1.40). In the external JSTAR cohort, discriminative performance remained moderate and stable (C-index = 0.68), and calibration was comparable (slope = 0.96) despite differences in baseline incidence and follow-up duration. Decision curve analysis showed net benefit in the temporal cohort and consistent risk stratification in the external cohort. Sensitivity analyses confirmed stable performance across varying follow-up horizons. The six-predictor model consistently stratified short-term memory decline risk across distinct East Asian populations. The findings support its cross-population transportability for relative risk stratification in aging cohorts.

IFN-β as a therapeutic agent for influenza A virus infection in old mice - Wenxin Wu; Jeremy S. Alexander; Yang Song; J. Leland Booth; Alexandra K. Ford; Jordan P. Metcalf; Douglas A. Drevets (GeroScience, 2026)

What percentage of neuromuscular strength reduction in older adults determines the decline in walking speed? - Yasmin Oliveira Machado; Mariane Marques Luiz; Roberta de Oliveira Máximo; Sara Souza Lima; Andrew Steptoe; Cesar de Oliveira; Tiago da Silva Alexandre (GeroScience, 2026)
Background/Objective Although different neuromuscular strength (NS) cutoff points have been proposed to identify low walking speed (WS) in older adults, the extent to which NS changes predict long-term WS decline remains unclear. This study aimed to determine the percentage of NS change associated with WS decline in older adults. Methods A longitudinal analysis was conducted using data from 4,541 participants aged ≥ 60 years in the ELSA Study. Changes in NS over four, eight, and twelve years of follow-up, compared to baseline, were categorised into nine groups: maintenance of NS within ± 5%, increases of 5–10%, 10–15%, 15–20%, or more than 20%, and reductions in the same ranges. Generalised linear mixed models were used to evaluate WS trajectories (m/s) as a function of NS changes, adjusted for sociodemographic, behavioural, and clinical factors. Results Participants who experienced a 15–20% (-0.007 m/s per year; 95% CI: -0.013 to -0.002) and more than 20% (-0.004 m/s per year; 95% CI: -0.007 to -0.001) reduction in NS had greater WS decline compared to those with stable NS (± 5%). Over 12 years, these reductions corresponded to WS declines of -0.189 m/s and -0.144 m/s, respectively. Conclusion Losing 15% or more of neuromuscular strength reduces walking speed over time. Therefore, monitoring the percentage change in NS can serve as a useful tool for early detection of the risk of WS decline, allowing for more personalised clinical investigations and timely neuromuscular strengthening interventions to minimise adverse effects on mobility in older adults. Graphical Abstract

The role of modifiable risk factors on the cerebral myelin content and cognition: findings from The Maastricht Study - Gerhard S. Drenthen; Walter H. Backes; Sebastian Köhler; Kay Deckers; Miranda T. Schram; Simone J. P. M. Eussen; Willemijn J. Jansen; Jacobus F. A. Jansen (GeroScience, 2026)
Lifestyle-related factors may affect cognition and increase the risk of developing dementia. However, the neurobiological mechanisms underlying the effect of lifestyle-related factors on the brain are not yet fully understood. Myelin, a vital element of brain health, has previously been shown to be involved in dementia-related cognitive decline. However, whether it plays a role in the relation between lifestyle-related factors and cognitive performance has not been studied. The cerebral myelin content of 4653 participants (51% female, aged 59 ± 9 years) from The Maastricht Study was estimated using the T1w/FLAIR-ratio, and lifestyle-related factors were summarized using the LIBRA-score. Multivariable linear regression models, corrected for the effects of age, sex and education, were used to investigate whether lifestyle-related factors are associated with myelin. Moreover, whether myelin can partly explain the relationship between lifestyle-related factors and cognition was explored using a mediation analysis across three cognitive domains (memory, executive functioning and processing speed). An unhealthy lifestyle (i.e. higher LIBRA score) is significantly associated to a lower cerebral myelin content ( β = −0.24, 95% CI [−0.26 −0.22], and p < 0.001). Furthermore, lower cerebral myelin content associates to worse cognitive performance ( β = 0.14, 95% CI [0.11 0.17], and p < 0.001). Moreover, myelin has a partially mediating effect of 15%, indicating that it partly explains the relation between lifestyle-related factors and cognition. These results show that myelin content might help explain the mechanisms through which lifestyle-related factors influence cognition, potentially allowing for specific and early lifestyle interventions aimed at preventing or delaying cognitive decline and dementia. Graphical abstract

Associations between cognitive frailty and circulating cardiovascular biomarkers in a memory clinic cohort - Xin Tong Tan; Joyce R. Chong; Eddie J. Y. Chong; Ming Ann Sim; Jiangbo Cui; Siew Pang Chan; Oi Wah Liew; Boon Yeow Tan; Narayanaswamy Venketasubramanian; Arthur Mark Richards; Mitchell K. P. Lai; Christopher Li-Hsian Chen (GeroScience, 2026)

Correction to: 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, 2026)

The stop signal stepping task: how action cancellation commands disrupt step initiation in young and healthy older adults - Rebecca Healey; Marlee J. Wells; Sauro E. Salomoni; Rohan Puri; Mark R. Hinder; Rebecca J. St George (GeroScience, 2026)
Action cancellation – the ability to rapidly cancel an initiated movement in response to unexpected events – has been extensively studied in the upper limb using the stop signal task (SST). During gait, action cancellation is critical to stop and modify steps to avoid unexpected hazards and prevent falls. By adapting the SST to step initiation, this study investigated how the anticipatory postural adjustment (APA) and foot-lift phases of forward stepping were influenced by action-cancellation commands, and whether these processes changed with healthy ageing. Twenty-seven young (M = 28.7 years) and 29 healthy older adults (M = 70.1 years) performed SST variants involving stepping, foot tapping, and finger button-pressing. Across conditions, older adults exhibited slower response execution speed and more slowing when stop cues were anticipated, yet their stopping speed did not differ from that of young adults. When an APA was initiated in a step cancellation trial, the magnitude of the preparatory weight shift toward the step leg did not differ between trials in which foot-lift was successfully cancelled and those in which foot-lift still occurred. Foot-lift could be cancelled when stop cues were presented at similar phases of step preparation for young and older adults. These results suggest that the initial loading of the step leg is ballistic, however as weight transfers toward the stance leg, external stop cues can decouple the APA and foot-lift step phases. While older adults exhibited slower action initiation, a greater reliance on proactive inhibition under conditions of uncertainty may help preserve stopping efficiency.

From stiffness to automaticity: visuomotor training alters postural control strategies in older adults - Jakub Malik; Natalia Główka (GeroScience, 2026)
Aging is often associated with a maladaptive “stiffness” strategy of postural control, which limits adaptability and increases fall risk. Complex visuomotor training (e.g., juggling) may counteract this decline, but the relationship between biomechanical reorganization and cognitive cost reduction remains unclear. We hypothesized that juggling would induce a shift from stiffness to “active monitoring” and reduce the dual-task cost. This exploratory secondary analysis of a randomized crossover trial consists of twenty-five older adults (70 ± 4 years). Participants underwent 4 weeks of juggling training versus a passive control period. Postural sway was assessed using a force platform to analyze kinematic metrics reflecting sway activity (path density) and spatial precision (radial standard deviation). Cognitive cost was assessed via dual-task cost during a counting task. Linear mixed models were used for analysis. Juggling training significantly increased path density ( p = 0.014) and improved central precision (reduced radial standard deviation, p = 0.040). This pattern indicates a transition to an “active monitoring” strategy, effectively “unfreezing” rigid postural control. However, this biomechanical reorganization was not accompanied by a statistically significant reduction in dual-task cost ( p = 0.08). Visuomotor training effectively “unfreezes” rigid postural strategies in older adults, promoting active, exploratory control. However, these findings should be interpreted as hypothesis-generating. The lack of significant cognitive cost reduction suggests a temporal dissociation: biomechanical flexibility is restored before full automatization occurs, warranting verification in larger, longitudinal studies. The study was retrospectively registered (30.10.2023) at ClinicalTrials.gov (NCT06108713).

Combined effects of ageing and type 2 diabetes mellitus on human dental mechanics - Sarolta Antal; Kata Sára Haba; Gábor Szebényi; Ildikó Horváth; Szigeti Krisztián; Dániel Sándor Veres; Miklós Kellermayer; Dóra Haluszka (GeroScience, 2026)
Dental collagen, a protein subject to essentially zero turnover, is highly susceptible to the accumulation of advanced glycation end-products (AGEs) due to elevated blood glucose in type 2 diabetes mellitus (T2DM). Progressive loss of collagen’s structural stability likely increases the risk of tooth decay and fracture complicating the proper fixation of dental restorations. Our study aimed at investigating the structural and mechanical alterations in T2DM-affected teeth by measuring the stiffness and detecting micro-traumas and fractures. By using computed tomography (CT) and static compression tests, caries-free human molars and front teeth from healthy and T2DM patients were analyzed. Our results revealed a significantly reduced enamel/dentin ratio and larger dentin crack sizes in T2DM molars compared to controls, indicating increased susceptibility to mechanical damage. Although statistical analysis showed age as a dominant factor in tooth deterioration, T2DM was associated with a clinically relevant increase in dentin fracture size, suggesting that diabetes aggravates tooth fragility. Our findings underscore the importance of the cooperative effect of age and diabetes in dental biomechanics which bears significant implications in restorative treatments. Altogether, while ageing significantly affects tooth mechanical stability, T2DM contributes to additional structural weakening, particularly in molars, due to altered mechanical properties and higher occurrence of dental wears.

Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice - Ron Korstanje; Randy Strong; Adam B. Salmon; Molly A. Bogue; Sean P. Curran; Vivian Diaz; Elizabeth Fernandez; Brett Ginsburg; Melissa Han; David E. Harrison; Catherine Kaczorowski; Matt Kaeberlein; et al. (GeroScience, 2026)

N-lactoyl-phenylalanine as a possible biomarker of cognition? Association between neuroproteins, cytokines, body composition, physical fitness and cognitive function in older adults - Zbigniew Jost; Maciej Chroboczek; Marta Skurewicz-Palicka; Angelika Sawicka; Milena Deptuła; Małgorzata Zawrzykraj; Radosław Laskowski; Robert Antoni Olek; Zsolt Radák; Sylwester Kujach (GeroScience, 2026)

Fish consumption and cognitive function in aging: a systematic review of observational studies - Justyna Godos; Giuseppe Caruso; Agnieszka Micek; Alberto Dolci; Carmen Lili Rodríguez Velasco; Evelyn Frias-Toral; Jason Di Giorgio; Nicola Veronese; Andrea Lehoczki; Mario Siervo; Zoltan Ungvari; Giuseppe Grosso (GeroScience, 2026)

Sex dimorphism in the cardiovascular responses to d-galactose-induced accelerated aging: effects of HO-1 modulation - Sally Wahba; Olufunto O. Badmus; Andrew R. Wasson; Landon D. Parrow; Elshymaa A. Abdel-Hakeem; Merhan Mamdouh Ragy; Hanaa Mohamad Ibrahim; David E. Stec (GeroScience, 2026)
Chronic d-galactose (d-gal) injection is an experimental model of accelerated aging in rodents. However, the cardiovascular phenotypes of this model have been poorly characterized, especially as they relate to sex differences. The goal of this study was to investigate the cardiovascular effects of chronic d-gal injection in male and female C57BL/6 mice and the impact of HO-1 induction or inhibition in this model. Forty-eight 8-week-old male and female C57BL/6 mice were divided randomly into four groups ( n = 6): control, d-gal, d-gal + CoPP, and d-gal + ZnBG. Body weight, echocardiography, blood pressure measurement, Doppler ultrasound, echoMRI, micro-CT, histopathology, and protein analysis were performed. Our results show a strong sexual dimorphism in the cardiovascular effects of d-gal treatment and the effects of HO-1 induction or inhibition. Male mice were found to be more prone to systolic dysfunction and oxidative stress upon d-gal treatment and benefited more from the protective effects of HO-1 induction. Female mice were found to be protected from the cardiac effects of d-gal treatment yet were more prone to the effects of HO-1 inhibition. Our results demonstrate a sexually dimorphic response to the cardiovascular effects of d-gal treatment and alterations in HO-1. Graphical Abstract

Fifteen years on: a review of the Cam-CAN study of the cognitive neuroscience of ageing - Henson R.N.; Cam-CAN (GeroScience, 2026)
The Cambridge Centre for Ageing and Neuroscience (Cam-CAN, www.cam-can.org ) was established 15 years ago to investigate the cognitive and brain bases of healthy adult ageing. Demographic, health and lifestyle data, cognitive data and a wide range of brain imaging data, were shared with other researchers around the world, resulting in many scientific findings. Here we review these findings under the broad headings of ‘neuroscience of ageing’, ‘methodological developments’ and ‘clinical/translational use’, and look to future longitudinal continuation and sharing of further data.

