Aging-related decline in the liver and brain is accelerated by refined diet consumption - Franziska Kromm; Haktan Övül Bozkir; Annette Brandt; Timur Yergaliyev; Amélia Camarinha-Silva; Ina Bergheim (GeroScience, 2025)
Studies suggest that diets rich in highly/ultra-processed foods may contribute to the development of diseases. In rodents, the intake of refined (purified) diets has also been associated with the development of various metabolic diseases. Here, performing two experiments, we assess the impact of a refined diet with and without fiber enrichment on aging related health decline in mice. Experiment 1: Male C57BL/6J mice were fed standard chow or refined diet until the age of 86 weeks. Experiment 2: Male C57BL/6J mice fed a refined diet until showing signs of aging related intestinal barrier dysfunction were fed a fiber enriched refined diet (7.5% oat β-glucan or 7.5% cellulose) for 18 weeks. Cognition was assessed at the beginning and end of the dietary fiber intervention, while glucose tolerance was determined at the end of each experiment. Markers of senescence, liver damage, neuroinflammation, intestinal barrier function, and microbiota composition were assessed. Refined diet-fed mice showed higher markers of senescence in plasma and aging-associated liver decline, impaired glucose metabolism and cognitive decline compared to standard diet-fed mice. These changes were associated with differences in intestinal microbiota composition and higher portal bacterial endotoxin levels. Enriching the refined diet with the fibers decelerated the aging-associated cognitive impairments while not affecting aging-related liver decline, insulin resistance or markers of intestinal barrier function. In conclusion, these data suggest that while decelerating aging-related cognitive decline, fiber fortification of a refined diet may not attenuate the diet-induced acceleration of aging related decline in other organs in mice.

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice - Kassandra R. Bruner; Isabella R. Byington; Tyler J. Marx; Anastasiia Vasileva; Temara Fletcher; Susma Ghimire; India J. Zappia; Yashika Shaju; Janan Zeng; Hallie R. Wachsmuth; Thadeus W. Carlyon; David G. Besselsen; et al. (GeroScience, 2025)
Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging, we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient-sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgr hep−/− ). Liver-specific deletion of the glucagon receptor decreases hepatic AMP kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice but not in Gcgr hep−/− mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction. Graphical Abstract

Functional assessments of short-term spatial memory in the Dog Aging Project identify strong associations with age that are not moderated by body mass - Stephanie H. Hargrave; Amber J. Keyser; Emma Kristal; Gene E. Alexander; Theadora A. Block; Emily E. Bray; Laura E. L. C. Douglas; Brenda S. Kennedy; Daniel E. L. Promislow; David A. Raichlen; Dog Aging Project Consortium; Evan L. MacLean (GeroScience, 2025)

Air pollution and impulsive choice in aging: evidence from delay discounting - Maya R. Kilcullen; Jamie-Nicole Luistro; Melanie Kos; Jeremy Mennis; David V. Smith; Ingrid R. Olson (GeroScience, 2025)
Heightened air pollution exposure is associated with an increased risk for developing neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, yet it is unclear how pollution impacts the aging brain more broadly. Rodent research has shown that higher air pollution exposure is associated with increased impulsive behavior, operationalized as a preference for immediate reward in delay discounting tasks. We examined this relationship in middle-aged and older humans by analyzing associations between residential pollution exposure and time-based reward preferences. One hundred three (103) adults aged 40–80 completed a delay discounting task. We estimated long-term residential exposure to fine particulate matter (PM 2.5 ), a prominent air pollutant, using participant address information and satellite pollution data. We found that higher residential PM 2.5 exposure was significantly associated with a higher preference for more immediate rewards, even after controlling for demographic factors including income and education. A preference for immediate rewards has been independently associated with a higher risk of addictive behaviors, including substance abuse and gambling disorders, indicating that PM 2.5 exposure may increase the emergence of these conditions. We discuss these results in detail along with potential underlying biological mechanisms, implications on human behavior, and future research directions.

Real-world walking patterns are associated with regional brain atrophy and white matter lesions in middle-aged and older people: a Watch Walk–UK Biobank study - Takahiro Tajimi; Lloyd L. Y. Chan; Yoshiro Okubo; Stephen R. Lord (GeroScience, 2025)

Impaired early type I interferon responses to influenza virus infection in aged mice are associated with subsequent increased pulmonary inflammation - Wenxin Wu; Jeremy S. Alexander; J. Leland Booth; Chaoqun Huang; Lin Liu; Craig A. Miller; Douglas A. Drevets; Jordan P. Metcalf (GeroScience, 2025)

Delirium in hospitalized COVID-19 patients is associated with dynamic changes in peripheral immune gene expression - Sara C. LaHue; Naoki Takegami; Rubinee Simmasalam; Abiya Baqai; Elena Munoz; Anya Sikri; Thibault du Buisson de Courson; Nilika S. Singhal; Walter Eckalbar; Charles R. Langelier; Carolyn M. Hendrickson; Carolyn S. Calfee; et al. (GeroScience, 2025)
Delirium is a neurologic syndrome characterized by inattention and cognitive impairment frequently encountered in medically ill older adults. As a hallmark of age-related brain vulnerability, delirium offers a clinical model to investigate how peripheral immune responses contribute to acute brain dysfunction. Peripheral inflammation is a key trigger of delirium, but the patient-specific immune responses that drive delirium onset and recovery remain poorly understood. This retrospective cohort study of prospectively collected biospecimens examines RNA sequencing from peripheral blood mononuclear cells of adults hospitalized for COVID-19 to better understand patient-specific factors associated with delirium ( n = 64). Longitudinal transcriptomic analyses highlight persistent immune dysregulation in delirium, marked by increasing expression trajectories of genes linked to innate immune pathways, including complement activation, cytokine production, and monocyte/macrophage recruitment. Genes involved adaptive immunity showed a declining trajectory over time in patients with delirium. Although corticosteroid treatment suppressed some aspects of immune hyperactivation, aberrant responses contributing to delirium were exacerbated. Delirium resolution was characterized by normalization of key transcripts such as CCL2 and innate immune markers. Novel associations with delirium included transcripts related to stress granule assembly and the T cell regulators DUSP2 and KLF10 . Delirium in COVID-19 is associated with distinct and dynamic peripheral immune trajectories that are modulated by corticosteroids. Further understanding these mechanisms has important implications for preventing delirium in older adults. These findings provide novel mechanistic insights with translational relevance for immunomodulatory strategies targeting maladaptive immune responses to prevent or treat delirium in medically ill populations.

Exploring the impact of metformin on testicular aging in Syrian hamsters - Alina Cavallotti Gomez; Soledad Paola Rossi; Thaisy Munduruca Pires; Ricardo Saúl Calandra; Vanina Gabriela Da Ros; Débora Juana Cohen; Juan Manuel Riaño Gómez; María Silvia Bianchi; María Susana Theas; María Eugenia Matzkin; Mónica Beatriz Frungieri (GeroScience, 2025)

Substrate stiffness dictates unique paths towards proliferative arrest in WI-38 cells - Alyssa M. Kaiser; Amirali Selahi; Wenjun Kong; J. Graham Ruby (GeroScience, 2025)
Finite replicative potential is a defining feature of non-transformed somatic cells, first established by Leonard Hayflick in vitro using WI-38 human lung fibroblasts. Once proliferative capacity is exhausted due to telomere shortening, cells enter into a state called replicative senescence, which can be avoided through ectopic expression of telomerase reverse transcriptase (hTERT). As WI-38 cells approach replicative arrest, molecular pathways linked to mechanotransduction are induced, including YAP signaling, but the potential interplay between replicative lifespan and the mechanical environment of the cell remains unexplored. Here, we investigate the influence of mechanosensation on the trajectory towards replicative arrest taken by WI-38 cells by growing cells on substrates of varying stiffnesses. Matrix softening slowed proliferation, altered cellular phenotypes, and shortened proliferative lifespan while hTERT expression abrogated or reduced these responses. Our analyses of bulk and single-cell RNA-sequencing and ATAC-sequencing revealed the emergence of a unique G1 transcriptional state on soft substrates, characterized by an AP-1 transcription factor program, which failed to manifest with hTERT expression. Together, these findings reveal how the mechanical environment alters WI-38 cell proliferative lifespan and dictates unique paths towards growth arrest.

Social frailty and mortality risk in middle-aged and older adults: a prospective cohort study - Meng Hao; Zixin Hu; Xu Zhang; Xiangnan Li; Shuming Wang; Yi Li; Jingdong Tang; Shuai Jiang; Hui Zhang (GeroScience, 2025)

Extension of lifespan by epicatechin, halofuginone and mitoglitazone in male but not female genetically heterogeneous mice - Randy Strong; James F. Nelson; Molly A. Bogue; Jerry R. Colca; Martin Denzel; Vivian Diaz; Brian N. Finck; Vadim N. Gladyshev; Steve Horvath; Nisi Jiang; Tracy Keller; Rolf F. Kletzien; et al. (GeroScience, 2025)
Mice bred in 2021 were tested by the Interventions Testing Program (ITP) for possible lifespan benefits of 2BAct (2BA), dichloroacetate (DCA), Epicatechin (EPI), Forskolin (FSK), Halofuginone (HAL) and Mitoglitazone (MIT). All agents were administered in the diet ad libitum beginning at 7 months of age. In male mice, EPI increased median lifespan by ~ 5%, and HAL and MIT each increased median lifespan by ~ 9%. EPI and HAL, but not MIT, increased 90% survival. In addition to adding 3 new agents to the list of interventions identified by the ITP that extend lifespan, this report continues the strong male bias in the efficacy of life-extending drugs identified so far.

Association between periodontal disease and intrinsic capacity in older adults: insights from NHANES 2009–2014 - Vittorio Dibello; Silvano Quarto; Raffaele Cavalcanti; Carlo Custodero; Claudia Chiapparino; Madia Lozupone; Domenico Lafornara; Fabio Castellana; Roberta Zupo; Giuseppe Pistoia; Antonio Dibello; Antonio Daniele; et al. (GeroScience, 2025)

Short-term mTOR inhibition by rapamycin improves cardiac and endothelial function in older men: a proof-of concept pilot study - Alexander J. Moody; Yubo Wu; Terry Q. Romo; Wouter Koek; Jinqi Li; Leslie A. Linehan; Geoffrey D. Clarke; Eric Y. Yang; Sara E. Espinoza; Nicolas Musi; Robert J. Chilton; Ellen Kraig; et al. (GeroScience, 2025)
Rapamycin (RAPA) and related mTOR-inhibitors have been shown to enhance healthy aging in animal models (2–10) and to be generally safe and tolerable in older people (11–13). However, studies to assess their effects on specific age-related pathologies in humans are limited. Since improvements in cardiovascular function with RAPA treatment have been reported in preclinical studies (5, 9, 10, 14–17), we posited that RAPA could be similarly efficacious in humans. Towards this end, we performed a pilot “proof of concept” trial to examine RAPA’s effects on cardiovascular and endothelial functions that are known to decline with age (18, 19). We hypothesized that RAPA would elicit beneficial cardiovascular effects in men. A cohort of older male subjects with no known cardiac disease (ages 70–76 years) were enrolled in the open-label study and received 1 mg RAPA/day for 8 weeks. To assess cardiovascular function, cardiac MRI (CMR) was performed twice: prior to initiation of the intervention and again after 8 weeks of treatment. Endothelial function was examined using laser-Doppler flowmetry (LDF) by measuring cutaneous, endothelium-dependent, local thermal hyperemic responses pre-intervention and after 4 and 8 weeks of RAPA (1). In all 6 subjects, transmitral blood flow, peak flow rate, and maximal blood acceleration showed statistically significant improvements while endothelial function also improved over the 8-week course of RAPA treatment. Thus, cardiac and endothelial function improvements with RAPA were found and support future placebo-controlled studies in larger cohorts of healthy older persons as well as in patients with compromised diastolic and endothelial function (20, 21).

Acute bilateral central deafness following cardioembolic ischemic stroke: insights from EEG spectral and connectivity analysis - Alessia Cacciotti; Francesca Miraglia; Giovanni Siconolfi; Francesco Iodice; Antonio Marrone; Cristiano Pecchioli; Petra Vukoja; Paolo Maria Rossini; Fabrizio Vecchio (GeroScience, 2025)

Bridging therapy versus direct endovascular thrombectomy in basilar artery occlusion stroke: a systematic review and meta-analysis - Esra Zhubi; Azamat Bissenov; Marie Anne Engh; Réka Tóth; András Attila Horváth; Peter Hegyi; Bence Gunda (GeroScience, 2025)
The benefits and safety of bridging therapy in basilar artery occlusion remain unclear, although current guidelines recommend it based on weak evidence and analogy to anterior circulation strokes. This study compares bridging intravenous thrombolysis and endovascular thrombectomy versus direct endovascular thrombectomy in a larger-than-ever basilar artery occlusion Population. Embase, PubMed, Scopus, Web of Science, and Cochrane Library were systematically searched. Studies that reported 90-day functional independence (mRS: 0–2), 90-day independent ambulation (mRS: 0–3), successful recanalization, symptomatic intracranial hemorrhage, any type of intracranial hemorrhage, and 90-day mortality were included. Two reviewers independently extracted data and assessed bias using ROBINS-I. A random-effects model was used. The protocol was registered in PROSPERO (CRD42024519161). Fifty-eight studies with 9372 subjects were included in the final analysis. Bridging therapy was associated with higher 90-day functional independence (OR 1.46; 95% CI 1.22–1.76; p < 0.001) and lower 90-day mortality (OR 0.63; 95% CI 0.49–0.82; p = 0.002). No significant differences were found in recanalization rate (OR 0.97; 95% CI 0.79–1.18; p = 0.707) or symptomatic intracranial hemorrhage (OR 0.88; 95% CI 0.65–1.18; p = 0.330). Benefits were consistent across subgroups defined by stroke severity, treatment window, occlusion site, and study site. Bridging therapy for basilar artery occlusion patients leads to a higher rate of functional independence and lower mortality without increasing the rate of intracranial hemorrhage compared to direct endovascular thrombectomy consistently across all subgroups.

Identifying novel modifiable risk factors for ischemic stroke through phenome-wide association study and Mendelian randomization analyses in a large-scale prospective cohort - Siyu Wu; Jialin Li; Xinyue Zhao; Jincheng Li; Shuaizhou Chen; Chengtong Zhang; Chen Suo; Yingzhe Wang; Xingdong Chen; Mei Cui; Qiuhong Man; Yanfeng Jiang (GeroScience, 2025)

Longevity through immunity: the unusual naked mole-rat immune system - Tanvi T. Patel; Rileigh Rubar; Vince G. Amoroso; Martha A. Delaney; Thomas J. Park; Rochelle Buffenstein (GeroScience, 2025)

A genome-wide association study identifies Asian-specific genetic susceptibility for epigenetic age acceleration - Kwangyeon Oh; Dabin Yun; Soyoun Yang; Minju Yuk; Changgyu Lee; Boyoung Kim; Suyeon Heo; Qian Dong; Zhaoming Wang; Hanseul Park; Nan Song (GeroScience, 2025)

Post-traumatic stress disorder, depressive symptoms, and cognitive function among middle-aged urban adults: Healthy Aging in Neighborhoods of Diversity across the Life Span study - Michael F. Georgescu; May A. Beydoun; Robert H. Pietrzak; Hind A. Beydoun; Nicole Noren Hooten; Sri Banerjee; Michele K. Evans; Alan B. Zonderman (GeroScience, 2025)
Post-traumatic stress disorder (PTSD) and depressive symptoms Have been linked to cognitive functioning. However, the impact of PTSD and depression on cognitive functioning, especially among middle-aged urban adults, is not well understood. Cross-sectional data were analyzed from 1434 participants from the Healthy Aging in Neighborhoods of Diversity across the Life Span study. We used multivariable adjusted linear regression and structural equation models (SM) to test the association between PTSD, CES-D, and cognitive test scores. We found PTSD to be strongly associated with depressive symptoms despite adjustment for potential confounders. SM with cognitive test scores as final outcomes found Delayed Free Recall and List A immediate recall inversely associated with PTSD score, with TEs of β ± SE − 0.08398 ± 0.02654, P = 0.002, and β ± SE − 0.10734 ± 0.02571, P < 0.001, respectively, and IEs of β ± SE − 0.06786 ± 0.02202, P = 0.002, and β ± SE − 0.07625 ± 0.02140, P < 0.001, indicating that depressive symptoms significantly mediated the potential association of PTSD with poorer verbal memory. Other cognitive test scores showed significant total or direct effects ( p < 0.05), suggesting different pathways not including depressive symptoms as a mediator. At higher intima-media thickness (IMT) tertiles, PTSD score was strongly associated with total CES-D score. This study provides evidence of an association between PTSD and cognitive functioning among middle-aged urban adults, partially mediated through depressive symptoms in verbal memory, with IMT enhancing the association between PTSD and depressive symptoms.

Spinal augmentation for vertebral body fractures in the elderly population - Alexander R. Evans; Taylor Niznik; Chao Li; Zachary A. Smith (GeroScience, 2025)

Association and predictive values of nine biological age measures for cardiovascular disease mortality: screening and validation from two prospective cohort studies - Solim Essomandan Clémence Bafei; Hankun Xie; Song Yang; Junxiang Sun; Yu Liu; Yao Fan; Wei Tang; Jiahui Liu; Changying Chen; Chong Shen (GeroScience, 2025)

Enhancing peripheral nerve regeneration in aging: the role of Schwann cells, c-Jun, and emerging therapeutic strategies - Melod Mehdipour; Vanshit Thakkar; Stephano Chang (GeroScience, 2025)
Peripheral nerve injuries (PNI) present a significant challenge, particularly in aging populations where Schwann cell dysfunction, reduced c-Jun expression, increased senescence, and impaired myelin clearance hinder regeneration. Targeted therapies aim to restore Schwann cell plasticity and improve nerve repair. These include gene therapy to upregulate c-Jun, senolytic agents to eliminate senescent Schwann cells, pharmacological activation of JNK, ferroptosis inhibition, and stem cell-based transplantation. Biomaterial advancements, such as nerve guidance conduits, extracellular matrix hydrogels, and 3D-printed scaffolds, provide structural and biochemical support. Despite these advances, clinical translation remains challenging due to patient heterogeneity, the need for personalized approaches, and regulatory considerations. Integrating multimodal strategies holds promise for optimizing peripheral nerve repair in aging individuals. Future research must refine these therapies to develop clinically viable solutions that enhance functional recovery and improve quality of life for patients with PNI.

Effects of age and musical training on resting-state periodic oscillatory brain activity - Sijia Guo; Ning Li; Liju Wang; Chenxi Qiu; Yuxin Chen; Yitian Yin; Hua Yang; Claude Alain; Jing Lu; Dezhong Yao (GeroScience, 2025)

Effect of hearing ability on inflammation and glymphatic function affecting cognition in older adults - Weijie Ye; Chunhua Xing; Jun Yao; Xiaomin Xu; Zihuai Fang; Xindao Yin; Richard Salvi; Yu-Chen Chen; Yuexin Cai (GeroScience, 2025)
The mechanisms linking hearing ability, inflammation, glymphatic system function, and cognitive impairment in older adults are largely unknown. To investigate this issues, magnetic resonance imaging (MRI) was used to test for dysfunctions in the glymphatic system of older adults with hearing loss and to determine the relationship of glymphatic dysfunction, inflammation and cognitive deficits. This cross-sectional observational study included participants with ARHL and healthy controls (HCs) between January 2021 and December 2023. Participants underwent MRI scans of the glymphatic indices and clinical assessment of auditory, neuropsychological, and inflammatory measures. Multimodal MRI indices were used as proxies of glymphatic function and compared with measures of inflammation and cognition dysfunction in the older adults with hearing loss and control groups. Mann–Whitney U test, Spearman rank correlation and Mediation analysis were conducted. A total of 130 hearing loss patients (mean age years, 64.10 ± 3.43 [SD], 67 males) and 121 healthy controls (mean age years, 63.55 ± 3.49 [SD], 68 males) were included. The hearing loss group differed significantly from normal hearing control on MRI glymphatic measures of choroid plexus volume (CPV) (1.48 vs 1.37, p = 0.0004), enlarged perivascular spaces (EPVS) (1.74 vs 1.55, p < 0.0001) and diffusion tensor image analysis along the perivascular space (DTI-ALPS) (1.47 vs 1.63, p < 0.0001). Hearing loss severity was associated with higher values of CPV and EPVS and lower values of ALPS and strongly correlated with higher levels of inflammation (all FDR q < 0.05). Mediation analysis showed that ALPS and CPV mediate the relationship between hearing loss and scores on the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST), respectively. Our findings support a potential associative pathway that inflammation and glymphatic dysfunction act as plausible intermediate factors facilitating the pathological relationship linking the increase in hearing loss in older adults to decline in cognition. Graphical Abstract

Increasing indices of frailty in aged female mice are associated with impaired skeletal muscle resilience to downhill running stress - Grant R. Laskin; Laís R. Perazza; Ted G. Graber; Baylah R. Mazonson; Yuhoung J. Kim; Laura J. Verdi; LaDora V. Thompson (GeroScience, 2025)
Frailty is a clinical syndrome marked by diminished physiological reserve and function. While skeletal muscle dysfunction is central to frailty, most preclinical models focus on basal function and place less emphasis on physiological stress responses. Here, we examined the influence of increased indices of frailty on skeletal muscle resistance and resilience using a physiologically relevant model of downhill running stress. Aged female C57BL/6JN mice ( n = 47; > 17 months) were stratified into Low (≤ 1 frailty markers) or High (≥ 2 frailty markers) groups based on their number of positive frailty markers. Mice were subsequently randomized to undergo two bouts of downhill running or remain cage sedentary. Twenty-four hours later, contractile function was assessed ex vivo in the extensor digitorum longus (EDL) and soleus muscles. RNA was extracted from the gastrocnemius of randomly selected samples and analyzed by RNA sequencing. Despite comparable specific tetanic force, High frailty marked mice exhibited greater fatiguability and impaired recovery kinetics in the EDL following running stress. RNA sequencing revealed divergent transcriptional signatures between mice in Low and High frailty marked groups in response to running, including upregulation of mitochondrial bioenergetic and complex assembly pathways in Low group mice and downregulation in High group mice. These data demonstrate that downhill running stress unmasks latent impairments with frailty in skeletal muscle, and that mitochondrial dysfunction and/or redox imbalance may be potential contributors to reduced muscle resilience. Overall, our results emphasize the importance of incorporating physiological stress paradigms to uncover frailty-associated muscle impairments that are not apparent under basal conditions. Graphical Abstract

A simplified clinical frailty scale predicts mortality in emergency department patients with acute dyspnea - Ahmad Zwawi; Torgny Wessman; Per Wändell; Olle Melander; Axel C. Carlsson; Toralph Ruge (GeroScience, 2025)

Phenotypic age acceleration as a novel predictor of benign prostatic hyperplasia: a prospective cohort study - Xuwen Li; Penghu Lian; Hongyan Chen; Liangzhe Zhang; Zhe Zhang; Jing Wang; Nianzeng Xing; Tao Jiang; Ziwei Chen; Xinlei Zhang; Xiongjun Ye (GeroScience, 2025)
This study aims to investigate the predictive value of combined phenotypic age and phenotypic age acceleration (PhenoAgeAccel) for benign prostatic hyperplasia (BPH) and develop a machine learning-based risk prediction model to inform precision prevention and clinical management strategies. The study analyzed data from 784 male participants in the US National Health and Nutrition Examination Survey (NHANES, 2001–2008). Phenotypic age was derived from chronological age and nine serum biomarkers. PhenoAgeAccel, representing biological aging acceleration, was calculated as the residual from regressing phenotypic age on chronological age. Recursive Feature Elimination (RFE) identified 34 BPH-associated features, which were integrated into an XGBoost prediction model. Logistic regression evaluated PhenoAgeAccel-BPH associations, while SHapley Additive exPlanations (SHAP) quantified feature contributions to enhance model interpretability. The XGBoost model achieved an area under the curve (AUC) of 0.833 in the test set. Phenotypic age was strongly correlated with chronological age ( r = 0.833), and individuals with PhenoAgeAccel exhibited a significantly elevated risk of BPH ( p < 0.001). Adjusting the model with phenotypic age improved predictive performance (AUC = 0.853). SHAP analysis identified phenotypic age as the third most influential predictor (after trailing cancer history and lead exposure), highlighting its clinical relevance. Chronological age and serum biomarkers are critical predictors of BPH, while PhenoAgeAccel independently contributes to risk stratification. Integrating phenotypic age with machine learning provides a robust framework for the early detection of BPH and personalized risk assessment, aligning with advancements in aging biomarker research. This approach supports targeted interventions to mitigate BPH progression in aging populations.

Slowing down the clock on ovarian aging—does the ovary hold the secret to the fountain of youth? - Paula Benny; Xi Yuan; Qian Yang; Jorge Chavarro; Brian Kennedy; Zhongwei Huang (GeroScience, 2025)

Mild cognitive impairment impacts association of functional brain connectivity with cognition in older adults with and without multiple sclerosis - Siddharth Nayak; Mark E. Wagshul; Roee Holtzer (GeroScience, 2025)

Resistance training, but not leucine, increased basal muscle protein synthesis and reversed frailty in older women consuming optimized protein intake - Kathryn J. Jacob; Guy Hajj-Boutros; Vita Sonjak; Jean-Phillippe Leduc-Gaudet; Felipe Broering; Charles Robb Flynn; Stéphanie Chevalier; Marie Lamarche; Sabah N. A. Hussain; José A. Morais (GeroScience, 2025)
Frailty, often linked to sarcopenia, involves reduced muscle strength and mass. While sarcopenia has multiple causes, impaired muscle protein synthesis may contribute. Leucine and resistance training (RT) are anabolic stimuli, but the long-term effects of leucine combined with RT in pre/frail older women remain unclear. This double-blind, placebo-controlled study aimed to assess their impact on muscle anabolism and characteristics in women consuming adequate protein. Pre/frail elderly women ( n = 19, 77.5 ± 1.3 y, BMI: 25.1 ± 0.9 kg/m 2 ), underwent 12 weeks of RT with protein-optimized diet (1.2 g ⋅ kg BW −1 ⋅ d −1 ) and were randomized to 7.5 g/d of leucine (Leu) or placebo 5.1 g/d alanine (Ala). The primary outcome was myofibrillar fractional synthesis rate (MyoFSR) in the postabsorptive and postprandial states. Secondary outcomes are changes in protein content and expression, 1-repetition maximum, body composition (DXA), and myofiber profiles were investigated. Overall MyoFSR increased by 47%, with a concomitant increase in type 1 and 2a myofiber cross sectional area (CSA) (16% and 28%, respectively), and total lean mass (2%). Total AKT, S6, and AMPKα levels were unchanged. However, AKT and S6 phosphorylation increased postprandially before RT, with no change following RT. The number of Frailty Criteria was reduced by 64%, with improvements in physical function and strength. Leucine had no added anabolic benefit. RT with optimal protein intake significantly improved the Frailty Phenotype and increased basal MyoFSR along with type 1 and 2a myofiber CSA and total lean mass, with no added benefit of leucine supplementation.

