Optimizing cognitive functions in healthy older adults: a network meta-analysis of dual- and single-task interventions - Barbara Cazzolli; Andrea Chirico; Federica Stefanelli; Michele Zacchilli; Elisa Cavicchiolo; Fabio Alivernini; Fabio Lucidi (GeroScience, 2026)

Metabolic signatures, vitamin D, and red cell distribution width in dementia risk: UK Biobank insights - May A. Beydoun; Tianyi Huang; Nicole Noren Hooten; Hind A. Beydoun; Mustapha Bouhrara; Jordan Weiss; Michele K. Evans; Alan B. Zonderman (GeroScience, 2026)

Hierarchical disruption of lateral prefrontal cortex gradients in cognitive aging - Hai-Yan Hou; Ping Wang; Sheng-Ju Guo; Hui-Jie Li (GeroScience, 2026)

Associations of air pollution and genetic risk and their interaction with risk of Alzheimer’s disease: identification of risk loci and potential biological pathways - Shanshan Ran; Jingyi Zhang; Miao Cai; Lan Chen; Zhengmin Qian; Fei Tian; Gan Wu; Ri’enna Boyd; Stephen Edward McMillin; Huai-cai Zeng; Yin Yang; Hualiang Lin (GeroScience, 2026)

DNA methylation-based surrogate markers of C-reactive protein and their associations with health-related traits - Danmeng Lily Li; Allison M. Hodge; Joanne Ryan; Melissa C. Southey; Graham G. Giles; Roger L. Milne; Pierre-Antoine Dugué (GeroScience, 2026)
Several methylation-based surrogate markers of C-reactive protein ( mCRP ) have been proposed and used to assess the risk of age-related phenotypes and construct novel ageing markers. We aimed to (i) assess the variance in plasma CRP explained by several mCRP markers; (ii) compare their associations with three health-related traits: mortality, body mass index (BMI), and PCGrimAge ; and (iii) assess the stability of CRP and mCRP over a decade. Blood samples were collected from 947 participants in the Melbourne Collaborative Cohort Study at baseline (1990–1994) and wave 2 (2003–2007). High-sensitivity CRP was measured in plasma samples. Five mCRP markers were calculated: mCRP-Ligthart , mCRP-Wielscher , mCRP-EpiScore , mCRP-GrimAge2 , and mCRP-Hillary . Intraclass correlation coefficients (ICCs) were calculated to assess the stability of CRP/ mCRP between baseline and wave 2. Associations of wave 2 CRP/ mCRP with mortality ( N deaths = 319) were assessed using Cox models and linear regression for BMI and age-adjusted PCGrimAge . mCRP explained 6.0% ( mCRP-Wielscher ) to 16.8% ( mCRP-GrimAge2 ) of the variance in plasma CRP. The ICCs for CRP and mCRP markers were similar, ranging from 0.44 ( mCRP-GrimAge2 ) to 0.63 ( mCRP-Wielscher ). Compared with CRP, mCRP had stronger associations with PCGrimAge , whereas for mortality and BMI, the associations were similar or weaker for mCRP . Associations between mCRP and mortality were greatly attenuated after adjusting for PCGrimAge but less so after adjusting for CRP. The association of CRP with mortality remained strong after adjusting for mCRP . Our study validated mCRP markers and clarified the role of CRP and mCRP in ageing, which may inform the use and development of ageing biomarkers.

Tai Chi modulating multimodal connectivity patterns and cognitive function in cerebral small vessel disease - Xiaoyong Zhong; Zhongpeng Dai; Liuxi Chu; Hongliang Zhou; Wanqing Lin; Bin Chen (GeroScience, 2026)

Is the emerging influenza A(H3N2) K subclade a specific threat for older adults? - Jorge Quarleri; M. Victoria Delpino (GeroScience, 2026)

Age and sex shape plasma lipid associations to skeletal muscle mitochondrial respiration and H2O2 emission - Nicholas A. Carlini; Bradley A. Ruple; Helya Rostamkhani; Huihui Shi; J. Alan Maschek; Brady E. Hanson; Namakkal Soorappan Rajasekaran; Russell S. Richardson; Micah J. Drummond; Ryan M. Broxterman; Joel D. Trinity (GeroScience, 2026)

Epigenetic insights of Olympic champions: nuclear and mitochondrial DNA methylation and regulators of aging - Timea Teglas; Ferenc Torma; Zoltan Bori; Dora Aczel; Gergely Babszky; Takuji Kawamura; Mitsuru Higuchi; Gu Yaodong; Muhammad Lee; Steve Horvath; Zsolt Radak (GeroScience, 2026)

Epigenetic age deceleration reflects exercise-induced cardiorespiratory fitness improvements - Menno Van Damme; Sanne Stegen; Bram Steenwinckel; Helene Schroé; Gustavo A. Reyes del Paso; Matias M. Pulopulos; Rudi De Raedt; Marie-Anne Vanderhasselt; Wim Derave; Femke Ongenae; Jan Boone; Wim Van Criekinge; et al. (GeroScience, 2026)

Metacontrol-related aperiodic and periodic neural activity in cognitive aging: enhancing the neural signal-to-noise ratio through anodal transcranial direct current stimulation - Yu Pi; Qinfei Zhang; Shuhui Lyu; Christian Beste; Lorenza Colzato; Bernhard Hommel (GeroScience, 2026)
Metacontrol, the ability to adapt cognitive control to task demands, declines with age and is thought to be reflected in aperiodic and periodic neural dynamics. Given that anodal transcranial direct current stimulation (atDCS) can modulate cortical excitability via membrane potential shifts, we tested whether atDCS alters the neurophysiological signatures of metacontrol in younger and older adults. In a mixed design, younger and older participants performed a Go/Nogo task under both atDCS and sham stimulation conditions; resting-state EEG data were also acquired. Aperiodic activity was analyzed using the FOOOF algorithm, and periodic activity was examined through time–frequency analysis. Behaviorally, younger adults showed higher accuracy and faster responses than older adults, but no significant stimulation effects emerged in either group. Results showed that, compared to sham, aperiodic activity (FOOOF exponent) increased after atDCS, particularly in older adults, indicating a steepening of the EEG spectrum and thus increased inhibitory tone in the aging process. However, resting-state aperiodic activity did not predict stimulation-induced effects within either group. In the periodic domain, we found no evidence that atDCS modulated task-related theta or alpha power. Moreover, exploratory analyses revealed no significant associations between atDCS-induced changes in the aperiodic exponent and oscillatory power. This dissociation indicates that, under the present conditions, the periodic and aperiodic components of the EEG signal reflect distinct and likely independent neurophysiological responses to neuromodulation. Targeting metacontrol mechanisms through neuromodulation may, with further validation, open new avenues for supporting cognitive health in older adults. Graphical Abstract

Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood–brain barrier dysfunction, metabolic reprogramming, and increased inflammation in the aging brain - Sarah Otu-Boakye; Duraipandy Natarajan; Bhuvana Plakkot; Ilakiya Raghavendiran; Paulina Hoppa; Tamas Kiss; Madhan Subramanian; Priya Balasubramanian (GeroScience, 2026)
Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood–brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo. Collectively, our findings indicate that lipid accumulation may drive structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.