Sensorimotor postural training induces multi-level cortical network reorganization in older adults enhancing efficiency and resilience - Yi-Ching Chen; Gwo-Ching Chang; Yi-Ying Tsai; Chen-Guang Zhao; Ing-Shiou Hwang (GeroScience, 2026)

Serum trace element levels and their associations with handgrip strength: a cross-sectional study among non-diabetic older adults in Germany - Barbaros Eroglu; Fabian Eichelmann; Julia Doerre; Olga Kuxhaus; Anna P. Kipp; Tanja Schwerdtle; Lutz Schomburg; Matthias B. Schulze (GeroScience, 2026)
Background Handgrip strength is an important marker of health status and is influenced by modifiable risk factors, including dietary intake. Trace elements (TE) copper, iron, iodine, manganese, selenium, and zinc are involved in physiological processes relevant to muscle function. However, the individual and interactive effects of these TE on handgrip strength have not been investigated in community-dwelling non-diabetic older adults. We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising 1432 participants (median age 67 years, 59% female). Serum TE levels were measured using inductively coupled plasma tandem mass spectrometry, and handgrip strength was measured using a dynamometer. Associations between TE and handgrip strength were investigated with multivariable regression models. Interactions and non-linear effects were assessed using Bayesian Kernel Machine Regression (BKMR). Higher serum manganese levels were inversely associated with handgrip strength in multivariable linear regression models ( β −0.011, 95% CI −0.019; −0.003). In logistic regression analyses, higher serum manganese levels were associated with higher odds of having low strength (OR per SD 1.25, 95% CI 1.10–1.48), and higher serum selenium levels were associated with lower odds of having low strength (0.83, 0.70–0.97). We did not observe any association between other TE and handgrip strength. BKMR analyses did not indicate strong interactive effects of TE on handgrip strength. Our findings indicate that higher serum manganese levels are associated with lower handgrip strength, and lower serum selenium levels are associated with higher odds of having low strength among community-dwelling non-diabetic older adults.

Resistance training effects on gait parameters in older adults—a systematic review with multilevel meta-analysis and meta-regression - Daniel Jochum; Stanislav D. Siegel; Gerit Plöschberger; Lea Fenske; Konstantin Warneke (GeroScience, 2026)
Falls are a leading cause of morbidity in older adults, and muscle weakness accompanied by gait impairments is a major contributing risk factor. Although current guidelines refer to resistance training, the literature lacks high-quality moderator analyses to evidentially guide clinicians to best treatment practice. This systematic review with meta-analysis opposed pooled resistance training effects to passive controls or active alternative interventions to distinguish specific resistance training effects from generally enhanced physical activity on gait and falls relevant outcomes. Effect sizes (ES) were pooled using robust variance estimation generally and for potential moderators. Ninety-two (92) studies with 5932 participants (mean age 73.1 ± 4.9 years) revealed large improvements in strength (ES = 0.86, p < 0.001) and moderate magnitude effects on gait outcomes (ES = 0.59, p < 0.001). Largest effects were reached for timed up-and-go (ES = 0.97), followed by gait distance (ES = 0.65), sit-to-stand (ES = 0.42), and gait speed (ES = 0.41) when compared with passive control. Active comparator analyses (stretching, walking, multicomponent exercises) outlined superior effectivity in the timed up-and-go performance (ES = 0.42) only. Supervision, progressive intensity regulation, and inclusion of multi-joint lower-limb exercises (leg press, squat, ankle plantarflexion, knee extension) positively affected results. Spatiotemporal and kinetic gait parameters were not significantly affected in general. Although some positive effects were observed when compared against a passive control, for most outcomes, the analysis questioned current guidelines as the specificity of resistance training effects was blurred by neglectable differences to alternative training interventions. This could be attributed to a dearth of high-quality evidence (long-term studies, reasonable intensity, and volume) on gait parameters in older adults. Graphical Abstract

Sex differences in stroke prognosis across reperfusion strategies: implications for prevention and quality of life - Henriette Mészáros; Péter Orosz; Zoltán Kővári; András Borbély; Balázs Kis; Máté Pásztor; Péter Pál Böjti; István Szikora; Gréta Zaja; Máté Kondor; Béla Merkely; Sándor Nardai (GeroScience, 2026)
Sex-specific trajectories of vascular aging may influence stroke recovery, yet their impact on access to reperfusion and long-term outcomes remains uncertain. We analysed 3760 consecutive patients with angiography-confirmed cerebral vessel occlusion transferred for endovascular therapy (EVT) between 2015 and 2022. Women accounted for 45.1% of patients and were significantly older (median 77 vs. 70 years) with greater baseline stroke severity (NIHSS 14 vs. 12). Access to acute stroke care was equivalent across sexes, including workflow intervals, intravenous thrombolysis, EVT use, and angiographic success (TICI 2b–3). In the full cohort, 12-month survival did not differ between sexes (log-rank p = 0.38). After 1:1 propensity score matching for age and NIHSS (1302 matched pairs), women showed markedly better 12-month survival (log-rank p < 0.0001). Among EVT-treated patients ( n = 2795), functional independence at 90 days was similar (mRS 0–2 in 49.2% of men vs. 47.8% of women; p = 0.58), while procedural safety profiles were largely comparable, with lower rates of PH2 haemorrhage in women (3.1% vs. 4.9%; p = 0.016). In a multivariable Cox model adjusting for comorbidities, intravenous thrombolysis, and reperfusion success, female sex remained independently associated with reduced 12-month mortality (HR 0.77, 95% CI 0.66–0.89; p < 0.001). These findings suggest a robust female survival advantage despite older age and similar access to modern reperfusion therapies. The results may implicate the presence of sex-specific resilience mechanisms relevant to vascular aging and postischaemic recovery, with implications for prevention and long-term poststroke management. Graphical Abstract

Associations of adherence to the EAT-Lancet and plant-based diets with mortality and life expectancy: two nationwide cohort studies - Xiaoqin Xu; Jiang Li; Jie Li; Wenqi Shen; Xiao Tan; Fei Xu; Wen Zhang; Ningjian Wang; Yingli Lu; Bin Wang (GeroScience, 2026)

Reproduction history and health-promoting behaviors are associated with successful aging and survival - Hanna Kujawska-Danecka; Barbara Wizner; Małgorzata Mossakowska; Jerzy Chudek; Monika Puzianowska-Kuźnicka (GeroScience, 2026)

Development and characterization of experimental β-cell senescence models revealing autophagy defects and altered stimulus–secretion coupling - Nanxiang Yin; Toshimasa Takahashi; Hiroki Hayashi; Taiki Sugimoto; Heedong Jeon; Weidong Liu; Yu Guo; Ziwei Wang; Cheng Wang; Akitoshi Hara; Yoichi Takami; Takashi Sakurai; et al. (GeroScience, 2026)

Graded normobaric hypoxia alters cerebral oxygenation and cognition in middle-aged adults: a single-blind counterbalanced randomized crossover trial - Ayoub Boulares; Corentin Faucher; Manuel Gimenes; Dimitri Theurot; Aurélien Pichon; Olivier Dupuy (GeroScience, 2026)

Independent and combined associations of maternal one-carbon nutrition biomarkers and dietary patterns with epigenetic age acceleration: Evidence from the Boston Birth Cohort - Nusrat Jabin; Guoying Wang; Xiumei Hong; Serena Rusk; Tina L. Cheng; Xiaobin Wang (GeroScience, 2026)

How should we study the impact of professional sport on female longevity? - George John; Ekaterina A. Semenova; Ildus I. Ahmetov (GeroScience, 2026)

CSF elevated Tau and P-Tau and normal Aβ42 mainly corresponds to Alzheimer’s disease with dementia with Lewy bodies - Olivier Bousiges; Benjamin Cretin; Lisa Battista; Caroline Schaeffer-Agalède; Nathalie Philippi; Lola Hamied; Alix Ravier; Catherine Demuynck; Candice Muller; Frédéric Blanc (GeroScience, 2026)

Modifiable risk factors associated with increased retinal age gap in an Australian population - Yuqing Lu; Ruiye Chen; Samantha Sze-Yee Lee; Gareth Lingham; Wenyi Hu; Michael Hunter; David A. Mackey; Zhuoting Zhu (GeroScience, 2026)
Retinal age gap (RAG)—the difference between retina-predicted age and chronological age—indicates biological ageing that has been linked to the risk of mortality and chronic disease. We aimed to identify risk factors associated with higher RAG in an Australian population. This cross-sectional study included 5107 participants from the Busselton Healthy Ageing Study (BHAS), a Western Australian community-based cohort. Retinal age was estimated using a validated deep-learning model applied to fundus photographs. Multivariable linear regression models were employed to examine associations between sociodemographic, lifestyle, and clinical factors and the RAG. RCS analysis was performed to investigate potential non-linear relationships and determine threshold effects between each risk factor and the RAG. A total of 4798 BHAS participants had available retinal images for RAG estimation, with a mean age of 58.0 years (SD = 5.8). Fifty-five percent were women, and around 1.5% identified as non-Caucasians. After adjusting for age, sex, and ethnicity, systolic blood pressure (SBP) ( β = 0.033, 95% confidence interval [CI]: 0.025–0.042, p < 0.001), diastolic blood pressure ( β = 0.052, 95% CI: 0.038–0.066, p < 0.001), body mass index (BMI) ( β = 0.065, 95% CI: 0.039–0.092, p < 0.001), alcohol consumption ( β = 0.146, 95% CI: 0.078–0.215, p < 0.001), and glycated haemoglobin (HbA1c) ( β = 0.461, 95% CI: 0.224–0.698, p < 0.001) were significantly, positively associated with RAG. This indicates the potential clinical use of RAG to facilitate epidemiological investigation, risk stratification, healthy ageing promotion, and reducing age-related disease burden.

Socio-economic position and healthy ageing across the life course: a systematic review of longitudinal studies - Yisheng Ye; Chengxu Long; Kia-Chong Chua; Darío Moreno-Agostino; Matthew Prina (GeroScience, 2026)
Increasing health inequalities among older adults globally illustrate the urgent need for effective interventions. Socio-economic position (SEP), which reflects an individual's social and economic standing, may affect healthy ageing through various life course mechanisms. However, longitudinal associations between life course SEP and healthy ageing as a multidimensional construct remain unclear. We conducted a comprehensive systematic review of longitudinal studies investigating the associations between life course SEP indicators (including education, income, occupation, wealth) and multidimensional healthy ageing outcomes. A systematic literature search was conducted across four databases (MEDLINE, Embase, PsycINFO, and Web of Science) from inception to April 2025. Due to the heterogeneity in the operationalisation of SEP and healthy ageing, a narrative synthesis was performed (Prospero CRD42023418728). 47 articles were included in the review. Across multiple SEP indicators and life stages, higher educational levels (39/43 studies) and higher income/wealth (31/36 studies) were positively associated with better healthy ageing outcomes. Occupation showed inconsistent evidence. Life-course evidence showed childhood SEP disadvantage predicted poorer later-life outcomes (13/17 studies), with cumulative multi-stage disadvantage showing additive effects (5 studies) and upward mobility conferring benefits (3 studies). These patterns manifested in three age-related inequality trajectories: widening (18/23 studies), convergence, and persistence, with education-cognitive disparities showing strongest widening effects. Cross-national evidence revealed regional specificities. Studies also identified sex/gender moderation effects (5 studies) and examined mediating pathways (6 studies). Higher education showed the most consistent protective effects, while income/wealth effects were complex. Health inequalities widened with age, highlighting lasting childhood impacts. Targeted interventions addressing early educational investment and life stage-specific strategies are needed for reducing healthy ageing inequalities.