Fluphenazine, an antipsychotic compound, ameliorates Alzheimer’s disease by clearing amyloid beta accumulation in C. elegans - Mayur Nimbadas Devare; Victoria Le; Vanessa Chung; T. J. Vu; Matt Kaeberlein (GeroScience, 2025)

The proBNPage reduction (PBAR) trial—results of a randomized, double blind, placebo-controlled, pilot study to fine tune an NT-proBNP-based method to assess the effect of anti-aging treatments - Antonio Muscari; Paola Forti; Donatella Magalotti; Mara Brizi; Filomena Piro; Eric Ramazzotti; Loredana Incorvaia; Paolo Maltoni; Daniele Casanova Borca; Eleonora Capelli; Barbara Ciuffi; Paolo Pandolfi; et al. (GeroScience, 2025)
NT-proBNP levels increase exponentially with age and are associated with cardiovascular and all-cause mortality. From NT-proBNP concentration a surrogate for biological age (“proBNPage”) can be obtained. The primary objective of this study was to define a method to design future trials on anti-aging treatments using proBNPage. The secondary objective was the tentative evaluation of 4 potential anti-aging dietary supplements. The trial lasted 2 years and involved 120 healthy subjects aged 71.7 ± 4.6 years divided into 3 groups: A) coenzyme Q10 100 mg bid + selenium 100 mcg, B) resveratrol 350 mg bid + TA-65 100U, C) placebo. ProBNPage was the primary outcome variable. Secondary variables included step test duration, handgrip strength, and self-reported health status. In group B, the study was interrupted at month 5 due to significant LDL-cholesterol increase, probably caused by the high-dose resveratrol. Partly because of dropouts and inadequate treatment intake, groups A and C showed non-significant differences in the primary and secondary variables. Therefore, these groups were considered a single group, in which after 2 years proBNPage increased by 2.5 years ( P = 0.01), particularly in subjects over 70 (+ 3.0 years, P = 0.009). It was thus calculated that 126 subjects over 70 could allow the assessment of a 2-year treatment vs. placebo with a power of 80%. This study has developed an NT-proBNP-based method to evaluate future interventions on biological age. The treatments did not induce significant changes in proBNPage. The marked increase in cholesterol in group B suggests that high-dose resveratrol should be avoided.

Association between overweight/obesity and oral health in adults aged 55 and older: a systematic review and meta-analysis - Maryam Raoof; Sami al Chafi; Hamid Reza Tohidinik; Ralph de Vries; Frank Lobbezoo (GeroScience, 2025)
The increasing prevalence of overweight/obesity among the elderly has significant implications for oral health due to shared pathophysiological mechanisms. Despite its importance, comprehensive reviews on this topic remain limited. This study investigates the association between overweight/obesity and oral health outcomes in adults aged 55 and older. This systematic review followed PRISMA guidelines and was registered with PROSPERO (CRD42020202108). A systematic literature search was conducted across PubMed, Embase.com, CINAHL, and Web of Science up to November 6, 2023. The study was structured using the Population, Intervention/Exposure, Comparison, Outcome, and Study Design (PICOS) criteria: Population (P) included adults aged ≥ 55 years; Intervention/Exposure (I/E) involved overweight/obesity; Comparison (C) included normal-weight individuals; Outcomes (O) focused on periodontal diseases, dental caries, tooth wear, and orofacial pain; and Study design (S) included case–control, cross-sectional, prospective, and retrospective cohort studies and randomized controlled trials. Eligible studies underwent data extraction and quality assessment using the Newcastle–Ottawa scale. Meta-analyses were conducted using fixed and random effects models in Stata v.18. From 6219 records, 16 studies met the inclusion criteria. Among these, 14 focused on periodontal diseases, while 2 examined dental caries. No studies met the eligibility criteria for tooth wear or orofacial pain. The included studies were predominantly of “good” or “very good” quality. Meta-analysis indicated that overweight or obese older adults had a significantly higher risk of periodontal disease compared with normal-weight counterparts (pooled odds ratio [OR] = 1.49; 95% confidence interval [CI] 1.13–1.97). The association was stronger in studies conducted in Asia (OR = 2.21; 95% CI 1.28–3.81) and in mixed-sex populations (OR = 1.52; 95% CI 1.02–2.28) compared with male-only samples. The two cross-sectional studies on dental caries yielded inconsistent findings, precluding a meta-analysis for this outcome. This systematic review demonstrates a significant association between overweight/obesity and increased prevalence of periodontal disease in adults aged 55 and older. These findings underscore the need to consider oral health as a key component of general health in this population. The current evidence base is insufficient regarding dental caries, tooth wear, and orofacial pain, highlighting the need for high-quality research in these domains.

Prediction of cognitive decline and Alzheimer’s disease conversion by a plasma biomarker panel in non-demented individuals - Min-Koo Park; Jinhyun Ahn; Jin-Muk Lim; Sung-Joo Hwang; Keun-Cheol Kim (GeroScience, 2025)

Subclinical knee extensor weakness predicts gait and balance impairment in degenerative cervical myelopathy - Viprav B. Raju; Roxanne Hauer; Mohamed Jalloh; Anjishnu Banerjee; Allison Hyngstrom; Brian D. Schmit; Aditya Vedantam (GeroScience, 2025)

Short communication and clear content of geriatric recommendations matter! Evaluation of geriatric recommendation acceptance in patients aged ≥ 85 years hospitalized for cardiac conditions - Renee C. M. A. Raijmann; Huiberdina L. Koek; Marielle H. Emmelot-Vonk; Willem R. P. Agema; Angele P. M. Kerckhoffs; Carolina J. P. W. Keijsers (GeroScience, 2025)
As patients with cardiovascular disease age, the need for cardiogeriatric care grows. Therefore, we aimed to identify facilitators and hindrances to the implementation of cardiogeriatric care by analysing geriatric recommendations content and acceptance rates. This retrospective cohort study included 100 patients aged > 85 years who received geriatric consultation and were admitted to a cardiology department. A random sample was generated, of which half received proactive geriatric consultation and half received usual care (geriatric consultation upon request). The recommendation content was categorized into geriatric domains (physical, mental, functional, social, and existential), and recommendation uptake was categorized into seven categories (e.g., accepted, declined by patient). Additionally, factors associated with acceptance rates were analysed using univariate logistic regression. The study population (mean age 88, 60% female) received 310 recommendations of which 56% were accepted. The acceptance rate was significantly higher if recommendations belonged to the functional (OR 3.10 (95% CI 1.41–6.82)), social (OR 5.55 (95% CI 2.40–13.00)), and existential domain (OR 6.09 (95% CI 2.62–14.16)) compared to the physical domain. Furthermore, higher acceptance rates were observed if recommendations were communicated verbally instead of electronically (OR 2.16 (95% CI 1.30–6.70)), when a clear tone was used instead of a doubtful one (OR 1.90 (95% CI 1.01–3.56)), and if the recommendation was concisely documented (OR 1.11 (95% CI 1.04–1.20) per average 10 words decrease). In this study, the acceptance rate of geriatric recommendations for older patients with cardiac disease was low. Recommendations regarding the functional, social, and existential domains had the highest acceptance rates. To improve acceptance rates, recommendations should be communicated verbally, documented concisely, and a doubtful tone should be avoided.

Distinct factors explain life space mobility below and above the age of 75 years old in older adults - Samar Assadi Khalil; Efrat Gil; Roy Tzemah-Shahar; Faisal Azaiza; Rachel Kizony; Maayan Agmon (GeroScience, 2025)
Life space mobility (LSM) is important for participation in daily life. It is influenced by individual and environmental factors and tends to decline with age. Although LSM has been studied in older adults, stratification of this population into age subgroups has not been performed, creating a gap in understanding the factors associated with LSM in a more granular manner. This cross-sectional study aimed to identify the factors associated with LSM in community-dwelling older adults below and above the age of 75. Participants aged 65 and older without neurological conditions or dementia were recruited. LSM was assessed using the Life Space Assessment (LSA), mobility with the Timed Up and Go test (TUG), cognition with the Montreal Cognitive Assessment (MoCA), fear of falling with the Activities-specific Balance Confidence scale (ABC), and depression with the Hospital Anxiety and Depression Scale (HADS). Additional self-reported data included employment/volunteering, frequency of leaving the house, functional status, and number of medications. Separate regression models were conducted for each age subgroup. Two-hundred forty-two older adults (28.9% men) were recruited (mean (SD) age 73.7(6.4) years), with 40.9% aged over 75. In the younger subgroup, sex, frequency of leaving the house, TUG, and employment/volunteer status significantly explained 42.8% of the variance in LSM. In the older subgroup, sex, age, ABC, MoCA, and TUG significantly explained 46.9% of the variance in LSM. Distinct factors are associated with LSM in each age subgroup. Accordingly, future interventions should be tailored for each subgroup individually.

The association of thigh myosteatosis with lower cognitive function in older cancer survivors - Brendan L. McNeish; Brian Kunzer; Sarah G. Bell; Caterina Rosano (GeroScience, 2025)
Introduction Cancer is associated with accelerated aging, including changes in muscle composition and cognition. However, the relationship between myosteatosis and cognitive function has not been investigated in older cancer survivors. This study evaluated the association between myosteatosis and cognitive function in this population. Methods The sample included 75 cancer survivors (age 76–85; 65% men; 31% Black; 41% prostate cancer; 21% breast cancer) from the Health ABC study who developed cancer within the first five years, completed CT imaging at Year 6, and cognitive testing at Year 10. Thigh intermuscular fat area (myosteatosis) was measured by CT at Year 6. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and Modified Mini-Mental Status Exam (3MS) at Years 5 and 10. Multivariable models adjusted for demographics, education, cognitive function, and thigh muscle area at Year 5. Sensitivity analyses adjusted for leg strength, race, dementia risk factors, BMI, abdominal visceral fat, and thigh subcutaneous fat. LASSO regression identified key predictors of DSST and 3MS scores. Results Greater thigh myosteatosis at Year 6 was associated with lower DSST (B = − 0.212, p < 0.05) and 3MS (B = − 0.145, p < 0.05) scores at Year 10. Associations remained significant after adjustment for strength, dementia risk, and adiposity. LASSO identified race, education, Year 5 cognition, and myosteatosis as key predictors for DSST as well as thigh muscle area and physical activity for 3MS. Discussion Thigh myosteatosis is independently associated with lower cognitive performance in older cancer survivors and may represent a rehabilitation target to improve cognitive outcomes.

Sex differences in brain glucose metabolism in alzheimer’s disease: A voxel-based study - Matilde Nerattini; Elisabetta Maria Abenavoli; Francesca Caramelli; Giulia Giacomucci; Benedetta Nacmias; Enrico Mossello; Valentina Bessi; Valentina Berti (GeroScience, 2025)
A growing body of evidence shows significant sex differences in Alzheimer’s Disease (AD) epidemiology, clinical presentation, and pathology burden; however, sex differences in neuroimaging biomarkers remain underexplored, prompting recent calls to action for more targeted research in this field. We analyzed static brain positron emission tomography (PET) imaging with 2-[ 18 F] fluoro-2-deoxy-D-glucose (FDG) from 247 elderly individuals with AD dementia, including 151 women and 96 men. Voxel-based analysis was used to detect reductions in FDG uptake in each sex relative to a publicly shared normative database and to identify sex differences in FDG uptake within the AD cohort. Both sexes exhibited glucose hypometabolism in AD-vulnerable regions, including the parieto-temporal cortex, posterior cingulate, hippocampus, parahippocampal gyrus, and frontal lobes ( P FWE ≤ 0.001 in women and ≤ 0.013 in men). Sex differences in regional FDG uptake were observed in both directions, with greater hypometabolism in limbic and frontal regions in women ( P FWE ≤ 0.023) and in parietal cortices in men ( P FWE ≤ 0.008). The sex-specific distribution of hypometabolism, with more pronounced anterior involvement in women and posterior involvement in men, aligns with known differences in brain reserve and hormone-sensitive regions. This pattern suggests that neurophysiological and neuroendocrine aging may contribute to AD neuropathology in a sex-dependent manner. Recognizing these variations could refine diagnostic approaches and inform the development of sex-specific therapeutic strategies.

The associations between playing a musical instrument and grey matter in older adults at risk for dementia: a whole-brain VBM analysis - Nicole Espinosa; Marshall A. Dalton; Hannes Almgren; Andrew C. McKinnon; Helen F. Mitchell; Zoe Menczel Schrire; Sharon L. Naismith (GeroScience, 2025)

Failure of efficient cardiac proteostatic adaptations to chronic cAMP-stress is associated with accelerated heart aging - Maria Grazia Perino; Miguel Calvo-Rubio Barrera; Daniel R. Riordon; Giulio Agnetti; Alexander Maltsev; Admira Parveen; Christopher H. Morrell; Ismayil Ahmet; Khalid Chakir; Yelena S. Tarasova; Jia-Hua Qu; Kirill V. Tarasov; et al. (GeroScience, 2025)

Longitudinal association of ultra-processed food consumption with biological aging: the mediating role of adiposity measures - Jinzhang Liu; Qida He; Linyan Li (GeroScience, 2025)

Frailty, malnutrition risk, and kidney function impairment in older adults: Singapore longitudinal ageing study - Chin Yee Cheong; Philip Yap; Yanxia Lu; Keng Bee Yap; Tze Pin Ng (GeroScience, 2025)

Physiological health Age (PhysAge): a novel multi-system molecular timepiece predicts health and mortality in older adults - Thalida Em Arpawong; Belinda Hernandez; Claire Potter; Robert J. Leigh; Eric T. Klopack; Claire Hill; Giovanni Fiorito; Laura J. Smyth; Aisling M. O’Halloran; Bernadette McGuinness; Jessica D. Faul; Rose Anne Kenny; et al. (GeroScience, 2025)
The complexity of epigenetic changes that accompany aging has been distilled into a number of molecular timepieces—termed epigenetic clocks—that characterize the pace of biological aging to differing degrees. Here, we develop and validate a DNA methylation-based Physiological health Age (PhysAge) score, comprised of eight DNA methylation surrogates to represent multi-system physiology and developed from commonly measured clinical biomarkers: CRP, peak flow, pulse pressure, HDL-cholesterol, Hba1c, waist-to-height ratio (WHR), cystatin C, and dehydroepianrosterone sulphate (DHEAS). We use data from the population-representative US Health and Retirement Study (HRS), split into a training ( n = 1589) and test sample ( n = 1588) and corroborate findings in two independent cohorts: The Irish Longitudinal Study of Aging (TILDA; n = 488) and the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA; n = 1830). PhysAge and the predominant second-generation epigenetic clocks, PhenoAge, GrimAge2, and DunedinPACE, were tested for their prediction of mortality and multiple age-related clinical measures (i.e., grip strength, gait speed, cognitive function, disability, frailty). PhysAge was comparable to extant clocks in predicting health measures and was indistinguishable from GrimAge2 in predicting mortality, despite not being trained on mortality. Moreover, the eight individual surrogates comprising PhysAge predicted health outcomes better than the measured values in many instances. The established clinical relevance of the biomarkers from which surrogates were derived opens up new opportunities for cross-study and cross-country comparisons of population health. Findings suggest that the DNA methylation PhysAge can be leveraged as a single biomarker to represent multiple physiological systems and offers utility in the context of clinical monitoring.

EEG neurofeedback for the treatment of neuropathic pain in the elderly—a mechanistic review - James Chmiel; Marta Kopańska; Jerzy Leszek; Julia Trojniak; Tomas Ros (GeroScience, 2025)
Neuropathic pain (NP) is a complex pain disorder that constitutes a significant problem in the aging population, impacting quality of life and everyday functioning. In the quest to develop effective treatments, much research effort has been made to understand brain activity in people with NP, revealing a number of disordered electroencephalogram (EEG) patterns. This information can then be used to inform neurofeedback therapy, a novel approach that involves volitionally training brain activity in a closed loop. In this review of the existent literature we had three main objectives: (1) to summarize the reported EEG signatures of NP, (2) to evaluate the therapeutic efficacy of neurofeedback in the treatment of NP, and (3) to present the potential mechanisms of neurofeedback action in NP. Consequently, literature searches were conducted on the PubMed/Medline, Research Gate, and Cochrane databases. We identified 18 studies that examined resting-state EEG patterns in NP, and seven studies that investigated EEG-based neurofeedback in NP. Most biomarker studies of NP showed typical EEG patterns consisting of excess theta activity and decreased alpha activity. Neurofeedback study outcomes were largely promising in terms of treatment efficacy, but their quality was low. In turn, based on these results, we proposed hypothesis-based neurofeedback protocols and discussed the potential mechanisms of neurofeedback in the treatment of NP, including why this treatment option may be beneficial in the elderly population. Neurofeedback is a promising treatment option for NP, but caution should be exercised in interpreting the results due to the low number and methodological quality of research studies. A larger body of research studies points to common patterns of EEG abnormality in NP, which could be directly targeted with neurofeedback. The main advantage of this therapeutic approach is that it has no side effects and may be considered a valuable form of treatment in more frail populations such as the elderly.

Longitudinal bidirectional association of biological aging acceleration with depressive symptoms in mid-to-late life: evidence from the China Health and Retirement Longitudinal Study - Zeshan Chen; Mengxue Su; Qiang Tu; Jianji Li; Haisheng Wu (GeroScience, 2025)
The longitudinal directionality between depressive symptoms and biological aging acceleration has yet to be thoroughly investigated. This study included 5442 Chinese adults aged 45–80 years from the 2011 and 2015 survey waves of China Health and Retirement Longitudinal Study. Multiple biomarker-based biological age was estimated using the Klemera and Doubal method, and biologically older was defined as biological age larger than chronological age. Depressive symptoms were identified using a threshold of ≥ 10 on the 10-item Center for Epidemiological Studies Depression Scale. Multivariate logistic regression was employed to explore two unidirectional associations between biological aging and depression. Cross-lagged panel models (CLPM) were also constructed to simultaneously examine the bidirectional relationship and the strength of the association. In the logistic regression model adjusted for potential confounders, biologically older at baseline was associated with a higher risk of subsequent depression (OR = 1.202, 95% CI: 1.020, 1.417) compared with biologically younger; conversely, individuals with baseline depression had a higher risk of being biologically older later (OR = 1.372, 95% CI: 1.148, 1.639) when compared to those without depression. CLPM identified bidirectional relationship over time, with standardized coefficients of 0.03 ( P < 0.01) for both longitudinal directional pathways, suggesting an equal contribution of biological aging acceleration and depression to their dynamic interplay. This study reveals a reciprocal interaction between biological aging acceleration and depression in mid-to-late life, suggesting that targeted interventions aimed at decelerating biological aging or alleviating depressive symptoms may confer reciprocal benefits over time. Graphical Abstract

From dark horse to front-runner: vascular contributions to brain health - Aditi Gupta; Paulo W. Pires; Sandra A. Billinger; S. Thomas Carmichael; Constanza J. Cortes; Richard Daneman; Xiao Hu; Daniela Kaufer; Swati R. Levendovszky; Farzaneh A. Sorond; Chelsea M. Stillman; Stefano Tarantini; et al. (GeroScience, 2025)

Task-based fMRI brain activation in mild cognitive impairment and Alzheimer’s disease: an ALE meta-analysis - Zheng Long Lee; Jesse Jianyi Li; Savannah Kiah Hui Siew; Charly Hugo Alexandre Billaud; Junhong Yu (GeroScience, 2025)

Assessment of surface EMG biomarkers in sarcopenic motor dysfunction during postural stabilization - I. Junquera-Godoy; J. L. Martinez-De-Juan; G. González Lorente; I. C. Vendramini; E. M. Scheeren; G. Prats-Boluda (GeroScience, 2025)
Purpose This study aimed to investigate neuromuscular adaptations in individuals with pre/sarcopenia during postural balance perturbations, using surface electromyography (sEMG) signal features as potential functional biomarkers of early motor decline. Methods Twenty-eight older adults (14 pre/sarcopenic, 14 controls) were subjected to a series of forward balance perturbations while standing on a force platform. sEMG signals were recorded from four lower limb muscles and analyzed across five defined postural epochs established by the perturbation. Six sEMG features were extracted to capture amplitude, frequency, shape, and complexity characteristics of the signals. Linear mixed-effects models were used to evaluate group differences and trial-by-trial adaptation. Results The Post-stab epoch (350–2350 ms post-perturbation) revealed the most pronounced differences between groups. The pre/sarcopenic group exhibited significantly lower amplitude and complexity values. Additionally, shape analysis showed a distribution more closely resembling a Laplacian profile in the pre/sarcopenic group, indicative of increased motor unit synchronization and diminished recruitment variability. Conclusion This study identifies specific sEMG-derived features, particularly signal shape and complexity metrics, as potential non-invasive biomarkers for neuromuscular decline in sarcopenia. The Post-stab epoch emerges as a sensitive window for detecting deficits in motor control, supporting the use of perturbation-based tasks and sEMG analysis for early detection, monitoring, and intervention planning in aging populations. Graphical Abstract

Five years later: no short answers for Long COVID - Marc A. Sala; Igor J. Koralnik (GeroScience, 2025)

History of falls in patients with atrial fibrillation and risk of major outcomes: analysis from the Prospective GLORIA-AF Registry - Giulio Francesco Romiti; Bernadette Corica; Tommaso Bucci; Giuseppe Boriani; Brian Olshansky; Tze-Fan Chao; Menno V. Huisman; Marco Proietti; Gregory Y. H. Lip (GeroScience, 2025)
Falls pose concerns for the management and prognosis of patients with atrial fibrillation (AF). Epidemiological data on patients with AF who fall are limited. From the prospective global GLORIA-AF Registry Phase III study, we evaluated patients with a recent diagnosis of AF and CHA 2 DS 2 -VASc score ≥ 1 according to previous history of falling at baseline. We analyzed the associations with use of oral anticoagulant (OAC) and other drugs, risk of OAC discontinuation, and risk of major outcomes using multivariable regression models. Primary outcome was a composite of all-cause death and major adverse cardiovascular events (MACE); exploratory secondary outcomes were also analyzed. 20,875 patients (age 70.1 ± 10.3 years, 45.0% females) were included: 874 (4.2%) had prior falls. Patients with falls had more complex clinical profiles, were older, and were more likely female. No difference in OAC use was observed at baseline based on prior falls (OR [95%CI] 0.90 [0.75–1.08]), but patients with previous falls who received OAC were more likely treated with a NOAC compared to VKA (OR [95%CI] 1.29: 1.07–1.55) and were more likely to discontinue OAC during follow-up (HR 1.18, 95%CI 1.02–1.36). Patients with prior falls had a higher risk of the primary composite outcome (HR 1.63, 95%CI 1.40–1.90) and all secondary outcomes explored, including thromboembolism and major bleeding. Patients in the GLORIA-AF Registry with prior falls were more likely to receive a NOAC (vs. VKA) and had a higher risk of major adverse events, including all-cause mortality, thromboembolism, and major bleeding.

Reference values for the five-times-sit-to-stand test: a pooled analysis including 45,470 participants from 14 countries - Jozo Grgic; Brad J. Schoenfeld; Andrea B. Maier; Zeljko Pedisic (GeroScience, 2025)
The aim of this study was to establish reference values for the Five-Times-Sit-to-Stand Test (FTSST) in a large, population-representative sample from 14 European countries. Data were collected among 45,470 participants aged 50 + years, as part of the 5th wave of the Survey of Health, Ageing and Retirement in Europe. The reference values for the FTSST were calculated as the 5th, 10th, 20th, 30th, 40th, 50th, 60th, 70th, 80th, 90th, and the 95th weighted percentile. The analyses were stratified by age and sex. For females, the best performance on the FTSST was observed among the 50–54-year-olds (5th percentile = 18 s; 50th percentile = 10 s; 95th percentile = 6 s) and the worst among 85–89-year-olds and ≥ 90-year-olds (5th percentile = 28 s; 50th percentile = 15 s; 95th percentile = 9 s). For males, the best performance was observed among the 55–59-year-olds (5th percentile = 18 s; 50th percentile = 9 s; 95th percentile = 5 s). The worst performance for males was observed among ≥ 90-year-olds (5th percentile = 26 s; 50th percentile = 15 s; 95th percentile = 9 s), even though the 10th percentile was higher (poorer performance) among 85–89-year-olds. The reference values indicate poorer performance on the test among females and in older age groups. The provided reference values for FTSST can be used for health screening, surveillance, and intervention planning, as they enable an interpretation of test results according to sex and age.

Integrative machine learning approach to risk prediction for dementia and Alzheimer’s disease - Amos Stern; Michal Linial (GeroScience, 2025)
Dementia, particularly Alzheimer’s disease (AD), presents a growing global health challenge characterized by cognitive decline, behavioral changes, and loss of independence. With increasing life expectancy, early diagnosis and improved clinical strategies are urgently needed. This study developed and evaluated machine learning (ML) models to predict AD risk using UK Biobank data, integrating health, genetic, and lifestyle factors. The cohort included 2878 AD cases and 72,366 controls. Among several algorithms, CatBoost performed best (ROC-AUC = 0.773), especially in females. Inputs included ICD-10 codes from 5 years pre-diagnosis, ApoE-ε4 genotype, and large collection of modifiable risk factors. Despite fewer cases, the risk predictive models for vascular dementia (VaD) outperformed the unique AD models. ApoE-ε4 was the most predictive genetic marker, while other common variants had limited utility. Key non-genetic predictors included comorbidities (e.g., diabetes, hypertension), education, physical activity, and diet. These findings highlight the value of integrating diverse data sources for dementia risk prediction and emphasize the role of sex-specific modeling and modifiable factors in early, personalized intervention strategies. Graphical Abstract

Sirtuins mediate the reduction of age-related oxidative damage in the cochlea under a cocoa-rich diet - Rosalía Fátima Heredia-Molina; Juan Ignacio Riestra-Ayora; Israel John Thuissard Vasallo; Ricardo Sanz-Fernández; Carolina Sánchez-Rodríguez (GeroScience, 2025)
Age-related hearing loss (ARHL) is a common condition among older adults. It has long been established that ARHL is more prevalent, is more severe, and tends to occur earlier in men than in women. A key factor contributing to ARHL is oxidative stress, which harms the inner ear cells. Sirtuins are a family of proteins that play critical roles in cellular regulation, particularly in response to stress and aging, and have demonstrated anti-aging effects. Cocoa flavonoids, due to their antioxidant properties, have been reported to provide numerous health benefits. The present study aimed to evaluate the efficacy of cocoa in preventing oxidative damage in the cochlea of aging mice mediated by Sirtuins, as well as to determine possible differences between sexes. Female and male C57Bl/6 J mice were randomly assigned to two study groups: standard diet and cocoa-supplemented diet. At the ages of 6, 14, and 22 months, the animals were sacrificed, and cochleae were harvested to measure the expression of Sirtuins-1, -3, forkhead box O3 (FOXO3), p53, antioxidant enzymes, oxidative DNA damage, and levels of reactive oxidative species (ROS). Our results indicated that cocoa attenuated oxidative DNA damage, reduced ROS levels, and induced the expression of SIRT1, -3, FOXO3, and p53 in the cochlea of ​​aged mice. Furthermore, the activity of antioxidant enzymes in aged mice was restored with the cocoa diet. Sex differences were observed in several of these variables. These results indicate that cocoa protects against oxidative damage through Sirtuins. In conclusion, cocoa may have therapeutic potential against ARHL. Graphical Abstract

A prospective study on the regulation of osteoarthritis risk through inflammatory pathways in clonal hematopoiesis - Ping Li; Zijian Kang; Ruiqi Ma; Chen Zhu; Ying Zhu; Iris Tang; Jianzheng Zhang; Kai Li; Qiang Tong (GeroScience, 2025)

Effects of resistance-based training and polyphenol supplementation on physical function, metabolism, and inflammation in aging individuals - Mathias Flensted-Jensen; Cecilie Moe Weinreich; Ann-Sofie Kleis-Olsen; Filip Hansen; Nadia Stenner Skyggelund; Jeppe Rahbek Pii; Ryan Whitlock; Marie-Louise Brødsgaard Abrahamsen; Thomas Isbrandt Petersen; Anders Karlsen; Dace Reihmane; Flemming Dela (GeroScience, 2025)
Aging is associated with declines in muscle mass, strength, aerobic capacity, and metabolic health, accompanied by increased low-grade inflammation. The purpose of this study was to assess the effects of 12 weeks of resistance training (RT) combined with minimal high-intensity interval training (HIIT), with or without polyphenol supplementation, on muscular, cardiovascular, metabolic, and inflammatory adaptations in healthy older adults. Forty-one men and women aged 55–70 years ingested either polyphenol supplementation or placebo for 30 days, then underwent 12 weeks of supervised RT combined with once-weekly HIIT, continuing polyphenol supplementation or placebo throughout. The training intervention increased whole-body and thigh lean mass, vastus lateralis cross-sectional area, type II fiber size, and muscle and functional strength (all p < 0.001). Maximal oxygen uptake significantly increased ( p = 0.0001), accompanied by reductions in heart rate and plasma lactate during submaximal exercise, as well as increases in total blood volume and hemoglobin mass ( p < 0.05). Training led to reductions in respiratory exchange ratio and plasma cortisol during exercise, which, together with decreased cholesterol levels and trends toward increased peak fat oxidation, may suggest enhanced substrate utilization. Polyphenols alone lowered cholesterol levels but had no other effects. Although no changes were observed in basal systemic or muscle inflammation, the exercise intervention attenuated the acute exercise-induced inflammatory responses of IL-10, IFN-γ, and TNF-α ( p < 0.05). These results indicate that a combined RT and minimal HIIT program improves muscular, aerobic, and metabolic health, and may improve inflammatory regulation in aging adults.