Microbiota-derived indole-3-propionic acid extends lifespan in Drosophila and improves muscle and bone health in mice - Sagar Vyavahare; Ford Berger; Shelton G. Swint; Bharati Mendhe; Mansi Shukla; Ian Duchesne; Roger Zhong; Marion A. Cooley; Meghan E. McGee-Lawrence; Carlos M. Isales; Jessica M. Hoffman; Sadanand Fulzele (GeroScience, 2026)

Group dance interventions for community dwelling older adults to prevent and treat sarcopenia: a mixed methods systematic review - Nan Hua; Ruth Harris; Shalini Ahuja; Xiangmin Tan; Kia-Chong Chua; Yihan Mo; Joanne M. Fitzpatrick (GeroScience, 2026)
Group dance is an engaging physical activity that may benefit the prevention and management of sarcopenia among older adults. However, current evidence on this topic is limited. We aimed to evaluate published evidence on group dance for sarcopenia in community dwelling older adults. Studies published in English and Chinese between 2014 and 2024 were identified through searches in MEDLINE, Embase, and PsycINFO via Ovid, CINAHL via EBSCO, Chinese National Knowledge Infrastructure, Wan Fang, Google Scholar, and Web of Science Core Collection. Two reviewers independently performed screening, data extraction, and risk of bias assessment. Quantitative data were meta-analysed, and qualitative findings were analysed using thematic analysis. The protocol was registered with PROSPERO (CRD42024554152). 24 studies were included, comprising 1840 participants across 12 countries and involving nine types of group dance interventions. Meta-analysis showed significant improvements in the Short Physical Performance Battery (MD = 1.32, 95%CI: 0.56, 2.08, I 2 = 37%), Sit and Reach Test (MD = 1.91, 95%CI: 0.29, 2.91, I 2 = 0), Montreal Cognitive Assessment (MD = 0.94, 95%CI: 0.01, 1.87, I 2 = 0) and Trail Making Test (SMD = 0.12, 95%CI: 0.03, 0.21, I 2 = 34%). No significant differences were observed in muscle strength, 5 times Sit-To-Stand, Time Up and Go, Single Leg Test, 30s Chair Stand, and gait speed. Qualitative analysis identified three overarching themes: psychosocial, physical, and cognitive wellbeing. Group dance is a safe, acceptable, and promising community intervention that improves physical performance in older adults. Enjoyment-driven and socially engaging group dance interventions are encouraged to support the prevention and management of sarcopenia. Future investigation should use sarcopenia-specific assessments, and consider cultural context, baseline physical status, and individual preferences when designing and evaluating group dance interventions. Graphical Abstract

Association between cardiovascular-kidney-metabolic syndrome and risks of 14 age-related health outcomes in primary prevention older population - Zhen Zhou; Kevan R. Polkinghorne; Andrew M. Tonkin; Robyn L. Woods; Anping Cai; Sophia Zoungas; Michelle A. Fravel; Michael E. Ernst; Chao Zhu; Mark Nelson; Johannes T. Neumann; Kerry M. Sheets; et al. (GeroScience, 2026)

Adoptive T-cell therapies for persistent COVID-19 in immunocompromised patients: Comparison of IFN-γ virus-specific T-cell therapy and CD45RA+ T-cell depleted donor lymphocyte infusion - László Gopcsa; Borisz Rabán Petrik; Bálint Gergely Szabó; Marienn Réti; Hajnalka Andrikovics; Ilona Bobek; Gabriella Bekő; Judit Bogyó; Andrea Ceglédi; Katalin Dobos; Laura Giba-Kiss; Orsolya Kis; et al. (GeroScience, 2026)

Circulating microRNAs in pulmonary arterial hypertension: biomarkers for diagnosis, prognostic stratification, and treatment - Beatrice Polini; Sandra Ghelardoni; Gerarda Capone; Emilia Monti; Grazia Chiellini; Vincenzo Lionetti; Raffaele De Caterina; Rosalinda Madonna (GeroScience, 2026)

Higher burden of neuropsychiatric symptom-like behaviors associated with canine cognitive dysfunction compared to normal aging in the Dog Aging Project - Daniel W. Fisher; Jillian R. Fisher; Silvan R. Urfer; NhiVan A. Tran; Kathleen F. Kerr; Martin Darvas (GeroScience, 2026)

The aging gut–glia–immune axis in alzheimer’s disease: microbiome-derived mediators of neuroinflammation and therapeutic innovation - Prince Ahad Mir; Nishant Kumar; Gyamcho Tshering Bhutia; Preeti Chaudhary; Gurkiran Kaur; Sukesh Kumar Gupta (GeroScience, 2026)

Life-course body shape trajectories and cerebral oxygen metabolism in community-dwelling older adults - Yifan Yan; Yaping Zhang; Xuhao Zhao; Renwei Chen; Shenghao Fang; Yi Zhou; Jingkai Huang; Fuyan Wang; Christopher Chen; Zixuan Lin; Xin Xu (GeroScience, 2026)
Obesity and lifelong body-shape fluctuation are associated with late-life structural brain damage, suggesting the involvement of metabolic pathways. The cerebral metabolic rate of oxygen (CMRO₂) reflects hemodynamic and oxidative stress and precedes structural atrophy, but its role in adiposity-related brain change remains unclear. We examined whether current and life-course adiposity relate to CMRO₂ and to structural change. A total of 303 community-dwelling adults aged 50 years and older were included. Body shape was assessed using Body Mass Index (BMI) and Body Roundness Index (BRI). Global CMRO₂ was derived from TRUST and phase-contrast MRI. T1-weighted MPRAGE provided volumetry, and medial temporal atrophy (MTA) grading. General linear models estimated associations of BMI and BRI with CMRO₂, including age interactions. Age-stratified mediation tested CMRO₂ as a mediator of adiposity to MTA associations. Body-shape trajectories at ages 25, 40, 60, and current age were modeled and related to CMRO₂ and metabolism-related regions. Adiposity was associated with lower CMRO₂: with overweight (β = -1.12 μmol/100 g/min, 95%CI = (-1.96, -0.28)) and higher BRI (β = -1.31, 95%CI = (-2.36, -0.27)) showing stronger effects with advancing age. Among participants aged 70 years, CMRO₂ mediated the association between BMI and MTA (indirect β = 0.06, 95%CI = (0.01, 0.14)). Three adulthood body-shape patterns emerged, and CMRO₂ was lower in moderate increasing (β = -11.40; 95%CI = (-20.90, -1.90)) and high-rising (β = − 12.23; 95%CI = (-23.56, -0.90)) groups. Metabolism-related regions were larger in higher-risk patterns, particularly the left hypothalamus. Greater and prolonged adiposity is linked to reduced CMRO₂ and related structural differences in older adults.

SOD1 deficiency drives ferroptosis-linked oxidative and reproductive aging, mitigated by ginseng root extract - Juewon Kim; Shuichi Shibuya; Yusuke Ozawa; Yorino Sato; Kazuhiro Kawamura; Takahiko Shimizu (GeroScience, 2026)
Aging is accompanied by cumulative oxidative stress that promotes tissue degeneration and reproductive decline. Here, we show that deficiency of superoxide dismutase 1 (SOD1) accelerates oxidative injury and reproductive aging through a ferroptosis-linked redox imbalance, and that ginseng root extract (GR) confers protection across species. Aged hairless Sod1 ⁻ / ⁻ mice exhibited markedly elevated skin and plasma oxidative stress markers—including 8-isoprostane, malondialdehyde (MDA), and pentosidine—together with dermal cyst formation and atrophic pathology. Complementary studies in C . elegans revealed that SOD1-deficient strains displayed increased reactive oxygen species, depleted glutathione, and elevated iron and lipid peroxidation—canonical features of ferroptosis-associated oxidative stress. These redox alterations coincided with shortened reproductive span and reduced progeny output, both rescued by ferroptosis inhibition or GR supplementation. In female Sod1 ⁻ / ⁻ mice, GR restored folliculogenesis, normalized estrous cyclicity, and improved ovarian morphology. Collectively, these findings identify SOD1 loss as a driver of ferroptosis-associated oxidative and reproductive aging and highlight GR as a promising redox-targeted intervention.