A compound enhancing lysosomal function reduces tau pathology, microglial reactivity and rescues working memory in 3xTg AD mice - Zachary Mayeri; Georgia Woods; Anand Rane; Alex Kifle; Manish Chamoli; Shikha Shukla; Chaska C. Walton; Julie K. Andersen (GeroScience, 2026)

Escitalopram accelerated aging via impaired IIS/autophagy signaling pathway - Zi-Yi Chen; Cao-Yan Qi; Ji Feng; Kun Xue; Hong-Bo Quan; Jing Zhou; Wu-Zhong Liu; Guo-Dong Lu (GeroScience, 2026)

Women’s reproductive factors predict local brain aging profiles mapped using deep neural networks - Rachel Fox; Nikhil N. Chaudhari; Samayan Bhattacharya; Phoebe E. Imms; Teal S. Eich; Wendy J. Mack; Margaret Gatz; Andrei Irimia (GeroScience, 2026)
Deep neural networks (DNNs) trained on magnetic resonance images can estimate global brain age (GBA), which reflects women’s neurological disease risk. GBA gap (GBAG), the difference between GBA and chronological age (CA), quantifies excessive global aging; local BAG (LBAG) has not been examined despite allowing voxelwise resolution. Using a novel DNN architecture, we estimate LBAG for 12,284 UK Biobank females with chronological ages (CAs) ranging between 46 and 82 years (y) and quantify how it relates to cognition and women’s health variables (CA at menopause, reproductive span, menopausal hormone therapy (HT), contraceptive use (CU), number of births). Women with longer reproductive spans (-0.042/y ≤ β ≤ -0.037/y, p < 0.001) had older CAs at menopause onset (-0.052/y ≤ β ≤ -0.046/y, p < 0.001), more births (-0.230 ≤ β ≤ -0.190 per birth, p < 0.001) and younger brains (more negative LBAGs, younger GBAs); a 1-unit increase in each of these variables reflects an LBAG change of β y. Left temporal lobe effects of CA at menopause onset are strongest (-0.0517 ≤ β ≤ -0.0510, p < 0.001). Cognitive scores are related to LBAGs negatively and most strongly in subcortical and right-hemisphere cortex (-0.021 ≤ β ≤ -0.017 per score unit, p < 0.01). In postmenopausal women, delayed regional brain aging is predicted by longer endogenous hormone exposure indexed by later menopause onset, longer reproductive span, and more births. This research highlights the complex role of women’s health factors upon brain aging and related cognitive trajectories.

Association of physical activity with incident dementia and cognitive decline among Australian older adults - Yang Chen; Danijela Gasevic; Alice Owen; Shivangi Shah; Dragan Ilic; Joanne Ryan; Robyn L. Woods; Stella Talic; Rory Wolfe; Suzanne G. Orchard (GeroScience, 2026)

Knowledge of lifespan and healthspan and interest in Healthy Longevity Medicine among the general population in Singapore: the Singapore HEalthy LOngevity (HELO) survey - Jonas John Posko Amalaraj; Belinda Wang; Anna Szücs; Louis Island; Laureen Yi-Ting Wang; Liz J. Horberg; Paul A. O’Keefe; Sonny Rosenthal; Yap-Seng Chong; Johannes J. Meij; Andrea B. Maier (GeroScience, 2026)
Given the growing global interest in Healthy Longevity Medicine (HLM), the field lacks understanding about public knowledge and interest, which are crucial for any public health intervention relying on HLM. This study presents findings from the Healthy Longevity (HELO) survey conducted in Singapore, assessing public knowledge regarding lifespan (number of years a person is alive), healthspan (number of years a person spends in good health), and interest in HLM. This nationwide cross-sectional survey, conducted between June and August 2024, involved 3034 participants. Main domains including questions on demographics, living arrangements, medical information, health behaviours, income and financial status were tested for associations with knowledge about lifespan and healthspan, and interest in HLM clinics using binary logistic regression. While 82.3% of 46 years old [IQR, 34–59] participants correctly defined lifespan, 41.3% accurately defined healthspan and 55.5% expressed interest in HLM clinics. Younger age, male gender, Chinese ethnicity, higher education and income, full-time employment, lower body mass index, supplement use, moderate (vs. no) alcohol consumption, high exercise frequency and enrolment in (self-paid) annual health screenings were associated with better knowledge and stronger interest in HLM clinics. These findings highlight the need for targeted education to enhance understanding of healthspan and implement evidence-based preventive health programmes, supporting the clinical translation of geroscience into Precision Geromedicine through HLM clinics.

Longitudinal association of chronic periodontitis with all-cause dementia, Alzheimer disease, vascular dementia, and mild cognitive impairment: a distributed network analysis - Gyubeom Hwang; So Hee Lee; Sang-Won Han; YoungSoon Yang; Soyoung Lee; Yeshin Kim; Yerim Kim; Rae Woong Park (GeroScience, 2026)

Changes in ApoE and TIMP-1 expression correlate with outer blood-retinal barrier disruption in an in vitro model of retinal aging - Dillon Weatherston; Justin A. Jones; Elizabeth Vargis (GeroScience, 2026)
Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Unfortunately, the early stages of this disease are poorly understood, which has led to limited treatment options. Investigating normal changes in tissues eventually affected by AMD can further elucidate the mechanisms of disease progression and lead to novel therapeutic targets. The primary cell layer affected in AMD is the retinal pigment epithelium (RPE), which forms the outer blood-retinal barrier (oBRB). Beneath the RPE lies Bruch’s membrane, a proteinaceous layer that naturally thickens and stiffens with age. These changes to Bruch’s membrane are also implicated in RPE dysfunction and AMD progression. To investigate the relationship between normal, age-related changes in Bruch’s membrane and AMD development, we engineered a tunable in vitro model of Bruch’s membrane to support primary porcine RPE cells. We performed transepithelial electrical resistance (TEER) measurements, viability assays, morphological analysis, immunocytochemistry, and enzyme-linked immunosorbent assays (ELISA) to evaluate monolayer integrity and angiogenic factor expression. Cells cultured on our aged model exhibited changes similar to those seen in AMD, including reduced monolayer integrity, the formation of sub-RPE deposits, and eventual cell death. Notably, apolipoprotein E (ApoE), a known drusen component and Alzheimer’s disease marker, was overexpressed prior to deposit accumulation and cell death. Regions of ApoE overexpression corresponded with disrupted expression of zonula occludens-1, a junctional protein. While most angiogenic factors remained unchanged, tissue inhibitor of metalloproteinases-1 (TIMP-1) was transiently overexpressed before cell death. These findings suggest that ApoE and TIMP-1 may play key roles in early AMD pathogenesis and represent potential targets for future therapeutic intervention.

Age-related increase of NLRC4 inflammasome and TGF-β1 signaling exacerbates airway inflammation and remodeling in asthma - Jin-Hwa Kim; Hyun-Tae Kim; Jeong-Won Kim; Ji-Soo Jeong; Su-Ha Lee; Kwan-Hoo Kim; Na-Young Kim; Young-Hun Kim; Je-Won Ko; Tae-Won Kim (GeroScience, 2026)

Bidirectional prognostic predictions of conversion and reversion in amnestic mild cognitive impairment - Esther Zhiwei Zheng; Yue Gu; Rachel R. Jin; Tatia M. C. Lee (GeroScience, 2026)
Amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) are closely related. While some aMCI patients convert to AD (conversion), some revert to age-appropriate cognitive functioning (reversion). Early identification of these bidirectional trajectories informs aMCI-AD pathology and aids patient management. Data from 129 aMCI participants in the Alzheimer’s Disease Neuroimaging Initiative, who either converted or reverted, were analyzed. Baseline and longitudinal data relative to exact conversion and reversion times were incorporated to evaluate predictive power using support vector machine analysis. The accuracy of three models, each utilizing different data modalities, was compared. Neurobiological markers associated with these clinical trajectories were examined. The model incorporating brain volumetric changes achieved 92.31% accuracy in classifying conversion vs. reversion. Key neural markers included left inferior lateral ventricle volume for conversion times, left inferior temporal gyrus volume for cognitive status at conversion, and hippocampal and amygdala volumes for memory performance at conversion. The models offer bidirectional, prognostic predictions in aMCI patients. Identified markers provide valuable insights for early intervention. This study informs strategies to reduce AD incidence and optimize resource allocation, contributing to a more comprehensive understanding of disease trajectories and effective management.

Progression of fiber bundle damage in amnestic Alzheimer’s disease and LATE: a 2-year fixel-based study - Aurélie Lebrun; Yann Leprince; Pauline Olivieri; Martin Moussion; Camille Noiray; Michel Bottlaender; Marie Sarazin; Julien Lagarde (GeroScience, 2026)
Alzheimer’s disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are two neurodegenerative diseases underpinned by distinct proteinopathies, which share a similar initial amnestic clinical phenotype but have a different clinical course. Some pathophysiological models suggest a role for white matter (WM) fiber bundles in disease progression, but they remain discussed, as does their applicability to LATE. Using longitudinal fixel-based analysis, we investigated the progression of WM fiber bundle alterations over 2 years in early amnestic AD ( n = 16; clinical-biological diagnosis based on CSF biomarkers and amyloid/tau PET imaging), probable LATE ( n = 12; diagnosis based on recently published diagnostic criteria), and amyloid-negative controls ( n = 15). We explored the associations between baseline and longitudinal WM fiber bundle alterations and (i) cognitive/functional decline in both patient groups and (ii) baseline amyloid and tau load in patients with AD. In both AD and LATE, we found a 2-year progression of WM fiber bundle alterations in temporo-parietal and temporo-frontal tracts, most of which were altered at baseline, and to a lesser extent in the temporopulvinar bundle of Arnold. We also found a differential 2-year progression of the alterations according to pathology, affecting temporal, limbic tracts and the cingulum in AD, and bilateral superior longitudinal fasciculi in LATE. Low metrics within these fiber bundles at baseline were associated with a more rapid cognitive decline. We found only weak associations between WM fiber bundle alterations and baseline amyloid and tau PET. These results suggest a functional role for WM fiber bundle alterations in the progression of cognitive impairment, making this parameter a potential predictive marker of cognitive decline.

The protective role of companion animal ownership in cognitive aging: current status of the literature - Eszter Bálint; Virág Zábó; György Purebl (GeroScience, 2026)
Cognitive aging reflects underlying biological aging processes and is a key driver of late-life functional outcomes. Emerging evidence indicates that cohabitation with companion animals may influence multiple systemic pathways involved in cognitive aging, yet this potentially modifiable lifestyle factor remains underrecognized. The present narrative review synthesizes current evidence on how companion animals may influence cognitive aging through multilevel pathways, including both direct biological mechanisms and proximal psychosocial mediators. The reviewed literature suggests that companion animal ownership may counteract cognitive decline through several primary biological pathways, including stress regulation and neuroendocrine buffering, cerebrovascular and metabolic health, neuroplasticity and neuroimmune modulation, and neurovascular aging and vascular cognitive impairment processes. In parallel, companion animals may exert their effects through psychosocial pathways that ultimately operate via biological systems and indirectly affect cognitive aging through intrapersonal emotion regulation, interpersonal social facilitation, behavioral activation, and cognitive stimulation. We further identify possible key moderating factors shaping these associations, including gender, attachment strength, type and number of animals, cultural context, and the presence versus absence of a companion animal. Finally, we provide a concise overview of methodological approaches for assessing cognitive aging within the context of companion animal research. Overall, this perspective highlights possible cognitive benefits that can be associated with companion animal ownership which may arise from a dynamic interplay of biological, psychological, and social processes differentially modulated by individual, relational, and contextual factors.