Different association of GDF15 and FGF21 with glycemic status and aging in the context of obesity - Laura Salmón-Gómez; Victoria Catalán; Beatriz Ramírez; Maite Aguas-Ayesa; Amaia Rodríguez; Sara Becerril; Jorge Baixauli; Sonsoles Gutiérrez-Medina; Carmen Mugueta; Inmaculada Colina; Carolina M. Perdomo; Camilo Silva; et al. (GeroScience, 2025)
Growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) are stress-induced cytokines increased in age-related and metabolic disorders. The aim of the present study was to analyze the association between circulating concentrations of GDF15 and FGF21 in obesity and type 2 diabetes (T2D) in the context of aging. Serum samples from 405 participants (33 with normal weight and normoglycemia (NG), 156 with obesity and NG, 157 with obesity and impaired glucose tolerance (IGT), and 59 with obesity and T2D) aged 47 ± 13 years, were recruited to study the serum GDF15 and FGF21 concentrations and their relationship with obesity, T2D, and aging. Adipokines (leptin and adiponectin) and other cardiometabolic risk factors were also measured. The circulating concentrations of GDF15 and FGF21 were significantly increased with obesity and further increased with IGT and T2D. Both GDF15 and FGF21 showed positive associations with glucose ( r = 0.25, P < 0.001 and r = 0.40, P < 0.001, respectively) and insulin ( r = 0.16, P < 0.01 and r = 0.27, P < 0.001, respectively) levels. Similarly, GDF15 and FGF21 were positively correlated with age ( r = 0.55, P < 0.001 and r = 0.15, P < 0.01, respectively). Interestingly, the FGF21/adiponectin and GDF15/adiponectin ratios emerged as good biomarkers for the presence of T2D (AUC = 0.807 and 0.779, respectively). Our findings support that obesity, T2D, and aging increase the concentrations of both GDF15 and FGF21. Furthermore, GDF15 concentrations are more associated with aging while FGF21 levels are more related to the metabolic status. Finally, we propose the FGF21/adiponectin ratio as a novel biomarker for the detection of the presence of T2D.

Patterns of transcriptomic aging in the hippocampus of rhesus macaques highlight midlife transitions - Tanner J. Anderson; Marina M. Watowich; Kenneth L. Chiou; Elisabeth A. Goldman; Sam Peterson; Jordan A. Anderson; Noah Snyder-Mackler; Lucia Carbone; Steven G. Kohama; Kirstin N. Sterner (GeroScience, 2025)
Patterns of brain aging are generally conserved among primates; however, there is marked variation in the observed rate among individuals, species, and brain regions. The hippocampus is a region particularly susceptible to the aging process. To better understand how the hippocampus changes over the lifespan, we measured gene expression in 96 banked hippocampus samples from adult male and female rhesus macaques aged 3–35 years old. Importantly, our dataset included representation across adulthood allowing us to characterize age-related patterns in gene expression during midlife, a period often underrepresented in studies of aging. We used autoregressive integrated moving average models to examine age-associated changes in gene expression to identify 2679 differentially expressed genes (FDR < 0.05) that fit four broad patterns of expression: linearly upregulated or downregulated across age, and two clusters with nonlinear patterns. Importantly, the nonlinear clusters highlight transitions in expression trajectories centered around ~ 10 years of age (~ 30 years of age in humans) indicating an important period that may have a critical impact on hippocampal aging. Changes in gene expression variance across age found that genes in individuals > 20 years of age (> 50 years of age in humans) have greater variance in expression than individuals aged 10–20 years (FDR < 0.05). Collectively, our results highlight molecular changes occurring during midlife which may shape brain aging in longer lived primates and may offer insight into increased susceptibility to neurodegenerative disease in humans.

BrainAGE in superagers: cross-sectional and longitudinal analyses in older adults aged 80+ with youthful episodic memory - Christian Gaser; Marta Garo-Pascual; Bryan A. Strange (GeroScience, 2025)
Episodic memory, the ability to recall past events, is particularly vulnerable to ageing. A decline in episodic memory performance is generally considered part of ageing. However, the episodic memory performance of superagers —defined as individuals aged 80+ years old with episodic memory of people 30 years younger— is superior to that typical of their chronological age. The aim of this study was to determine whether the discrepancy between the superager's episodic memory and chronological age is also evident in their brain age. A BrainAGE (Brain Age Gap Estimation) approach, a multidimensional computational neuroanatomical method that uses structural neuroimaging data to estimate biological brain age, was applied. The study population comprised 64 superagers (mean age = 81.9 ± 1.9) and 55 age-matched typical older adults (82.4 ± 1.9). Cross-sectional analyses revealed a negative BrainAGE score for superagers (mean = -0.95 ± 2.36) indicating a deceleration of the ageing process. By contrast, typical older adults showed an average score close to zero (0.05 ± 3.03) consistent with their chronological age. The BrainAGE score of superagers was found to be lower relative to typical older adults, and the progression over a 5-year follow-up period was slower in superagers, in keeping with their youthful memory ability. Therefore, superagers have a younger brain than those of typical older adults, suggesting that their ageing mechanisms may involve resistance to age-related brain structural changes. However, despite a 30-year gap in episodic memory, their BrainAGE score differed by only one year, indicating that factors beyond brain structure contribute to the superager phenotype. Graphical Abstract

Lower diet quality accelerates DNA methylation-based age - Botong Shen; Nicole Noren Hooten; Nicolle A. Mode; Marie Fanelli Kuczmarski; Alan B. Zonderman; Michele K. Evans (GeroScience, 2025)
A new DNA methylation biomarker, Dunedin Pace of Aging Calculated from the Epigenome (DunedinPACE), is associated with healthy lifespan in several European ancestry cohorts. Few studies have examined the relation between dietary quality and DunedinPACE in African American and White adults with longitudinal assessments. To assess the relationship between diet quality and DunedinPACE, we used longitudinal data from African American and White 30–64 year old adults living above and below poverty. Participants’ DunedinPACE scores and dietary assessments were calculated at two time points, approximately 5 years apart. Numbers of participants ( n = 421; mean age 49 years) were balanced by race, sex, and poverty status. Diet quality was assessed using two different dietary indexes: Dietary Inflammatory Index (DII) and Healthy Eating Index-2010 (HEI). Linear mixed model regression examined the longitudinal association of DunedinPACE with DII and HEI adjusted by age, race, poverty status, BMI, and smoking status. Initial mean values of DII were 3.34 (SD = 2.16) and HEI was 40.67 (SD = 11.69), indicating a pro-inflammatory dietary pattern and low diet quality in this cohort. The initial mean DunedinPACE score was 1.07. We found that a higher DII score was associated with higher DunedinPACE score (β = 0.009; p < 0.001), higher HEI score was associated with lower DunedinPACE score (β = − 0.001; p = 0.032), and that these relationships were consistent over time. Overall, lower dietary quality was associated with a faster pace of aging captured by DunedinPACE score. Our findings demonstrate the independent contribution of diet quality to healthy aging-related epigenetic mechanisms. Graphical Abstract

Quantitative assessment of asymptomatic spinal cord compression using MRI: a multi-center study - Ali F. Khan; Sanaa Hameed; Alaa Baha; Fauziyya Muhammad; Grace Haynes; Amber Dastgir; Suresh K. Gulla; Hakeem J. Shakir; Michael L. Rohan; Yasin Y. Dhaher; Zachary A. Smith (GeroScience, 2025)

Muscle-brain crosstalk as a driver of brain health in aging - B. L. McNeish; I. Miljkovic; T. Liu-Ambrose; F. Ambrosio; K. Esser; M. Fahnestock; C. Rosano (GeroScience, 2025)
Cognitive impairment and dementia in older adults represent significant global health challenges. Although the bidirectional relationship between physical function and brain health is well established, the mechanistic drivers of this link remain poorly understood. Muscle function and quality are central to physical function, and muscle’s secretome is increasingly recognized for its systemic health effects—supporting the potential for muscle-to-brain crosstalk. This concept was explored at the 3rd International Research Symposium on Brain Health, jointly hosted by Vancouver Coastal Health and the University of British Columbia. We present the findings of this symposium, which reviewed the current state of the literature on muscle-to-brain crosstalk from multiple perspectives, spanning population studies to preclinical models. A key focus was the muscle secretome, particularly myokines and extracellular vesicles, as potential messengers influencing brain health. The symposium also identified critical takeaways and proposed next steps to further elucidate the underlying mechanisms of muscle-to-brain crosstalk and explore how these pathways might be harnessed through exercise or pharmacologic interventions to promote brain health in older adults.

Mitochondrial bioenergetics in resilience of older adults with gynecologic cancer: design and rationale of a pilot study - Anna Kuan-Celarier; Michelle L. Wallander; Jennifer Hartzell; Brittany Lees; Xiaoyan Iris Leng; Philip A. Kramer; Nicholas J. Day; Wei-Jun Qian; Bumsoo Ahn (GeroScience, 2025)
Resilience—the ability to recover and maintain function following stresses—is a critical factor influencing treatment tolerance and recovery in older adults with cancer. Despite the high incidence of gynecologic cancers in postmenopausal individuals, resilience in this population remains underexplored, even though patients commonly face compounded stress from both chemotherapy and surgery. The goal of our research is (1) to test the feasibility of cognitive and physical function assessments in older women with gynecologic cancers and (2) to discover reliable predictors that enhance clinical decision-making and guide personalized treatment strategies. Current clinical assessments focus on isolated physiological systems. As such, there is a need for a reliable predictor that captures systemic resilience more comprehensively. A reliable predictor of resilience following cancer treatment could improve clinical decision-making and identify potential targets for therapeutic intervention. Both mitochondrial bioenergetics and oxidative stress are presumably mechanistically linked to resilience of patients with gynecologic cancers because of widely known effects of chemotherapy and tumor burden on mitochondrial bioenergetics. Mitochondria generate more than 95% of cellular ATP through oxidative phosphorylation, a process essential for recovery following physiological stress. Oxidative stress disrupts excitation–contraction coupling and reduces metabolic efficiency in skeletal muscle, contributing to weakness and fatigue. In the brain, oxidative modifications have been associated with impaired neurotransmission and cognitive dysfunction. This protocol paper describes a longitudinal study design aimed at evaluating the feasibility of resilience assessment and testing mitochondria and oxidative stress as predictors of resilience in older adults diagnosed with advanced endometrial or ovarian cancer.

The University of Oklahoma Inpatient Spine Protocol: optimizing surgical outcomes through standardized perioperative care - David Barkyoumb; William C. Kaiser; Lonnie Smith; Lance M. Villeneuve; Graham Mulvaney; Chao Li; Christopher S. Graffeo; Andrew M. Bauer; Hakeem J. Shakir; Karl Balsara; M. Burhan Janjua; John F. Burke; et al. (GeroScience, 2025)

Quantifying placebo and trial participation effects on cognitive outcome measures in aging dogs - Katherine E. Simon; Katharine Russell; Alejandra Mondino; Chin-Chieh Yang; Beth C. Case; Zachary Anderson; Christine Whitley; Emily Griffith; Margaret E. Gruen; Natasha J. Olby (GeroScience, 2025)
The placebo effect, or the positive effects observed after an inert treatment which result from patients’ expectations for the therapy, is well documented in human medicine. However, in veterinary medicine, where owner’s expectations serve as a proxy for their pets, it remains underexplored, particularly for elderly dogs with cognitive decline. To address this gap, we examined 21 dogs (mean age: 12.85 years, SD: 1.46) from a placebo group in a randomized controlled trial (RCT) and compared their results to 17 dogs (mean age: 13.24 years, SD:1.56) from an observational, longitudinal study to distinguish placebo effect from trial participation effect. Both populations had statistically comparable baseline data. Cognitive changes were evaluated with two remotely administered owner questionnaires (Canine Cognitive Dysfunction Scale (CCDR) and Canine Dementia Scale (CADES)) and three in-house cognitive assessments (Cylinder Task, Detour and Sustained Gaze). We hypothesized that placebo effect would be greater than trial participation effect, particularly in owner-reported measures. Matched pairs T -tests and effect size calculations (Hedge’s g ) were used to calculate changes across 6 months. A strong ( g = 0.76), significant ( p = 0.021) improvement in CADES was observed in the placebo cohort after 6 months, while no changes were detected with CCDR. Conversely, the observational cohort showed a small ( g = 0.35) and significant ( p = 0.03) deterioration on CCDR, and no change in CADES. No significant changes were noted on the in-house cognitive assessments in either cohort. We conclude that study context influences remotely delivered owner assessments and CCDR is more robust against caregiver placebo effect in RCTs than CADES.

Analysis of variability and epigenetic age prediction across microarray and methylation sequencing technologies - Maxim N. Shokhirev; Adiv A. Johnson (GeroScience, 2025)

Epigenetic dysregulation of transposable elements in cognitive impairment and Alzheimer’s disease - Alyssa N. Cavalier; Meghan E. Smith; Gabriella T. McWilliams; Cali M. McEntee; Brianne M. Bettcher; Christina Coughlan; Thomas J. LaRocca (GeroScience, 2025)

Association between weight-adjusted waist index and cardiometabolic multimorbidity in older adults: Findings from the English Longitudinal Study of Ageing - Setor K. Kunutsor; Sae Young Jae; Jari A. Laukkanen (GeroScience, 2025)
The weight-adjusted waist index (WWI) is a novel anthropometric measure designed to better reflect central obesity than traditional indices such as body mass index and waist circumference (WC). This study examined the prospective association between WWI and cardiometabolic multimorbidity (CMM) and evaluated its predictive utility. We included 3,348 participants (mean age 63 years; 45.1% male) from the English Longitudinal Study of Ageing who were free from hypertension, coronary heart disease, diabetes, and stroke at baseline (wave 4: 2008–2009). WWI was calculated as WC (cm) divided by the square root of body weight (kg). CMM was defined as the presence of ≥ 2 of the following conditions at wave 10 (2021–2023): hypertension, cardiovascular disease, diabetes, or stroke. Multivariable logistic regression and measures of discrimination were used to assess associations and predictive value. Over 15 years, 197 participants developed CMM. Restricted cubic spline analysis indicated a linear dose–response relationship between WWI and CMM risk ( p for nonlinearity = .44). Each 1 SD increase in WWI was associated with higher odds of CMM (odds ratio, OR = 1.30; 95% CI: 1.12–1.51), persisting after adjustment for physical activity (OR = 1.28; 95% CI: 1.10–1.49). Similar associations were observed across WWI tertiles. Adding WWI to conventional risk models slightly improved discrimination (ΔC-index = 0.0065; p = .29), with a significant improvement in model fit (-2 log likelihood, p = .001). Higher WWI levels were independently and linearly associated with increased CMM risk in older adults. WWI also improved CMM risk prediction beyond conventional risk factors.

Nicotinamide riboside combined with exercise to treat hypertension in middle-aged and older adults: a pilot randomized clinical trial - Yi Lin; Rola S. Zeidan; Stephanie Lapierre-Nguyen; Hannah M. Costello; Stephen D. Anton; Thomas W. Buford; Demetra D. Christou; Michelle L. Gumz; Christiaan Leeuwenburgh; Christopher R. Martens; Mary M. McDermott; Marie E. Migaud; et al. (GeroScience, 2025)
Aerobic exercise lowers blood pressure (BP) with varying effects in hypertensive adults, potentially due to age-related nicotinamide adenine dinucleotide (NAD) metabolism dysregulation. This pilot randomized clinical trial (RCT) tested the efficacy of combining aerobic exercise with the NAD booster nicotinamide riboside (NR) to enhance BP control. In this double-blinded RCT, 54 sedentary adults (≥ 55 years) with mean daytime systolic BP (SBP) ≥ 130 mmHg were randomized to 6 weeks of 1000 mg/day of NR combined with 3 days/week of supervised 30-min walking exercise (NR + Ex), Placebo combined with the same exercise regimen (PL + Ex), or NR alone (NR). The primary outcome was daytime SBP. Other outcomes included pulse wave velocity (PWV), NAD catabolites, and nighttime BP. The primary comparison was between NR + Ex and PL + Ex. Of 54 participants (mean age 67 years, 61% female), 49 (NR + Ex: n = 15, PL + Ex: n = 16, NR: n = 18) completed all study visits (93% adherence to exercise and 90% to supplementation). NR + Ex (mean change = 5.19 ± 13.2 mmHg) did not reduce SBP more than PL + Ex (− 2.71 ± 10.5 mmHg). NR + Ex (− 0.31 ± 0.77 m/s) showed a trend toward a greater reduction in PWV. Levels of NAD catabolites were higher in NR groups. In a post hoc analysis, NR + Ex showed a trend toward greater nighttime BP reductions (systolic: − 9.6 ± 9.22; diastolic: − 4.51 ± 7.12 mmHg) in participants without antihypertensive medications. NR + Ex was not superior to PL + Ex in reducing BP in hypertensive middle-aged and older. However, trends toward greater nighttime BP reduction in NR + Ex in participants without antihypertensive medication warrant further investigation in a Phase IIb RCT. Graphical Abstract

Mitochondrial dysfunction in peripheral mononuclear blood cells (PBMC) of individuals with mild cognitive impairment - Fabian Dieter; Karlotta Jacobs; Alice Quentin; David Prvulovic; Andreas Reif; Johannes Pantel; Ulrich Pilatus; Elke Hattingen; Silke Matura; Gunter Peter Eckert (GeroScience, 2025)
Mitochondrial dysfunction is a hallmark of aging and many age-related neurodegenerative diseases. Mild cognitive impairment (MCI) refers to a clinical condition characterized by noticeable cognitive decline that exceeds normal age-related changes but does not significantly interfere with daily functioning. MCI is often considered an early stage of neurodegenerative conditions, including Alzheimer’s disease. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cognitive performance in individuals with amnestic (aMCI) and nonamnestic mild cognitive impairment (naMCI). Control groups consisted of young (YC) and older adults (OC) who were physically and mentally healthy. Cross-sectional observational study involving 90 participants, including young adults, cognitively healthy older adults, and individuals with MCI. Mitochondrial function was determined in cryopreserved PBMCs. Cognitive status was assessed using the German version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test battery. ATP levels in cryopreserved PBMC isolated from individuals with aMCI were significantly lower than those of OC and YC. Endogenous respiration varied significantly between groups, with the MCI group exhibiting the lowest respiration. Linear regression analyses with ATP as a predictor for cognitive performance showed a significant positive relationship between ATP levels and both immediate recall and fluency. The regression coefficients indicated a moderate positive correlation between ATP levels and performance in both tests. This suggests that higher ATP levels are associated with improved cognitive performance. Our data suggest that mitochondrial dysfunction in PBMC is associated with MCI and correlates with cognitive impairment. Subjects who performed poorly on neuropsychological tests also exhibited lower ATP levels. Given that PBMC are easily accessible, they offer valuable insights into the bioenergetic status of individuals at increased risk for dementia. The study (PEM-MCI) has been retrospectively registered at the German Register of Clinical Trials (DRKS) DRKS00036017 (registered on 30.01.2025). Graphical Abstract

The senescence-inhibitory p53 isoform Δ133p53α: enhancing cancer immunotherapy and exploring novel therapeutic approaches for senescence-associated diseases - Shinji Nakamichi; Leo Yamada; Christopher Roselle; Izumi Horikawa; Carl H. June; Curtis C. Harris (GeroScience, 2025)

EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework - Amin Haghani; Ake T. Lu; Qi Yan; Juan Carlos Izpisua Belmonte; Pradeep Reddy; Victor Cheng; X. William Yang; Nan Wang; Khyobeni Mozhui; Kevin Murach; Alejandro Ocampo; Robert W. Williams; et al. (GeroScience, 2025)
Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.

Midlife aging and performance study (MAPS): evaluating biological aging through a physical capacity battery - Roy Tzemah-Shahar; Ilona Shapiro; Einat Kodesh; Merav Asher; Yechiel Friedlander; Hagit Hochner; Maayan Agmon (GeroScience, 2025)
Aging is a risk factor for the development of chronic diseases; however, it is heterogeneous. Measuring aging in midlife, commonly done using laboratory markers and statistical methods for estimation of biological age (BA), cannot directly inform behavioral intervention goals aiming to promote healthier aging. The Midlife Aging and Performance Study (MAPS) examined the association between an extended, inclusive assessment of physical capacity (PC), as a behavioral marker of aging, and BA, estimated using the Klemera-Doubal method from 11 laboratory and physiological biomarkers, in 112 individuals aged 42–46 (47% women). PC was comprehensively measured by a battery covering five domains: muscle strength, endurance, balance, agility and flexibility. Better performance in strength, endurance, balance, and flexibility domains was correlated with younger BA (Pearson’s r 0.33–0.49, p < 0.001). A lower composite PC score based on all five domains was significantly associated with an accelerated aging state in which BA was greater than chronological age. In a logistic regression, a composite PC score had an odds ratio of 0.40 (95% CI 0.25–0.64), demonstrating each incremental rise in PC corresponds with a 60% odds reduction of being in an accelerated aging state. The proposed PC battery could be used as a functional behavioral assessment for aging state, relevant for population wide risk-screening assessments, communicating intervention goals, and as a means to evaluate temporal changes in health, independent of laboratory tests.

Chronic inflammation mediates the relationship between physical activity and telomere length - Anamika Nanda; Daniel H. Aslan; M. Katherine Sayre; Pradyumna K. Bharadwaj; Madeline Ally; Hyun Song; Amit Arora; Silvio Maltagliati; Mark H. C. Lai; Rand R. Wilcox; Yann C. Klimentidis; Gene E. Alexander; et al. (GeroScience, 2025)
A physically active lifestyle benefits cellular aging, however the mechanisms linking physical activity (PA) with longevity remain unclear. PA is associated with longer telomere length (TL), while shorter TL has been associated with increased cellular aging. Some research suggests increased levels of inflammatory markers, such as C-reactive protein (CRP), are associated with telomere dysfunction. We tested the hypothesis that CRP levels mediate the association between PA and TL. Using data from the UK Biobank, we analyzed adjusted leukocyte T/S ratio (relative telomere to single gene copy), serum CRP, and moderate-to-vigorous physical activity (MVPA) data via device-measured actigraphy. We applied general linear regressions and a causal mediation analysis with 10,000 bootstraps while controlling for a range of covariates (age, BMI, smoking status, sex, ethnicity, time between data collection, time wearing the accelerometer, and the Townsend Deprivation Index). Variables of interest were transformed to approximate normality. A total of 79,873 participants were included in the final analytic sample. MVPA and CRP were both significant predictors of TL (β MVPA = 3.03e − 03 [95%CI = 1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP = − 1.36e − 03 [95%CI = − 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07, respectively). The association between MVPA and TL was mediated by CRP, accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). Our analysis supports the hypothesis that CRP mediates the relationship between MVPA and TL. These novel findings suggest a potential pathway where PA is associated with lower CRP concentrations, which in turn is associated with longer average TL. Graphical abstract

Treatment of age-related decreases in GTP levels restores endocytosis and autophagy - R. A. Santana; J. M. McWhirt; G. J. Brewer (GeroScience, 2025)
Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer’s model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free GTP colocalized in the mitochondria decreased with age accompanied by the accumulation of free GTP-labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. Twenty-four-hour supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates, improved viability, and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path. Graphical Abstract

Comparison of the acute effects of breaking up prolonged sitting time with single-task or a dual-task walking on cognitive function and cerebral blood flow in older adults: a randomized crossover trial - Paolo M. Cunha; Gustavo O. Silva; Liye Zou; Max D. Oliveira; Hélcio Kanegusuku; Qian Yu; Yanxia Chen; Zhihao Zhang; Fabian Herold; Ryan S. Falck; Boris Cheval; Olivier Dupuy; et al. (GeroScience, 2025)

High-intensity interval and moderate-intensity continuous training on cerebral energy metabolism in older rats - Cécile Marcourt; Claudio Rivera; Jürgen Tuvikene; Antoine Langeard; Eli-Eelika Esvald; Florencia Cabrera-Cabrera; Tõnis Timmusk; Jean-Jacques Temprado; Jérôme Laurin (GeroScience, 2025)
Aging is associated with metabolic decline in the brain, increasing susceptibility to neurodegenerative diseases. While exercise is a well-established strategy to counteract these changes, no study has directly compared the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on cortical and hippocampal energy metabolism—key regulators of brain plasticity in aging. To address this gap, we investigated how 4-week MICT and HIIT protocols, structured according to the lactate threshold, affect endurance performance and brain metabolic markers in older Wistar rats. Both training modalities improved endurance, with HIIT demonstrating superior gains in maximal performance. However, molecular analyses revealed that MICT induced more extensive metabolic and angiogenic adaptations in the cortex and hippocampus, including the upregulation of key regulators of energy metabolism and vascularization. RNA sequencing confirmed broader transcriptomic changes following MICT, implicating pathways associated with neurogenesis, metabolic homeostasis, and cellular plasticity. While HIIT provided a time-efficient means of improving cardiovascular endurance and mitochondrial activity through different molecular pathways when compared to MICT, its impact on brain metabolism was more limited. These findings suggest that MICT is the preferred regimen for enhancing cerebral metabolic function and neurovascular adaptation, while HIIT serves as a complementary strategy to involve other brain metabolism-associated pathways and maximize aerobic fitness. A direct comparison of these modalities, as presented here, is essential for refining exercise prescriptions to support brain health in aging.