Multilevel regulation of skeletal muscle ferroptosis in aging: sex- and exercise-dependent effects on histological, molecular, and genetic markers - Fujue Ji; Hyeonseung Rheem; Haesung Lee; Minyeong Eom; Jong-Hee Kim (GeroScience, 2026)

Knockdown of the fly spliceosome component Rbp1 (orthologue of SRSF1) extends lifespan - Dan J. Hayman; Mirre J. P. Simons (GeroScience, 2026)
Biological regulation is an intricate process involving many layers of complexity, including at the RNA level. Alternative splicing is crucial in the regulation of which components of a protein-coding gene are spliced into a translatable mRNA. During ageing, splicing becomes dysregulated, and alternative splicing is implicated in disease and known anti-ageing treatments such as dietary restriction (DR) and mTOR suppression. In prior work, we have shown that DR and mTOR suppression modulate the expression of the spliceosome in the fly ( Drosophila melanogaster ). Here, we manipulated the five top genes that change in expression in both these treatments. We found that knockdown (using conditional in vivo RNAi in adults) of some spliceosome components rapidly induces mortality, whereas one, Rbp1 , extends lifespan. Treatments that have more instant benefits on longevity are more translatable. We therefore subsequently repeated the Rbp1 experiment but initiated Rbp1 knockdown at later stages in adult life. We find that irrespective of the age of induction, knockdown of Rbp1 extends lifespan. Our results posit the spliceosome itself as a hub of regulation that when targeted can extend lifespan, rendering it a promising target for geroscience.

Association between cagemate number and risk of death in mice: a time-varying covariate analysis using Cox frailty models - Thirupathi R. Mokalla; Erik S. Parker; Daniel L. Smith; Luis-Enrique Becerra-Garcia; Olivia C. Robertson; Deependra K. Thapa; Mounika Kandukuri; Bret M. Rust; David B. Allison (GeroScience, 2026)
Social housing is desirable for the health and well-being of laboratory mice, as social interactions with conspecifics influence both behavioral and physiological outcomes. Although group housing benefits social species, it can introduce variability in mortality outcomes, and raise welfare concerns, particularly with the emergence of aggression or fluctuating cage densities. Despite this, few studies have evaluated how changes in the number of living cagemates over time are associated with survival, particularly in a sex-specific manner. We analyzed data from the National Institute on Aging’s Interventions Testing Program (ITP; n = 2635 UM-HET3 mice), across three research sites to assess whether housing density influenced longevity differently in male and female mice. Mice were housed in same-sex cages (median = 3 per cage) without reassignment after cagemate death. We applied Cox frailty models incorporating nested random effects for cage and site, with fixed effects for sex, treatment, and time-varying number of living cagemates to estimate hazard ratios, which allowed us to assess the instantaneous risk of death associated with changes in cagemate number. Results showed a significant main effect of the number of living cagemates on mortality and a significant interaction between sex and cagemate count, indicating sex-specific responses. Female mice exhibited a pronounced increase in mortality rate as cage density declined, suggesting a potential role of social buffering in longevity. These findings emphasize the importance of considering social housing dynamics, particularly for female mice, in both experimental design and animal welfare protocols. Graphical Abstract

Frailty and postoperative risk in geriatric neurosurgery: a prospective cohort study using multidimensional assessment - Chukwuma Okoye; Valentina Stella; Louis-Georges Roumy; Chiara Benedetta Rui; Alice Margherita Ornago; Paola Signorelli; Benedetta Maisano; Beatrice Tonus; Alberto Finazzi; Maria Cristina Ferrara; Elena Pinardi; Carlo Giorgio Giussani; et al. (GeroScience, 2026)

Lifestyle for Brain health (LIBRA) score, cognition, brain volume, and dementia risk in the UK Biobank - Kelsey R. Sewell; James D. Doecke; Samantha L. Gardener; Blossom Stephan; Kirk I. Erickson; Belinda M. Brown (GeroScience, 2026)

Review: Systemic inflammation after stroke. Therapy and perspective - Abuzan Mihaela; Andreea Cercel; Thorsten R. Doeppner; Dirk M. Hermann; Roxana Surugiu; Denisa F. V. Pirscoveanu; Aurel Popa-Wagner (GeroScience, 2026)
Systemic inflammation following ischemic stroke is driven by a complex interplay among pro-inflammatory cytokines, immune cell activation, and neurovascular dysfunction. Both aging and obesity significantly amplify this inflammatory response, exacerbating stroke severity and impeding recovery. Aging induces a chronic low-grade inflammatory state—referred to as inflammaging —that heightens vulnerability to stroke-induced brain injury. Similarly, obesity promotes a persistent pro-inflammatory milieu that disrupts metabolic and immune homeostasis, further worsening neurological outcomes. The combined effects of aging and obesity pose a substantial barrier to effective stroke rehabilitation and long-term recovery. To improve post-stroke care, future research should focus on three key areas. First, there is a pressing need for targeted therapies that modulate systemic inflammation with minimal side effects. Anti-inflammatory agents such as minocycline have shown promise in preclinical models, but clinical validation is needed. Second, elucidating the molecular mechanisms linking aging, obesity, and systemic inflammation—such as the roles of adipokines and immune cell phenotypes—may reveal novel therapeutic targets. Finally, personalized treatment strategies that consider individual risk factors like age and obesity are essential to optimize stroke management and rehabilitation. Given the limited efficacy of current stroke treatments, prioritizing prevention by identifying high-risk individuals is critical. Recognizing non-modifiable risk factors can support more intensive intervention on modifiable ones and guide vigilance toward vulnerable populations. Overall, advancing our understanding of systemic inflammation and its modifiers will be key to developing innovative, patient-specific therapies aimed at improving outcomes and quality of life for stroke survivors.

Aging kidney is associated with metabolic rewiring and epigenetic reprogramming - Pragney Deme; Rhea Bhargava; Heddwen L. Brooks; Norman J. Haughey; Prerna Kumar (GeroScience, 2026)
Understanding the direct connections between metabolism and chromatin dynamics may uncover potential mechanisms involved in the aging process of renal physiology. Despite known differences in incidence and aging renal disease, how biological aging intersects with renal metabolism and epigenetics in a sex-specific context remains poorly understood. Here, we determined the effect of age on renal metabolic pathways and metabolite cofactors of epigenetic modifiers in a sex-specific manner. We measured metabolites in kidney homogenates from young and aged mice by HPLC-TripleTOF (LC–MS). The major metabolic adaptations observed with aging include increased glycolysis, decreased fatty acid oxidation, mitochondrial dysfunction, oxidative stress, and impaired metabolic waste clearance in 24-month-old (aged) mice compared to 4-month-old (young) sex-matched mice. Additionally, we found elevated levels of methylation and acetylation of intermediate metabolites also known as ‘epimetabolites’ in aged mice. Furthermore, age-related alterations were detected in metabolites (acetyl-coenzyme A, flavin adenine dinucleotide, and α-ketoglutarate) that are essential cofactors for the activities of epigenetic enzymes. Sex-specific changes were observed with age such as, significantly enhanced amino acid catabolism and tryptophan metabolism and reduced lysophospholipase activity and ammonia clearance in aged female vs aged male mice. Our results reveal age- and sex-associated alterations in renal metabolic pathways, characterized by an increase in epigenetically modified intermediate metabolites with aging. These findings suggest a complex interplay between renal metabolomics and epigenetics and offer new insights into the mechanisms underlying sex-specific renal physiology of aging kidneys. Graphical Abstract