Clonal hematopoiesis mutation is associated with risk of incident lung cancer and death - Ying Zhu; Chen Zhu; Ping Li; Ruiqi Ma; Dan Zhou; Kai Li; Jianzheng Zhang; Qiang Tong (GeroScience, 2026)

A blood-based metabolomics study of cardiovascular diseases in Swedish twins reveals apolipoprotein B biology as important for myocardial infarction - Asmus C. Skovgaard; Jonathan K. L. Mak; Ida K. Karlsson; Sara Hägg; Juulia Jylhävä; Mette Soerensen (GeroScience, 2026)
Cardiovascular diseases are the leading cause of death globally. Consequently, metabolomics studies have in recent years aimed at identifying relevant biomarkers, yet no studies have been performed in twin populations, which reduce confounding due to genetic and environmental factors. We included 11,217 twins (age at intake, 47–94 years (mean = 65)) from the Swedish Twin Registry, holding data on 173 nuclear magnetic resonance metabolomic biomarkers and nationwide register-based data on diagnoses of ischemic stroke, ischemic heart disease, myocardial infarction, angina pectoris, and coronary artery disease. Only incident cases (i.e., exclusively holding diagnosis after blood sampling) were included for statistical analyses, which were performed at the individual level and the twin-pair level by Cox regression analyses. Lastly, biomarkers significant in both analyses were inspected, hence conditioning on the twin pair design. Fifty-one biomarkers were found to be associated with myocardial infarction after correction for multiple testing, all showing a hazard ratio above 1. LASSO regression analysis of these biomarkers identified four biomarkers, all related to ApoB lipoprotein biology, potentially reflecting a pro-atherogenic effect. Investigation of biomarkers with p -values < 0.05 identified 20 biomarkers for ischemic heart disease, all showing hazard ratios below 1 and primarily related to ApoA1 lipoprotein biology, potentially reflecting an anti-atherogenic effect. Lastly, three biomarkers, i.e., acetoacetate, bOHbutyrate, and isoleucine, were found for ischemic stroke, all showing a hazard ratio above 1. Taken together, different biomarkers associated with the disease phenotypes indicate that their molecular profiles are different, despite their common basis. The ApoB stands out as a promising biomarker for myocardial infarction. Graphical abstract

Long-term risk of dementia with angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors in hypertensive patients: A 15-year follow-up using the 45 and Up Study - Eyayaw Ashete Belachew; Gregory M. Peterson; Mohammed S. Salahudeen; Jan Radford; Woldesellassie M. Bezabhe (GeroScience, 2026)
It is still unclear whether hypertensive patients using angiotensin II receptor blockers (ARBs) have a different risk of developing dementia compared with those taking angiotensin-converting enzyme inhibitors (ACEIs). We conducted a prospective cohort study using the 45 and Up Study Cohort in patients aged ≥ 45 years with hypertension who initiated ARB or ACEI therapy between 2004 and June 30, 2022. ARB/ACEI exposure was defined as having a supply that covered at least 80% of their follow-up period. Propensity score matching was used to balance baseline characteristics. We used the Cox proportional hazards model to estimate the risk of incident dementia. We included 51,574 patients with hypertension (mean age 66.3 (9.0) years; 48.2% women), with a mean follow-up of 11.3 (5.2) years. After controlling for major modifiable lifestyle factors such as diet and physical activity, ARB use was linked to a significantly reduced risk of dementia compared with ACEI use (hazard ratio [HR] = 0.72; 95% confidence interval [CI]: 0.65–0.80, p < 0.001). In exploratory agent-level analyses, compared with lisinopril, olmesartan (HR = 0.32; 95% CI: 0.16–0.62), candesartan (HR = 0.41; 95% CI: 0.24–0.69), telmisartan (HR = 0.42; 95% CI: 0.25–0.71), irbesartan (HR = 0.45; 95% CI: 0.27–0.75), and perindopril (HR = 0.52; 95% CI: 0.31–0.87) were associated with a significantly lower risk of dementia, while captopril showed a significantly increased risk (HR = 4.9; 95% CI: 1.04–23.4). The findings were consistent across subgroup analyses (sex, head-to-head ARBs vs ACEIs) and sensitivity analyses (excluding hypertension defined only by antihypertensive medication use, adjusting for competing risk of death or inverse probability of treatment weighting analysis). Among hypertensive patients, ARB use was linked to a reduced risk of dementia compared with ACEI treatment, regardless of diet and physical activity, and the effect varied across specific agents. These findings highlight the potential role of ARBs in dementia prevention; however, further randomised controlled trials are needed to confirm them.

Reference values for gait speed, five-times-sit-to-stand test, balance, and handgrip strength: analysis of data from the English Longitudinal Study of Ageing - Jozo Grgic; Vanessa Kristina Wazny; Ben Kirk; Eric Tsz-Chun Poon; Pedro L. Valenzuela (GeroScience, 2026)
Simple performance-based tests such as gait speed, the Five-Times-Sit-to-Stand Test (FTSST), balance tests, and handgrip strength are associated with health outcomes. We aimed to establish age- and sex-specific reference (normative) values for these tests in the English population. Adults aged ≥ 50 years (female n = 4,234; male n = 3,424) from the English Longitudinal Study of Ageing were included. Weighted percentiles ranging from the 5th to the 95th percentile [P5-95] were calculated. Best gait speed performance was found among 60–64-year-olds (female P5-95: 0.54–1.46 m/s; male P5-95: 0.60–1.56 m/s) and the worst among ≥ 85-year-olds (female P5-95: 0.23–0.98 m/s; male P5-95: 0.26–1.05 m/s). Best FTSST performance was found among 50–54- and 55–59-year-olds (female P5-95: 15.6–5.6 s; male P5-95: 14.1–5.5 s) and the worst among ≥ 85-year-olds (female P5-95: 26.3–9.8 s; male P5-95: 23.4–8.6 s). Balance tests showed variable age patterns; however, performance in single-leg balance with eyes closed was best among the youngest available age group and worst among the oldest available age group. The highest handgrip strength (standing position) was found among 50–54- and 55–59-year-olds (female P5-95: 15–38 kg; male P5-95: 32–58 kg) and lowest among ≥ 85-year-olds (female P5-95: 9–24 kg; male P5-95: 19–38 kg), with a similar pattern for the sitting testing position. These values can serve as a benchmark for clinical assessment, guide interventions, and support future research on physical function and healthy ageing.

Cardiovascular risk factors and vascular neuropathological findings in primary age-related tauopathy versus Alzheimer’s disease - Lisa Y. Xiong; Myuri Ruthirakuhan; Si Won Ryoo; Che-Yuan Wu; Jodi D. Edwards; Jennifer S. Rabin; Maria Carmela Tartaglia; Sandra E. Black; Julia Keith; Walter Swardfager (GeroScience, 2026)

Intrinsic capacity across the adult lifespan in China: baseline analysis from the nationwide longitudinal PENG ZU cohort - Ju Cui; Yujia Gu; Jing Pang; Huafang Gao; Li-Qun Zhang; Xiaolan Wu; Junwu Dang; Juan Li; Xinyi Zhu; Senlin Luo; Zhao Wang; Fuyi Tu; et al. (GeroScience, 2026)

Tracking the eyes to track decline: Global eye movement similarity as a novel neuropsychological marker of mild cognitive impairment - Zhan Wang; Hong-Zhou Xu; Fang Fang; Xue-Rui Peng; Ying-Chen Liu; Zhi-Jun Zhan; Jing Yu (GeroScience, 2026)

Aging increases visual dependency and disrupts sensory strategies in upright standing - Christophe Barbanchon; Stéphane Baudry (GeroScience, 2026)

Computerized cognitive training on touchscreen for elderly: a systematic review of randomised controlled trials - Maxime Macé; Tassadit Amghar; Paul Richard; Emmanuelle Ménétrier; Frédérique Robin (GeroScience, 2026)

Genome-wide association study of frailty and integrative functional analysis to elucidate its relationship with aging - Yujin Kwak; Soyoun Yang; Minju Yuk; Kwangyeon Oh; Changgyu Lee; Taehyun Lee; Hyun Jeong Kim; Boyoung Kim; Minseo Kang; Hanseul Park; Ji Min Han; Kyung Eun Lee; et al. (GeroScience, 2026)

Relationship between frailty and disease progression in Parkinson’s disease: a 3-year longitudinal study - Matteo Costanzo; Marco Canevelli; Maria Ilenia De Bartolo; Martina Valletta; Francesco Marchet; Marco Toccaceli Blasi; Giorgio Leodori; Antonella Conte; Giuseppe Bruno; Giovanni Fabbrini; Daniele Belvisi (GeroScience, 2026)
Parkinson’s disease (PD) shows substantial variability in presentation and progression. Frailty, a multidimensional construct reflecting biological aging, is a determinant of clinical outcomes in several neurodegenerative disorders. While cross-sectional studies suggest that frailty modulates the clinical phenotype of PD, affecting motor and non-motor symptoms, its longitudinal prognostic relevance remains unclear. In this 3-year, single-center cohort study, we investigated whether frailty, measured using a validated 50-item frailty index (FI), predicts clinical progression, motor complications, and mortality in a cohort of 109 PD patients. Clinical assessment included MDS-UPDRS parts III and IV, Non-Motor Symptoms Scale, Hoehn & Yahr stage, Montreal Cognitive Assessment, and levodopa equivalent daily dose (LEDD). Associations between baseline FI and follow-up outcomes were examined using simple and multiple linear regression models. Patients were stratified into three frailty groups at baseline to examine group-level differences in clinical progression and mortality, which were assessed using mixed-effects models and contingency analyses. Higher baseline FI independently predicted greater severity of treatment-related motor complications at follow-up ( β = 8.3; p = 0.04) and greater worsening of these complications over time ( β = 11.4; p = 0.017) and showed trends toward greater non-motor symptom burden and cognitive decline. No significant association was observed between baseline FI and motor progression. Patients classified as frail at baseline displayed greater clinical deterioration across multiple domains, higher LEDD requirements, and had increased mortality (χ 2 = 16.5, p < 0.001) compared to less frail counterparts. In conclusion, frailty predicts worse clinical trajectories and increased mortality in PD, supporting its utility as a prognostic biomarker. Incorporating frailty assessment into routine care may improve risk stratification and guide personalized therapeutic approaches in PD patients.

Circulating endotrophin reflects inflammaging and mortality risk in older adults - Clara F. G. Laursen; Federica Genovese; Morten Baltzer Houlind; Aino Leegaard Andersen; Morten Karsdal; Line J. H. Rasmussen; Juliette Tavenier (GeroScience, 2026)
Although interest in biomarkers of biological aging is growing, consensus on reliable, non-invasive indicators remains limited. Endotrophin, a bioactive fragment released during collagen type VI formation, reflects fibroblast activation and extracellular matrix remodeling and has been linked to chronic diseases, metabolic dysfunction, and inflammation. Whether circulating endotrophin also captures aging-related phenotypes and mortality risk in older adults remains unclear. We quantified serum endotrophin by the PRO-C6 assay in 1) acutely hospitalized Older patients ( n = 121) at admission (T -1 ), one-month post-discharge (T 0 ), and after 12 months (T 12 ); 2) Older controls ( n = 52) at T 0 (inclusion) and T 12 ; and healthy Young controls ( n = 59) at T 0 and one-month follow-up (T 1 ). Group differences and longitudinal trajectories were analyzed using linear mixed-effects models, and mortality associations were evaluated using Cox regressions. At T 0 , endotrophin levels were significantly elevated in Older patients compared to Older controls, while Young controls displayed substantially lower levels. Endotrophin remained stable over 12 months in Older controls, while Older patients showed a modest but significant overall increase. Higher endotrophin at T 0 correlated with markers of inflammation, frailty, and reduced physical function. Among Older patients, elevated endotrophin levels at T -1 and T 0 were associated with all-cause mortality, independent of demographic and clinical factors, though adjustment for inflammatory biomarkers attenuated the associations. These findings suggest that circulating endotrophin reflects disease burden, frailty, and prolonged physiological stress in acutely hospitalized older adults, while potentially overlapping with pathways of biological aging. Further studies in larger and more diverse cohorts are needed to establish its predictive and clinical utility.