Task-specific dynamical entropy variations in EEG as a biomarker for Parkinson’s disease progression - Fatih Onay; Bilge Karaçalı (GeroScience, 2025)

Health-related quality of life trajectories and loss of independence among community-dwelling older adults - Atsushi Takayama; Kenji Omae; Takeshima Taro; Takashi Yoshioka; Hiroaki Nakagawa; Ozaka Akihiro; Shunichi Fukuhara; Shunichi Fukuhara; Sugihiro Hamaguchi; Takao Tsuchiya; Mitsuru Munakata (GeroScience, 2025)
Health-related quality of life (HRQOL) is a key determinant of loss of independence (LOI) among older adults. However, the relationship between late-life HRQOL trajectory patterns and the risk of LOI remains unclear. This study utilized 5-year longitudinal data from the Sukagawa Study, and group-based trajectory modeling. HRQOL trajectories were analyzed using the mental component scale (MCS) and physical component scale (PCS) from the SF-8. Hazard ratios (HRs) and 95% confidence intervals (CIs) for LOI or death were calculated using Cox proportional hazards regression. Among 4043 participants (median age 78.8 years, interquartile range [IQR] 75.8–82.5; 56% women), HRQOL change score trajectories were categorized as decline, stable, and increase for MCS (11.7%, 81.0%, 7.2%) and PCS (10.9%, 81.4%, 7.6%). Over a mean follow-up of 66.4 months (IQR 48.0–73.0), LOI or death incidence was 42.5 per 1000 person-years (95% CI 39.8–45.2). Compared to the stable group, MCS decline was associated with higher LOI or death risk (HR 1.51, 95% CI 1.04–2.18), and an increase was associated with lower risk (HR 0.26, 95% CI 0.11–0.57). PCS decline was linked to higher LOI risk (HR 1.66, 95% CI 1.17–2.37), while an increase showed no significant association (HR 1.07, 95% CI 0.61–1.89). Longitudinal HRQOL trajectory is closely related to LOI risk among community-dwelling older adults. A declining trajectory in physical and mental components is strongly associated with higher LOI risk, while an increasing trajectory in the mental component is possibly associated with lower risk. Graphical Abstract

From the plate to the brain: associations between dietary patterns and reduced dementia prevalence and white matter lesions in older Japanese adults - Liying Chen; Yasuko Tatewaki; Benjamin Thyreau; Kazuhiro Uchida; Hikari Iki; Shigeyuki Nakaji; Tetsuya Maeda; Kenjiro Ono; Moeko Noguchi-Shinohara; Masaru Mimura; Kenji Nakashima; Jun-ichi Iga; et al. (GeroScience, 2025)
Diet is widely considered essential in dementia, but its association with white matter lesions (WMLs) remains unclear. This cross-sectional study investigated the associations between dietary patterns, dementia, and WMLs in a large, nationwide, multicenter population of older Japanese adults. A total of 8,938 adults (aged ≥ 65; 73 ± 6.3 years old) from the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) were included. Dietary intake was assessed using a Food Frequency Questionnaire. Principal component analysis was used to derive dietary patterns. A trained Convolutional Neural Network model segmented WMLs from brain MR images. Logistic regression estimated odds ratios (ORs) for dementia by dietary pattern quartiles, while linear regression assessed associations with WML volumes. Five dietary patterns were extracted. A Japanese diet including protein and minerals was significantly associated with lower prevalence of all-cause dementia (OR = 0.56) and Alzheimer’s disease (OR = 0.47), and with reduced WML volume ( β = − 0.03). Similar directional trends in ORs were observed across study sites. The reverse association with WMLs remained significant among individuals without dementia, reducing the likelihood of reverse causation. A Japanese diet including protein and minerals was associated with lower dementia prevalence and smaller WML volume in older Japanese adults. Drawing on nationwide, large-scale, multicenter data, these findings advance our understanding of dietary patterns in older Japanese adults and provide valuable insights for future intervention studies targeting diet and age-related brain changes.

A simple blood biomarker based on gene expression describes cardiovascular health-related biological age - Natalia Hernández-Bellido; Adrián Hernández-Vicente; Laura García-Mendívil; Estel Ramos-Marquès; David Hernando; Alberto Cebollada; Ralf Köhler; Nuria Garatachea; Esther Pueyo; Laura Ordovás (GeroScience, 2025)
The need to monitor the aging process as a risk factor for disease and mortality beyond chronological age (CA) has led to numerous investigations into the estimation of the biological age (BA) of individuals. However, the accuracy of BA estimation tools is often judged by their ability to approximate CA, questioning their value in capturing the variance in health status and thus correctly estimating BA. Their biological relevance is often assessed in relation to health outcomes or mortality, underexploiting their potential for real-time monitoring of BA. Furthermore, their complexity may limit their clinical translation to large populations. Here, we describe the gene expression-based age monitoring Clock (GamC), a simple biomarker of aging (BOA), and characterize its biological relevance with synchronous cardiovascular (CV) health-related functional data. GamC is calculated from the expression levels of three genes consistently dysregulated with age in blood ( ABLIM1 , CCR7 , and LEF1 ). GamC shows moderate but reliable association with CA in three independent cohorts, supported by transcriptome-wide changes. It demonstrates specialized biological meaning, as it specifically describes current physical activity levels, but poorly correlates with autonomic nervous system function, both age-related factors associated with CV health. Finally, it expresses BA monitoring capacity by modestly responding to an effective exercise-based intervention in centenarians. In conclusion, GamC is proposed as a simple and affordable candidate BOA for reporting the individuals’ current CV health-related BA, thus promoting its broad translation and application into measures aimed at promoting healthy aging in relation to CV health, the leading cause of death worldwide.

Methylation array signals are predictive of chronological age without bisulfite conversion - Hunter L. Porter; Victor A. Ansere; Ram Babu Undi; Walker Hoolehan; Cory B. Giles; Chase A. Brown; David Stanford; Mark M. Huycke; Willard M. Freeman; Jonathan D. Wren (GeroScience, 2025)
DNA methylation data has been used to make “epigenetic clocks” which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. We found that non-methylation factors lead to “pseudomethylation” signals that are both confounding of epigenetic clocks and uniquely age predictive. We also failed to predict age using human genotyping arrays, but found that epigenetic clocks were overrepresented near genomic regions whose methylation state is dependent upon sequence variants. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

Dual-channel mechanism of groove music fused with Tai Chi to improve cognitive-emotional abilities in older adults based on a coupled fNIRS-EMG analysis: a randomized controlled study - Haojie Li; Xinyu Lin; Xie Wu (GeroScience, 2025)

Peak oxygen uptake in older adults with heart failure: a systematic review and meta-analysis - Veronika Schmid; Sarah Paterson; Christopher Weinkauf; Jing Wang; Corey R. Tomczak; David Niederseer; Jan Vontobel; Daniel E. Forman; Martin Halle; Michael D. Nelson; Stephen J. Foulkes; Mark J. Haykowsky (GeroScience, 2025)

Cellular senescence—from solid organs to vascularized composite allotransplants - Leonard Knoedler; Andreas Schroeter; Jasper Iske; Jillian Dean; Sam Boroumand; Thomas Schaschinger; Tobias Niederegger; Samuel Knoedler; Adriana C. Panayi; Max Heiland; Stefan G. Tullius; Bohdan Pomahac; et al. (GeroScience, 2025)
Vascularized composite allotransplantation (VCA) has emerged as a novel therapy approach to restore form and function in patients with severe tissue defects of the face, hand, and abdominal wall, among other anatomical regions. The composite allografts comprise different tissues such as skin, muscle, or bone. Clinical data demonstrate promising mid- and long-term outcomes following VCA surgery, but our understanding of the cellular interactions and molecular pathways in VCA surgery is oftentimes deduced from solid organ transplantation (SOT). In SOT, the concept of cellular senescence has grown increasingly popular which is characterized by a permanent cellular proliferation arrest in response to endogenous and exogenous stimuli. Senescent cells, through the release of mitochondrial DNA and secretion of proinflammatory proteins, can amplify the immunogenicity of transplants, hindering graft acceptance and longevity. This understanding has paved the way for novel interventions, including the use of senolytics—agents that selectively eliminate senescent cells—to modulate immune responses and mediate immunotolerance. There is a body of evidence that underlines the therapeutic potential of senescence to improve SOT outcomes; however, the relevance of senescence to VCA outcomes remains elusive. In this review, we aim to summarize the current literature on senescence in different solid organ transplants and outline the potential impact of senescence on VCA outcomes. This knowledge may help providers develop a broader understanding of the cellular and molecular landscape in VCA to develop targeted therapies and advance VCA patient care.

Ultra-processed foods, biological ageing, and all-cause mortality risk: a prospective cohort study using 172,225 participants from UK Biobank - Yifan Wang; Tianchen Qi; Xiaoli Wu; Chunhao Li; Boyan Zeng; Peiqi Huang; Dan Liu; Shuang Liang; Fan Yang; Feifei Xu; Chang Su; Bo Zhang; et al. (GeroScience, 2025)

Design and test–retest reliability of a new test to assess motor competence in healthy older adults - José Carlos Cabrera Linares; Pedro Ángel Latorre Román; Manuel Lucena Zurita; Juan Antonio Párraga Montilla (GeroScience, 2025)
The objective of this study was to design and analyze the test–retest reliability of a test to assess holistic motor competence in older adults (HMCT-OA), as well as the capacity of this test to discriminate between sex and age. A total of 239 older adults (age = 72.44 ± 5.93 years old) joined in this study. The test was divided into motor cognitive section, locomotor section, and manipulative section. Each section and the total time to complete the test was registered. Intraclass correlation coefficient analysis showed 0.997 (95% CI = 0.996–0.998; p < 0.001) for the total test. Also, a strong correlation between the total test and each section was found. No significant differences between sexes were found; however, the participants over 80 years old showed worse performance. The HMCT-OA showed excellent test–retest reliability parameters for older adults. The test is safe, easy to set up, and was also able to discriminate per age in healthy older adults.

Liver injury severity determines skeletal deterioration: a shared pathophysiological axis between MASLD and osteoarthritis - Mercedes del Rio-Moreno; Sher Bahadur Poudel; Lukas Stilgenbauer; Jose Cordoba-Chacon; Marianna Sadagurski; Rhonda D. Kineman; Shoshana Yakar (GeroScience, 2025)

Alterations in mitochondria and cellular senescence in aged sEH null female kidneys - Ala Yousef; Liye Fang; Mobina Heidari; Andy Huang; Patrick Kondraciuk; Kristen A. Yee; Michael Mengel; John M. Seubert (GeroScience, 2025)
Age-related structural and functional deterioration of the kidneys is common among elderly individuals and contributes to increased mortality and morbidity. Mitochondrial dysfunction and cellular senescence are two hallmarks of aging that drive a progressional renal decline; however, the underlying molecular mechanisms and endogenous regulators behind these processes remain incompletely understood. The metabolism of polyunsaturated fatty acids by CYP450 enzymes produces numerous bioactive lipid mediators that can be further metabolized by soluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH) into diol metabolites, often with reduced biological effects. The objective of this study was to assess renal mitochondrial alterations and cellular senescence in young and aged wild-type (WT) and sEH-deficient (sEH null) female mice. We found aged sEH null mice exhibited better physiological health, as reflected by lower frailty index scores and reduced circulating levels of GDF-15 levels, creatinine, and urea nitrogen. Notably, the expression of both sEH and mEH was significantly elevated in aged WT kidneys, accompanied by increased expression of the kidney injury marker ( Kim-1 ) and evidence of structural abnormalities. In contrast, sEH deletion attenuated the age-related upregulation of senescence markers (p53, p21, p16) and SASP components (MCP-1, IL-1β, and caspase-1), as well as the inflammatory zBP1 expression and downstream interferons. Additionally, sEH deletion preserved age-related disruption of mitochondrial dynamics, content, and respiratory function. Together, these data suggest that sEH deletion confers renoprotective effects in aging, characterized by improved systemic health, reduced renal injury and inflammation as preserves mitochondrial integrity and function.

A proper combination of movement and stillness: the interaction effect of sleep duration and physical activity on longitudinal cognitive performance in Chinese middle-aged and older adults - Xiaolei Li; Chen Gao; Yiru Yang (GeroScience, 2025)

Psychological predictors of gerascophobia among middle-aged and older adults: the role of health anxiety and body image satisfaction - Samira Ahmed Alsenany (GeroScience, 2025)

Identification of gut microbiota causally associated with aging and longevity and mediation roles of the cerebrospinal fluid proteins: proteomic genetic evidence from Mendelian randomization - Ruonan Liu; Zheng Zhu; Yuanyue Zhu; Xin Lin; Hongjie Li; Tiange Wang; Jie Zheng; Mian Li; Zhiyun Zhao; Yu Xu; Jieli Lu; Weiqing Wang; et al. (GeroScience, 2025)

Predicting delirium in critically Ill COVID-19 patients using EEG-derived data: a machine learning approach - Ana Viegas; Cristiana P. Von Rekowski; Rúben Araújo; Luís Ramalhete; Inês Menezes Cordeiro; Manuel Manita; Miguel Viana-Baptista; Paula Macedo; Luís Bento (GeroScience, 2025)
Delirium is a severe and common complication among critically ill patients, particularly those with SARS-CoV-2 infection, contributing to increased morbidity and mortality. Early identification of at-risk patients is crucial for timely intervention and improved outcomes. This prospective observational cohort study explores the potential of electroencephalography (EEG) combined with machine learning (ML) models for predicting delirium in critically ill patients with SARS-CoV-2 infection. A stepwise modeling approach was applied, starting with the independent analysis of specific EEG variables to assess their predictive value. Subsequently, three ML models were developed using data from 70 patients (31 with delirium, 39 without): two relied solely on EEG data, while the third integrated demographic, clinical, laboratory, and EEG data. An additional model analyzed EEG data before and after delirium diagnosis in 11 patients. Several EEG features were identified as predictors of delirium, with increased theta activity emerging as the most consistent. The best EEG-only model achieved an area under the curve (AUC) of 0.733 (sensitivity = 0.645, specificity = 0.692), indicating moderate predictive performance. Including demographic, clinical, and laboratory variables improved performance (AUC = 0.825, sensitivity = 0.613, specificity = 0.795). The model analyzing EEG features before and after delirium diagnosis achieved the highest accuracy (AUC = 0.950, sensitivity and specificity = 0.818), reinforcing the value of EEG-based monitoring. EEG-based ML models show promise for predicting delirium in critically ill patients, with increased theta activity identified as a key predictor. However, their moderate AUC, sensitivity, and specificity highlight the need for further refinement. Graphical Abstract

A novel synthetic 3,4,5-tri-feruloylquinic acid enhances learning and memory via neurotrophin signaling in an aging model senescence-accelerated prone 8 mice - Hongyu Lin; Kazunori Sasaki; Farhana Ferdousi; Shinji Kondo; Hiroko Isoda (GeroScience, 2025)
This study is the first to investigate the anti-aging effects of the newly synthesized compound, 3,4,5-tri-feruloylquinic acid (TFQA), in vivo using the senescence-accelerated mouse prone 8 (SAMP8) model, through integrated whole-transcriptomic and biochemical analyses. Oral administration of TFQA (1 mg/kg body weight) for 37 days led to significant cognitive improvements, as demonstrated by enhanced performance in the Morris water maze (MWM) test, including reduced escape latency and increased time spent in the target zone, target crossings, distance traveled, and swimming speed. Gene Ontology (GO) analysis of hippocampal microarray data revealed that TFQA upregulated genes associated with neurotransmitter and synaptic functions, while downregulating inflammatory pathways. Protein–protein interaction (PPI) analysis indicated that neurotrophin signaling was a critical upstream regulator in TFQA-treated mice. Further biochemical validation showed elevated levels of neurotransmitters (serotonin, noradrenaline, and dopamine) in the brain. Additionally, mRNA expression of tumor necrosis factor ( Tnf ), an inflammatory cytokine, was significantly reduced in the brain. Examination of the neurotrophins involved in neurotrophin signaling revealed that TFQA most prominently regulated brain-derived neurotrophic factor ( Bdnf ) co-expressed genes, which was validated by increased B dnf expression in both the brain and serum of SAMP8 mice. Bioluminescence imaging demonstrated that a single oral dose of TFQA significantly increased BDNF expression in the brains of BDNF-IRES-AkaLuc mice. Binding studies showed that TFQA has a strong affinity for the tyrosine receptor kinase B (TrkB) receptor. In summary, TFQA holds potential as a neuroprotective agent, mitigating learning and memory deficits in aging mice via neurotrophin signaling, particularly through BDNF upregulation. Graphical Abstract

Associations of accelerated epigenetic aging with cancer and mortality risk in the USA - Tongyan An; Hui Zhang; Yaqian Xu; Chongyu Ding; Yulu Gong; Darong Hao; Jing Wang; Xinyi Zhang; Tianlang Tong; Zhaojun Wang; Shuaiyin Chen; Xiangwei Li (GeroScience, 2025)

Cross-sectional and longitudinal associations of circulating bile acids and dementia: a systematic review - Yasi Zhang; Jialin Li; Jincheng Li; Yingzhe Wang; Mei Cui; Wenyan Li; Xingdong Chen; Yanfeng Jiang (GeroScience, 2025)

Ambient air pollution exposure accelerates the occurrence of 78 non-communicable chronic diseases: an accelerated failure time analysis of a nationwide cohort - Fei Tian; Shengtao Wei; Zhengmin Qian; Jinde Zhao; Yuhua Wang; Kin-fai Ho; Lauren D. Arnold; Tom Burroughs; Hualiang Lin (GeroScience, 2025)

Neural features underlying high-accuracy classification of amnestic mild cognitive impairment using multi-sensory-evoked potentials - Lei Zhang; Malcolm Binns; Ricky Chow; Rahel Rabi; Nicole D. Anderson; Jing Lu; Morris Freedman; Claude Alain (GeroScience, 2025)

Variations in perfusion detectable in advance of microstructure in white matter aging - Tyler D. Robinson; Yutong L. Sun; Paul T. H. Chang; Claudine J. Gauthier; J. Jean Chen (GeroScience, 2025)

The aging choroid plexus and its relationship with gut dysbiosis and Klotho decline: possible intervention strategies - Giovanni Lai; Lisa Bevilacqua; Maria Elisa Giuliani; Giorgia Bigossi; Serena Marcozzi; Tiziana Casoli; Pasqua Abbrescia; Antonio Frigeri; Marco Malavolta; Marta Balietti (GeroScience, 2025)
The choroid plexus (ChP) is a complex ventricular structure that forms a semi-permeable barrier between the blood and cerebrospinal fluid (CSF). It is responsible for CSF secretion and clearance, contains macrophages, and is one of the few sites within the central nervous system (CNS) where T cells are present. Additionally, the ChP plays a role in detecting peripheral inflammation, which leads to the modulation of its epithelial cell function. Despite its critical importance in maintaining brain homeostasis, the ChP is often overlooked, particularly concerning the changes it undergoes with aging, such as reduced barrier function, impaired CSF production, and altered immunosurveillance. These age-related alterations may contribute to several harmful effects, including neuroinflammation and oxidative damage, potentially predisposing individuals to neurodegenerative conditions. Although knowledge is still limited, gut dysbiosis and decreased Klotho levels—of which the ChP is one of the main sources—appear to be significant contributors to ChP impairments. This narrative review will examine the impact of age-related gut dysbiosis on the CNS, focusing on the ChP, and explore the effects of reduced Klotho levels in this brain structure. We will also propose the hypothesis that combining the administration of probiotics capable of restoring gut microbiota eubiosis with gene therapy to upregulate Klotho in the ChP could help preserve the structural and functional integrity of the aging brain. Finally, we will provide a technical overview to ensure that vectors encoding Klotho cDNA achieve maximum specificity for the ChP, thereby avoiding off-target effects. Graphical abstract

Vitamin D deficiency as a risk factor for cognitive decline in individuals aged 50 or older - Natália Cochar-Soares; Thaís Barros Pereira da Silva; Mariane Marques Luiz; Patricia Silva Tofani; Maicon Luis Bicigo Delinocente; Roberta de Oliveira Máximo; Andrew Steptoe; Cesar de Oliveira; Tiago da Silva Alexandre (GeroScience, 2025)

Advancing clinical trial readiness in white matter disease and related dementias: key steps for future research progress - Pradoldej Sompol; Gregory A. Jicha; Jason D. Hinman; Adam M. Brickman; Steven M. Greenberg; Konstantinos Arfanakis; Marion S. Buckwalter; Irene Lorenzo Llorente; Jeff D. Williamson; Michael S. Wolf; Eric E. Smith; Aditi Gupta; et al. (GeroScience, 2025)

Unraveling functional decline: the relationship between muscle strength and ultrasound evaluation of biceps brachii thickness - Maria Chiara Brunese; Grazia Daniela Femminella; Leonardo Bencivenga; Francesco Tafuri; Corrado Caiazzo; Giuseppe Rengo; Germano Guerra; Klara Komici (GeroScience, 2025)
Skeletal muscle characteristics play a crucial role in understanding physical capacity, overall health, and outcomes. Muscle strength and muscle mass are key indicators of muscular function and sarcopenia. While previous research has explored biceps brachii muscle characteristics in isolation, there is a notable gap in comprehensive studies examining the direct correlation between biceps brachii muscle thickness (BMT), as measured by ultrasound, and muscle strength. In community-dwelling elderly individuals following physical capacity evaluations, anthropometric measurements, HGS, bioimpedance analysis, and muscle ultrasound for the measurement of biceps brachii muscle thickness were performed. The study population consisted of 156 participants; ICC for ultrasound measurements resulted in 0.96 and 95% CI 0.95–0.98, indicating excellent reliability. The Kruskal–Wallis analysis revealed that muscle thickness differed between age tertiles in both male ( p = 0.0005) and female populations ( p = 0.001). Regression analysis adjusted for age, sex, BMI, muscle mass in percentage, and comorbidities revealed a significant and independent positive correlation between muscle strength and muscle thickness: R 2 = 0.70, β = 0.9, 95% CI: 0.7–1.2, and p < 0.001 in male population and R 2 = 0.17, β = 0.2, 95% CI: 0.1–0.4, and p = 0.005 in female population. Muscle thickness of biceps brachii measured by ultrasound and handgrip strength is characterized by a significant and positive relationship in older adults. In both female and male populations, the reduction of muscle thickness is parallel to increased age. Implementation of noninvasive ultrasound evaluation of muscle thickness could be helpful in the early detection of physical decline associated with the aging process. Graphical Abstract

Circular RNAs as regulators and biomarkers of mammalian ovarian ageing - Arkadiusz Grzeczka; Sharif Iqbal; Kejun Ying; Pawel Kordowitzki (GeroScience, 2025)

Development of a laboratory-based frailty index for risk prediction in elderly trauma patients with hip fractures - Malou-Sophie Dietrich; Emmanouil Liodakis; Stephan Sehmisch; Marcel Winkelmann; Manfred Gogol (GeroScience, 2025)
This study aimed to develop a laboratory-based frailty index (FI-Lab) to predict 12-month mortality risk in elderly patients following a hip fracture (HF). A retrospective analysis of 235 consecutive patients over 70 years old, who underwent HF surgery, was conducted. The FI-Lab, based on 21 routine blood parameters, was evaluated using Receiver Operating Characteristics, Area Under the Curve (AUC), Kaplan–Meier curves, and Cox proportional Hazard ratios. The FI-Lab showed an AUC of 0.7177 for 6-month and 0.7423 for 1-year survival. High FI-Lab values correlated with higher preoperative ASA scores, longer time-to-surgery times, more perioperative transfusions, and higher postoperative complication rates. The Cox hazard ratio revealed a significant increase in the risk of death for 1 year and 6 months from a score of 0.4 and higher. These findings highlight the FI-Lab’s clinical relevance and validity as a predictive tool, emphasizing the need for differentiated perioperative risk stratification.

Optimizing Statin Therapy in Older Adults: A Systematic Review of Dosing, Titration, and Combination Strategies - Anna Artner; Romána Zelkó; Balázs Hankó (GeroScience, 2025)

One-year concurrent training improves physical performance and handgrip strength in nursing home residents - Duarte Barros; Jonas Johansson; Tom Wilsgaard; José Magalhães; Joana Carvalho; Elisa A. Marques (GeroScience, 2025)

Nicotinamide riboside treatment enhances stress sensitivity and modulates hematological dynamics in aged mice - Luka Culig; Amogh Kashyap; Wakako Kuribayashi; Quia C. Claybourne; Isabel Beerman (GeroScience, 2025)
Nicotinamide riboside (NR) is a precursor to NAD + , a vital molecule for cellular energy metabolism whose levels decline with age. Aging is associated with loss of cognitive and immune function, alterations in hematological parameters, and increased vulnerability to stress. Although NR supplementation can mitigate age-related declines, it remains uncertain whether these positive effects persist when the organism is exposed to chronic physiological stress. We investigated this by exposing aged mice to NR supplementation alongside daily physiological stress and assessed various indices before and after treatment. Our results revealed that 6 weeks of NR supplementation protected against stress-induced thrombocytopenia and increased the frequencies of B and T cells. However, NR also heightened stress sensitivity, as evidenced by increased anxiety-like behaviors, while not affecting cognitive function. These findings suggest a dual role for NR in potentially enhancing immune function while exacerbating behavioral responses to stress. Future research on NR should consider stress as a variable to optimize its therapeutic usage in aging populations. Graphical Abstract

Serum ACE2 activity as a novel biomarker of assessment of severe aortic stenosis - Anita Kurczina; Arnold Péter Ráduly; Ivetta Mányiné Siket; Zsófia Pólik; Bertalan Kracskó; Attila Béla Kertész; Ágnes Balogh; Andrea Molnár; Tibor Fülöp; Laura Antal; Csaba Ötvös; Miklós Fagyas; et al. (GeroScience, 2025)
Aortic stenosis (AS) is the most prevalent valve disease in developed countries, with its incidence rising in the aging population. The current criteria for aortic valve replacement (AVR) are based on subjective symptoms and left ventricular ejection fraction (LVEF), which may not adequately reflect left ventricular (LV) dysfunction. This highlights the necessity for objective biomarkers to evaluate subclinical LV dysfunction. Serum angiotensin-converting enzyme 2 (sACE2) has emerged as a promising novel biomarker for cardiovascular diseases. To investigate the association between sACE2 activity and different flow-grade categories of severe AS, compare it with the traditional biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP), and assess the utility of sACE2 as a biomarker for AS. sACE2 and NT-proBNP were measured in 175 patients (97 male, 78 female, mean age 75 ± 8 years) diagnosed with severe AS (aortic valve area, AVA ≤ 1 cm 2 ). Patients were classified into 5 groups depending on LV flow state and pressure gradient levels: normal flow-low gradient (NF-LG), normal flow-high gradient (NF-HG), low flow-high gradient (LF-HG), low flow-low gradient (LF-LG), and paradoxical low flow-low gradient (PLF-LG) AS. Both biomarkers showed a general increase with advanced stages of severe AS (NF-LG: 65.0 ± 3.5 U/ml; LF-LG: 148.1 ± 16.8 U/ml; P < 0.05 for sACE2 and NF-LG: 687 ± 193 pg/ml; LF-LG: 5966 ± 1076 pg/ml; P < 0.05 for NT-proBNP). Notably, PLF-LG patients exhibited NT-proBNP levels similar to NF groups (PLF-LG: 1010 ± 218 pg/ml). Both biomarkers negatively correlated with LVEF and AVA. Receiver operating characteristic (ROC) analysis revealed that sACE2 provides incremental value over NT-proBNP in detecting subclinical LV dysfunction, with a 44% specificity for sACE2 compared to 6% for NT-proBNP at 98,67% sensitivity. The assessment of sACE2 activity in patients with AS provides valuable insights into disease stage and progression, supporting clinical decision-making and optimizing the timing of AVR. Furthermore, sACE2 activity serves as a moderately sensitive blood biomarker for identifying patients at risk of AS.