Changes in transposable elements expression in male and female mice liver throughout aging - Bairon Hernandez-Rojas; Paola Murgas; Gonzalo Riadi (GeroScience, 2026)

Heart failure with preserved ejection fraction shows no excess mortality in older patients: a population-matched relative survival analysis - Christophe de Terwangne; Nassiba Menghoum; Marin Boute; Sibille Lejeune; Agnès Pasquet; Bernhard Gerber; David Vancraeynest; Benoit Boland; Christophe Beauloye; Anne-Catherine Pouleur (GeroScience, 2026)
Both heart failure with preserved ejection fraction (HFpEF) and advanced age are associated with increased mortality. However, HFpEF patients have not been compared with a similar age group from the general population. This study aimed to compare the mortality of HFpEF patients with an age- and gender-matched population, for two age groups (< 80 years and ≥ 80 years). Real-life cohort study of HFpEF patients with complete cardiac assessments carried out at an academic hospital since 2015. The observed mortality rates of the two age groups were compared to the expected mortality rate, using standardised mortality ratios (SMR). Of 334 HFpEF patients (mean age 79 ± 8.2 years, 64% women), 166 (50%) were ≥ 80 years. Older patients ≥ 80 years, compared to younger ones, had more frequently atrial fibrillation (73% vs. 61%), chronic kidney disease (67% vs. 53%), but less diabetes (24% vs. 45%), and lower BMI. During the follow-up (median: 4.1 years), 108 patients (32%) died. Compared to an age- and gender- matched population, HFpEF patients < 80 years had a three times higher mortality risk (SMR 3.37, 95% CI: 2.4–4.7), while HFpEF patients ≥ 80 years had a similar mortality risk (SMR 1.13, 95% CI:0.84–1.15). Consistently, no excess mortality was observed in the older patient group. Excess mortality is observed in HFpEF patients < 80 years but not in patients ≥ 80 years. This unexpected divergence likely reflects distinct HFpEF phenotypes and demographics across age groups. This trial was registered on 4 December 2014 at ClinicalTrials.gov (NCT03197350). Graphical Abstract

Skeletal muscle metabolomic markers underlying the enhanced exercise-induced hypertrophy response to resistance training in older adults - Changhyun Lim; Manoel Lixandrão; Dakshat Trivedi; Yun Xu; Konstantinos Prokopidis; Hamilton Roschel; Stuart M. Phillips; Howbeer Muhamadali; Masoud Isanejad (GeroScience, 2026)
Resistance training (RT) is an effective intervention for improving muscle health and metabolism in ageing, but the degree of responsiveness (hypertrophy) to RT varies substantially. We examined muscle metabolomic profiles before and after 10-weeks RT in older adults classified into upper (UPPER) and lower (LOWER) tertiles of hypertrophy to identify key metabolic adaptation differences. Fifty older adults (23 males, 27 females, mean 68.2 years old) completed 10 weeks of RT combined with whey protein supplementation. Quadriceps cross-sectional area (CSA) was assessed via magnetic resonance imaging before and after RT. Participants were grouped into UPPER (n = 25, 10.3 ± 2% CSA increase) or LOWER (n = 25, 3.3 ± 2% CSA increase) based on ranked CSA changes. We profiled skeletal muscle tissues from the UPPER and LOWER groups using a metabolomics platform. Over 2,500 metabolites were mapped to 104 metabolic pathways. In the UPPER group, upregulation of tryptophan-indole metabolites and the kynurenine pathway suggests a potential role of gut function and anti-inflammatory effect on RT-induced hypertrophy. Also, leucine, isoleucine and valine were significantly upregulated in the absence of their catabolites. Enrichment of urea cycle/amino group metabolism alongside mitochondria-matrix metabolites in the UPPER group indicates improved amino acids and energy homeostasis. Our findings highlight distinct RT-induced skeletal muscle metabolic profiles between UPPER and LOWER in older adults, underscoring the value of metabolic data. These metabolic pathways are important for understanding what contributes to the heterogeneity of hypertrophic response to RT in older adults. Graphical Abstract

Psycho-socio-economic factors and risk of cardiorenal multimorbidity in middle to older-aged adults: prospective findings from the Canadian longitudinal study on aging - Setor K. Kunutsor; Reyhaneh Rikhtehgaran; Anita Soni (GeroScience, 2026)
Psycho-socio-economic factors (PSEFs) such as income and homeownership may influence the prevalence of cardiorenal multimorbidity (CRM), yet their prospective associations with CRM risk remain unclear. This study aimed to estimate CRM incidence and examine its relationships with multiple PSEFs in a nationally representative Canadian cohort. We analyzed data from 16,557 participants (mean age: 60.4 years; 48.9% men) in the Canadian Longitudinal Study on Aging (CLSA) who were free of CRM at baseline (2010–2015). Incident CRM was defined as the co-occurrence of at least one cardiovascular disease and kidney disease at second follow-up (2018–2021). Survey-weighted multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for PSEFs and CRM risk. Over 3–11 years follow-up, 194 participants (1.2%) developed CRM, corresponding to 8.80 per 1,000 individuals (95% CI: 6.77–11.40). CRM incidence increased with age, was higher in men than women (10.63 vs. 7.35 per 1,000), urban than rural residents (9.69 vs. 3.72 per 1,000), and immigrants than non-immigrants (10.87 vs. 8.49 per 1,000). Greater tangible social support reduced CRM risk (OR = 0.65; 95% CI: 0.43–0.97), while depression (OR = 1.68; 95% CI: 1.07–2.65) and PTSD (OR = 3.14; 95% CI: 1.74–5.67) increased risk. In middle- to older-aged Canadian adults, higher social support appears protective, whereas depression and PTSD increase CRM risk. Although incidence was low, CRM burden rose with age and was higher among men, urban residents and immigrants. These findings highlight the importance of psychosocial well-being and social connectedness in preventing CRM and reducing multimorbidity burden in aging populations.

Structural and mitochondrial dendritic degenerations in old hypoglossal motor neurons - Trace A. Christensen; Matthew J. Fogarty (GeroScience, 2026)
Hypoglossal motor neurons (MNs) within the medullary hypoglossal nucleus innervate the striated muscles of the intrinsic and extrinsic tongue. Dysfunction of the control of the tongue muscles may lead to problems such as dysphagia, dysphonia and the increased risk of aspiration pneumonia in the elderly. In the human and Fischer 344 (F344) rat motor systems, age-related muscle weakness and behavioural dysfunctions are contemporaneous to MN death. In other neurons, dendritic and mitochondrial degenerations are fundamental pathophysiological components preceding neuronal death. We aimed to determine if dendritic, dendritic spine and dendritic mitochondrial pathology were present in old age. We used golgi-cox and serial block-face scanning electron microscopy (SBFSEM) to evaluate dendritic and mitochondrial morphology, respectively in young (6-month) and old (24-month) female and male F344 rats. Dendritic regression and dendritic spine loss occurs in old age, predominantly in larger hypoglossal MNs. In addition, reduced dendritic mitochondrial volume density and mitochondrial fragmentation are apparent in old age. Our results are consistent with established age-related deficits in F344 rats, including tongue muscle sarcopenia, hypoglossal MN loss and dysphagia. Although more work is needed to determine if synaptic and mitochondrial degenerations are causative for age-related neuromotor dysfunctions, our results suggest that strategies to preserve dendrites and mitochondria may be of therapeutic utility.