Evaluating dementia risk prediction in mild cognitive impairment: an early health technology assessment of the AI-Mind tool - Robin J. Vermeulen; Marcel G. M. Olde Rikkert; Ron Handels; Ira R. J. Hebold Haraldsen; Hanna Renvall; Paolo M. Rossini; Camillo Marra; Fernando Maestú; Maroeska M. Rovers; Tim M. Govers (GeroScience, 2026)
This study aimed to evaluate the potential cost-effectiveness of implementing a prediction tool for estimating mild cognitive impairment (MCI) to dementia conversion risk. A decision-analytic model was developed to compare the costs and effects of current practice for subjects with MCI to a situation in which the risk of dementia is estimated using a prediction tool. Different scenarios in terms of prediction horizons, prediction characteristics (e.g. sensitivity and specificity), and treatment availability were evaluated. The model was applied to the AI-Mind tool, which is currently under development for predicting MCI to dementia risk. In a clinical situation, with no widely applicable and highly effective disease-modifying treatment available, implementing a dementia risk prediction tool leads to lower QALYs and higher costs compared to current practice without such a prediction tool (9.32 vs 9.36 QALYs and €115,837 vs €115,032 for the analyses in this paper). This loss in QALYs was caused by the impact on quality of life associated with predicted dementia conversion risk. Risk prediction followed by efficient treatment strategies based on the predicted risk could lead to a cost-effective alternative in case of specific treatment characteristics. These findings suggest that standalone (i.e. without highly effective treatment options) use of a dementia risk prediction tool may not be cost-effective, but it could result in a cost-effective alternative in combination with a treatment with favourable efficacy and cost profile. Graphical abstract

Aging-associated autoimmunity in genetically diverse UM-HET3 mice shows an early female sex bias - Harini Bagavant; Natalia Guzniczak; Magdalena Makuch; Makayla Tillett; Angelika Mazur; Elizabeth Fernandez; Umesh S. Deshmukh (GeroScience, 2026)

Sleep disturbances and Alzheimer’s disease: a multiscale approach from exposome to neurobiology and precision medicine - Masoud Tahmasian; Jorik D. Elberse; Reihaneh Ahmadi; Wen Liu; Ivana Rosenzweig; Sarah Genon; Simon B. Eickhoff; Bryce A. Mander (GeroScience, 2026)
Sleep disturbances and Alzheimer’s disease (AD) are interconnected public health challenges. However, the underlying mechanisms of their complex relationships remain elusive. Here, we propose a hypothetical integrative, stream-like model outlining how external and internal exposome factors accelerate brain aging, thereby exacerbating circadian dysregulation, orexin-mediated hyperexcitability, metabolic imbalance, and inflammaging. These changes can lead to increased sleep fragmentation and reduced slow-wave sleep, triggering widespread neuroinflammation, glymphatic dysfunction, and the accumulation and dissemination of beta-amyloid and tau peptides. These processes collectively accelerate synaptic dysfunction, neuronal loss, and cognitive decline. We also highlight recent neuroimaging evidence that elucidates the neural substrates underlying the relationship between poor sleep and AD. Moreover, tackling their shared burden necessitates the active consideration of inter-individual variability in vulnerable populations through artificial intelligence and computational approaches, aligning with the core tenets of precision medicine. We hope this review encourages clinicians to prioritize monitoring and treating sleep disturbances to reduce the incidence, severity, and consequences of dementia in the general population.

Integrated analysis of load-velocity profiles, muscle ultrasound measures, and lifestyle determinants in older adults with and without fall history - Daniel Jiménez-Lupión; Rodrigo Lizama-Pérez; Luis Chirosa-Ríos; Daniel Jerez-Mayorga (GeroScience, 2026)

Whole blood transcriptional signatures of age and survival identified in long life family and integrative longevity omics studies - Mengze Li; Zeyuan Song; Eric Reed; Tanya T. Karagiannis; Stacy Andersen; Michael Brent; Chase Mateusiak; Sandeep Acharya; Wooseok J. Jung; Shu Liao; Mary K. Wojczynski; Mary F. Feitosa; et al. (GeroScience, 2026)
Although aging is a universal event, some individuals are able to achieve extreme longevity. The Long-Life Family Study (LLFS) enrolls participants from families enriched with long-lived individuals, serves as a valuable dataset for studying ageing phenotypes and identify potential intervention targets. We analyzed the association between age at blood draw and 16,284 RNAseq-based blood transcriptomic data from 2,167 LLFS participants with ages ranging from 18 to 107, replicated the results in the Integrative Longevity Omics Study (ILO) dataset of 20,884 RNAseq-based blood transcriptomic data from 419 participants, with ages ranging from 60 to 108, and further compared our findings to a published reference aging signature. We identified 4,227 transcripts increasing and 4,044 transcripts decreasing with age, and enrichment analysis revealed age-related upregulation of inflammatory and senescence-related pathways, and downregulation of MYC and Wnt/β-catenin targets, among others. Further, a subset of transcripts showed age associations unique to the longevity-enriched cohorts (LLFS and ILO). We also identified 314 transcripts significantly associated with mortality risk and found that pro-survival gene sets included NK cell-mediated cytotoxicity and GPCR signaling. Finally, increased transcriptomic age predicted using transcriptomic clock was strongly associated with increased mortality. In summary, this study identified robust transcriptomic signatures of aging and mortality in a longevity-enriched population, highlighting key biological pathways such as immune modulation, inflammation, and senescence. Graphical abstract

Plasma-based strategies for systemic rejuvenation: critical perspectives on clinical translation - Rafal Gulej; Roland Patai; Anna Ungvari; Attila Tordai; Derek M. Huffman; Stefano Tarantini; Andriy Yabluchanskiy; Zoltan Ungvari; Anna Csiszar (GeroScience, 2026)
Experimental models such as heterochronic parabiosis and heterochronic plasma transfer have profoundly advanced our understanding of systemic aging, demonstrating that circulating factors can influence brain, vascular, and immune aging through cell nonautonomous mechanisms. These preclinical models have revealed that both pro-geronic and anti-geronic signals in blood can modulate neuroinflammation, neurovascular health, and cognitive resilience. However, despite their experimental promise, the clinical translation of these findings, particularly through plasma-based interventions in humans, remains fraught with uncertainty. This review critically examines the strengths and limitations of parabiosis-based paradigms as platforms for discovery, contrasts them with early human plasma infusion studies, and evaluates the current biological, medical, and ethical challenges associated with young plasma therapies. Therapeutic plasma exchange has also emerged as a potential rejuvenation strategy, but its mechanisms, efficacy, and longterm safety remain incompletely understood. We argue that future progress in systemic rejuvenation will depend on precise, mechanistically informed interventions—rather than broad, premature applications of plasma therapies, which require further validation through rigorous scientific investigation.

Functional fibrinolysis in older adults: clinical relevance and implications for personalised anticoagulation - Attila Besenyei; Zoltán Vajda; Gyula Domján; Dorina Markovics; Andrea Virág; Klára Gadó (GeroScience, 2026)
Age-related alterations of the haemostatic system substantially contribute to the heightened thrombotic and bleeding risk observed in older adults. While age-associated changes in coagulation have been extensively characterised, impairment of fibrinolysis remains comparatively underexplored, particularly in the context of anticoagulation management. Ageing promotes a hypofibrinolytic milieu through endothelial dysfunction, chronic low-grade inflammation, cellular senescence, and structural alterations of fibrin, resulting in reduced clot susceptibility to lysis. This narrative review synthesises current evidence on the biological mechanisms underlying age-related fibrinolytic suppression, critically evaluates available methods for functional fibrinolytic assessment, and discusses their potential clinical relevance in anticoagulated older adults. Throughout the manuscript, we explicitly distinguish between findings supported by clinical data in older populations, evidence extrapolated from non-geriatric or preclinical studies, and hypothesis-generating concepts. Although fibrinolytic phenotyping represents a compelling framework to explain thrombotic and bleeding events occurring despite guideline-concordant anticoagulation, its clinical implementation is currently constrained by limited assay standardisation, absence of validated thresholds, and lack of outcome-driven studies in geriatric populations. At present, fibrinolytic phenotyping should be regarded as a translational research tool rather than a basis for routine clinical decision-making. Prospective studies are required to determine whether phenotype-guided anticoagulation strategies can improve outcomes in older adults. Graphical Abstract Mechanisms, modifiers, and clinical framework of fibrinolytic ageing. Graphical overview summarising the biological mechanisms, lifestyle and metabolic modifiers, and conceptual clinical implications of age-related changes in fibrinolysis. The graphical abstract highlights key processes contributing to hypofibrinolysis in older adults and illustrates their potential relevance for thrombotic and bleeding susceptibility without implying clinical decision-making or therapeutic guidance.

Young blood-induced rejuvenation of neurovascular coupling involves endothelial IGF-1/IGF-1R signaling: evidence from heterochronic parabiosis using endothelial IGF-1R deficient and systemic IGF-1 knockdown mice - Rafal Gulej; Roland Patai; Siva Sai Chandragiri; Mark Nagykaldi; Evelyn Brunner; Peter Mukli; Dorina Nagy; Kiana Vali Kordestan; Shoba Ekambaram; Santny Shanmugarama; Raghavendra Yelahanka Nagaraja; Andriy Yabluchanskiy; et al. (GeroScience, 2026)
Aging is accompanied by progressive impairment of neurovascular coupling (NVC), the mechanism that matches local cerebral blood flow to neuronal activity, contributing to cognitive decline and the development of vascular cognitive impairment and dementia. Exposure to a young systemic milieu through heterochronic parabiosis has been shown to restore NVC in aged mice, suggesting that circulating factors can rejuvenate cerebrovascular function. Yet, the molecular mediators responsible for this effect remain poorly defined. Building on our long-standing research demonstrating that age-related decline in insulin-like growth factor-1 (IGF-1) signaling contributes to cerebrovascular aging and NVC dysfunction, and on recent transcriptomic evidence implicating IGF-1 receptor (IGF-1R) activation in vascular rejuvenation, we hypothesized that the IGF-1/IGF-1R axis plays a role in the young blood-induced restoration of NVC. To test this, we combined heterochronic parabiosis with two complementary transgenic approaches: systemic IGF-1 knockdown (TBG-Cre-AAV8/Igf1 fl/fl ) and endothelial-specific IGF-1R deficiency (VE-Cadherin-Cre ERT2 /Igf1r fl/fl ). NVC responses to whisker stimulation were assessed in the somatosensory cortex using laser speckle contrast imaging. Exposure of aged wild-type parabionts to young circulation markedly improved NVC responses, confirming the rejuvenating effect of young blood. This improvement was significantly blunted in aged parabionts paired with IGF-1–deficient young partners and in endothelial IGF-1R–deficient aged parabionts exposed to young blood. These findings demonstrate that both circulating IGF-1 and endothelial IGF-1R signaling contribute to, but do not fully account for, the restoration of NVC in aged mice. Together, our results identify IGF-1/IGF-1R signaling as a critical component of the molecular network through which young blood exerts its neurovascular rejuvenating effects, while indicating that additional circulating and endothelial pathways also participate in the systemic regulation of cerebrovascular aging.

The mediating role of muscle strength and body composition on the association between movement behaviours and health-related quality of life in Spanish older adults: the IMPACT65 + study - Julia Wiedmaier-Barros; Sara Higueras-Fresnillo; Kabir P. Sadarangani; Verónica Cabanas-Sánchez; David Martínez-Gómez (GeroScience, 2026)

Frailty assessment tools in the emergency department and their predictive value for clinical outcomes: review of the literature - Dana Shiffer; Francesco Reggiani; Antonio Voza (GeroScience, 2026)

Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease - Qi Zeng; Minghui Wang; Erming Wang; Xianxiao Zhou; Peng Xu; Vahram Haroutunian; Dongming Cai; Bin Zhang; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; et al. (GeroScience, 2026)
Alzheimer’s disease (AD) disproportionately affects women and carriers of the apolipoprotein E ε4 allele (APOE4), yet little is known about how sex and APOE interact to influence white matter (WM) integrity during disease progression. We integrated diffusion MRI and matched blood transcriptomic data to investigate these interactions and their underlying biological mechanisms. WM microstructure was quantified using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), and regional vulnerability was assessed with a composite vulnerability score (CVS) derived from associations between diffusion features and AD severity across clinical traits in each of the four sex-APOE groups (female or male, with or without APOE4). Brain parcellation with the Eve atlas revealed regions consistently affected across sex-APOE groups (e.g., parahippocampal and superior temporal gyri) and regions specific to individual groups (e.g., the cingulum in females with APOE4 and the middle frontal gyrus in males without APOE4). Gene co-expression network analysis of the matched blood expression data identified gene subnetworks linked to group-specific regional vulnerability, including a muscle tissue morphogenesis module regulated by NEURL1B and HIST1H2BN associated with middle frontal gyrus vulnerability. These findings demonstrate that sex and APOE genotype jointly shape region-specific WM vulnerability and its molecular signatures in AD. Understanding these interactions provides novel mechanistic insights and may inform precision approaches to drug development, biomarker discovery, and clinical trial design for AD.

Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity - Irini Topalidou; Nicolas Lehrbach (GeroScience, 2026)

Association between backward walking speed and physical balance and fall risk in community-dwelling older adults - Ziming Gong; Cen Chen; Lefei Wang; Ryuya Tanigawa; Eisei Harayama; Sitong Li; Hiro Kishimoto (GeroScience, 2026)
Backward walking is increasingly recognized as an alternative task for detecting balance deficits and fall risk in older adults. However, its utility as a functional indicator in healthy populations remains underexplored. This study aimed to investigate the potential associations between the backward walking speed (BWS), physical balance, and fall risk in community-dwelling older adults. In this cross-sectional study, 90 community-dwelling older adults were recruited. Self-selected backward walking speed (SBWS) was assessed together with the Berg Balance Scale (BBS), the Performance-Oriented Mobility Assessment (POMA), and the Fall Risk Index (FRI). Grip strength and cognitive function, evaluated using the Montreal Cognitive Assessment (MoCA), were also measured as covariates. Fear of backward walking (FoBW) was investigated using a self-administered questionnaire prior to the walking tests. Pearson correlation and multiple regression analyses were performed to examine the associations between SBWS, physical balance, and fall risk. The data of 84 participants (mean ± SD age 75.7 ± 5.0 years) were analyzed. Their mean forward and backward walking speeds were 1.36 ± 0.23 m/s and 0.73 ± 0.24 m/s, respectively. The SBWS showed moderate correlations with the Timed Up and Go (TUG) test (r = –0.52), forward speed (r = 0.49), and grip strength (r = 0.41), and weaker correlations with the BBS (r = 0.38), MoCA (r = 0.23) and FES-I (r = –0.34) . No statistically significant correlations were found between SBWS and POMA-Total (r = 0.20), FRI (r = 0.09). In adjusted regression models, SBWS was significantly associated with higher BBS scores (β = 3.744, p = 0.023) and lower TUG times (β = –1.488, p = 0.029) but not with the POMA-Total (β = 1.052, p = 0.344) or FRI (β = 3.001, p = 0.096). BWS may serve as a multidimensional indicator of physical and psychological vulnerability in older adults. Longitudinal studies with dynamic or dual-task assessments are necessary to validate its predictive value for fall risk screening.

Treatment with a selective androgen receptor modulator (RAD140) is linked to better cardiac function, with male-specific effects that are graded by interleukin-6 - Stefan S. Heinze; David G. Sapp; Alexander P. Young; Susan E. Howlett (GeroScience, 2026)

Pro-longevity compounds extend Caenorhabditis elegans male lifespan and reproductive healthspan - Rose S. Al-Saadi; Patrick C. Phillips (GeroScience, 2026)
Sex differences in aging are robust and ubiquitous. Demographic differences in aging generated by sex have long been recognized, but the underlying biological basis for these differences and the potential for sex-specific interventions remain understudied. To explore sex differences in the response to pro-longevity interventions, we utilized the C. elegans aging model and asked whether male lifespan and reproductive healthspan can be extended via compounds known to have pro-longevity effects in hermaphrodites. We tested seven different compounds at two concentrations each and found that lifespan was extended under all tested conditions. However, reproductive healthspan measured by mating success in late life improved under only two tested conditions, sulforaphane and metformin. These results demonstrate that lifespan and healthspan can be decoupled in C. elegans males and offer a new framework for screening pro-longevity compounds and for studying sex differences in aging in a classical aging model.

Peucedanum japonicum Thunb. ameliorates age-related muscle loss by improving mitochondrial function in aged mice - Young In Kim; Young-Soo Kim; Chang Hwa Jung; Jiyun Ahn (GeroScience, 2026)

Subtype-specific sirtuin expression signatures link mitochondrial–epigenetic networks to breast cancer survival - Zoltan Ungvari; Otília Menyhárt; Alberto Ocana; Andrea Lehoczki; Monika Fekete; Giampaolo Bianchini; Balázs Győrffy (GeroScience, 2026)
Sirtuins (SIRT1–SIRT7) are NAD⁺-dependent regulators of mitochondrial metabolism, chromatin remodeling, and stress resilience pathways—processes that are central to both aging biology and breast cancer (BC) heterogeneity. We systematically evaluated their prognostic and transcriptional patterns across molecular subtypes of BC. We constructed an integrated BC dataset comprising gene expression and survival data containing tumors from 55 datasets. Prognostic associations with recurrence-free survival (RFS, n = 4384) were evaluated by univariate Cox and Kaplan–Meier analyses using best cutoffs with FDR control, first for individual sirtuins and then for multigene combinations. Differential expression across normal, tumor, and metastatic tissues, as well as pairwise coexpression (Spearman’s ρ ), was assessed using the TNMplot platform. Among individual genes, SIRT3 showed the most consistent association with improved RFS across PAM50 subtypes. Multigene signatures outperformed individual sirtuins and displayed clear subtype specificity. A three-gene panel (SIRT3+SIRT5+SIRT6) stratified risk in Luminal A ( p = 8.1e-7), Luminal B ( p = 6.6e-6), HER2-enriched ( p = 1.0e-4), and Basal-like BC ( p = 3.8e-5). In Basal-like tumors, the combination of SIRT3, SIRT6, and SIRT7 achieved the best performance ( p = 2.6e-7). Top-performing panels were not simple aggregates of individually significant genes, indicating synergistic, context-dependent effects. Expression analyses revealed concordant downregulation of SIRT3 and SIRT5 in tumors, accompanied by consistent upregulation of SIRT7. Coexpression analysis revealed disease-specific rewiring: tumors exhibited a reinforced axis linking SIRT3/SIRT5/SIRT6/SIRT2, and attenuation of SIRT1 and SIRT4 coupling. Distinct integrated sirtuin scores thus capture subtype-specific metabolic/epigenetic states and provide robust RFS stratification across BC subtypes. These findings highlight sirtuins as integrators of longevity pathways and tumor metabolism, suggesting therapeutically exploitable vulnerabilities along NAD⁺-dependent regulatory axes.

Differences across males and females in cognitive aging and mortality risk: a trajectory-based approach - Elena Lobo; Concepción De la Cámara; Patricia Gracia-García; Raúl López-Antón; Pedro Saz; David Vaquero-Puyuelo; Antonio Lobo (GeroScience, 2026)
This study examined hypothesized differences across males and females in the relationship between cognitive trajectories and mortality in older adults. Data were drawn from the ZARADEMP study on dementia and depression in adults aged 55 and older in Zaragoza, Spain. A total of 2403 cognitively healthy individuals who completed at least three of four waves over a 12-year follow-up were included. Cognitive trajectories were derived from Mini-Mental State Examination (MMSE) scores. Using growth mixture modeling (GMM), four trajectories in men and three in women were previously identified. Mortality data, obtained from official records, covered up to 6 years after the final wave. Cox proportional hazards models assessed mortality risk across trajectories, adjusting for sociodemographic, medical, and lifestyle factors. Mortality was higher among participants with steeper cognitive decline in both sexes. In men, those in the declining-low and stable-medium trajectories had 133% and 36% higher mortality risk, respectively, compared to the stable-high group. In women, declining-low and stable-medium classes had 133% and 30% increased risk, respectively. The association in women followed a clear gradient; in men, this pattern was absent. Differences in mortality predictors were identified: medical conditions (e.g., hypertension, diabetes, alcohol use) were significant only in men, whereas psychosocial and functional variables (e.g., anxiety, ADL dependency, marital status) were significant only in women. This is the first report showing differences across males and females in the association between cognitive decline trajectories and mortality. Sex-specific strategies may be needed to mitigate mortality associated with trajectories of cognitive decline.

Capturing silent oxidative stress in early Alzheimer’s disease: prediction of CSF biomarkers from sleep qEEG data - Anna Michela Gaeta; Lorena Gallego Viñarás; Ferran Barbé; Pablo Martínez Olmos; Reinald Pamplona; Farida Dakterzada; Arrate Muñoz-Barrutia; Gerard Piñol-Ripoll (GeroScience, 2026)

Causes and extent of avoidable mortality across the european union: insights for advancing healthy aging - David Major; Vince Fazekas-Pongor; Nóra Kovács; Péter Pikó; Mónika Fekete; Zoltan Ungvari; Róza Ádány (GeroScience, 2026)
Although population aging is a global worldwide phenomenon, it is most pronounced in European Union countries. An unhealthy ageing population not only places a heavy burden on healthcare, but also hinders sustainable socio-economic development. Supporting healthy aging can be achieved through evidence-based strategies aimed at reducing avoidable mortality and interventions that promote these strategies. Our study is based on a secondary analysis of Eurostat data for 2022 to describe the extent and structure of avoidable (divided to preventable and treatable) mortality stratified by sex for each EU country. Cluster analyses based on avoidable mortality indicators (preventable mortality rate, treatable mortality rate, preventable-to-treatable mortality ratio, and male-to-female avoidable mortality rate ratio) and the cause-specific composition of avoidable mortality were used to highlight similarities and differences between countries. Classification based on the available mortality indicators revealed regional patterns. Western and Northern EU countries were predominantly in Cluster 1 which had the lowest preventable and treatable mortality rates, as well as relatively balanced sex ratios. However, these countries had a higher preventable-to-treatable mortality ratio indicating potential delays or gaps in preventive services. Mediterranean EU countries were in Cluster 2 showing moderate values for the avoidable mortality indicators and relatively low preventable-to-treatable mortality ratios. However, the male-to-female mortality ratio was high, indicating significant sex disparities. Central and Eastern-European EU countries were in Cluster 3 which had the highest burden of both preventable and treatable mortality. The preventable-to-treatable mortality ratio was lower than in Cluster 1, and the male-to-female mortality ratio was the highest in this cluster. Cluster analysis based on the cause-specific composition of avoidable mortality also identified three clusters with leading mortality causes as (1) cardiovascular diseases mainly in Clusters 2 and 3 countries; (2) cancer dominantly for Cluster 1 countries; and (3) high proportions of cardiovascular and alcohol-related mortality in mainly Cluster 3 countries. The clusters do not align perfectly (Adjusted Rand Index = 0.240, Normalized Mutual Information = 0.337), the two approaches complement each other. The first approach identified countries with similar levels and patterns in terms of preventable and treatable types of avoidable mortality, while the second approach highlighted similarities in the composition of health threats. Combining the two approaches offers a more detailed understanding of regional health profiles within the European Union, and enables the development of targeted interventions to reduce avoidable mortality and promote healthy aging.