Expression of progerin enhances disease-related endpoints in a tau seeding reporter cell system - Zhuang Zhuang Han; Sang-Gyun Kang; Erik Gomez-Cardona; Serene Wohlgemuth; Klinton Shmeit; Luis Arce; Jiri G. Safar; Olivier Julien; David Westaway (GeroScience, 2025)
Sporadic Alzheimer’s disease and some forms of frontotemporal lobar degeneration (FTLD-tau) are neurological disorders of later life where cognitive deficits follow from the progressive accumulation of microtubule-associated tau protein. Disease-related tau accumulation is marked by altered subcellular distribution and rearrangement of this natively unstructured protein into alternative conformational forms, including highly organized fibrillar assemblies. With a partial analogy to effects seen in prion diseases, pathological tau conformers have a templating activity called seeding that may be measured in cellular and cell-free systems. Moreover, cellular systems and disease models can recapitulate “strain effects” wherein the same tau amino acid sequence can adopt markedly different conformations. Here we analyzed FTLD-tau conformers in cellular reporter systems expressing a pro-aging mutant form of the lamin A protein termed “progerin.” Measured versus the baseline performance of a reporter system based on HEK293 cells, the addition of tau burden or progerin expression produced only mild changes in proteomic analyses or morphology, whereas application of both stressors produced a notable shift in ER stress and homeostasis, including increased levels of DNAJC10 and DNAJA2. The phenotypic effects scored here appear unrelated to the generation of new tau strains or to the type of strain input, insofar as progerin-expressing cells were more responsive to tau seeding by diverse brain samples containing different populations of tau conformers. Thus, premature aging and disease-associated tau conformers can exhibit an additive relationship in a model system.

Outdoor light at night and neuropsychiatric symptoms in dementia - Manuela Tondelli; Tommaso Filippini; Giulia Vinceti; Najara Iacovino; Teresa Urbano; Sofia Costanzini; Francesca Despini; Claudia De Luca; Simona Tondelli; Marco Vinceti; Annalisa Chiari; Giovanna Zamboni (GeroScience, 2025)
There is growing interest about the relation between exposure to artificial light at night (LAN) and mental health. This study aims, for the first time, to explore the association between LAN exposure and neuropsychiatric symptoms in individuals with dementia, investigating its role as a potential environmental risk factor. We collected data about 150 patients with dementia in Modena, Italy. We assessed LAN exposure using satellite imagery, while neuropsychiatric symptoms were evaluated through the Neuropsychiatric Inventory (NPI), a caregiver-administered questionnaire measuring the presence and severity of psychiatric symptoms. We used logistic regression models to examine associations between LAN exposure and neuropsychiatric features. Higher LAN exposure was associated with increased risk of psychiatric symptoms, particularly in the domains of psychosis and sleep disturbances. Specifically, individuals exposed to LAN levels above the median (LAN median = 26.32 nW/cm 2 /sr) demonstrated an elevated risk of delusions, hallucinations, and sleep disturbances (OR = 2.09, 95% CI 0.03–4.25), compared to those in the “below the median” category. Associations with other symptom domains, such as apathy and affective disturbances, showed weaker associations. Our findings indicate that artificial nighttime light exposure may negatively impact the mental well-being of individuals with dementia, potentially exacerbating psychotic symptoms and sleep disturbances. However, caution is warranted when interpreting these results due to the limited sample size and the possibility of unexamined residual confounding.

Testing retrogenesis and physiological explanations for tract-wise white matter aging: links to developmental order, fiber calibre, and vascularization - Tyler D. Robinson; Jordan A. Chad; Yutong L. Sun; Paul T. H. Chang; J. Jean Chen (GeroScience, 2025)

Quality of life in end of life - Lavinia Valeriani; Barbara Carrano; Fabrizio Vecchio (GeroScience, 2025)

Association of accelerometer-measured physical activity and sedentary behavior with unplanned hospitalization in older adults: a 6-year longitudinal study - Joan Ars; Giorgi Beridze; Pau Farrés-Godayol; Laura M. Pérez; Marco Inzitari; Amaia Calderón-Larrañaga; Anna-Karin Welmer (GeroScience, 2025)
Regular physical activity (PA) and reduced sedentary behavior (SB) are well-established factors in promoting health and lowering the risk of chronic diseases. However, their relationship with unplanned hospitalizations remains unclear. Our aim was to investigate the associations between PA and SB parameters and the risk of unplanned hospital admissions, and the length of hospital stays in older adults. We analyzed data from 657 older adults aged ≥ 66 years from the Swedish SNAC-K study (2016–2018). The ActivPAL3 accelerometer was used to assess PA and SB. Multi-adjusted Cox and Laplace regressions were applied to examine PA and SB in relation to 6-year unplanned hospitalizations. Negative Binomial Regression models were employed to examine their associations with the length of hospital stays. For each 1000 steps/day, 100 low-intensity PA (LPA) walking events, and 15 min/day of time spent in moderate-to-vigorous PA (MVPA), the risk of unplanned admissions decreased (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.91–0.99, HR 0.77, 95%CI 0.61–0.96, and HR 0.91, 95%CI 0.83–1.00, respectively). Higher step counts and MVPA were also associated with shorter hospital stays (IRR per 1,000 steps: 0.91, 95% CI: 0.86–0.96; IRR per 15 min MVPA: 0.85, 95% CI: 0.75–0.96). No significant associations were found for SB or walking events with hospital stay in fully adjusted models. Our results suggest that higher step counts and greater participation in MVPA are associated with a reduced risk of hospital admissions and shorter hospital stays in older adults. Additionally, a greater number of LPA walking events was linked to lower risk of hospital admissions. These results support the promotion of regular walking and frequent PA as strategies to reduce healthcare burden in aging populations.

Epigenetic information loss is a common feature of multiple diseases and aging - Naor Sagy; Chieh Chang; Maayan Gal; Daniel Z. Bar (GeroScience, 2025)
Aging is a major risk factor for a plethora of diseases. The information theory of aging posits that epigenetic information loss is a principal driver of the aging process. Despite this, the connection between epigenetic information loss and disease has not been thoroughly investigated. Here, we analyzed tissue-unique methylation patterns in healthy and diseased human organs, revealing that for several diseases these patterns degrade, regressing to a mean form. We interpret this as epigenetic information loss, where tissue-unique patterns erode. Information loss is not limited to diseases. Age-related erosion of unique methylation patterns was observed in some tissues and cells, while other tissues and cells diverged away from the mean. Our findings demonstrate that analyzing methylation patterns in tissue-unique sites can effectively distinguish between patients and healthy controls at least in some diseases, and underscore the role of epigenetic information loss as a common feature in various pathological conditions. Graphical abstract Tissue unique methylation pattern regress toward the mean upon disease. A single methylation site, showing low methylation in the liver and high in every other tissue, becomes more methylated in diseased livers.

Nervonic acid and 15-epi-PGA1 mediate systemic mitochondrial dysfunction in AD dementia - Stephanie Robyn Heimler; K. Allison Amick; Jaclyn Bergstrom; Marcos Moliné; Gargi Mahapatra; Suzanne Craft; Anthony J. A. Molina (GeroScience, 2025)
Systemic mitochondrial dysfunction is apparent in the pathophysiology of Alzheimer’s disease (AD). However, the factors driving bioenergetic decline remain unclear. This study utilized serum samples from older adults with normal cognition, mild cognitive impairment, and dementia to identify circulating molecules that can drive mitochondrial dysfunction in the context of AD. We used mass spectrometry to measure the abundance of lipid metabolites and applied tiered selection criteria to identify candidate “mito-inhibitory” molecules. These criteria were based on correlations with (1) in vitro bioenergetic effects of whole serum samples on naïve cells, (2) the bioenergetic capacity of blood cells from the serum donor, and (3) cognition, as measured by the modified mini-mental state exam. Mito-inhibitory lipid candidates were validated by examining their bioenergetic effects on neurons, myoblasts, and fibroblasts in vitro. Our results indicate that nervonic acid and 15-epi Prostaglandin A1 (15-epi-PGA1) are elevated in participants with dementia compared to those with normal cognition. Importantly, both metabolites inhibited mitochondrial function across multiple cell types in vitro. High resolution respirometric analyses reveal that inhibitory effects from lipid treatment occur via broad inhibition of the electron transfer system (ETS) with no change in overall mitochondrial content. This study provides insights into the mechanisms underlying systemic bioenergetic decline associated with AD dementia. The identification of circulating factors that drive mitochondrial bioenergetic decline may inform the development of mitochondrial therapeutics for AD. Graphical Abstract In this study, we describe the identification and validation of mito-inhibitory bioactive lipid metabolites through a combination of serum lipidomics, statistical analyses, and mitochondrial respirometry.

Kynurenine pathway dysregulation via loss of QPRT drives declines in activity and altered metabolism in mice - Reyhan Westbrook; Vinal Menon; Joy Cagmat; Timothy Garrett; Robert Schwarcz; Jeremy Walston; Peter M. Abadir; Tae Chung (GeroScience, 2025)
Chronic inflammatory pathway activation increases with age and is epidemiologically linked to multiple aging-related pathophysiological processes, phenotypes such as physical frailty and sarcopenia and early healthspan declines in aging organisms. Despite this, molecular mechanisms that directly connect chronic inflammation to these conditions remain poorly characterized. We hypothesize that chronic inflammation contributes to the development of age-related phenotypes by increasing the degradation of dietary tryptophan into multiple metabolites with unique physiological properties, called kynurenines, via the ‘kynurenine pathway’ (KP). To understand the impact of elevated KP metabolites on mammalian healthspan we utilized the quinolinate phosphoribosyltransferase knock-out (QPRT −/− ) mouse which lacks the terminal enzyme of the KP and thus develops increased levels of downstream kynurenines. We tested the effects of this mutation on glucose handling, spontaneous motor activity, body composition and metabolism using indirect calorimetry, in male and female, young, middle aged and older mice. QPRT − / − mice had significantly altered levels of numerous KP metabolites and nicotinamide. Phenotypic characteristics varied in a sex-specific manner with decreased activity, lean mass and VO 2 , and impaired glucose clearance as early as 12 months seen in female QPRT −/− compared to age and sex-matched mice. Male QPRT −/− mice developed reduced lean mass by middle age and had altered respiration and food intake. This data indicates that KP dysregulation can drive declines in activity and alter metabolism in mammals and is a potential target to intervene on frailty and functional decline.

Age-dependent impairment of cardiac function and physical performance in male mice with diet-induced obesity - Patricia Baumgarten; Justus Kamp; Niklas Hegemann; Stefanie Deubel; Nikolaus Berndt; Jana Grune; Wolfgang M. Kuebler; Christopher L. Axelrod; John P. Kirwan; Annika Höhn; Sophie Heider; Christiane Ott; et al. (GeroScience, 2025)
Aging in the context of obesity exacerbates the risk of morbidity and mortality related to cardiovascular disease. However, the maladaptive responses in the heart that arise from prolonged obesity and the specific influence of biological age remain somewhat elusive. This study investigated the effects of diet-induced obesity (DIO) and aging on physical performance and cardiovascular function in mice. 22- and 76-week-old male C57BL/6J mice were randomized to 8 weeks of chow or high-fat diet. Body weight was assessed weekly. Body composition was measured at the beginning and the end of the diet treatment. Muscular and cardiac function were evaluated at the end intervention. Aged mice with DIO exhibited faster and greater body weight gain and fat mass accumulation, reduced running distance, and lower aerobic capacity. Aged HFD mice also exhibited increased cardiac lipid accumulation and cardiomyocyte hypertrophy, with no major morphological changes observed in skeletal muscle. Proteomic analysis revealed differential expression of heart proteins associated with metabolic function in young mice, which was not observed in aged mice with DIO. Subsequently, aged mice with DIO developed overt heart failure with reduced ejection fraction, while cardiac function was unaffected by DIO in young mice. In conclusion, young mice with DIO were protected against diet-induced cardiac dysfunction, whereas DIO in aged mice led to heart failure and impaired physical performance. The protective effects observed in younger mice appear to be explained by proteomic-level remodeling of the heart oriented to sustain cardiac function.

Exploring motor unit and neuromuscular junction dysfunction in aging and sarcopenia: insights from electromyography in systematic review - Can Cui; Yong Hu; Ronald Man Yeung Wong; Ning Zhang; Yuzhou Guan; Wing-hoi Cheung (GeroScience, 2025)

Subjective memory concern, negative affect, and cortical microstructural integrity in community-dwelling middle-aged men - Rongxiang Tang; Tyler R. Bell; Jeremy A. Elman; Chandra A. Reynolds; Daniel E. Gustavson; Olivia K. Puckett; Matthew S. Panizzon; Rosemary Toomey; Ruth McKenzie; Michael J. Lyons; Donald J. Hagler; Christine Fennema-Notestine; et al. (GeroScience, 2025)
Concerns about memory often increase with age and have been suggested as a precursor to impending memory impairment or dementia. However, subjective memory concern (SMC) has also been shown to reflect an individual’s trait-like tendency to worry about memory, which is more strongly linked to negative affect than to objective memory performance. Despite behavioral evidence supporting a trait-like dimension of SMC, its neuroanatomical underpinnings remain underexplored. In 477 community-dwelling dementia-free men (56–72 years old), we investigated the association between SMC and cortical mean diffusivity (cMD)—a diffusion MRI-based metric of gray matter microstructural integrity—generating a brain-wide map of their association. Self-report trait anxiety and depressive symptoms were collected, along with objective memory scores based on three neuropsychological tasks for which brain maps of their association with cMD were also generated. Finally, we conducted spatial correlational analyses to compare the spatial patterns of these brain association maps to assess whether there were significant spatial resemblances between each. We found that the gray matter integrity correlates of SMC spatially resembled those of depressive symptoms and trait anxiety but not those of objective memory. The spatial correspondences between gray matter integrity correlates of negative affect measures and SMC were significantly stronger than those between SMC and objective memory. Together, these results suggest a neuroanatomical basis of trait-like SMC, which should be distinguished from state-related SMC that may be a precursor of objective memory deficits in research and clinical settings.

Factor analysis of multimodal MRI, biofluid, and vascular biomarkers reveals latent constructs of brain health - Ella Rowsthorn; Ming Ann Sim; William T. O’Brien; Stuart J. McDonald; Katherine Franks; Benjamin Sinclair; Trevor T.-J. Chong; Stephanie Yiallourou; Marina Cavuoto; Lucy Vivash; Terence J. O’Brien; Xingfeng Shao; et al. (GeroScience, 2025)
Individual imaging and fluid biomarkers provide insights into specific components of brain health, but integrated multimodal approaches are necessary to capture the complex, interrelated biological systems that contribute to brain homeostasis and neurodegenerative disease. Using data from the Brain and Cognitive Health (BACH) cohort study ( N = 127; mean age = 67 years, 68% women), we performed an exploratory factor analysis to identify latent constructs of brain health. We included multimodal neurovascular imaging markers, brain atrophy metrics, plasma Alzheimer’s disease (AD) biomarkers, and cardiovascular risk factors. Five constructs emerged: “Brain & Vascular Health” (greater hippocampal volume, basal ganglia enlarged perivascular spaces (ePVS), cerebral blood flow, and HDL cholesterol; lower ventricle volume and BMI), “Structural Integrity” (greater cortical thickness, fractional anisotropy, and basal ganglia ePVS), “White Matter (WM) Fluid Dysregulation” (greater WM ePVS and Free Water), “AD Biomarkers” (higher phosphorylated tau [pTau]181 and pTau217; lower amyloid-beta 42/40 ratio), and “Neuronal Injury” (higher glial fibrillary acidic protein and neurofilament light chain). All constructs were associated with age (β = - 0.70–0.39, p ≤ 0.014), except for WM Fluid Dysregulation ( p > 0.05). Brain and Vascular Health and Structural Integrity (partial r = 0.305, p < 0.001) and AD biomarkers and neuronal injury (partial r = 0.248, p = 0.005) were positively correlated. Only Brain and Vascular Health was associated with global cognition (β = 0.27, SE = 0.13, p = 0.043). These findings provide a data-driven framework for examining distinct constructs underlying vascular health, fluid regulation, and neurodegenerative pathology. We demonstrate the utility of using multiple biomarkers to probe these biological systems, paving the way for future research to explore how these systems change across diverse neurodegenerative conditions. Graphical abstract

The role of burnout prevention in promoting healthy aging: frameworks for the Semmelweis Study and Semmelweis-EUniWell Workplace Health Promotion Program - Virág Zábó; Andrea Lehoczki; Annamária Buda; Péter Varga; Monika Fekete; Vince Fazekas-Pongor; Marianna Moizs; Giorgia Giovannetti; Yura Loscalzo; Marco Giannini; Beatrix Busse; Miklos Kellermayer; et al. (GeroScience, 2025)
As the European Union undergoes a demographic shift toward an aging population, the rising prevalence of age-related diseases poses significant public health challenges. Across the EU, disparities in health indicators and life expectancies highlight the urgency of addressing factors that contribute to unhealthy aging. Burnout, characterized by emotional, physical, and mental exhaustion, has emerged as a critical determinant of healthy aging, with profound biological, psychological, and social implications. Burnout accelerates age-related decline, exacerbates health risks, and undermines overall well-being. This review explores the role of burnout in unhealthy aging, highlighting its underlying mechanisms and proposing actionable interventions. Workplace-based initiatives—such as the Caring University Model Program at Semmelweis University, which includes the Semmelweis Study and the Semmelweis-EUniWell Workplace Health Promotion Program developed within the European University for Well-Being (EUniWell) framework—offer a novel, integrated approach to embedding burnout prevention within broader public health strategies. By drawing on global best practices—including the Blue Zones model and Mediterranean lifestyle principles—and adapting them to diverse cultural contexts across Europe, these programs aim to foster resilience, reduce stress, and enhance workforce well-being. Addressing burnout as a critical determinant of health, these initiatives offer a scalable blueprint for promoting healthy aging and improving productivity throughout the EU. By incorporating burnout prevention into regional and national health policies, European countries can collectively extend healthspan, reduce healthcare costs, and enhance the quality of life for their aging populations.

Dietary supplement use in longevity: evidence from 2,877 centenarians - Jozo Grgic; Ajla Hodzic Kuerec; Brad J. Schoenfeld (GeroScience, 2025)

A physically and mentally active lifestyle relates to younger brain and cognitive age - Niklas Behrenbruch; Svenja Schwarck; Beate Schumann-Werner; Eóin N. Molloy; Berta Garcia-Garcia; Anne Hochkeppler; Larissa Fischer; Anna-Therese Büchel; Enise I. Incesoy; Jose Bernal; Niklas Vockert; Patrick Müller; et al. (GeroScience, 2025)
Resistance to age-related pathological changes (brain maintenance), including Alzheimer’s disease, cerebrovascular disease, and neurodegeneration may promote cognitive resilience in aging. However, how lifestyle and health profiles relate to successful cognitive and brain aging remains poorly understood. In a novel, deeply phenotyped cohort of 211 cognitively unimpaired older adults (age = 71.0 ± 7.4 years, 46% female), we characterized principal components of lifestyle and health using questionnaire, fitness, and blood data. We estimated cognitive age gap (CAG) based on comprehensive neuropsychological data and brain age gap (BAG) based on brain-pathology markers, including plasma biomarkers of Alzheimer’s pathology (pTau 217 and Aβ 1-42 /Aβ 1-40 ), MRI-based measures of white matter hyperintensities, perivascular spaces, and brain atrophy. Regression analyses tested how the observed lifestyle-health profiles were related to CAG and BAG. Seven principal components explained 49% of the variance in health and lifestyle. The second component, characterized by a mentally and physically active life and low cardiovascular risk, was associated with lower CAG ( β = − 0.66, p < 0.001) and BAG ( β = − 0.52, p = 0.003), reflecting a younger-than-expected brain and cognitive age, respectively. The association of an active lifestyle and lower CAG was partially mediated by BAG. Higher CAG was also associated with other lifestyle components characterized by low mental stimulation. APOE-ε4 carriers exhibited higher BAG. In conclusion, a lifestyle combining low cardiovascular risk, high mental engagement throughout life and high physical activity/fitness is jointly associated with less-than-expected brain pathology and better-than-expected cognitive performance, supporting its involvement in brain maintenance and cognitive resilience to aging.

Gene expression and co-expression heterogeneity patterns and biodemography analyses during the cell cycle encourage aging studies in archaea - Yuping Dai; Miguel V. Gomez-Raya-Vilanova; Jérôme Teulière; Mouhammad Toucourou; Eduardo Corel; Louis-Patrick Haraoui; Philippe Lopez; François-Joseph Lapointe; Claudio Franceschi; Annette Baudisch; Debashish Bhattacharya; Virginija Cvirkaite-Krupovic; et al. (GeroScience, 2025)

Increased genetic protection against Alzheimer’s disease in centenarians - Harold Bae; Zeyuan Song; Amanat Ali; Takashi Sasaki; Niccolò Tesi; Hannah Lords; Anastasia Leshchyk; Yukiko Abe; Nobuyoshi Hirose; Yasumichi Arai; Nir Barzilai; Erica F. Weiss; et al. (GeroScience, 2025)

Centenarians and near-centenarians in India: empirical insights on health and well-being characteristics - Sunil Rajpal; William Joe; Shreya Ronanki; Rockli Kim; S. V. Subramanian (GeroScience, 2025)

Immunosenescence accelerates atherosclerosis development in AAV-PCSK9 mouse model - Jill de Mol; Virginia Smit; Mireia N. A. Bernabé Kleijn; Peter J. van Santbrink; Ilze Bot; Amanda C. Foks (GeroScience, 2025)
Aging is a dominant risk factor for atherosclerotic cardiovascular disease and is associated with compositional and functional changes in our immune system, called immunosenescence. To gain insights into the impact of immunosenescence on atherosclerosis, we investigated plaque development and the immune landscape in an AAV-PCSK9 mouse model. Young (3 months) and aged (18 months) male C57Bl/6 mice received a single i.v. injection of a recombinant adeno-associated virus encoding murine PCSK9 (rAAV8-D377Y-mPCSK9) and were fed a Western-type diet (WTD) for 10 weeks to induce atherosclerosis. At sacrifice, cholesterol and serum PCSK9 levels showed no difference. Atherosclerosis development in the aortic root was significantly enhanced with 59% in aged compared to young mice. Additionally, plaques in aged mice showed a more advanced phenotype, with an increased collagen/macrophage ratio. While the T cell percentage declined in the periphery and lymphoid organs upon aging, leukocytes, including T- and B cells, increased within the aged aortic arch. Moreover, we observed a shift towards effector (memory) subsets, including Th1 cells and Tregs, with elevated cytokine production and a senescent phenotype within the T cell compartment of aged mice. We also observed increased percentages of splenic age-associated B cells, regulatory B cells and plasma cells in aged mice, which coincided with increased levels of circulating antibodies. In conclusion, aged WTD-fed AAV-PCSK9 mice displayed pro-atherogenic immune alterations, including elevated plaque inflammation, increased cellular senescence and impaired humoral immune responses, contributing to accelerated atherosclerosis development compared to young mice. Targeting or reversing age-associated immunity could represent a promising strategy to combat atherosclerotic cardiovascular disease. Graphical Abstract

End-of-life pathology in UM-HET3 mice treated with 16 α‑hydroxyestradiol or late‑start canagliflozin - Jessica M. Snyder; David E. Harrison; Ron Korstanje; Brett Ginsburg; Peter C. Reifsnyder; James Nelson; Scott Leiser; Catherine Kaczorowski; Denise M. Imai; Adam B. Salmon; Randy Strong; Warren Ladiges; et al. (GeroScience, 2025)
Canagliflozin (Cana) started at 16 months of age and 16-hydroxy-estradiol (OH_Est) started at 12 months each led to significant increases in lifespan in male UM-HET3 mice but significant decreases in female lifespan. To seek insights into the basis for these sex-specific effects, we performed end-of-life histopathological analyses of control and treated mice for all three interventions testing program sites. There were no significant drug-induced alterations in inferred cause of death, although statistical power was low for such comparisons. Tabulation of incidental lesions (i.e., combining lethal and non-lethal lesions) revealed a complex set of significant and near-significant changes caused by each of the two agents, in some cases absent, or even opposite in direction, in one of the two sexes. The analysis did not, however, reveal a clear pattern that would explain the selective sex-specific effects of either agent on lifespan. It is plausible that the female-specific harm induced by each of these agents could reflect harmful or toxic effects that are not easily detectable by histopathological examination.

Growth differentiation factor 15 predicts physical function impairment in Spanish older adults: a real-world prospective study - Karine Ferreira de Campos; Esther García-Esquinas; Antonio Buño-Soto; Mercedes Sotos-Prieto; Adrián Carballo-Casla; Fernando Rodríguez-Artalejo; Rosario Ortolá (GeroScience, 2025)
Growth differentiation factor 15 (GDF15) is an emerging biomarker of disease burden, but few studies explore its association with physical function impairment using validated objective measures. We evaluated the cross-sectional and longitudinal association between GDF15 and impaired physical function in older adults, assessed with five validated tools. Data were collected from 2481 individuals ≥ 65 years-old in the Seniors-ENRICA-2 cohort. Serum GDF15 was measured once, at baseline, and physical function was assessed at baseline and after 2.2 years using the following measures: lower-extremity performance (Short Physical Performance Battery), agility (Nagi scale), mobility (Nagi and Rosow & Breslau questionnaires), weakness (measured grip strength) and frailty (Deficit Accumulation Index). Analyses were performed with logistic regression and adjusted for relevant potential confounders.The odds ratios (95% confidence interval) per 25% increment in GDF15 in cross-sectional and prospective analyses were: 1.06 (1.01–1.12) and 1.18 (1.08–1.30) for reduced lower-extremity performance; 1.18 (1.12–1.26) and 1.21 (1.08–1.35) for impaired agility; 1.19 (1.11–1.27) and 1.21 (1.08–1.35) for impaired mobility; 1.15 (1.09–1.22) and 1.13 (1.02–1.25) for weakness; and 1.24 (1.16–1.33) and 1.18 (1.06–1.31) for frailty. Results were similar among participants without cardiovascular disease or diabetes. Higher levels of serum GDF15 are associated with prevalent and incident impaired physical function in older adults. GDF15 could serve as a convenient biomarker to identify older adults at risk of functional decline. Further studies should elucidate the underlying mechanisms, explore its potential to improve risk prediction, and assess the therapeutic value of modifying GDF15.