Dynamic frailty trajectories and risk of age-related macular degeneration: a prospective cohort study in UK Biobank - Yu Peng; Yuzhou Zhang; Ka Wai Kam; Mary Ho; Simon Sezto; Sunny Au; Charlene C. Yim; Xiujuan Zhang; Mandy P. H. Ng; Patrick Ip; Alvin Young; Chi Pui Pang; et al. (GeroScience, 2026)
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the aging population. Although frailty has been recognized as a potential risk factor, previous studies relying on static assessments cannot capture its dynamic nature. This study aims to prospectively evaluate the association between dynamic frailty trajectories and incident AMD. The baseline cohort included 462,573 UK Biobank participants who were free of AMD and had frailty phenotype (FP) data at enrollment. Among them, 53,059 with at least one follow-up FP assessment comprised the trajectory cohort. Participants were categorized as nonfrail, prefrail, or frail based on their FP scores. Annualized frailty progression (ΔFP/year) was estimated via linear regression. Cox models assessed hazard ratios (HRs) and 95% confidence intervals (CIs) for AMD. During a median follow-up of 11.8 years in the baseline cohort, 13,428 incident AMD cases (2.9%) were documented. Prefrail (HR:1.14; 95% CI:1.10–1.18) and frail (HR:1.36; 95% CI: 1.26–1.47) individuals had significantly higher AMD risks compared to nonfrail participants. In the frailty trajectory analysis with a median follow-up duration of 3.3 years, 852 incident AMD cases (1.6%) were recorded. Each 1-point FP increase conferred 28% higher AMD risk (HR: 1.28; 95% CI: 1.18–1.38), while each 0.1-point/year ΔFP increase independently elevated risk by 15% (HR: 1.15; 95% CI: 1.10–1.21). Compared to stable nonfrail, prefrailty aggravation showed highest AMD risk (HR: 2.26; 95% CI: 1.51–3.37), followed by frailty alleviation (HR: 1.73; 95% CI: 0.98–3.04) and frailty maintenance (HR: 1.72; 95% CI: 0.86–3.41). Progressive frailty trajectories, independent of baseline status, is associated with increased incident AMD risk. Early interventions targeting frailty progression may mitigate AMD risk in aging populations.

Plasma proteomic signatures of social support and their association with cardiovascular disease and mortality: exploratory analyses in a national cohort study - Pei Qin; Jessica Gong; Andrew Steptoe; Daisy Fancourt (GeroScience, 2025)
Social support has been related to cardiovascular disease (CVD) incidence and mortality in longitudinal cohort analyses, but the biological pathways underpinning this remain underexplored. This exploratory study examined the associations between social support and a wide range of proteomic biomarkers and performed the mediating effect of proteomic biomarkers in the association between social support and CVD and mortality to identify potential biological pathways linking social support to health outcomes. Data from 3141 adults over the age of 50 in the English Longitudinal Study of Ageing who had plasma proteome data were analyzed, with CVD and mortality outcomes followed up for 16 years following through Hospital Episode Statistics and the National Health Service’s Central Registry. Linear and Cox regression analyses were used to identify proteins associated with social support, CVD, and mortality. Mediation analysis was then performed on the identified proteins to explore their role as a potential mediator between social support and CVD and mortality risk. Over a median of 15.8-year follow-up, 889 participants have died, and 627 developed CVD. Of 276 plasma proteins measured, greater social support was associated with lower levels of 13 proteins and higher TN-R levels, after adjusting for baseline socioeconomic confounders. We also identified 49 protein-CVD and 70 protein-mortality associations after minimal adjustments, including 11 and 14 proteins simultaneously associated with social support. All the significant proteins together mediated about 20.9% and 26.4% of the associations for CVD and mortality, respectively. The main enriched biological pathways involved death receptor activity and carbohydrate binding. Social support was related to a cluster of proteomic biomarkers, which may be linked to inflammation, apoptosis, and atherosclerosis/vascular pathways. The identified plasma proteins partly mediated the association between social support and CVD and mortality risk, independently and cumulatively. These findings deepen our understanding of the intricate connections between relationship quality, proteomic signatures, and CVD and mortality development.

Dynamic brain functional connectivity in age-related hearing loss during auditory selective spatial attention - Hongxing Liu; Yanru Bai; Mingkun Guo; Ran Zhao; Jianing Zhu; Guangjian Ni (GeroScience, 2025)

Geroscience insights into difficult-to-treat rheumatoid arthritis: the role of unhealthy aging, comorbidity, and therapeutic complexity - Andrea Lehoczki; Zoltan Ungvari; Ágnes Szappanos; Mónika Fekete; Lilla Gunkl-Tóth; György Nagy (GeroScience, 2025)
Difficult-to-treat rheumatoid arthritis (D2T RA) is an emerging challenge in aging populations, where disease persistence and therapeutic failure often reflect not only autoimmune dysregulation but also the cumulative effects of age-related biological changes across multiple organ systems. This review reframes D2T RA through the lens of geroscience, highlighting how immunosenescence, inflammaging, and organ system vulnerability converge to create a treatment-resistant disease phenotype. Age-associated alterations in adaptive and innate immunity—such as diminished T cell diversity, impaired regulatory function, expansion of age-associated B cells, and heightened inflammasome activation—closely intersect with the immunopathogenesis of RA. The potential contribution of clonal hematopoiesis of indeterminate potential (CHIP) to systemic inflammation and myeloid dysfunction is also discussed as a novel mechanistic link. In parallel, aging of the musculoskeletal system magnifies joint damage, sarcopenia, and pain sensitization. Furthermore, advancing age is also accompanied by multimorbidity, polypharmacy, and frailty, which in turn constrain therapeutic options and increase the risk of adverse events. We argue that D2T RA in the elderly should not be viewed in isolation, but as part of a broader syndemic of age-related diseases driven by shared inflammatory and metabolic pathways. This perspective calls for a shift toward integrated, individualized care strategies that balance efficacy, safety, and quality of life. Future directions include the development of age-adapted treatment guidelines, expanded inclusion of older adults in clinical trials, and the application of artificial intelligence and machine learning to predict high-risk trajectories and personalize management. A geroscience-informed approach offers the conceptual foundation to meet the growing complexity of RA care in aging populations.

High-definition tDCS of the motor cortex affects prefrontal and primary motor activity differently in young and older adults - Yasra Arif; Peihan J. Huang; Seth D. Springer; Hannah J. Okelberry; Jason A. John; Nathan M. Petro; Grant M. Garrison; Kennedy A. Kress; Kellen M. McDonald; Giorgia Picci; Tony W. Wilson (GeroScience, 2025)