Cardiorespiratory fitness in relation to cerebral vascular and metabolic health in older adults with coronary artery disease - Safa Sanami; Stéfanie A. Tremblay; Zacharie Potvin-Jutras; Ali Rezaei; Dalia Sabra; Christine Gagnon; Brittany Intzandt; Amélie Mainville-Berthiaume; Lindsay Wright; Mathieu Gayda; Josep Iglesies-Grau; Anil Nigam; et al. (GeroScience, 2026)

Evolvable soma theory of ageing: observations from the natural world - Alessandro Fontana (GeroScience, 2026)

Low-dose tamoxifen ameliorates ovariectomy-induced metabolic and immune dysfunction - Heather E. McClurg; Amanda Ferraro; Gina Pham; Itzel Morales-Hernandez; Estefania Valencia-Rincon; Kevin D. Pham; Willard M. Freeman; Jacquelyn A. Gorman; Marisol Castillo-Castrejon (GeroScience, 2026)
The decline in estrogen following menopause is a major driver of metabolic and immune dysfunction in aging females. While hormone replacement therapy improves many of these outcomes, its clinical use remains limited due to concerns regarding estrogen-sensitive malignancies. Tissue-selective estrogen complexes (TSECs), which combine estrogens with selective estrogen receptor modulators (SERMs) such as tamoxifen (TAM), represent a promising strategy to preserve the metabolic and immunological benefits of estrogen while reducing oncogenic risk. However, the systemic effects of TAM under conditions of estrogen deficiency remain incompletely defined. In this study, we investigated the metabolic and immunomodulatory actions of low-dose TAM, alone or in combination with 17β-estradiol (E2), in adult ovariectomized (OVX) female mice. OVX resulted in increased adiposity, hepatic steatosis, glucose intolerance, insulin resistance, immunoglobulin G3 (IgG3) concentration, and systemic inflammation, along with decreased immunoglobulin G1 (IgG1) concentration. E2, TAM, and E2 + TAM each attenuated OVX-induced adipose expansion, adipocyte hypertrophy, and proinflammatory cytokine production. TAM improved insulin sensitivity but did not fully restore glucose tolerance. Transcriptomic analysis of visceral adipose tissue-resident B cells revealed that E2 and E2 + TAM modulate overlapping yet distinct immune-regulatory networks, including suppression of pro-inflammatory signaling, regulation of immune checkpoints, and genes linked to adipose homeostasis. Low-dose TAM emerges as a modulator of estrogen receptor signaling that attenuates multiple features of OVX-induced metabolic and inflammatory dysfunction, though its limited effect on glycemic control highlights the need for tissue-specific evaluation of SERM-based interventions. These findings provide mechanistic insight into endocrine–immune–metabolic interactions and inform strategies to reduce aging-related disease risk in postmenopausal women. Graphical Abstract Created in BioRender ( https://BioRender.com/7ouhlqq ), Castillo M. (2025)

Randomized controlled trial of resistance exercise and brain aging clocks - Raul Gonzalez-Gomez; Naiara Demnitz; Carlos Coronel; Anne Theil Gates; Michael Kjaer; Hartwig R. Siebner; Carl-Johan Boraxbekk; Agustin M. Ibanez (GeroScience, 2026)
Exercise improves cognition, mental wellbeing, and protects against neurodegeneration. However, most prior neuroscience studies have focused on localized brain changes without quantifying their impact on brain ageing. To quantify the effect of resistance training on brain health using longitudinal assessments. Using resting-state functional magnetic resonance imaging (rs-fMRI) data from 2,433 healthy adults, we trained models to predict brain age and applied them to 309 participants from the Live Active Successful Aging (LISA) randomized trial. Participants in this trial were assigned to one of three groups: heavy-resistance training, moderate-intensity training, or a non-exercise control group. They underwent repeated rs-fMRI and physical fitness assessments at baseline, with follow-up assessments at 1 and 2 years. First, we examined changes in local connectivity between groups. Second, we assessed the impact of resistance training on brain ageing using brain clock models trained on the independent dataset of 2,433 adults. Local analyses revealed increased prefrontal functional connectivity following heavy training, while moderate- and heavy-resistance training significantly reduced brain age (–1.4 to –2.3 years, p FDR < 0.05). These effects emerged at the whole-brain level, rather than within isolated networks such as the default mode, motor, or cerebellar systems. These findings suggest a hierarchical organization of brain aging, driven by distributed network-level changes and expressed through focal regional patterns. Resistance exercise training decelerates brain ageing, as indexed by brain clocks, reinforcing its role as a preventive strategy for brain health.

Kidney function and all-cause mortality in the oldest-old population: a three-cohort longitudinal study - Hideaki Kurata; Shu Meguro; Yukiko Abe; Takashi Sasaki; Yasumichi Arai; Nobuyoshi Hirose; Kaori Hayashi (GeroScience, 2026)

The many meanings of Alzheimer’s disease and why they matter for policy, research, and care - Roderick A. Corriveau (GeroScience, 2026)
Alzheimer’s disease (AD) is a national priority with far-reaching implications for patients, families, clinicians, researchers, and policymakers. Yet the term AD refers to multiple distinct meanings that are often overlooked or ambiguously applied, risking misaligned research and policy priorities that affect patient outcomes. Recent FDA approvals of passive immunotherapies and related biomarker developments show that differing interpretations of AD complicate research, regulatory decisions, payer coverage, and clinical use. In contrast to efforts aimed at revising AD nomenclature, this paper clarifies five key meanings of AD as currently used. It provides a practical framework to indicate how the term AD is applied in different ways within and across clinical, research, regulatory, and policy contexts. Each key meaning—clinical (symptom-focused), genetically determined (mutation-driven), pathological (autopsy-confirmed), plaque-defined (amyloid-beta–plaque-positive), and broad (can encompass multiple dementia types)—may apply alone or in combination depending on context. These distinctions also raise ethical considerations, particularly for biomarker-based diagnoses and their impact on patient communication and decision-making. Using this framework helps decision-makers identify the intended AD meaning and align research, policy, and care for better patient outcomes.

Early-life exposures, biological age acceleration, and type 2 diabetes in adulthood: mediation analyses in the UK Biobank - Denghui Hu; Diana van Heemst; Qiuyu Feng; Ko Willems van Dijk; Raymond Noordam (GeroScience, 2026)
Early-life exposures could affect the risk of type 2 diabetes (T2D) in adulthood, but the mechanisms remain unclear. We included 319,951 (54.5% women) UK Biobank participants free of T2D at baseline and within the first year of follow-up to investigate whether early-life exposures contribute to T2D through biological aging estimated using the Klemera–Doubal (KDM) and PhenoAge methods. We first examined associations of exposures with biological age and T2D, respectively, using multivariable-adjusted linear models and Cox regression models. Next, we investigated the role of biological age acceleration in exposure-T2D associations using mediation analyses. Overall, the mean (standard deviation) chronological age of participants was 56.3 (8.1) years, KDM age was 40.9 (13.1) years, and PhenoAge was 44.4 (10.0) years. 17,062 T2D cases developed during a median (interquartile range) follow-up of 14.3 (13.5–15.0) years. Maternal smoking around birth, being part of a multiple birth, earlier puberty, and being relatively plumper or thinner at age ten were associated with both a higher biological age and T2D risk, while having a higher birth weight and being breastfed were associated with a lower T2D risk. Biological age acceleration partly mediated the exposure-T2D associations, ranging from a proportion of 8.3% (95%CI: 6.0–13.1%) of the association between birthweight-T2D being mediated by PhenoAge to a proportion of 27.7% (95%CI: 15.3–48.5%) of the association between breastfeeding-T2D being mediated by KDM. In conclusion, early-life exposures were associated with biological age acceleration that partly mediated the exposure-T2D associations, highlighting the importance of addressing early-life risks and biological aging in prevention strategies.

PTUPB improves cognitive function in Alzheimer’s disease associated with enhancing cerebral vascular myogenic response and attenuating vascular remodeling - Gilbert C. Morgan; Andrew Gregory; Chengyun Tang; Sung Hee Hwang; Jane J. Border; Jing Xu; Yedan Liu; Shan Bai; Tae Jin Lee; Cameron Cantwell; David Bunn; Karen M. Wagner; et al. (GeroScience, 2026)

Biopsychosocial frailty and the incident risk of cardio- and cerebrovascular diseases: an 8-year follow-up of the italian longitudinal study on aging - Vincenzo Solfrizzi; Emanuele Scafato; Madia Lozupone; Carlo Custodero; Vittorio Dibello; Donato Cirrottola; Claudio Pace; Marika Rizzato; Andrea Schilardi; Claudia Gandin; Silvia Ghirini; Rodolfo Sardone; et al. (GeroScience, 2026)

Spatial memory in Alzheimer’s disease 5XFAD mice is enhanced by XPO1 inhibitor KPT-330 - Shi Quan Wong; Adia Ouellette; Laura Harrison; Avery McNamara; Rachel A. Tam; Alexander Alexandrov; Acacia Nawrocik-Madrid; Jesus J. Sanchez; Brett C. Ginsburg; Arturo A. Andrade; Louis R. Lapierre (GeroScience, 2026)
The proteostatic decline in Alzheimer’s disease is well established, and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that the XPO1 inhibitor KPT-330 (Selinexor), an FDA-approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila . Here, we find that KPT-330 increases autophagy in murine neuronal cells. In a murine model of Alzheimer’s disease (5XFAD), KPT-330 improved spatial memory performance. Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that, despite overall increases in amyloid plaque burden, XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.

Correction to: Association of accelerated phenotypic aging, lifestyle and genetic risk with progression of cardiometabolic multimorbidity: a multi‑state model analysis - Yunxin Shi; Hongxian Wu; Lulu Pan; Yahang Liu; Chen Huang; Yongfu Yu; Guoyou Qin; Leqi He (GeroScience, 2026)

Histone modifications in biological age determination: mechanisms, biomarkers, and therapeutic perspectives - Anjali Tripathi; Garima Sharma; Vinay Kumar Pandey; Sarvesh Rustagi; Ashish Ranjan Sharma; Meenakshi Jha; Abhijit Debnath; Jomon George Joy; Jin-Chul Kim; Abhimanyu Kumar Jha (GeroScience, 2026)

Age-related changes in proprioception are of limited size, outcome-dependent and task-dependent - Stien Van De Plas; Jean-Jacques Orban de Xivry (GeroScience, 2026)

Plasma proteomic biomarkers as mediators for the associations between frailty phenotypes and chronic respiratory diseases - Yujia Bao; Shenghao Yuan; Jiawei Gu; Chen Shen; Linli Chen; Yibin Zhou; Jinjun Ran (GeroScience, 2026)
Frailty, a hallmark of systemic vulnerability in aging populations, is increasingly recognized in the clinical management of chronic respiratory diseases (CRDs). Molecular mechanism underpinning the relationships remain insufficiently elucidated. This study hence aimed to investigate whether proteomic biomarkers—circulating plasma proteins reflecting systemic inflammation, metabolism, and tissue remodeling—are associated with CRDs and may serve as potential mediators of the observed links. We analyzed data from a population-based cohort of 22,802 adults with proteomic measurements. Frailty was assessed by three phenotypes, including frailty index, physical frailty, and psychological frailty. Related-proteomic signatures were estimated by both linear and elastic regression models. Cox regression models were applied to explore the associations of frailty phenotypes and their proteomic signatures with incident CRDs, including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), as well as lung function outcomes, with full adjustments for potential confounders. Furthermore, mediation analyses were conducted to explore underlying mechanisms, complemented by pathway enrichment analyses to reveal relevant biological functions. Over a median follow-up of 13.2 years, 617 participants developed asthma, 701 developed COPD, and 228 developed IPF. Higher frailty index was associated with elevated risks of asthma (HR 1.95, 95% CI 1.64 to 2.31) and COPD (2.02, 1.71 to 2.38). Corresponding proteomic signature also related to increased risks of asthma (HR 1.22, 1.11 to 1.34) and COPD (1.65, 1.53 to 1.78). Mediation analysis suggested that the frailty index partially mediated the association with COPD, accounting for 26.0% (95% CI: 18.7 to 37.5%) of the total effect, respectively, particularly for GDF15, WFDC2, and PLAUR. Pathway enrichment analysis showed that these mediating proteins were predominantly involved in immune activation, inflammatory signaling, and metabolic stress responses. Frailty phenotypes contribute to elevated CRDs risks, partly through proteomic dysregulation in inflammatory and metabolic pathways. Graphic Abstract

Flavonoid intake and telomere length attrition among middle-aged women: a cross-sectional analysis of the Nurses’ Health Study - Sidong Li; Immaculata De Vivo; Sergio Davinelli; Martin Van Denburgh; Vincenzo Sorrenti; Giovanni Scapagnini; Howard D. Sesso; Aedín Cassidy (GeroScience, 2026)

Explainable AI reveals temporal risk pathways in fall prediction: Extracting clinical insights from multi-horizon machine learning models - Masoud Khani; David R. Friedland; Michael Widlansky; Michael S. Harris; Jazzmyne Adams; Lei Fan; Hyunkyoung Oh; Qiang Lu; Jake Luo (GeroScience, 2026)
Falls are a leading cause of injury in older adults, making risk prediction a clinical priority. While many machine learning (ML) models exist, they typically provide a static assessment, predicting risk for a single, fixed timeframe. This approach overlooks how the clinical drivers of risk evolve over time, failing to distinguish between acute factors that signal an imminent fall and chronic conditions that confer long-term vulnerability. This study uses an explainable ML framework across multiple time horizons to unlock deeper clinical insights into the temporal nature of fall risk. We conducted a retrospective, matched case-control study using electronic health record (EHR) data from 99,078 patients who fell and 99,078 matched controls. Seven ML models were trained to predict fall risk across seven distinct prediction windows (3, 6, 12, 24, 36, 48, and 60 months). The best-performing model for each horizon, consistently XGBoost, was interpreted using SHAP (SHapley Additive exPlanations) to identify how the importance of clinical and demographic predictors changed over time. A clear performance trade-off emerged across time horizons. Short-term models (3–12 months) delivered balanced discrimination (best model XGBoost, AUC ≈ 0.75), while long-term models became progressively better at identifying eventual fallers (recall ≈ 80% at 60 months) at the cost of lower specificity (≈ 46%). SHAP analysis revealed distinct temporal patterns: short-term risk was driven by acute conditions like syncope, respiratory symptoms, and urinary tract infections, while long-term risk was predicted by chronic, cumulative factors such as spondylopathies, nutritional deficiencies, and benign neoplasms. Three primary risk trajectories (increasing, steady, and decreasing) were identified, each corresponding to distinct underlying clinical profiles. Fall risk is a dynamic process, not a static state. By analyzing risk across multiple timeframes, we can distinguish between acute triggers requiring immediate intervention and chronic vulnerabilities demanding long-term management. This multi-horizon framework provides a data-driven foundation for a new paradigm in fall prevention: moving beyond generic “high-risk” labels to personalized, temporally aware strategies that align the type and timing of interventions with the specific nature of a patient’s evolving risk.