Combined effects of vitamin D and cumulative dietary risk score on fatty liver and mortality in vulnerable individuals: a prospective analysis from the UK Biobank - Xiaoyan Wang; Yongqi Liang; Chenxi Jin; Jingjing Liang; Yining Xu; Xianbo Wu; Mengchen Zou (GeroScience, 2025)
Frailty is a global public health issue associated with multiple adverse outcomes in later years, however, studies have shown exercise, diet, and vitamin D supplements can help reverse frailty. There is a lack of further risk stratification and evidence for secondary interventions in populations that have undergone primary prevention. This was a prospective cohort study involving 53106 physically active vulnerable individuals from the UK Biobank. We combined vitamin D with cumulative dietary risk scores to evaluate its predictive value. Correlation and predictive power were assessed using restricted cubic spline (RCS) analysis, corrected Cox models, stratified analysis, Kaplan–Meier analysis, and Harrell's c-index. During 12.7 years of follow-up, there were 870, 1317 new-onset metabolic dysfunction-associated fatty liver disease (MAFLD) and mortality. RCS analysis revealed a J-shaped negative or positive correlation in vitamin D and dietary risk score respectively. The hazard ratios (95% confidence interval) for MAFLD and mortality in the vitamin D deficiency and high dietary risk groups were 1.80 (1.45–2.24) and 1.99 (1.67–2.38), compared to those with no vitamin D deficiency and low dietary risk. Kaplan–Meier analysis suggested vulnerable individuals with vitamin D deficiency and a poor diet were at a higher risk of disease in the future. Further, separate analyses of vitamin D and dietary risk scores did not demonstrate better efficacy. The combination of vitamin D and dietary risk score offers a more effective method for assessing disease risk in vulnerable populations. This provides evidence for secondary guidance following exercise interventions, which is significant for older population. Graphical abstract

Unveiling Selenoprotein T as a novel regulator of cardiomyocyte senescence: pivotal role of the CD36 receptor in AC16 human cardiomyocytes - Anna De Bartolo; Vittoria Rago; Naomi Romeo; Marika De Cicco; Benjamin Lefranc; Jérôme Leprince; Giuseppe Passarino; Pasquale Pagliaro; Youssef Anouar; Carmine Rocca; Tommaso Angelone (GeroScience, 2025)

Self-testing for symptoms and signs of prodromal alpha-synucleinopathies: results from the Tasmanian ISLAND Sleep Study - Samantha Bramich; Alastair J. Noyce; Anna E. King; Eddy Roccati; Sharon L. Naismith; James C. Vickers; Jane Alty (GeroScience, 2025)
Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) may occur at least 10 years before a clinical diagnosis of an α-synucleinopathy, such as dementia with Lewy bodies (DLB), Parkinson’s disease (PD) or multiple system atrophy (MSA). The extent to which people with iRBD manifest subtle features of these conditions is an area of active research and whether these changes can be measured remotely in the community is an important aim. Better characterisation may aid early detection and monitoring for people at risk of neurodegeneration. The aim of this study was to investigate remote tests of subjective and objective features of α-synuclein-related conditions in probable iRBD (pRBD). We hypothesised that α-synuclein-related symptoms and signs would be more frequent in pRBD than healthy controls. 2,891 participants aged 50 + from the Tasmanian ISLAND Sleep Study completed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), and several online questionnaires and unsupervised objective assessments of motor, cognitive and olfactory function. People with pRBD ( n = 267; mean (SD) age 63 (7.6) years; 53% female) reported more α-synuclein-related features than controls ( n = 2,624; mean (SD) age 64 (7.7) years; 75% female), especially orthostatic intolerance, neuropathic pain, falls, olfactory impairment and hand motor dysfunction. These results show that people with pRBD exhibit a range of symptoms and signs of α-synuclein-related conditions that can be measured using remote (online and postal) assessment tools. Remote monitoring in the community may aid early detection of progression to DLB, PD and MSA and facilitate enrolment into clinical trials.

Alzheimer’s disease polygenic risk’s association with all-cause dementia through the plasma metabolome in the UK Biobank study - May A. Beydoun; Yi-Han Hu; Zhiguang Li; Michael F. Georgescu; Hind A. Beydoun; Nicole Noren Hooten; Keenan A. Walker; Mustapha Bouhrara; Lenore J. Launer; Michele K. Evans; Alan B. Zonderman (GeroScience, 2025)
Dementia, with Alzheimer’s Disease (AD) accounting for 60–70% of its occurrences, is a multifactorial disorder marked by cognitive and functional decline. Polygenic risk scores (PRS) stratify genetic risk for complex diseases, including AD. Integrating PRS with metabolomics offers a pathway to better understand AD etiology and identify biomarkers for early detection. We explored the association between AD PRS, metabolomics, and dementia risk using data from the UK Biobank. The analysis emphasizes sex-specific associations and the mediating role of metabolites between AD PRS and dementia risk. The study utilized data from 205,219 UK Biobank participants aged ≥ 50 years at baseline. Dementia outcomes were derived using ICD-10 codes. AD PRS were computed using genome-wide association study data, while metabolomic data included 249 biomarkers measured via Nuclear Magnetic Resonance. Time-to-event analyses (Cox proportional hazards models) and generalized structural equation modeling assessed associations and mediation effects, adjusting for age, sex, and genetic principal components. Higher AD PRS was associated with increased risks of all-cause dementia (HR: 1.75, 95% CI: 1.70–1.79, P < 0.001) and AD (HR: 2.02, 95% CI: 1.95–2.09, P < 0.001), with stronger effects in women for both outcomes when considering the main AD PRS which was related to APOE4 status. Metabolomic analyses identified lipid-related markers as key mediators. LDL phospholipid content was the metabolite marker with the strongest positive relationship with AD genetic risk (effect size, b = + 0.11), while HDL phospholipids percentage showed a similarly strong inverse association (effect size b = -0.09). No metabolomic markers were significantly associated with another version of AD PRS that was less correlated with APOE4 status. Mediation analyses applied to the main AD PRS revealed modest effects, with LDL-related metabolomic components partially mediating the effect of genetic risk on dementia incidence, through a protective type of mediation (< -2%). Nevertheless, most genetic risk operated independently of metabolites. AD PRS is significantly associated with dementia risk, with sex differences and metabolomic pathways providing further insights. Lipid metabolism, particularly LDL-centric measures, emerged as potential mediators. This integrative approach highlights the utility of combining genetic and metabolomic data to identify biomarkers and potential targets for early intervention in AD and dementia.

Sex-specific associations between homelessness and cerebrovascular disease among aging US veterans in the Veterans Affairs healthcare system - Hind A. Beydoun; May A. Beydoun; Sameed Ahmed M. Khatana; Neil Nixdorff; Nishant K. Mishra; Jack Tsai (GeroScience, 2025)

Targeting angiopoietin like-2 positive senescent cells improves cognitive impairment in adult male but not female atherosclerotic LDLr−/−;hApoB100+/+ mice - Mélanie Lambert; Géraldine Miquel; Gael Cagnone; Pauline Mury; Louis Villeneuve; Frédéric Lesage; Nathalie Thorin-Trescases; Eric Thorin (GeroScience, 2025)
Cellular senescence contributes to cognitive decline in brain diseases. In dyslipidemic and atherosclerotic LDLr −/− ;hApoB100 +/+ (ATX) mice—a model exhibiting vascular dysfunctions and cognitive impairment—the role of senescence was investigated by targeting angiopoietin-like 2 ( angptl2 ), a senescence marker. Adult ATX mice of both sexes received AAV1-sh- angptl2 ; cognition was assessed via the Morris Water Maze, cerebrovascular functions were evaluated in vitro and in vivo and hippocampal transcriptomic signatures were analyzed using single-nuclei RNA-sequencing. Sh- angptl2 restored delayed memory retention in male mice, but impaired learning and short-term memory in females. Sh- angptl2 had no effect on cerebrovascular functions. Transcriptomic analyses revealed sex-specific responses: endothelial senescence pathways were predominantly activated in male cells and repressed by sh- angptl2 . In contrast, sh- angptl2 up-regulated senescence pathways in all cell types in females. Key impacted senescent cell types were neurons, choroid plexus epithelial (CP-epithelial) cells, and oligodendrocyte precursor cells (OPCs), not endothelial cells. In male neurons, CP-epithelial cells and OPCs, gene-related pathways induced by sh- angptl2 revealed enhanced neuronal energy metabolism but reduced synaptic pathways, higher synaptic formation with reduced intracellular signaling, structural remodeling and reduced synaptic development. In female cells, sh- angptl2 disrupted GABAergic signaling despite promoting neuronal growth, up-regulated stress-response and decreased gene and protein processing, leading to inefficient neurogenesis. Although neuroprotective ApoE was upregulated in both sexes, males had higher expression of ApoE receptor subtypes, supporting better synaptic resilience. In conclusion, accumulation of non-vascular senescent cells contributes to cognitive impairment in male ATX mice, not females, highlighting the need for sex-specific senotherapies strategies in cardiovascular diseases.

Adaptations of mitochondrial, autophagy and nutrient sensing pathways in the liver from long-lived mice overexpressing CYB5R3 are sex-dependent and involve inter-organ responses - Luz Marina Sánchez-Mendoza; José A. González-Reyes; Sandra Rodríguez-López; Cristina García-Caballero; Juan Antonio Moreno; Rafael de Cabo; M. Isabel Burón; José M. Villalba (GeroScience, 2025)
Cytochrome b 5 reductase 3 (CYB5R3) overexpression mimics several metabolic benefits of calorie restriction, with sex- and tissue-specific effects. This study aimed to investigate how CYB5R3 overexpression impacts hepatic metabolism in young mice, focusing on mitochondrial biogenesis, lipid metabolism, autophagy and nutrient sensing pathways thus establishing a baseline that allows for subsequent comparisons with older animals. The accrual of CYB5R3 polypeptide exhibited marked sexual dimorphism as it was increased by transgenesis only in females with predominant microsomal targeting but mainly located in the mitochondria in males. Nevertheless, key metabolic markers, including TFAM (biogenesis), p62 and LC3 (autophagy), AKT and mTOR (nutrient sensing), SIRT1/SIRT3 (enzymatic regulation and gene expression) and ACC1/ACAA2 (lipid metabolism), were significantly altered in transgenic males. Wild-type males exhibited higher levels of mitochondrial complexes III and IV than females, and these differences were attenuated by transgenesis. TFAM was increased in transgenic mice of both sexes, indicative of enhanced mitochondrial biogenesis. Changes of lipid metabolism markers indicated reduced hepatic lipid accumulation in females while males showed changes in ACC1 and ACAA2, affecting lipid storage and oxidation. Autophagy markers (p62, LC3I/II) were altered in males, whereas mitophagy markers (PINK1, PARKIN) were upregulated in females, suggesting efficient mitochondrial turnover. In conclusion, CYB5R3 expression is regulated by post-transcriptional and post-translational mechanisms and induces sex-dependent hepatic metabolic adaptations. While females exhibit increased CYB5R3 protein and associated mitochondrial improvements, males respond with distinct metabolic reprogramming despite unchanged CYB5R3 levels, underscoring the relevance of sexual dimorphism and systemic regulatory mechanisms in the response to longevity-promoting interventions.

Exploring the transformative effects of calorie restriction on the lacrimal gland in adult mice - Olivier Mauduit; Prashant Kumar; Kaitlin K. Scholand; Emre Aksan; Laura Schaefer; Anmar Abu-Romman; Vanessa Delcroix; Zhiyuan Yu; Aude I. Sindikubwabo; Ron Korstanje; Helen P. Makarenkova; Cintia S. de Paiva (GeroScience, 2025)
Advanced age is one of the most recognizable risk factors for dry eye. Dry eye disease affects millions worldwide and can result from age-related lacrimal gland dysfunction, which correlates with a decline in lacrimal gland secretory cell function and chronic inflammation. This study investigated the potential of calorie restriction to maintain lacrimal gland and ocular surface health. Adult female C57BL/6 J mice were subjected to a 40% calorie restriction for 4 months, starting at 6–7 months and continuing until 10–11 months. These mice were compared to controls fed ad libitum. Bulk RNA sequencing of lacrimal glands, conjunctiva, and cornea subjected to calorie restriction compared to ad libitum revealed significant differentially expressed genes (DEGs). Pathways enriched in the upregulated DEGs indicate enhanced circadian rhythm, secretory functions, and lipid metabolism. These findings were confirmed using individual qRT-PCR and western blotting. In contrast, pathways enriched in the downregulated DEGs were associated with immune cell activation, adaptive immune responses, extracellular matrix remodeling, and metalloproteinase activity. Histological sections of calorie-restricted lacrimal glands revealed reduced mononuclear cell infiltration and fewer positive cells for CD4, CD19, and MHC II than in ad libitum lacrimal glands. Calorie restriction also prevented age-related corneal barrier dysfunction and mitigated age-related conjunctival goblet cell loss, hallmarks of dry eye disease. These findings suggest that calorie restriction supports lacrimal gland and ocular surface health by reducing inflammation and extracellular matrix remodeling and by enhancing the lacrimal gland’s secretory function.

International Consortium on Ageing-Related Pathologies (ICCARP) Audiovestibular Group: fostering international consensus to refine International Classification of Diseases (ICD-11) codes for hearing loss across the life course - Dialechti Tsimpida; Michael A. Akeroyd; Barry L. Bentley; Shuvarthi Bhattacharjee; Michael R. Bowl; Emma Broome; Stuart R. G. Calimport; Sian Calvert; Gary Christopher; Tom Dening; Silvia Di Bonaventura; Ankita Goswami; et al. (GeroScience, 2025)

Plasma lipidomic fingerprinting enables high-accuracy biomarker discovery for Alzheimer’s disease: a targeted LC-MRM/MS approach - Xia Gao; Xiaoqin Cheng; Peipei Chen; Ling Lin; Xiaoyu Wang; Runbing Xu; Huali Shen; Qian Yang (GeroScience, 2025)

PCSK9 expression and cancer survival: a prognostic biomarker at the intersection of oncology and geroscience - Zoltan Ungvari; Otília Menyhart; Andrea Lehoczki; Monika Fekete; Giampaolo Bianchini; Balázs Győrffy (GeroScience, 2025)
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in cholesterol metabolism; however, emerging evidence suggests it plays a broader role in the regulation of cellular aging mechanisms and the pathogenesis of age-related diseases. Given that cancer is an age-related disease, PCSK9 has garnered attention for its potential impact on tumor progression and patient survival. In this study, we conducted a comprehensive analysis of PCSK9 expression across multiple tumor types, assessing its prognostic significance using RNA sequencing data from The Cancer Genome Atlas (TCGA) and gene expression microarray data from the Gene Expression Omnibus (GEO). Cox proportional hazards regression models and Kaplan–Meier survival analyses were employed to evaluate overall survival (OS) associations. Our findings reveal that elevated PCSK9 expression is associated with improved OS in breast and ovarian cancers, particularly in Luminal B breast cancer subtypes. Conversely, high PCSK9 expression correlates with worse OS in bladder cancer, renal clear cell carcinoma, melanoma, and pancreatic cancer. Notably, while PCSK9 expression is significantly upregulated in melanoma and bladder tumors, it is downregulated in renal clear cell carcinoma, yet relatively higher expression among renal tumors still predicts poorer survival. No significant associations between PCSK9 expression and OS were observed in colon, liver, gastric, lung, prostate, head and neck cancers, or low-grade gliomas in the available datasets.In conclusion, our study identifies PCSK9 as a prognostic biomarker with distinct, tumor-specific survival implications. Its dual role—associating with improved survival in some cancers while correlating with worse outcomes in others—suggests that PCSK9 may influence cancer progression through context-dependent mechanisms. Future research should focus on elucidating the mechanistic underpinnings of these associations and exploring the diagnostic and therapeutic potential of targeting PCSK9 in oncology.

Deep learning predicts onset acceleration of 38 age-associated diseases from blood and body composition biomarkers in the UK Biobank - Mica Xu Ji; Marjola Thanaj; Léna Nehale-Ezzine; Brandon Whitcher; E. Louise Thomas; Jimmy D. Bell (GeroScience, 2025)
A major challenge in multimorbid aging is understanding how diseases co-occur and identifying high-risk groups for accelerated disease development, but to date associations in the relative onset acceleration of disease diagnoses have not been used to characterize disease patterns. This study presents the development and evaluation of a neural network Cox model for predicting onset acceleration risk for age-associated conditions, using demographic, anthropomorphic, imaging, and blood biomarker traits from 60,396 individuals and 218,530 outcome events from the UK Biobank. Risk prediction was evaluated with Harrell’s concordance index (C-index). The model performed well on internal (C-index $$0.6830 ± 0.0902$$ 0.6830 ± 0.0902 , $$n=8,931$$ n = 8 , 931 ) and external (C-index $$0.6461 ± 0.1264$$ 0.6461 ± 0.1264 , $$n=855$$ n = 855 ) test sets, attaining C-index $$\ge 0.6$$ ≥ 0.6 on 38 out of 47 ( $$80.9%$$ 80.9 % ) conditions. Inclusion of body composition and blood biomarker input traits was independently important for predictive performance. Kaplan-Meier curves for predicted risk quartiles (log-rank $$p \le 1.16E-16$$ p ≤ 1.16 E - 16 ) indicated robust stratification of individuals into high and low risk groups. Analysis of risk quartiles revealed cardiometabolic, vascular-neuropsychiatric, and digestive-neuropsychiatric disease clusters with strong statistically significant inter-correlated onset acceleration ( $$r \ge 0.6$$ r ≥ 0.6 , $$p \le 3.46E-5$$ p ≤ 3.46 E - 5 ), while 13 and 19 conditions were strongly associated with onset acceleration of all-cause mortality and all-cause morbidity, respectively. In prognostic survival analysis, the proportional hazards assumption was met (Schoenfeld residual $$p > 0.05$$ p > 0.05 ) in 435 out of 435 or 100% (1238 out of 1334 or 92.8%) of cases across outcomes, $$aHR= 6.11 ± 9.00$$ a H R = 6.11 ± 9.00 ( $$aHR = 3.67 ± 5.78$$ a H R = 3.67 ± 5.78 ) with (without) Bonferroni correction. The neural architecture of OnsetNet was interpreted with saliency analysis, and several significant body composition and blood biomarkers were identified. The results demonstrate that neural network survival models are able to estimate prognostically informative onset acceleration risk, which could be used to improve understanding of synchronicity in the onset of age-associated diseases and reprioritize patients based on disease-specific risk.

The CAIDE dementia risk score indicates elevated cognitive risk in late adulthood: a structural and functional neuroimaging study - Katalin Farkas; Timea Lazar; Melinda Becske; Janos Andras Zsuffa; Viktoria Rosenfeld; Dalida Borbala Berente; Gergo Bolla; Janos Negyesi; Andras Attila Horvath (GeroScience, 2025)
While the CAIDE score is an established mid-life risk assessment tool for the longitudinal prediction of dementia, its application as a measure of elevated cognitive risk in late adulthood is unclear. One hundred one healthy individuals (aged > 55) were tested using detailed neuropsychological assessments, as well as structural and functional MRI. Participants were divided into a low-risk group (CAIDE < 7) and a high-risk group (CAIDE > 6). High-risk participants had significantly worse cognitive performance in the Trail-Making Test results (TMT-B: t = -4.03, p = 0.0001), and significantly smaller global brain volumes (e.g., brain segmentation volume: t = 2.898, p = 0.0485) and regional volumes (e.g., accumbens volumes: t left = 3.928, p = 0.036, Cohen’s d = 0.828; t right = 3.151, p = 0.0485, Cohen’s d = 0.656). High-risk participants also showed a trend for reduced functional connectivity in the default mode, salience, and central attention networks. Overall, the CAIDE score might help identify cognitively high-risk individuals in a late adulthood population.

Quinacrine and rimonabant prolong the life span of Caenorhabditis elegans - Qin He; Shupan Guo; Aolan Zhou; Xin Gong; Wei Cheng; Haiyan Ren (GeroScience, 2025)

Osteoimmunology and aging — a frontier to explore - Mihailo Ille; Iannis E. Adamopoulos; Mindy J. Fain; Janko Ž. Nikolich (GeroScience, 2025)

Misalignment of age clocks - Xiaoyue Mei; Hannaneh Kabir; Michael J. Conboy; Irina M. Conboy (GeroScience, 2025)
Biological aging is a complex non-linear process, with markedly distinct starting and end points, yet the biomarkers of its progression remain elusive. A key assumption of most machine learning (ML) approaches for age clocks is that predictive biomedical features can be identified via mathematical transformations of data to favor a linear transition from start to end, even if they erase any natural biological pattern. It is given that expected correlations, e.g., time lived (age) and time left to live (mortality), would persist in such mathematically optimized models, biologically meaningful or not. Here, we further clarify the workings of the clocks, explain the trade-off between mathematical optimization and biological interpretability, and discuss a hallmark of aging, inflammaging, that age clocks struggle to detect. We expand on the negative consequences of incoherence in linear models where some DNA methylation (DNAm) features increase with aging and disease, while others correspondingly decrease, yet positive weights are assigned to both. We quantify the misalignment between major DNAm clocks and actual changes in DNAm, providing an interactive visualization of these errors for each model. We demonstrate that major conventional age clocks are both incoherent and skewed toward leukocyte fractions and that rectifying incoherence makes the model balanced and not skewed toward neutrophils and better detects inflammaging. We briefly outline non-linear ML age clocks and the advantages of identifying a natural trajectory of aging directly from the primary data. Graphical Abstract

Indicators of mortality risk in ageing horses - Z. Kelemen; C. Vogl; L. Torres Borda; U. Auer; F. Jenner (GeroScience, 2025)
Clinical care for patients with limited life expectancy often requires adjustments, prioritizing immediate benefits over long-term outcomes, as the relevance of future complications diminishes. This study identifies indicators of mortality risk in horses with chronic orthopaedic conditions to enhance individualized care and welfare. Over 3 years, 123 chronically lame horses and 6 healthy control horses at an animal sanctuary underwent regular (every 3 months) comprehensive health assessments and activity monitoring using wearable sensors. Data collected included body condition scores, musculoskeletal pain scores, lameness evaluations, and time budgets for eating, resting, and activity. Of the 123 chronically lame horses, 31 horses died ( n = 31/123, 25.2%), with 10 succumbing to acute decompensation of their chronic condition (DAC, n = 10/123, 8.1%), while 21 were euthanized due to intractable pain or progressively deteriorating health and function (DCC, n = 21/123, 17.1%). Statistical modelling using death as outcome measure revealed body condition, pain scores, and time budget data to be strongly associated with equine mortality. Notably, low body condition score and reduced eating time predicted mortality in DAC horses, aligning with human studies linking weight loss to frailty and increased mortality risk. Additionally, depression-like behaviours were prevalent in DAC horses, mirroring the link between depression and mortality in humans. While pain scores were elevated in all deceased horses, weight loss was specific to DAC, suggesting multifactorial influences beyond pain. These findings provide a foundation for developing equine-specific tools to predict outcomes and guide clinical and end-of-life decisions, enabling individualized treatment to enhance the welfare and quality of life for aging horses. These insights may also offer valuable information for human medicine, particularly for at-risk groups such as individuals with cognitive impairments who may struggle to communicate their symptoms.

Rapid repetitive syllable sounds associate with episodic memory, executive function, and working memory in cognitively healthy and subjectively impaired older adults - Julia Giffard; Renjie Li; Eddy Roccati; Adam P. Vogel; Aidan D. Bindoff; Lynette R. Goldberg; Quan Bai; Jane Alty (GeroScience, 2025)
Non-invasive screening tools for Alzheimer’s disease (AD) risk are needed. Decline in episodic memory and subjective cognitive impairment (SCI) are both associated with elevated AD risk. We investigated associations between three cognitive domains (episodic memory, executive function, and working memory) and motor speech performance in older adults with healthy cognition (HC) or SCI. In total, 1014 community-dwelling participants (cross-sectional sample: 843 HC, mean 66.9 years, 72.8% female; 171 SCI, mean 66.3 years, 70.8% female) remotely completed cognitive tests (Paired Associates Learning and Spatial Working Memory from the Cambridge Neuropsychological Test Automated Battery) and motor speech tests (Tasmanian [TAS] Test). We evaluated whether acoustic motor speech features extracted from 10-s tests of “pa,” “ta,” or “ka” syllable repetition improved episodic memory, executive function, and working memory regression models over age, sex, education, anxiety, and depression (ΔAIC > 2). Motor speech features improved estimation of cognitive scores over fixed demographic and clinical variables in each group and cognitive domain. In summary, we found associations between motor speech performance and cognition in older adults. Short motor speech tests demonstrate potential for non-invasive, cost-effective AD risk screening. Longitudinal research is needed to investigate relationships between individual motor speech features and cognitive changes confirmed to result from the progression of AD.

The future of biomarkers for vascular contributions to cognitive impairment and dementia (VCID): proceedings of the 2025 annual workshop of the Albert research institute for white matter and cognition - Matthew J Lennon; Nikolaos Karvelas; Aravind Ganesh; Shawn Whitehead; Farzaneh A Sorond; Violeta Durán Laforet; Elizabeth Head; Konstantinos Arfanakis; Vijaya B Kolachalama; Xiao Liu; Hanzhang Lu; Joel Ramirez; et al. (GeroScience, 2025)
Advances in biomarkers and pathophysiology of vascular contributions to cognitive impairment and dementia (VCID) are expected to bring greater mechanistic insights, more targeted treatments, and potentially disease-modifying therapies. The 2025 Annual Workshop of the Albert Research Institute for White Matter and Cognition, sponsored by the Leo and Anne Albert Charitable Trust since 2015, focused on novel biomarkers for VCID. The meeting highlighted the complexity of dementia, emphasizing that the majority of cases involve multiple brain pathologies, with vascular pathology typically present. Potential novel approaches to diagnosis of disease processes and progression that may result in VCID included measures of microglial senescence and retinal changes, as well as artificial intelligence (AI) integration of multimodal datasets. Proteomic studies identified plasma proteins associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; a rare genetic disorder affecting brain vessels) and age-related vascular pathology that suggested potential therapeutic targets. Blood-based microglial and brain-derived extracellular vesicles are promising tools for early detection of brain inflammation and other changes that have been associated with cognitive decline. Imaging measures of blood perfusion, oxygen extraction, and cerebrospinal fluid (CSF) flow were discussed as potential VCID biomarkers, in part because of correlations with classic pathological Alzheimer’s disease (AD) biomarkers. MRI-visible perivascular spaces, which may be a novel imaging biomarker of sleep-driven glymphatic waste clearance dysfunction, are associated with vascular risk factors, lower cognitive function, and various brain pathologies including Alzheimer’s, Parkinson’s and cerebral amyloid angiopathy (CAA). People with Down syndrome are at high risk for dementia. Individuals with Down syndrome who develop dementia almost universally experience mixed brain pathologies, with AD pathology and cerebrovascular pathology being the most common. This follows the pattern in the general population where mixed pathologies are also predominant in the brains of people clinically diagnosed with dementia, including AD dementia. Intimate partner violence-related brain injury, hypertension’s impact on dementia risk, and the promise of remote ischemic conditioning for treating VCID were additional themes.