Facial skin aging: an integrative analysis of genetics, epigenetics, and lifestyle factors - Rezvan Noroozi; Aleksandra Pisarek-Pacek; Bożena Wysocka; Kamila Migacz-Gruszka; Paulina Pruszkowska-Przybylska; Magdalena Kobus; Dagmara Lisman; Julia Zacharczuk; Joanna Rudnicka; Aleksandra Iljin; Kathryn C. Fitzgerald; Małgorzata Michalczyk; et al. (GeroScience, 2025)
Facial wrinkling is a prominent sign of aging, yet individuals exhibit unique trajectories of biological aging, contributing to the variability in facial appearance. Here, we present a pioneering study exploring the association between lifestyle choices, DNA methylation, and SNP genotypes with a range of facial skin aging phenotypes. The study demonstrated that age-related facial skin phenotypes are influenced by multiple environmental stressors. Epigenome-wide association analyses identified differentially methylated cytosines mapped to 151 loci , including novel genes associated with facial wrinkles, such as EDAR (cg02925966, p = 4.96 × 10 −8 ) and NRG1 (cg26267340, p = 4.64 × 10 −8 ), both involved in wound healing. Sensitivity analysis, conditioning on the top meQTLs, showed minor attenuation, suggesting an association independent of genetic variants. Accelerated epigenetic aging, measured in the blood of over 700 Polish individuals, was found to correlate with facial wrinkle area, photoaging, telangiectasias, and perceived facial age, with the GrimAge and FitAge clocks showing the most robust associations. Genome-wide SNP analysis identified rs73943403 (RP11-78F17.1, p = 3.72 × 10 −8 ) associated with wrinkle area and rs113125564 ( ZC3H4 , p = 1.23 × 10 −8 ) associated with perceived facial age, potentially implicating stress response and adiposity in skin aging. Finally, the study revealed the additive value of methylation and SNP data for predicting two continuous skin phenotypes, with 59.0% of the variation explained in facial wrinkle area and 26.2% in perceived facial age. The findings underscore the relevance of genetic and epigenetic factors, revealing novel candidate genes and molecular pathways involved in skin aging. These insights hold substantial translational value for dermatology, the cosmetics industry, and anti-aging strategies.

MASLD in the oldest-old: lack of association with cognition or functional autonomy and poor predictive utility of the hepatic steatosis index - Maximilian Joseph Brol; Martin Groth; Frank Erhard Uschner; Juliana Stadtmann; Tina Schomacher; Jonel Trebicka; Michael Praktiknjo; Elena Vorona (GeroScience, 2025)
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition increasingly recognized in aging populations. However, its clinical relevance in older adults—particularly in relation to sarcopenia, cognitive function, and rehabilitation outcomes—remains poorly defined. This retrospective observational study included in-patients admitted for geriatric rehabilitation in 2022 with available abdominal ultrasound. MASLD was defined according to AASLD/EASL criteria. Demographics, comorbidities, medications, and the hepatic steatosis index were recorded. Cognitive function (MMSE, clock-drawing, GDS), hand grip strength, mobility (Tinetti, Timed Up and Go), and functional status (Barthel Index, discharge autonomy) were assessed. Analyses included regression and AUROC, with significance at p below 0.05. MASLD was present in 49.6% of the study population. No significant association was observed between MASLD and cognitive impairment. Patients with higher hand grip strengths showed higher proportions of MASLD (p = 0.01). In this cohort, hepatic steatosis index has poor capacity to detect hepatic steatosis (AUC = 0.503, 95%-CI: 0.437–0.570). Furthermore, MASLD did not predict poorer functional outcomes following the rehabilitation stay. In adjusted models, Barthel Index —but neither MASLD nor hand grip strength— was independently associated with reduced functional autonomy at discharge (p = 0.006). In elderly patients, MASLD was associated with diabetes mellitus and higher hand grip strength, while sarcopenia was linked to a lower prevalence of steatosis. MASLD showed no association with cognitive performance, functional outcomes, or prediction by the hepatic steatosis index. These findings highlight age-specific characteristics of MASLD requiring tailored clinical approaches. Graphical Abstract

Age-related degradation of cerebellar functional network topology - Mingzhu Ye; Haishuo Xia; Tao Song; Zijin Liu; Antao Chen (GeroScience, 2025)

Is grip strength a marker for cognitive function, neurodegeneration, and resilience? - Alexander Ivan B. Posis; Hilary L. Colbeth; Mihika S. Deshpande; Kristen M. George; Batool Rizvi; Rifat B. Alam; Ruijia Chen; Dan M. Mungas; Paola Gilsanz; María M. Corrada; Rachel A. Whitmer (GeroScience, 2025)
Assessing whether grip strength is associated with cognitive decline and brain health could help identify a target to prevent or delay cognitive impairment. Therefore, we tested whether grip strength is associated with brain health as indicated by magnetic resonance imaging and domain specific cognitive decline. We also assessed whether grip strength was a cognitive resilience proxy using moderation tests. This study included cognitive and neuroimaging data from 861 participants in three harmonized cohorts. We fit multivariable linear mixed-effects and linear regression models to test associations between grip strength, neuroimaging markers, and cognition. We also tested moderation by gender and age. Greater grip strength was associated with slower verbal episodic memory decline and greater total gray matter volume. Associations of grip strength with executive function, total hippocampal volume, and white matter hyperintensities were not significant, but in the expected direction. Age moderated associations of grip strength and white matter hyperintensities. Grip strength was a significant proxy for cognitive resilience related to white matter hyperintensity volume and verbal episodic memory decline only. Future research should examine other measures of physical performance that are associated with later-life cognitive and brain health.

Transcranial alternating current stimulation improves ballistic motor performance in trained and untrained limbs of healthy older adults - Nishadi N. Gamage; Wei-Yeh Liao; Philip J. Atherton; Mathew Piasecki; George M. Opie; John G. Semmler (GeroScience, 2025)

Age-dependent modulations of hemispheric small-world networks in different eye states: resting-state electroencephalogram research - Chang Xu; Chuqiao Li; Tong Cui; Shaoqi Li; Xiaodong Han; Boye Wen; Cuibai Wei (GeroScience, 2025)
Normal aging triggers substantial topological transformation within resting-state electroencephalography (rs-EEG) networks. Given that the small-world (SW) architecture of hemispheric EEG networks may reflect an evolutionarily and developmentally optimized organization, investigating their modulations with age offers critical insights into the dynamic reorganization of functional connectivity (FC) patterns throughout adulthood. Utilizing rs-EEG data from a single-site public repository collected under eyes-closed and eyes-open conditions, we employed graph-theory methods to delineate age-related alterations in the SW architecture of hemispheric functional networks across a broad adult age range (20–70 years). In 539 cognitively intact individuals, undirected weighted FC networks were constructed using eLORETA-based lagged linear connectivity for each hemisphere and three subnetworks: default mode network (DMN), frontal network (FN), and attentional network (AN). Further quantitative analyses revealed that age-related changes in SW metrics were observed exclusively in the right hemisphere, evident during eyes-closed rest and in network reconfiguration upon eye opening (ΔSW). Right-hemispheric SW and ΔSW showed frequency- and network-specific modulation with age: in the alpha2 band, all three subnetworks exhibited increasing trends, with U-shaped trajectories in DMN and AN and a linear rise in FN. In other frequency bands, specific SW metrics displayed an inverted-U curve relationship with age (DMN: alpha1 SW, delta ΔSW; FN: gamma SW; AN: theta, alpha1, gamma SW, theta ΔSW) in later adulthood, whereas beta2 SW and gamma ΔSW in FN decreased linearly. These findings revealed a right-lateralized pattern of age-related changes in intrinsic SW architecture and provided an eyes-state-dependent baseline for evaluating hemispheric network impairments in age-related neuropsychiatric disorders.