Extracellular exosome signature links hypertension and Alzheimer’s disease - Joakim A. Bastrup; Jonas Folke; Sanne S. Kaalund; Michel Rasmussen; Susana Aznar; Thomas Jepps (GeroScience, 2026)
Untreated hypertension is a risk factor for late-onset Alzheimer’s disease (AD); however, this association is not well understood. The aim of this study was to reveal protein signatures that bridge the pathophysiological changes in hypertension to AD. Using untargeted proteomics, we analyzed brain samples from aged (30- and 40-week-old) spontaneously hypertensive rats (SHRs, n = 12), and age-matched normotensive Wistar Kyoto (WKY, n = 8) controls, and human AD patients (Braak stages 4–6) ( n = 30), cerebral amyloid angiopathy (CAA) ( n = 5), non-demented controls (Braak stages 0–3) ( n = 37). Differential expression and pathway analyses in SHRs highlighted the ‘extracellular exosome’ pathway. This pathway also showed significant associations to differentially expressed proteins in AD and CAA patients. Comparison between species identified 24 proteins in SHRs and AD, whose trajectory pattern over the progression of hypertension, aligned with those observed during AD Braak stage progression, compared to respective controls. The proteins were similarly associated with extracellular exosomes. Immunostaining and spatial proteomics support vesicle accumulation and dysregulated exosome protein signatures in the cerebrovasculature of both SHR and AD brains. Additionally, the extracellular exosome pathway-association was not identified in a traditional model of familial AD (5xFAD). Our findings demonstrate cross-species translatability between AD and the SHR and provide novel mechanistic insights into a shared dysregulation of cerebral artery-associated exosomes. Graphical Abstract

Polluting cooking fuels and life satisfaction among middle-aged and older adults: a cross-sectional study from the Longitudinal Ageing Study in India - Imnameren Longkumer; Soohyeon Ko; Priyanka deSouza; Rohit Bhatia; Rockli Kim; S. V. Subramanian (GeroScience, 2026)

Novel multi-omic biomarkers to combat oocyte and ovarian aging - Pawel Kordowitzki; Shakchhi Joshi; Xutong Gong; Albert Kejun Ying; Jakub Wyroba; Joanna Kochan; Marcia C. Haigis (GeroScience, 2026)

Serum metabolomic signatures associated with frailty-related phenotypes in a cohort of older people - Céline Bougel; Rémi Servien; Nathalie Vialaneix; Elise Maigne; Yves Boirie; Clément Lahaye; Cécile Canlet; Laurent Debrauwer; Valentin Max Vetter; Kristina Norman; Dominique Dardevet; Ilja Demuth; et al. (GeroScience, 2026)

Quantile regression of the relationship between demographic factors and leukocyte telomere length, measured by Southern blot and qPCR - Kyra Jennifer Waligora Mendez; Sang Kyu Lee; Casey Dagnall; Tsung-Po Lai; Hormuzd Katki; Stephen R. Spellman; Valerie Stewart; Abraham Aviv; Shahinaz M. Gadalla; Hyokyoung G. Hong (GeroScience, 2026)
Telomere length (TL) is associated with health outcomes. Southern Blotting (SB) is the gold standard of TL measurements, while qPCR-based TL measurements are the most used because of their high throughput. We compared leukocyte TL (LTL) measurements by SB and qPCR, and their ability to capture LTL associations with demographic factors. This study included 908 healthy donors for hematopoietic cell transplantation who had blood samples and data available at CIBMTR®. We used quantile regression (QR) to assess the associations between selected demographic factors and LTL across the LTL distribution. Pearson correlation coefficient and Bland–Altman plot were used to compare SB-LTL and qPCR-LTL measurements. SB-LTL and qPCR-LTL were modestly correlated ( r = 0.58, P < 0.001). On average, SB-LTL shortened by 29 base pairs (bp) per year and was 190 bp longer in females than in males. QR analyses showed that the association between SB-LTL and age varied across the LTL distribution, with stronger age-related shortening at higher percentiles (25 bp at the 25th percentile vs. 31 bp at the 75th percentile; P = 0.003). Females had longer SB-LTL than males across all percentiles ( P < 0.05 in SB-LTL analysis), and the magnitude of this sex difference did not vary significantly across the LTL distribution (157 bp at the 25th percentile vs. 221 bp at the 75th percentile; P = 0.33). Both SB and qPCR showed an inverse relationship between LTL and age, though the magnitudes differed between methods. Considering the full LTL distribution in studies of lifestyle factors and diseases may provide better molecular insights and guide LTL utilization in health applications.

Single-cell immune atlas of mouse testes unveils metabolic reprogramming of FOLR2 + macrophages in orchestrating testicular immunity during aging - Xinyu Li; Min Zhang; Ani Chi; Jiahui Mo; Xiaofeng Tan; Hongde Chen; Chunhua Deng; Xiangzhou Sun; Xin Feng; Zhihong Chen (GeroScience, 2026)

Functional connectivity correlates of sequence memory decline in healthy older adults - Catalina Trujillo-Llano; Nina M. Ehrhardt; Anna Elisabeth Fromm; Friederike Thams; Dayana Hayek; Shu-Chen Li; Agnes Flöel; Daria Antonenko (GeroScience, 2026)
Episodic sequence memory is crucial for daily functioning and typically declines during aging. However, the neural mechanisms underlying this decline remain poorly understood. We examined the resting-state functional connectivity (FC) correlates of sequence memory in healthy older adults (OA), with a young adult (YA) group included for comparison. Thirty-eight OA (mean ± SD age: 69.9 ± 3.9 years; 24 women) and 20 YA (mean ± SD age: 24.2 ± 3.4 years; 14 women) completed a sequence memory task and resting-state functional magnetic resonance imaging (rsfMRI). Participants encoded sequences of greyscale pictures presented in colored frames and retrieved their sequential order. We compared the sequence memory performance (% correct) between age groups and examined associations between performance and seed-based FC patterns within each group, focusing on hippocampal and default mode network (DMN) regions. OA exhibited poorer sequence memory performance than YA. In OA, lower performance was associated with reduced FC between the left posterior hippocampus and DMN hubs, and the DMN and right posterior parietal cortex, suggesting that reduced intrinsic coupling within memory networks and between memory and attention networks contributes to sequence memory decline in aging. In YA, superior sequence memory performance correlated with higher FC between the left posterior hippocampus and right medial occipital cortex, indicating that hippocampal-perceptual integration benefits memory function. The FC in these networks did not differ between age groups, indicating a potential shift in memory-relevant connectivity in older adults rather than reduced network function per se. Our findings provide novel evidence of large-scale network correlates underlying sequence memory decline in old age and suggest qualitatively distinct connectivity patterns supporting sequence memory in young and older adults.

Factors associated with the risk of falls and their relationship with cognitive function in older adults with cognitive impairment: a cross-sectional study - María del Mar Carcelén-Fraile; María del Carmen Carcelén-Fraile; Fidel Hita-Contreras; Yolanda Castellote-Caballero; Agustín Aibar-Almazán (GeroScience, 2026)

Cytokine-induced senescence in tumors is based on sustained activation of STAT1- and NFκB-dependent gene regulatory signatures - Maximilian Rentschler; Mohamed Ali-Jarboui; Christoph M. Griessinger; Michael Rosen; Grégory Doré; Oliver Bischof; Manfred Kneilling; Martin Röcken; Heidi Braumüller; Thomas Wieder (GeroScience, 2026)
Senescence is a tripartite cellular phenotype characterized by permanent growth arrest, resistance to apoptosis, and high secretory activity. Besides its physiological role in embryonic development and pathophysiological contribution to age-related tissue degeneration, in the context of tumor development senescence is an important suppressor mechanism, that counteracts accelerated proliferation. Among the many stressors that induce senescence is the external stimulation by cytokines. Although cytokine-induced senescence (CIS) has repeatedly been reported in the literature, the signaling networks leading to the senescent phenotype remained enigmatic. Here, we used two models of tumor-associated (TA)-CIS: (i) in vitro treatment of human A204 cancer cells with interferon (IFN)-γ and tumor necrosis factor (TNF) and (ii) in vivo senescence induction by adoptive transfer of T helper 1 (T H 1) cells into tumor-bearing RIP-Tag2 mice. In both models, gene expression profiling and signal transduction analysis highlighted the persistent activation of IFN-receptor/STAT1 and TNF-receptor/NF-κB/p38 signaling leading to downregulation of cell cycle genes, upregulation of secretory factors and, remarkably, upregulation of pro-apoptotic as well as anti-apoptotic genes. Protein analysis further demonstrated that the growth-arrested tumor cells were not subject to apoptotic death. Altogether, we define a cross-species TA-CIS core gene and signal transduction signature that may be exploited for therapeutic ends for cancer. Graphical abstract

Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults - Malte Schmücker; Cathrine Tranberg; Jacob Borch; Mette Killerup Kaae; Michelle Damgaard; Mathias Flensted-Jensen; Ida Blom; Marco Morosetti; Sara Barbarossa; Patrick Orlando; Luca Tiano; Flemming Dela; et al. (GeroScience, 2026)

Liver-specific phenotypic aging, behavior and genetic risks, and long-term liver-related outcomes - Tianhao Wu; Chengnan Guo; Huangbo Yuan; Mingyi Du; Tiejun Zhang; Xingdong Chen; Zhenqiu Liu (GeroScience, 2026)

Lifetime non-relational traumatic experiences are associated with biological ageing - Thole H. Hoppen; Nexhmedin Morina; Monica Aas; Julian Mutz (GeroScience, 2026)
Exposure to non-relational trauma, such as serious accidents, war or life-threatening illness, is linked to poor mental and physical health. Its relationship with biological ageing markers, however, remains underexplored. This study's aim was to examine associations between non-relational trauma and multiple biological ageing markers, and to assess whether associations vary by trauma burden, trauma type and sex. We analysed UK Biobank data from 152,863 participants (mean age = 56.4 years; 56.5% female). Lifetime exposure to six non-relational traumatic experiences was assessed. Biological ageing markers included metabolomic age (MileAge) delta, a metabolomic mortality profile score, frailty, leukocyte telomere length and grip strength. Regression models, adjusted for demographic and socioeconomic confounders, estimated associations between trauma and biological ageing markers. We also examined trauma burden, trauma type-specific and sex-specific associations. Non-relational trauma was associated with a metabolite-predicted age exceeding chronological age (MileAge delta; β = 0.047, 95% CI 0.032–0.062), elevated metabolomic mortality scores ( β = 0.102, 95% CI 0.051–0.153) and greater frailty ( β = 0.298, 95% CI 0.290–0.307), with a graded, approximately linear pattern for frailty (i.e., higher non-relational trauma sum scores were associated with higher frailty scores). All trauma types were associated with greater frailty, with the strongest association for life-threatening illness. There was no evidence of associations with telomere length, and mixed findings for grip strength. Several associations differed by sex, for example overall trauma burden was more strongly associated with greater frailty in females compared to males. Lifetime non-relational trauma was associated with older biological ageing profiles, with the strongest associations with frailty. These findings support the notion that non-relational trauma exposure is associated with long-term health status, underscoring the need for mitigating ageing-related health decline in trauma-exposed populations.