Cognitive decline before and after incident chronic respiratory disease - Xiaoli Ji; Yuanyue Zhu; Fariba Ahmadizar; Hui Gao; Daoyuan Sun; Jingbo Zhang; Kan Wang (GeroScience, 2025)

Proteoglycan-4 (PRG4) serum concentration is lower in aged mice, and genetic deficiency impacts survival probability, blood parameters, and bone during aging - Adam P. Tanguay; Nikhil G. Menon; Emma Slavin; Mikayla Moody; Erin McEwen; Gregory D. Jay; Joseph Lorenzo; Jenna M. Bartley; Vanessa M. Scanlon; Alix C. Deymier; Tannin A. Schmidt (GeroScience, 2025)

NRF2 pathway activation predicts poor prognosis in lung cancer: a cautionary note on antioxidant interventions - Zoltan Ungvari; Otília Menyhart; Andrea Lehoczki; Monika Fekete; Vince Fazekas-Pongor; Alberto Ocana; Peter Varga; Balázs Győrffy (GeroScience, 2025)
Lung cancer is a leading cause of cancer-related mortality worldwide. As an age-related disease, its pathogenesis is shaped by several molecular hallmarks of aging, including impaired DNA repair and diminished stress resilience. The transcription factor NRF2 (nuclear factor erythroid 2–related factor 2) is a master regulator of oxidative stress defense and cellular survival. While NRF2 activation is protective in aging tissues, it may also be exploited by cancer cells to promote tumor progression and therapy resistance. This study aims to evaluate whether NRF2 pathway activation predicts clinical outcomes in lung cancer, with potential implications for the use of NRF2-inducing compounds. We analyzed transcriptomic and survival data from 2167 lung cancer patients using the KM Plotter database. A validated 14-gene NRF2 activation signature was used to stratify tumors by NRF2 pathway activity. Associations with overall survival (OS), first progression (FP), and post-progression survival (PPS) were assessed using Cox regression models and Kaplan–Meier analysis. High NRF2 signature expression was significantly associated with poorer OS (HR = 1.59, p = 1.3E−9), FP (HR = 1.61, p = 2.6E−5), and PPS (HR = 1.6, p = 0.002). The negative prognostic effect was most pronounced in patients with adenocarcinoma, node-negative disease, and in female patients. These findings highlight the dual role of NRF2 in promoting stress resilience and enabling cancer cell survival. NRF2 activation is a predictor of poor clinical outcomes in lung cancer. Given the widespread use of NRF2-inducing compounds such as resveratrol and sulforaphane, these findings raise important concerns about their safety in individuals at risk for or living with cancer. Our results underscore the importance of context-specific evaluation of NRF2-targeted interventions and caution against the indiscriminate use of NRF2-activating agents in aging populations, particularly in individuals at risk for lung cancer.

Correction to: Lifespan effects in male UM‑HET3 mice treated with sodium thiosulfate, 16-hydroxyestradiol, and late‑start canagliflozin - Richard A. Miller; David E. Harrison; Gino A. Cortopassi; Ishmael Dehghan; Elizabeth Fernandez; Michael Garratt; John G. Geisler; Brett C. Ginsburg; Melissa L. Han; Catherine C. Kaczorowski; Navasuja Kumar; Scott F. Leiser; et al. (GeroScience, 2025)

Plasma p-tau231 and NfL differently associate with functional connectivity patterns in cognitively unimpaired individuals - Alejandra García-Colomo; David López-Sanz; Martín Carrasco-Gómez; Federico Ramirez‑Toraño; Soraya Alfonsín; Carlos Spuch; María Comis-Tuche; Fernando Maestú (GeroScience, 2025)
Amid the rising relevance of early and non-invasive markers for neurodegenerative diseases, such as Alzheimer’s disease, this study addresses the relationship between two promising candidates: electrophysiology and plasma markers. Specifically, functional connectivity, which underlies cognitive function, with p-tau231 (i.e., a marker of incipient Aβ pathology) and neurofilament light chain (NfL, i.e., a neurodegeneration marker) were considered. Seventy-five cognitively unimpaired individuals underwent a blood extraction and two magnetoencephalography recordings, approximately 3 years apart. First, correlation analyses were conducted to examine the association between the pathology markers’ concentration and FC. Subsequently, longitudinal FC changes were assessed, and their relationship with the markers’ concentration was evaluated. Default mode network regions, including the middle temporal gyrus, precuneus, hippocampus, and inferior parietal lobe, presented a positive association between their alpha FC and p-tau231 positively. In contrast, NfL levels were negatively associated with theta FC in frontotemporal regions. Moreover, these areas exhibit a longitudinal theta FC decrease. Importantly, the theta FC reduction was more pronounced as NfL concentrations increased. The described alpha FC alterations do not follow a maturation trajectory and are age-independent. Thus, the alpha FC increase associated with p-tau231 levels could constitute an early electrophysiological biomarker of Aβ pathology. In contrast, the longitudinal theta FC decrease, enhanced by NfL, could constitute an early sign of neurodegeneration.

Associations of physical frailty and polygenic score with incident heart failure in cardiovascular patients: unraveling the mediating role of inflammation - Jiajin Chen; Sicheng Li; Shichen Bu; Xiaoqing Nie; Le Zhang; Lingjun Jie; Ya Fang; Cuilian Dai; Yan Wang (GeroScience, 2025)

Characterization of adult hippocampal neurogenesis in adult and aged genetically diverse mice - Adele E. Finch; Avery D. McNamara; Kristen D. Onos; Kelly J. Keezer; Gareth R. Howell; Ashley E. Webb (GeroScience, 2025)
Adult hippocampal neurogenesis—the generation of new neurons in the adult brain—declines with age, contributing to cognitive deficits in aging. While the majority of mammalian studies on neurogenesis have utilized inbred mouse strains, these models do not fully capture the genetic diversity of humans, limiting the translational relevance of their findings. The Diversity Outbred (DO) mouse model, a genetically heterogeneous population, provides a promising alternative to traditional inbred strains. In this study, we investigated how genetic diversity influences hippocampal neurogenesis by comparing neurogenesis in adult and aged Diversity Outbred (DO) mice with the commonly used C57BL/6J inbred strain. While both strains exhibited a decline in neurogenesis with age, DO mice showed significantly lower levels of neurogenesis compared to C57BL/6J mice, even in young adults. Additionally, we observed that the wild-derived CAST/EiJ strain, one of the eight founder strains in the DO model, contributed to this reduction in neurogenesis. Our findings highlight the importance of genetic diversity in neurogenesis research and suggest that the DO model may better represent human genetic diversity associated with age-related decline in neurogenesis.

Correction to: Sex differences in body mass index and waist circumference trajectories and dementia risk: the HUNT4 70+ study - Ekaterina Zotcheva; Bjørn Heine Strand; Vegard Skirbekk; Kay Deckers; Steinar Krokstad; Gill Livingston; Archana Singh‑Manoux; Geir Selbæk (GeroScience, 2025)

Correction to: The COVID‑19 legacy: consequences for the human DNA methylome and therapeutic perspectives - Carlo Gaetano; Sandra Atlante; Michela Gottardi Zamperla; Veronica Barbi; Davide Gentilini; Barbara Illi; Marco Malavolta; Fabio Martelli; Antonella Farsetti (GeroScience, 2025)

HealthAge: evaluation of intrinsic capacity changes in humans, mice, and killifish to explore the biology of aging - Sophie Guyonnet; Claudie Hooper; Heike A. Bischoff-Ferrari; Angelo Parini; Yohan Santin; Jean-Philippe Pradère; Cédric Dray; Bruno Vellas; Sophie Guyonnet; Bruno Vellas; Lauréane Brigitte; Agathe Milhet; et al. (GeroScience, 2025)
HealthAge was devised by a conglomerate of research groups in Toulouse, France, with the combined goal of narrowing the lifespan-healthspan gap through novel translational bench-to-bedside research studies. HealthAge comprises the “INStitute for Prevention” “healthy aging” and “medicine Rejuvenative” (INSPIRE) human translational, outbred SWISS mice and African turquoise killifish (GRZ strain) cohorts in which aging is studied based on the concept of intrinsic capacity (IC). In this narrative review, we describe the three INSPIRE aging models (human cohort, n = 1109, age range 20 –102 years old with mean age ± standard deviation, 62.4 ± 19.0 years and 61.9% female; outbred SWISS mice, n = 1576 and African Turquoise killifish, n = 300) and explain how IC is assessed at the clinical (in humans) and biological level over time. HealthAge strives to elucidate the underlying biology of IC and to identify biomarkers of IC declines and novel gero-therapeutics using the clinical and biological data and biospecimens collected prospectively in the three species. The data sharing policy will foster scientific discovery through new multi-disciplinary collaborations. Thus, HealthAge will promote healthy aging using a unique translational platform based on IC phenotyping with the ultimate goal of preventing loss of human independence and alleviating health costs associated with an aging population.

Age-independent anti-angiogenic therapy for choroidal neovascularization by targeting secretogranin III - Chengchi Huang; Hong Tian; Wei Li (GeroScience, 2025)

Synaptic pruning genes networks in Alzheimer’s disease: correlations with neuropathology and cognitive decline - Cristina Sanfilippo; Paola Castrogiovanni; Rosa Imbesi; Paolo Fagone; Grazia Scuderi; Manlio Vinciguerra; Michelino Di Rosa (GeroScience, 2025)

Linking sleep microstructure, blood markers of inflammation and metabolism, and cognition: mediation analysis in the osteoporotic fractures in men study - Claire Suen; Julia Ma; Xihong Lin; Robert J. Thomas; M. Brandon Westover; Katie Stone; Kristine Yaffe; Kristine E. Ensrud; Susan Redline; Rudolph E. Tanzi; Haoqi Sun; Can Zhang (GeroScience, 2025)

Impact of lifestyle factors on quantitative motor and cognitive performance: insights from a longitudinal study on healthy ageing - Milan Zimmermann; Ulrike Sünkel; Isabel Wurster; Stefanie Lerche; Markus A. Hobert; Claudia Schulte; Anna-Katharina von Thaler; Daniela Berg; Walter Maetzler; Andreas Fallgatter; Gerhard W. Eschweiler; Thomas Gasser; et al. (GeroScience, 2025)

Impact of sarcopenia and obesity on skeletal muscle size, gene expression, and mitochondrial function - Hector G. Paez; Christopher R. Pitzer; Jessica L. Halle; Peter J. Ferrandi; James A. Carson; Junaith S. Mohamed; Stephen E. Alway (GeroScience, 2025)
Skeletal muscle is a primary tissue of dysfunction during both aging and obesity. Recently, the coincidence of obesity and aging has gained attention due to the intersection of the obesity epidemic with an aging demographic. Both aging and obesity are associated with marked defects in skeletal muscle metabolic health. Despite these findings, we have a poor understanding of how obesity and aging may interact to impact skeletal muscle mass and metabolic health. Therefore, we investigated the impact of high-fat diet (HFD)-induced obesity on skeletal muscle mass, mitochondrial function, transcriptomics, and whole-body metabolism in young and aged mice. We observed main effects of diet and age on several measures of whole-body metabolic function (VO 2 , VCO 2 , and RER). Complex I-driven mitochondrial proton leak was significantly elevated by HFD-induced obesity across both age groups; however, a main effect of aging for reduced complex I leak was detected in the soleus muscle. Interestingly, aged animals fed a HFD did not exhibit lower muscle mass than chow-fed young animals, but did present with stark increases in muscle triglyceride content and a unique transcriptional response to HFD. HFD-induced obesity impacted the muscle transcriptome differently in the muscles of young and aged mice, indicating that obesity can change altered gene expression with age. Our findings suggest that the presence of obesity can both compound and counteract age-associated changes to muscle mass, gene expression, and mitochondrial function.

Epigenetic aging mediates the association between life course socioeconomic status and decrements in kidney function across a decade - Agus Surachman; Meera N. Harhay; Rose Ann DiMaria-Ghalili; Anthony S. Zannas; David M. Almeida; Christopher L. Coe (GeroScience, 2025)
Epigenetic aging measures are novel molecular indicators of biological aging that predict age-related chronic disease. We examined whether several established indices of epigenetic aging mediated the association between life course socioeconomic status (SES) and decrements in kidney function across a decade. Biomarker data were from 252 non-Hispanic (NH) Black and white participants who had consented to genetic analyses in Wave 2 (2004–2009) and 3 (2014–2021) of the Midlife in the United States study (MIDUS). Life course SES included parental education, a proxy of early life SES, and a composite score of adult SES based on the highest education level, household income to poverty line ratio, health insurance coverage, perception of the availability of money to meet needs, and difficulty level paying monthly bills. We included five measures of epigenetic age accelerations (EAA), based on the residuals after each epigenetic clock was regressed on chronological age (Horvath, Horvath blood and skin, Hannum, PhenoAge, and GrimAge) and one measure of the pace of aging (DunedinPACE) obtained during MIDUS 2. Kidney function was based on serum creatinine–based estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI formula (without race adjustment). We calculated absolute decrements in eGFR across 11 years between MIDUS waves 2 and 3. Analyses were adjusted for age, sex, and health-related covariates (currently smoking, obese, hypertension, and insulin resistance). Lower adult SES and accelerated epigenetic aging, especially accelerated GrimAge and faster DunedinPACE pace of aging, mediated the association between lower parental education and larger decrements in eGFR. Accelerated epigenetic aging is associated with larger decrements in kidney function across a decade and may be one of the critical explanatory pathways for the higher burden of chronic kidney disease (CKD) among lower SES individuals.

The compensatory effect of education as revealed by resting-state electroencephalographic alpha rhythms in patients with dementia due to Parkinson’s disease: findings from an exploratory study - Susanna Lopez; Claudio Del Percio; Roberta Lizio; Giuseppe Noce; Dharmendra Jakhar; Andrea Soricelli; Marco Salvatore; Bahar Güntekin; Görsev Yener; Federico Massa; Dario Arnaldi; Francesco Famà; et al. (GeroScience, 2025)
Here, we investigated whether educational attainment influences the neurophysiological mechanisms underlying vigilance regulation, as reflected in resting-state eyes-closed electroencephalographic (rsEEG) rhythms, in patients with dementia due to Parkinson’s (PDD) and Lewy body disease (DLB). Clinical, demographic, and rsEEG data were obtained from an international database, including PDD patients ( N = 75), DLB patients ( N = 50), and cognitively unimpaired older controls (Healthy; N = 54). Each group was partitioned into low (Edu-) and high (Edu+) educational attainment subgroups, matched for age, sex, and cognitive-motor status. We analyzed rsEEG rhythms across the individual delta, theta, and alpha frequency bands. Cortical rsEEG source topography was estimated using eLORETA freeware. In the Healthy group, Edu+ participants exhibited significantly greater widespread rsEEG alpha source activities compared to Edu- participants, possibly reflecting neuroprotective neurophysiological mechanisms. Conversely, in the PDD group, Edu+ patients showed lower widespread rsEEG alpha source activities than Edu- patients, possibly indicating compensatory mechanisms. No significant differences in rsEEG source activities were observed between DLB-Edu+ and DLB-Edu- patients. Educational attainment may be associated with compensatory mechanisms that counteract the abnormal neurophysiological processes underlying rsEEG alpha rhythms and vigilance regulation in PDD patients, but not in DLB patients. Future studies combining rsEEG and neuroimaging techniques should investigate the metabolic and functional connectivity correlates of these putative compensatory mechanisms in the PDD brain. Early education may be a key investment for national governments, especially in low-income countries, to prevent the cognitive deficits of Parkinson’s disease along aging, thereby reducing the unbearable social and economic burden.

Quantifying the impact of treatment delays on breast cancer survival outcomes: a comprehensive meta-analysis - Zoltan Ungvari; Mónika Fekete; Annamaria Buda; Andrea Lehoczki; Gyöngyi Munkácsy; Paola Scaffidi; Tiziana Bonaldi; János Tibor Fekete; Giampaolo Bianchini; Péter Varga; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Treatment delay in breast cancer care represents a significant concern in oncology, potentially impacting patient survival outcomes. While various factors can contribute to delayed treatment initiation, the quantitative relationship between specific delay intervals and survival remains incompletely understood in breast cancer management. Our study aims to explore the impact of treatment delays on survival outcomes in breast cancer. A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases, covering publications from 2000 to 2025. From an initial 6222 records, 18 eligible studies comprising 25 cohorts were included. Hazard ratios (HRs) for all-cause and breast cancer–specific mortality were extracted or calculated for treatment delays of 4, 8, and 12 weeks. Random-effects meta-analyses were performed, and heterogeneity and publication bias were assessed using I 2 statistics, funnel plots, and Egger’s test. This meta-analysis revealed progressively increasing mortality risks with longer treatment delays. For all-cause mortality, HRs increased from 1.12 (95% CI 1.08–1.15) at 4 weeks to 1.25 (95% CI 1.17–1.33) at 8 weeks, and 1.39 (95% CI 1.26–1.53) at 12 weeks. Breast cancer–specific mortality showed more pronounced effects, with HRs of 1.20 (95% CI 1.06–1.36), 1.43 (95% CI 1.11–1.84), and 1.71 (95% CI 1.18–2.49) for 4-, 8-, and 12-week delays, respectively. Analyses combining both survival outcomes demonstrated consistent risk elevation across all time intervals (4 weeks: HR = 1.12, 95% CI 1.09–1.16; 8 weeks: HR = 1.26, 95% CI 1.18–1.34; 12 weeks: HR = 1.41, 95% CI 1.29–1.55). While heterogeneity was significant ( I 2 = 54–92%), no substantial publication bias was detected. Delays in initiating breast cancer treatment are associated with significantly worse survival, particularly for cancer-specific mortality. Each additional 4-week delay increases the hazard of death by over 10%, underscoring the urgency of minimizing delays in diagnosis-to-treatment pathways. These findings have critical implications for healthcare systems, clinical decision-making, and public health policy.

Retinal vessel diameter reflects altered resting-state fMRI connectivity and cognitive performance: A community-based study - Yan Min; Chang Liu; Yanli Zhang; Yuesong Pan; Tao Liu; Hongyu Zhou; Zixiao Li; Yongjun Wang (GeroScience, 2025)

Systematic analysis of associations between obesity and memory decline - Ying Yue Huang; Wei Sen Zhang; Jiao Wang; Chao Qiang Jiang; Feng Zhu; Ya Li Jin; Kar Keung Cheng; Tai Hing Lam; Lin Xu (GeroScience, 2025)
Despite the development of numerous obesity indicators, the optimal measure associated with memory remains to be elucidated. We examined and compared these associations whilst also exploring potential interactions with education. We analysed the associations between 20 obesity indicators and memory (measured by Delayed Word Recall Test (DWRT)) in middle-aged and older participants from Guangzhou Biobank Cohort Study by linear regression and stratification analyses. We used two-sample Mendelian randomisation (2SMR) to analyse the associations of obesity with cognitive performance. Of 20 obesity indicators, 6 and 7 were associated with poorer memory function measured by baseline and follow-up DWRT; 7 and 10 with faster memory decline measured by mean annual change (MAC) and MAC rate of DWRT. Central obesity measured by waist-to-hip-to-height ratio (WHHR) z -score showed the greatest effect size, with the β s (95% CIs) being − 0.09 (− 0.11 to − 0.07), − 0.07 (− 0.09 to − 0.04), − 0.02 (− 0.03 to − 0.01) and − 0.49 (− 0.69 to − 0.29), respectively. The associations were weaker in those with higher education ( P for education-interaction from 0.008 to 0.049). In 2SMR, body mass index (BMI), waist circumference and BMI-adjusted waist-to-hip ratio were negatively associated with cognitive performance using inverse-variance weighted method, with β s (95% CIs) being − 0.11 (− 0.15 to − 0.07), − 0.07 (− 0.12 to − 0.02) and − 0.06 (− 0.09 to − 0.02), respectively. In conclusion, obesity, especially central obesity measured by WHHR, was associated with poorer memory function and faster memory decline in middle-aged and older people, with a weaker association observed amongst those with higher education. Graphical Abstract

Epigenetic biomarkers of mortality risk in mice under chronic social stress - Samuel D. Anderson; Maria Razzoli; Brian Chen; Matteo Pellegrini; Alessandro Bartolomucci (GeroScience, 2025)
A strong association exists between exposure to life stressors and accelerated aging in humans and animal models. However, the molecular mechanisms that underlie the adverse effect of stress on aging remain poorly characterized, and there is a paucity of prognostic predictors of stress-induced disease outcomes and life expectancy. To address this gap, we developed mathematical models to predict remaining lifespan based on healthspan data across two independent cohorts which were part of a large study (350 + mice) on social stress and aging in mice. We then relate remaining lifespan to changes in DNA methylation, due to its strong association with age as well as environmental factors such as stress exposure. Multivariate multiple regression identified blood glucose as a major trait associated with DNA methylation. An independent neural network analysis also identified blood glucose among the traits most associated with mortality risk. Finally, elastic net regression identified several DNA methylation sites, including Ptp4a3, Lrrc3b, Adgrb1, Mron5, and Gm6549, which represent possible targets at the intersection of glucose, stress and survival. Overall, the main finding of our analysis is that epigenetic biomarkers of mortality risk reveal an association with blood glucose levels, informing on individual life trajectories shaped by the impact of chronic social stress.

Brain precapillary sphincters modulate myogenic tone in adult and aged mice - Christina L. Fjorbak; Nikolay P. Kutuzov; Teddy Groves; Martin Lauritzen; Søren Grubb (GeroScience, 2025)
Brain precapillary sphincters, which are surrounded by contractile pericytes and are located at the junction of penetrating arterioles and first-order capillaries, can increase their diameter by ~ 30% in a few seconds during sensory stimulation, allowing for rapid control of capillary blood flow over a wide dynamic range. We hypothesized that these properties could help precapillary sphincters maintain the capillary blood flow and shield the downstream capillaries during surges in blood pressure. To test this, we visualized microvessels in adult and old anaesthetized mice using in vivo two-photon microscopy. We showed that a blood-pressure surge disrupts both microvascular myogenic response and neurovascular coupling in both adult and old mice, with old mice exhibiting a more diminished myogenic response. Similarly, laser ablation of contractile pericytes encircling precapillary sphincters disrupted neurovascular coupling and myogenic response. The resistance provided by precapillary sphincters may be increasingly important in old mice, where we found changes in the topology of microvessels, potentially affecting microvascular blood flow. Old mice displayed more tortuous penetrating arterioles, reduced pial collateral arteriolar density, and altered capillary densities: reduced in the arterial end and increased in the venous end. Our results illustrate how blood-pressure surges affect brain microvascular function, underscore the protective role of precapillary sphincters during cerebrovascular autoregulation in response to blood pressure surges, and compare vascular topology in adult and old mice in vivo.

Subcortical white matter hyperintensities and motor function in parkinson’s disease: findings from the ONDRI study - Daniela Cristina Carvalho de Abreu; Frederico Pieruccini-Faria; Anthony E. Lang; Benjamin Cornish; William McIlroy; Mandar Jog; Mario Masellis; Joel Ramirez; Christopher Scott; Sean Symons; Sandra E. Black; Stephen R. Arnott; et al. (GeroScience, 2025)

Age-related and dual task-induced gait alterations and asymmetry: optimizing the Semmelweis Study gait assessment protocol - Peter Mukli; Mihaly Muranyi; Ágnes Lipecz; Zsofia Szarvas; Tamás Csípő; Anna Ungvari; Mónika Fekete; Vince Fazekas-Pongor; Anna Peterfi; Ágnes Fehér; Norbert Dosa; Noémi Mózes; et al. (GeroScience, 2025)
Gait alterations are recognized as early markers of age-related decline and cognitive impairment. Dual-task assessments, which impose cognitive load while walking, provide valuable insights into gait control limitations and cognitive-motor interactions in aging populations. This study evaluates age-related and cognitive load-induced changes in gait parameters, with a particular focus on asymmetry, and aims to optimize the gait assessment protocol for the Semmelweis Study framework. The Semmelweis Study is a large-scale workplace cohort investigating the determinants of unhealthy aging and promoting healthy brain aging by identifying risk factors and protective mechanisms influencing vascular, metabolic, and neurocognitive decline. As part of this initiative, gait analysis is emerging as a critical tool for assessing functional aging, detecting early signs of mobility and cognitive impairment, and contributing to biological age assessment. A cross-sectional analysis was conducted on adults aged 23 to 87 years using a pressure-sensitive walkway system. Participants were evaluated under single-task conditions (normal walking) and dual-task conditions (walking while performing a concurrent cognitive task). Spatiotemporal gait parameters, asymmetry indices, and dual-task costs were analyzed to assess age-related changes in gait performance and cognitive-motor interactions. Aging was associated with significant reductions in gait speed, step length, and stride length, along with a corresponding increase in gait asymmetry. Dual-task conditions exacerbated these alterations, indicating age-related impairments in cognitive-motor integration. Asymmetry indices were sensitive to aging effects, suggesting their potential as biomarkers for functional decline. The dual-task cost on gait was significantly greater in older adults, reinforcing the interplay between cognitive and motor systems in aging. Age-related gait alterations, particularly under cognitive load, underscore the importance of comprehensive gait assessments in aging research. Our findings contribute to the optimization of the Semmelweis Study gait assessment protocol by identifying key gait parameters that capture functional decline and biological aging. Integrating dual-task gait analysis into large-scale epidemiological studies has the potential to enhance early detection of brain health decline, refine biological age estimation, and guide targeted interventions to support healthy aging and neuromotor resilience.

In vivo labeling reveals that degranulation is increased under supraphysiological TCR stimulation, but not infection, in CD8+ T cells from old mice - Korbyn J. V. Dahlquist; Emma M. Dehm; Declan M. Smith; Erin D. Lucas; Mark Pierson; Sara E. Hamilton; Christina D. Camell (GeroScience, 2025)
CD8 + T cells exhibit distinct changes with aging, including a diminished naïve cell pool, an expansion of memory and exhausted cells, and altered effector molecule production, altogether leading to increased susceptibility to infection. They have reduced cytotoxicity in vivo, but increased granule content and faster cytotoxic kinetics to target cells in vitro . Whether CD8 + T cells from old mice degranulate when activated in vivo , within the aged environment, is unknown. This study investigates in vitro and in vivo degranulation of CD8 + T cells from young and old mice during supraphysiological aCD3 stimulation and two types of infection. Actively degranulating CD8 + CD44 + T cells were identified by positive labeling after a two-hour exposure to granule-specific fluorescent antibodies (CD107a and CD107b). Surprisingly, CD8 + T cells from old mice challenged with supraphysiological TCR-specific stimulation exhibited higher levels of degranulation as compared to their young counterparts. This effect is more prominent in vitro and can be partially explained by the age-specific increase in CD8 + CD44 + CD62L − cells. However, during microbial exposure or LCMV Armstrong infection, we show that CD8 + CD44 + and antigen-specific T cells from old mice have reduced degranulation, consistent with the diminished cytotoxic capacity. These data highlight the preserved intrinsic cytotoxic capacity of memory CD8 + T cells from old mice and suggest that the aged microenvironment and type of stimulation are contributing factors to the lower degranulation and cytotoxic capacity of these cells. This provides insight into the potential of increasing T cell activation to improve vaccine approaches in the elderly.