The impaired hemodynamics of choroid plexus and its interactions within the glymphatic system in Parkinson’s disease - Song’an Shang; Shaohua Ding; Yuting Xia; Hongying Zhang; Xiang Lv; Beilei Chen; Daming Shen; Jing Ye; Yu-Chen Chen (GeroScience, 2025)

Beyond strength: dietary nitrate augments self-selected functional mobility after resistance training in middle-aged adults - Brandon M. Peoples; Mason C. McIntosh; Kenneth D. Harrison; Bria R. Smith; Keven G. Santamaria Guzman; Silvia E. Campos-Vargas; Damaris C. Cifuentes; Breanna J. Mueller; Andreas N. Kavazis; Darren T. Beck; Michael D. Roberts; Jaimie A. Roper (GeroScience, 2025)
This study aimed to assess whether dietary nitrate supplementation with resistance training (RT) augments gait performance and functional mobility in inactive middle-aged and older adults. We hypothesized that combining nitrate-rich beetroot juice (BRJ) with RT would yield improvements in gait and functional mobility compared to RT with nitrate-depleted beetroot juice placebo (PLA) supplementation. In this 12-week, randomized, double-blind, placebo-controlled pilot trial, 28 healthy, inactive adults (56 ± 7 years) were assigned to either a BRJ (~ 12.8 mmol nitrate/day) or PLA group while completing a supervised, full-body RT program (2×/week). Pre- and post-intervention assessments included the instrumented stand and walk (iSAW), 6-min walk test (i6MWT), and timed up and go (iTUG) tests. Supplement adherence, training compliance, and volume were equivalent between groups. ANCOVA analyses controlling baseline values revealed significant between-group differences favoring the BRJ group for gait speed (adjusted means: 1.38 vs 1.27 m/s, p = .010), stride length ( p < .001), and iTUG duration ( p < .05). Within-group analyses confirmed that the BRJ group experienced significant improvements in gait speed ( p < 0.001) and iTUG duration ( p < 0.05), while the PLA group showed no functional changes, indicating that 12 weeks of RT alone was insufficient to improve functional mobility in our sample despite equivalent training responses ( p > .05). In our middle-aged sample, supplementing dietary nitrate alongside RT led to clinically meaningful improvements in functional mobility during self-selected conditions, exceeding the gains from 12 weeks of twice-weekly RT alone. Preliminary descriptive analyses revealed sex-specific group-level differences that might suggest emerging trends. Although no inferential statistics were conducted, the patterns provide potential directions for future research investigating the effects of RT in middle-aged adults. Graphical Abstract

The relationship between frailty status and psychosocial indices in older Korean adults - Ji Young Kim; Taesic Lee; Sangbaek Koh (GeroScience, 2025)
Frailty is a heightened vulnerability to physiological stressors caused by cumulative physiological decline over a lifespan. Psychological issues (depression and stress) and social problems (such as loneliness and social isolation) serve as potential risk factors for unfavorable comorbidities, including frailty, cardiometabolic disorders, and unexpected mortality. In this study, we aimed to elucidate the relationship between frailty and psychosocial factors in an aging population. The Aging-Cognition Cohort, a subset of the Wonju-Pyeongchang Arirang Cohort, included 930 participants aged 55–79 between 2020 and 2022. Participants underwent a frailty assessment based on Fried’s criteria. Pearson’s method-based network analysis identified key factors among five psychosocial indices (PSIs). Univariate and multivariate regression (linear and logistic methods) analyses were used to explore the relationship between frailty and the five PSIs. Network analysis revealed differential connectivity between the five PSIs and clinical biomarkers across different frailty conditions. Among psychosocial factors, the University of California Los Angeles (UCLA) Loneliness Scale emerged as a key indicator. The association of summarized values of the five PSIs (eigenvalue) and UCLA with frailty exhibited significant results independent of the covariates (eigenvalue: beta-coefficient (B) = −0.018, 95% confidence interval (CI) −0.022–0.014; UCLA: B = 0.018, 95% CI 0.012–0.024). The relationship between PSIs and frailty was maintained across all subgroup analyses. This study highlights the robust association between frailty and psychosocial factors in older Korean population.

Adults up to 80 years old maintain effective movement planning when facing complex body dynamics - Anouck Matthijs; Anda de Witte; Dante Mantini; Jean-Jacques Orban de Xivry (GeroScience, 2025)

Engagement in more light physical activity and less sedentary time does not protect against age-related declines in cerebrovascular reactivity in healthy older adults - Molly K. Courish; Abigail V. Wickens; Said Mekary; Myles W. O’Brien; Derek S. Kimmerly (GeroScience, 2025)

Blood-based biomarkers of Alzheimer’s disease and olfactory decline over 15 years in older adults - Ingrid Ekström; Davide Liborio Vetrano; Martina Valletta; Robert Ruane; Maria Larsson; Claudia Fredolini; Bengt Winblad; Giulia Grande; Erika J. Laukka (GeroScience, 2025)
Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer’s disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin’ Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes. Graphical Abstract

Multi-omic analysis of canine aging uncovers conserved aging pathways - Zane Koch; Jessica L. Graves; Steve Annan; Phillip A. Frankino; Michelle Nelson; James E. McMahon; Ashley P. Tovar; Hubert C. Chen; Celine-Lea Halioua-Haubold; Matthew Peloquin (GeroScience, 2025)
Aging is a complex biological process characterized by molecular changes across multiple biological scales. While these alterations have been extensively studied in humans and rodents, the molecular changes associated with aging in dogs remain underexplored despite their relevance as a model for human aging. In this study, we profiled gene expression ( n = 16,273 genes) and protein abundance ( n = 2041 proteins) in whole blood and blood plasma from 40 laboratory beagles across young (3–5 years old, n = 10), old (8–9 years old, n = 17), and geriatric (10–14 years old, n = 13) life stages. We identified 816 genes and 40 proteins that significantly changed in abundance during aging, converging on pathways involved in DNA repair, collagen processing, and inflammation. Notably, these canine aging signatures overlapped with human age-associated genes, including those tied to the hallmarks of aging, reinforcing the existence of conserved aging mechanisms across species.

Genetic links between multimorbidity and human aging - Phuong-Anh Dinh; HyeRim Han; Seungsoo Kim; Qinghua Guo; Zhengdong D. Zhang; Jan Vijg; Yousin Suh (GeroScience, 2025)
The growing epidemiological burden of multimorbidity among older adults underscores an urgent need to develop interventions that can address multiple age-related diseases (ARDs) at once. Yet, the biological mechanisms driving their co-occurrence remain poorly understood. In this study, we conducted a multivariate genome-wide association analysis to dissect the shared genetic architecture of five common ARDs: heart attack, high cholesterol, hypertension, stroke, and type 2 diabetes. We defined this shared genetic component as the multivariate age-related disease factor (mvARD) and identified 263 independent variants across 180 genomic loci associated with mvARD. These variants were significantly enriched for associations with extreme human longevity, lending empirical support for the geroscience hypothesis in humans. Integrative gene prioritization using transcriptome-wide association studies, colocalization analysis, and Mendelian randomization identified four high-confidence genes in blood— DCAF16 , PHF13 , MGA , and GTF2B —with putative causal roles on mvARD. Using two-sample Mendelian randomization, we also found several modifiable lifestyle factors, including body mass index and dietary intake, that causally influenced the risk for multiple ARDs. Together, our findings revealed a shared genetic basis for common ARDs that overlapped with the biology of human aging and pointed to potential molecular and behavioral targets for delaying disease onset and promoting healthy aging. Graphical Abstract

Sensorimotor function as an early marker of cognitive decline and alzheimer’s biomarker burden - Semere Bekena; Ramkrishna K. Singh; Yiqi Zhu; David B. Carr; Ganesh M. Babulal (GeroScience, 2025)

Smartphone self-testing of hand and speech motor functions: a study of reliability and usability in older adults - Renjie Li; Kaylee Rudd; Eddy Roccati; Lynette R. Goldberg; Aidan D Bindoff; Katherine Lawler; Mimieveshiofuo Aiyede; Cristina Simonet; Diriba Mulisa; Anna E. King; James C. Vickers; Quan Bai; et al. (GeroScience, 2025)