Ndufs4−/− mice: a testing ground for longevity interventions - Jackson Nuss; Matt Kaeberlein; Alessandro Bitto; Anthony S. Grillo (GeroScience, 2025)
Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the pathophysiology of mitochondrial disease and mitochondrial dysfunction in sporadic disorders. Intriguingly, longevity interventions are very effective at treating symptoms of disease in this model. Herein, we introduce the model and its notable features that may help provide insights in longevity research. We performed a retrospective analysis of historical data from our laboratories over the past 10 years regarding the use of this animal model in aging studies, the manifestation and progression of mitochondrial disease, and factors that influence their premature death. We observed a correlation between weight and lifespan in female animals and a sex-independent correlation between the onset of clasping, a typical neurodegenerative symptom, and overall survival. We observed a sexual dimorphism in lifespan with female mice being more resilient despite a similar age of onset of disease symptoms. Lastly, we report increased lifespan and delayed onset of disease symptoms following treatment with 17-alpha-estradiol, a non-feminizing estrogen which can extend lifespan in genetically heterogeneous mice. This analysis serves as a useful guide for researchers utilizing this animal in the discovery of effective interventions for longevity and to prevent the onset of disease. It suggests there may be unprecedented underlying sex-specific differences in patients with Leigh syndrome and further strengthens the connection between normative aging and mitochondrial dysfunction.

Morphological features of the domestic house cricket (Acheta domesticus) for translational aging studies - Gerald Yu Liao; Sherwin Dai; Elizabeth Bae; Swastik Singh; Jenna Klug; Christina Pettan-Brewer; Warren Ladiges (GeroScience, 2025)
Aging alters morphology and locomotor function in diverse organisms, yet standardized model systems for studying these changes remain limited to a relatively few species. Here, we present a comprehensive analysis of age- and sex-dependent morphological variations in house crickets ( Acheta domesticus ), integrating refined husbandry protocols to enhance reproducibility and translational relevance. To ensure data consistency, we implemented a standardized husbandry framework incorporating self-determined photoperiods, co-housing both sexes, and controlled diet and hydration strategies. We observed progressive increases in body weight, length, and appendage dimensions with age, with pronounced sexual dimorphism emerging post-maturity. Structural adaptations, including increased femoral volume and cross-sectional area, suggest compensatory mechanisms for age-related declines in muscle efficiency, while reduced hind leg-to-body length ratios indicate potential biomechanical constraints on locomotion. Furthermore, antennal growth patterns highlight prolonged sensory investment, potentially offsetting declining mobility in aging individuals. Our results underscore the necessity of harmonizing environmental conditions in gerontological research, as variations in lighting, substrate availability, and microbiome exposure may significantly impact physiological resilience and behavioral fidelity. Future work should explore the influence of microbiome diversity on lifespan and stress resilience while refining methodologies for cricket rearing from egg to adulthood. By bridging invertebrate and vertebrate aging research, this study positions house crickets as a scalable, high-throughput animal model for investigating age-related functional decline, behavioral plasticity, and lifespan-extending interventions. Integrating behavioral assays, biomechanical analyses, and molecular markers of aging will further elucidate the interplay between morphology, function, health, and longevity, advancing the utility of crickets in comparative geroscience.

Platelet hyperreactivity and frailty in a mouse model of Alzheimer’s disease are prevented by anti-oxidant treatment - Mauro Vismara; Silvia Maria Grazia Trivigno; Marta Zarà; Stefania Momi; Paolo Gresele; Marina Camera; Ilaria Canobbio; Gianni Francesco Guidetti; Mauro Torti (GeroScience, 2025)
Frailty is an age-related syndrome commonly associated with different comorbidities, and its occurrence is particularly frequent in patients with Alzheimer’s disease (AD). A persisting low-grade inflammation has been suggested to favor the onset of both AD and frailty. Besides their role in hemostasis and thrombosis, blood platelets are true inflammatory cells, and their direct contribution to the onset and progression of AD has been documented. In this work, we investigated whether platelet hyperreactivity and pro-oxidative functions are implicated in the development of frailty in a mouse model of AD, the APP23 mice. Assessment of 31 specific clinical signs of deterioration in mice at 3, 9, and 18 months of age demonstrated that the development of frailty was significantly more pronounced in the APP23 mice compared to wild-type littermates. In 18-month-old APP23 mice, a significant platelet hyperreactivity was detected as shown by a significantly stronger platelet aggregation in response to submaximal stimulation of both collagen and thrombin receptors. Moreover, the pro-inflammatory function of platelets, evaluated as circulating and agonist-induced platelet-neutrophil aggregate formation, was significantly increased in aged APP23 mice compared to wild-type littermates. Platelet hyperreactivity was partially prevented by prolonged treatment with the anti-oxidant agent Tempol, which reduced both agonist-induced aggregation and platelet-neutrophil aggregate formation. Importantly, prolonged treatment of APP23 mice with Tempol significantly reduced also the frailty index score in 18-month-old animals. These results outline the possible beneficial effect of an anti-oxidant treatment in hampering platelet hyperreactivity and preventing the onset of frailty associated to AD.

Sustained and reversible effects of a dietary phosphate intake on bone and mineral metabolism during aging - Jamie L. Arnst; Uma D. Alappan; Manjula Viggeswarapu; George R. Beck (GeroScience, 2025)

Association between the Planetary Health Diet Index and growth differentiation factor-15: the Seniors ENRICA-2 cohort - María del Carmen Aznar de la Riera; Rosario Ortolá; Blanca Fabre-Estremera; Antonio Buño-Soto; Fernando Rodríguez-Artalejo; Mercedes Sotos-Prieto (GeroScience, 2025)
The growth differentiation factor-15 (GDF-15) is an inflammaging biomarker, predictor of cardiovascular disease (CVD), and several other non-communicable diseases (NCD) that represent the main causes of death globally, for which prevention is essential. Current worldwide threats include NCD and environmental burden, where diet is a key determinant. Therefore, the EAT-Lancet Commission developed the Planetary Health Diet Index (PHDI), a dietary pattern designed to ameliorate human and environmental health. The objective of the study was to evaluate the association between the PHDI and serum concentrations of GDF-15 in older adults. Study participants were 2497 people aged + 65 years from the Seniors-ENRICA-2 study. Food consumption was obtained through a validated diet history, and adherence to the PHDI was estimated with a score of 15 food groups (range 0–140), where higher scores indicated better adherence. Analyses for the association between the PHDI and GDF-15 concentrations were performed using multivariable linear regression models, adjusting for main potential confounders. The PHDI showed an inverse dose–response association with GDF-15 concentrations. Compared with participants in the lowest quartile of the PHDI, those in the highest quartile had a mean percentage difference (95% CI) of − 6.8% (− 11.1, − 2.4) in GDF-15 concentrations. The mean percentage difference (95% CI) per 20-point increase of adherence was − 4.4% (− 7.7, − 0.9). Consumption of whole grains, fruits, nuts, and a low intake of trans and saturated fat were important drivers of this association. Results remained robust after adjustment for other inflammation (interleukin 6), renal and cardiac (creatinine, NT-proBNP, cardiac troponin T) biomarkers, and after excluding participants with CVD, type 2 diabetes, and obesity. The PHDI was associated with lower concentrations of GDF-15. Adopting the PHDI may be a useful approach to reduce chronic inflammation and target NCD prevention in the older adult population, while staying within planetary boundaries.

Development of a multimorbidity health conditions outcome index for caloric restriction interventional studies in older adults: a preliminary investigation in an observational cohort study - Michael E. Miller; Haiying Chen; Mark A. Espeland; Fang-Chi Hsu; Denise K. Houston; Anne B. Newman; W. Jack Rejeski; Barbara J. Nicklas; Stephen B. Kritchevsky (GeroScience, 2025)
Using multiple sources, we provide the conceptual justification and statistical support for a multimorbidity outcome associated with obesity-related conditions, which we term the Health Conditions Index (HCI). This index was designed to capture the health effects of multi-year studies of caloric restriction for older adults with BMIs in the overweight or obesity classification. We used a subset of participants in the Health, Aging and Body Composition Cohort Study to evaluate multiple aspects of the index and its components over 5 years of follow-up. The 937 participants in the subset had an average age of 73 years and a BMI of 30.7 kg/m 2 ; 53% were female and 43% were Black; 80% were hypertensive and 14% had type 2 diabetes. Results demonstrated that the components of the index were consistently related to initial BMI and percent body fat on cohort entry, generally showed an increasing prevalence over the 5-year follow-up, and, as a composite index, exhibited an association between faster progression and higher initial levels of age, BMI, and percent body fat. Further, the initial HCI was associated with a statistically significant increase in the rate of mortality over 5 years of follow-up (hazard ratio = 1.22, 95% CI 1.04 to 1.44). By using outcomes like the HCI, clinical trials of caloric restriction in older adults may gain a better understanding of how intentional weight loss relates to future risk of multiple chronic conditions associated with aging.

MicroBayesAge: a maximum likelihood approach to predict epigenetic age using microarray data - Nicole Nolan; Megan Mitchell; Lajoyce Mboning; Louis-S. Bouchard; Matteo Pellegrini (GeroScience, 2025)
Certain epigenetic modifications, such as the methylation of CpG sites, can serve as biomarkers for chronological age. Previously, we introduced the BayesAge frameworks for accurate age prediction through the use of locally weighted scatterplot smoothing (LOWESS) to capture the nonlinear relationship between methylation or gene expression and age, and maximum likelihood estimation (MLE) for bulk bisulfite and RNA sequencing data. Here, we introduce MicroBayesAge, a maximum likelihood framework for age prediction using DNA microarray data that provides less biased age predictions compared to commonly used linear methods. Furthermore, MicroBayesAge enhances prediction accuracy relative to previous versions of BayesAge by subdividing input data into age-specific cohorts and employing a new two-stage process for training and testing. Additionally, we explored the performance of our model for sex-specific age prediction which revealed slight improvements in accuracy for male patients, while no changes were observed for female patients.

Citrinin delays muscle aging and extends lifespan in C. elegans and prevents senescence in C2C12 through SKN-1/Nrf2 activation - Yejin Cho; Woo Jin Lee; Hee Soo Kim; Hyo-Deok Seo; Chang Hwa Jung; Jiyun Ahn; Hong-Seok Son; Jeong-Hoon Hahm (GeroScience, 2025)

Functional characterisation of rare variants in genes encoding the MAPK/ERK signalling pathway identified in long-lived Leiden Longevity Study participants - Maarouf Baghdadi; Helena Hinterding; Thies Gehrmann; Pasquale Putter; Mara Neuerburg; Nico Lakenberg; Erik B. van den Akker; P. Eline Slagboom; Joris Deelen; Linda Partridge (GeroScience, 2025)
Human longevity, which is coupled to compression of age-related disease, is a heritable trait. However, only few common genetic variants have been linked to longevity, suggesting that rare, family-specific variants may also play a role. We therefore investigated whole-genome sequencing data of long-lived individuals from the Leiden Longevity Study and identified family-specific variants residing in genes involved in the mitogen-activated protein kinase (MAPK) cascade, a lifespan-associated and evolutionarily conserved pathway emerging from studies in model organisms. We subsequently generated and functionally characterised mouse embryonic stem cells (mESCs) harbouring these variants. Two variants, located in NF1 (Phe1112Leu) and RAF1 (Asp633Tyr), reduce MAPK/extracellular signal-regulated kinase (ERK) signalling pathway activity in mESCs. At the proteomic and transcriptomic level, we observed prominent changes that were shared (e.g. upregulation of ribosomal proteins and Foxo3 expression) and opposing between the variants (e.g. downregulation of mTORC1 signalling-related proteins and Ets2 expression in the RAF1 Asp633Tyr variant cell line versus upregulation in the NF1 Phe1112Leu variant cell lines). These changes were accompanied by opposing effects on proliferation. Moreover, the RAF1 Asp633Tyr variant improved resistance to replication stress, while this was not the case for the NF1 Phe1112Leu variant. In conclusion, we identified two rare genetic variants in long-lived families that influence MAPK/ERK signalling in a manner that has previously been linked to increased lifespan in model organisms. Our findings suggest that mESCs offer a suitable starting point for studying rare genetic variants linked to human longevity, allowing for the identification of promising variants to pursue in in vivo studies using model organism.

A tongue resistance training program improves strength, endurance, and swallowing in frail older adults with mild cognitive impairment: a double-blind randomized controlled trial - Shu-Hua Kao; Ruey Chen; Pi-Yu Su; Kondwani Joseph Banda; Chien-Mei Sung; Chia-Hui Wang; Kai-Jo Chiang; Melati Fajarini; Kuei-Ru Chou (GeroScience, 2025)

Olfactory dysfunction increases progression to dementia in cognitively impaired older adults: a 12-year population-based study - Javier Oltra; Ingrid Ekström; Maria Larsson; Jane Yan; Giulia Grande; Erika J. Laukka (GeroScience, 2025)
Olfactory deficits are hypothesized to precede cognitive decline and be independently associated with future dementia. Conversely, the concurrency of cognitive and olfactory impairments is expected to represent an advanced stage, associated with shorter time to diagnosis. Limited research has examined the association of isolated and concurrent cognitive and olfactory impairments with incident dementia. We aimed to estimate the 12-year dementia hazard for cognitive impairment no dementia (CIND), olfactory dysfunction (OD), and their combination in a population-based cohort of older adults. We classified 2406 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) based on baseline CIND and OD. Dementia hazard was estimated with Cox regressions for the whole period and two timeframes (baseline to 6-year follow-up and 6- to 12-year follow-up), and time until receiving a diagnosis via Laplace regressions. CIND+OD was associated with increased hazard ratio (HR) of dementia over 6 years (HR 11.38; 95% CI 6.70, 19.32; p < 0.001), higher for amnestic CIND+OD (HR 22.23; 95% CI 11.79, 41.90; p < 0.001). Isolated CIND was associated with dementia closest to baseline (HR 3.38; 95% CI 1.75, 6.49; p < 0.001), while isolated OD was associated with dementia closest (HR 2.56; 95% CI 1.48, 4.43; p < 0.001) and furthest (HR 2.12; 95% CI 1.41, 3.19; p < 0.001) to baseline. CIND+OD received their dementia diagnosis 3 years earlier. This study demonstrated that individuals with both cognitive and olfactory impairments have a higher short-term risk of progression to dementia and that OD may be a valuable early marker of dementia on its own.

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, 2025)

Geroprotective applications of oleuropein and hydroxytyrosol through the hallmarks of ageing - Anna Calabrò; Anna Aiello; Paula Silva; Calogero Caruso; Giuseppina Candore; Giulia Accardi (GeroScience, 2025)
Geroprotectors are compounds that target the underlying mechanisms of ageing to delay the onset of age-related diseases and extend both lifespan and health span. As ageing is driven by the accumulation of cellular damage, DNA instability, epigenetic changes, mitochondrial dysfunction, and chronic inflammation, the concept of geroprotection focuses on compounds that can mitigate these processes. Oleuropein (OLE) and its derivative hydroxytyrosol (HT), both phenolic molecules derived from Olea europaea (olive tree), have gained significant attention as potential geroprotectors due to their potent antioxidant and anti-inflammatory properties. These phytochemicals, central to the Mediterranean diet, activate key molecular pathways such as nuclear factor erythroid 2-related factor 2, reducing oxidative stress and modulating inflammatory responses. Through these mechanisms, OLE and HT help counteract inflammageing, a critical factor in age-related dysfunction. This review highlights the role of OLE and HT as geroprotective agents, emphasising their ability to target the hallmarks of ageing and their potential to improve health span by slowing the progression of age-related conditions. With proven efficacy in various biological models, these compounds represent promising tools in the ongoing search for strategies to enhance the quality of life in ageing populations.

Tilorone attenuates high-fat diet-induced hepatic steatosis by enhancing BMP9-Smad1/5/8 signaling - Barnabas Horvath; Judit Halasz; Norman Noel Tanner; Zoltan Marton Kohler; Gyorgy Trencsenyi; Laszlo Juhasz; Laszlo Rovo; Andras Kiss; Aniko Keller-Pinter (GeroScience, 2025)
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing and is caused by excessive fat deposition in the liver due to non-alcoholic factors. Aging is a major risk factor for the development and progression of MASLD. In this study, we investigated the metabolic effects of tilorone, a synthetic small molecule, in a high-fat diet (HFD) mouse model, with a focus on the liver function and signaling. We demonstrate that tilorone attenuated HFD-induced steatosis by restoring bone morphogenetic protein 9 (BMP9)-Smad1/5/8 signaling and upregulating peroxisome proliferator-activated receptor gamma (PPARγ) expression. Tilorone reduced HFD-induced increases in body weight, adipose tissue and liver weight, and blood glucose levels, and improved glucose tolerance in HFD mice. PET/MRI imaging demonstrated enhanced 18 FDG ( 18 F-fluoro-2-deoxyglucose) uptake in liver, skeletal muscle, adipose tissue, and myocardium of tilorone-treated HFD animals. Histological analysis showed that tilorone reduced the HFD-induced diffuse, macrovesicular steatosis (S3/3), and machine learning-based image analysis revealed a decrease in lipid droplet size and lipid content. HFD caused the disappearance of liver glycogen, but tilorone increased glycogen levels. High-resolution respirometry indicated that tilorone reduced HFD-induced increases in mitochondrial complex II-linked oxidative phosphorylation and complex IV activity. These findings revealed the beneficial effects of tilorone on HFD and highlight its therapeutic potential in MASLD, particularly given that tilorone is a synthetic small molecule and can be administered orally. Further studies are required to explore its clinical application.

Loss of microstructural integrity in left hemispheric white matter tracts is associated with poorer digits in noise understanding - Jordi H. C. Boons; Gertjan Dingemanse; Elisabeth J. Vinke; Bernd Kremer; Meike W. Vernooij; André Goedegebure (GeroScience, 2025)
Age-related hearing loss (ARHL) is a prevalent condition among older adults and is regarded as a potentially modifiable risk factor for dementia. Although multiple studies have investigated pure-tone thresholds as a measure for ARHL and its relationship to dementia, the potential role of the central auditory system has received little attention. To address this gap in the literature, this study investigates the relationship between central auditory functioning, assessed using the speech-reception-threshold (SRT) of the digits-in-noise (DIN) test, and the microstructural integrity of white matter tracts in the Rotterdam Study. A total of 1669 participants underwent the DIN test and had diffusion imaging data available. The SRT was found to be significantly associated with the microstructural integrity of the left inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and posterior thalamic radiation. After accounting for audibility effects, the association with the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was even stronger, while the association with the posterior thalamic radiation was no longer significant. These findings suggest that age-related declines in specific brain regions may contribute to difficulties in speech-in-noise understanding among the elderly.

Effects of aerobic exercise and cardiorespiratory fitness on white matter free water fraction in older adults: a 1-year randomized controlled trial - Takashi Tarumi; Junyeon Won; Tsubasa Tomoto; Norman Scheel; David C. Zhu; John Ashley; Karen M. Rodrigue; Kristen M. Kennedy; Denise C. Park; Rong Zhang (GeroScience, 2025)

Cognitive and neuroimaging outcome of very prodromal dementia with Lewy bodies - Frédéric Blanc; Vincent Bouteloup; Claire Paquet; Marie Chupin; Florence Pasquier; Audrey Gabelle; Mathieu Ceccaldi; Paulo Loureiro de Sousa; Pierre Krolak-Salmon; Renaud David; Clara Fischer; Jean-François Dartigues; et al. (GeroScience, 2025)

How aging impacts cortical dynamics and gait during dual-task turning revealed by fNIRS - Yuqi Dong; Chen Yang; Yan Chen; Feng Pan; Jinwei Wang; Cui Zhang (GeroScience, 2025)

Sensory impairments and epigenetic aging: insights from self-rated hearing and vision in United States adults - Jamaji C. Nwanaji-Enwerem; Dennis Khodasevich; Nicole Gladish; Hanyang Shen; Anne K. Bozack; Saher Daredia; Belinda L. Needham; David H. Rehkopf; Andres Cardenas (GeroScience, 2025)
Sensory impairments are common with aging, but studies examining the relationships of these impairments with DNA methylation–based biomarkers of aging, strong predictors of morbidity and mortality, remain sparse. We investigated whether subjective measures of sensory impairment are associated with epigenetic age biomarkers. We conducted a cross-sectional analysis in a representative sample of 2344 U.S. adults from the 1999–2000 and 2001–2002 cycles of the National Health and Nutrition Examination Survey (NHANES). We examined the relationships of self-rated auditory and vision function with seven epigenetic aging biomarkers: HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge2, DNA methylation telomere length, and DunedinPoAm. We adjusted for potential confounders including chronological age, other demographics, lifestyle factors, and general health. In adjusted survey-weighted models, self-reported deafness was associated with a significantly higher GrimAge2 ( β = 4.19-years, 95% CI 2.29, 6.09, P = 0.004) and DunedinPoAm ( β = 0.07, 95% CI 0.04, 0.09, P = 0.002) compared to good hearing. Deafness was also associated with significantly higher GrimAge2 estimates of TIMP1 ( β = 459.51, 95% CI 287.00, 632.03 P = 0.002) and marginally higher estimated levels of ADM ( β = 10.06, 95% CI 1.76, 18.36, P = 0.03), CRP ( β = 0.34, 95% CI 0.11, 0.56, P = 0.01), and cigarette pack-years ( β = 6.55, 95% CI 2.62, 10.47, P = 0.01). No associations were observed with self-rated vision. We describe associations of self-rated deafness with accelerated epigenetic aging, as measured by GrimAge2 and DunedinPoAm. These results provide a foundation for future research exploring epigenetic biomarkers as tools for predicting and understanding the biological processes underlying sensory impairments like deafness.

Amyloid neuropathy, tauopathy, decreased cholinergic and dopaminergic neurons, long-term memory and motor deficits, and sleep disturbance in motopsin deficient mice - Fumiaki Yokoi; Yuuna Tanaka; Akari Sakai; Nao Isogai; Shiori Miyata; Shinichi Mitsui (GeroScience, 2025)

Impacts of systemic milieu on cerebrovascular and brain aging: insights from heterochronic parabiosis, blood exchange, and plasma transfer experiments - Rafal Gulej; Roland Patai; Anna Ungvari; Attila Kallai; Stefano Tarantini; Andriy Yabluchanskiy; Derek M. Huffman; Michael J. Conboy; Irina M. Conboy; Mika Kivimäki; Anna Csiszar; Zoltan Ungvari (GeroScience, 2025)
Aging is a complex biological process that detrimentally affects the brain and cerebrovascular system, contributing to the pathogenesis of age-related diseases like vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). While cell-autonomous mechanisms that occur within cells, independent of external signals from neighboring cells or systemic factors, account for some aspects of aging, they cannot explain the entire aging process. Non-autonomous, paracrine and endocrine, pathways also play a crucial role in orchestrating brain and vascular aging. The systemic milieu modulates aging through pro-geronic and anti-geronic circulating factors that mediate age-related decline or confer rejuvenative effects. This review explores the impact of systemic factors on cerebrovascular and brain aging, with a particular focus on findings from heterochronic parabiosis, blood exchange, and plasma transfer experiments. We discuss how these factors influence fundamental cellular and molecular processes of aging and impact cerebrovascular endothelial function, neurovascular coupling mechanisms, blood–brain barrier integrity, neuroinflammation, capillary density, and amyloid pathologies, with significant consequences for cognitive function. Additionally, we address the translational potential and challenges of modifying the systemic milieu to promote brain health and prevent age-related cognitive impairment.

A non-invasive approach to monitoring microcirculatory health before and after hemodialysis in renal patients using nailfold video capillaroscopy with optical reflectance analysis - Hiroki Suzuki; Hiroki Nagano; Keiji Kawagoe; Ichiro Miura; Kazuto Masamoto (GeroScience, 2025)

Cross-sectional associations of epigenetic clocks with intrinsic capacity and functional ability in older adults with frailty and cognitive impairment: the COGFRAIL study - Pedro L. Valenzuela; Juan Luis Sánchez-Sánchez; Paul Bensadoun; Jean-Marc Lemaître; Bruno Vellas; Sandrine Sourdet; Philipe de Souto Barreto (GeroScience, 2025)

Association of APOC1 with cortical atrophy during conversion to Alzheimer’s disease - Sewook Oh; Sunghun Kim; Jun Pyo Kim; Sang Won Seo; Bo-yong Park; Hyunjin Park (GeroScience, 2025)
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, with its progression influenced by aberrant gene expression and alterations in the brain network topology. Although APOE has been extensively studied in relation to AD, the role of APOC1 remains relatively underexplored. This study investigated the impact of APOC1 on changes in cortical thickness (CTh) during conversion to AD in a longitudinal setting. Using a normative modeling approach, we examined changes in CTh in patients with mild cognitive impairment (MCI). The spatial patterns of CTh changes were then correlated with APOC1 mRNA expression levels. We estimated the time to conversion to AD and compared progression rates between the low and high APOC1 expression groups. Finally, mediation analysis was performed to assess the indirect effects of APOC1 expression on memory function via CTh changes. In patients with MCI and AD, reduced CTh was observed in the limbic and default mode regions, with a notable impact on the entorhinal cortex, parahippocampus, and fusiform gyrus when comparing baseline and follow-up measurements. The degree of change in CTh was significantly associated with APOC1 expression, with the paralimbic regions identified as particularly vulnerable. Furthermore, the high APOC1 expression group demonstrated more rapid conversion to AD than that observed in the low expression group. Mediation analysis indicated a trend suggesting that APOC1 expression indirectly affected memory and cognitive function through its influence on CTh. These results highlight the potential of APOC1 as an additional focus of AD research, offering insights into the genetic influences on AD pathology.

Cartilage degradation is followed by PAC1 receptor reduction in articular cartilage of human knee joints - Kálmán Rácz; Yonatan Segal; Kinga Lénárt; Csaba Fillér; Anna Tóth; Vince Szegeczki; Péter Gergely; Róza Zákány; Dóra Reglődi; Tamás Juhász (GeroScience, 2025)
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide expressed in the nervous system and also in various peripheral tissues, including the musculoskeletal system. PACAP has an important function in the regulation of chondrogenesis and plays a protective role in cartilage oxidative and mechanical stress. PACAP knockout (KO) mice show early signs of aging and osteoarthritis in knee joint articular cartilage. Its specific, most potent receptor is the PAC1 receptor, the activation of which leads to enhanced Sox9 expression and subsequently, it increases the expression of collagen type II, glucosaminoglycans and aggrecan. In the present study, we investigated articular cartilage of human knee joints taken from cadavers of varying ages. Thickness and extracellular matrix content of articular cartilage of knee joints decreases with aging. The cartilage degeneration process most likely begins between the ages of 40 to 50. Expression of PAC1 receptor decreases in parallel with the reduction of cartilage thickness, leading to subsequent reduced Sox9 expression with cartilage specific matrix production. In summary, we found correlation in the reduction of cartilage thickness and quality together with PAC1 receptor expression and activity.

Dietary patterns and mortality risk in geriatric patients with atherosclerotic cardiovascular disease: an analysis of the National Health and Nutrition Examination Survey - Meiqi Wang; Xuerong Jia; Dongyue Chen; GaoJin Pei; Zhiruo Song; Mengna Peng; Kangmo Huang; Xinfeng Liu (GeroScience, 2025)