Effectiveness of acetylcholinesterase inhibitors and memantine in patients affected by severe dementia - Giovanni Zuliani; Gloria Brombo; Tommaso Romagnoli; Michele Polastri; Francesco di Paola Dario; Marco Zuin (GeroScience, 2025)
The efficacy of acetylcholinesterase inhibitors (AChEI) and memantine (ME) in severe dementia remains uncertain, and real world data are limited. We evaluated the progression of cognitive decline and mortality rates in a cohort of outpatients with severe dementia treated with AChEI and/or ME or not treated, from the National Alzheimer’s Coordinating Center Uniform Data Set (NACC-UDS). Overall, 703 patients (mean age:78.3 ± 7.2 years; females:56.1%) with severe dementia (Mini-Mental State Examination—MMSE ≤ 10/30) were included [407 late-onset Alzheimer’s disease (LOAD), 126 Lewy body dementia (LBD), 170 vascular dementia (VD)]. Patients were grouped by treatment status: untreated (AChEI − /ME − ; n.70), AChEI only (AChEI + ; n.294), ME only (ME + ; n.215), combined therapy (AChEI + /ME + ; n.124). During follow-up (mean:1.7 ± 0.3 years; range:0.2–2.9 years) the mean MMSE scores declined by − 1.7 points (Standard Deviation: -1.55 to -1.9) in AChEI − /ME − (p for trend:0.001), − 1.5 points (-1.55 to -1.9) in AChEI + ( p :0.001), − 0.7 points (-0.5 to -0.9) in ME + ( p :0.09), while it increased by + 0.7 points (+ 0.4 to + 1.0) in AChEI + /ME + ( p :0.001). Survival rates were 8% in AChEI − /ME − , 10% in AChEI + , 28% in ME + , and 49% in AChEI + /ME + . In Cox proportional hazards analysis (age and sex adjusted), AChEI + /ME + exhibited a 39% reduction in total mortality compared with no treatment (HR:0.61; 95%CI:0.49–0.77; p < 0.001), ME + displayed a 22% reduction (HR:0.78; 95%CI:0.65–0.94; p :0.007), while AChEI + showed no association (HR:0.97; 95%CI:0.80–1.18; p :0.75). When the Cox proportional hazards models were stratified by dementia subtype, consistent significant patterns were observed in LOAD and LBD. In this real-world cohort of older adults with severe dementia, the combination therapy (ME + AchEI) seems to be associated with the best outcomes, including a stabilization of cognitive function and reduced total mortality. Graphical Abstract

Discrimination of normal from slow-aging mice by plasma metabolomic and proteomic features - Bretton Badenoch; Oliver Fiehn; Noa Rappaport; Pranjal Srivastava; Kengo Watanabe; Sriram Chandrasekaran; Richard A. Miller (GeroScience, 2025)
Tests that can predict whether a drug is likely to extend mouse lifespan could speed up the search for anti-aging drugs. We have applied a machine learning algorithm, XGBoost regression, to seek sets of plasma metabolites ( n = 12,000) and peptides ( n = 17,000) that can discriminate control mice from mice treated with one of five anti-aging interventions ( n = 278 mice). When the model is trained on any four of these five interventions, it predicts significantly higher lifespan extension in mice exposed to the intervention which was not included in the training set. Plasma peptide data sets also succeed at this task. Models trained on drug-treated normal mice also discriminate long-lived mutant mice from their respective controls, and models trained on males can discriminate drug-treated from control females. Triglycerides are over-represented among the most influential features in the regression models. Triglycerides with longer fatty acid chains tend to be higher in the slow-aging mice, while triglycerides with shorter fatty acid chains tend to decrease. Plasma metabolite patterns may help to select the most promising anti-aging drugs in mice or in humans and may give new leads into physiological and enzymatic targets relevant to the discovery of new anti-aging drugs.

Western Hunter-Gatherer genetic ancestry contributes to human longevity in the Italian population - Stefania Sarno; Vincenzo Iannuzzi; Marco Sazzini; Chiara Pirazzini; Maria Giulia Bacalini; Davide Gentilini; Giuseppe Passarino; Daniela Mari; Daniela Monti; Benedetta Nacmias; Sandro Sorbi; Davide Pettener; et al. (GeroScience, 2025)
The genetics of human longevity has been primarily studied using classical methods developed in genome-wide association studies. With the recent advances in paleogenomics, it is now possible to investigate to what extent ancient population ancestries contribute to complex traits. In this study, we explored the role of ancient genetic components in human longevity by focusing on the Italian Peninsula, whose genetic heritage includes several past genetic ancestries that have contributed to the current European genetic make-up. We analyzed genome-wide data of 333 Italian centenarians and 690 geographically matched healthy controls, and compared their genetic composition to 103 ancient genomes representative of the main past European population ancestries. Our findings indicate that Italian centenarians have a higher genetic affinity with Western Hunter-Gatherer (WHG)-related ancestry compared to controls, according to PCA and f4-statistics. Logistic regression models based on supervised admixture revealed a significant association between higher WHG ancestry and the centenarian status. Additionally, residual-based predictive analysis showed that centenarians exhibit a significantly higher WHG contribution independent of the genetic structuring of the general Italian population. By painting the chromosomes of modern Italians, we also showed a significantly higher number of WHG alleles at pro-longevity SNPs. In the present study, we demonstrate the contribution of ancient genetic components to the longevity phenotype. In particular, we showed a greater contribution from Western Hunter-Gatherer-related ancestry to Italian centenarians, thus suggesting that this pre-Neolithic genetic component, which has been linked to population shifts occurring within Europe after the Last Glacial Maximum, could be beneficial for longevity today. Graphical Abstract

Ovarian somatic tissue rejuvenates circulating apolipoproteins and promotes cognitive health in postreproductive female mice - Nathan D. McCoy; Steven P. Gawrys; Samuel G. Mackintosh; Stephanie Byrum; Negar Kosari; Anhong Zhou; Mishfak A. M. Mansoor; Yuji Ikeno; José V. V. Isola; Michael B. Stout; Augusto Schneider; Michal M. Masternak; et al. (GeroScience, 2025)
Women experience more pronounced lipidomic changes with aging than men, which may contribute to the higher rates of Alzheimer’s disease seen in postmenopausal women. Our earlier findings showed that transplantation of young ovarian somatic tissues or cells produced positive health-enhancing results in postreproductive females. In the current experiments, we looked to find key health-enhancing ovarian cells and pathways involved in this phenomenon. We conducted physiological and molecular analysis on animals/samples from old, postreproductive mice that received young ovarian tissue/cell transplants. Our analysis revealed a loss with age and a restoration with ovarian tissue/cell exposure, of serum biomarkers of lipid signaling and histological and behavioral markers of cognitive function. We further found, with single-cell transcriptomics and Raman spectroscopy, two candidate ovarian somatic cell types implicated in the restoration of health through a lipid signaling-based process. These results have identified key factors toward the determination of how germ cell-independent ovarian somatic tissues restore health through regulation of lipid signaling and dementia in postreproductive female mice. Graphical Abstract

Elevated mtDNA copy number in older adults is linked to methylation of mitochondrial and nuclear regulatory regions - Hongbo Chi; Hongying Shu; Yingmei Yang; Yuji Ikeno; Jiong Wu; Zhihong Wang; Habil Zare; Mikhail Alexeyev; Yidong Bai (GeroScience, 2025)

Deep neural networks and genome-wide associations reveal the polygenic architecture of local brain aging - Nicholas J. Kim; Ayati Mishra; Nahian F. Chowdhury; Samuel D. Anderson; Owen M. Vega; Nikhil N. Chaudhari; Kenneth H. Buetow; Paul M. Thompson; Andrei Irimia (GeroScience, 2025)
Local brain age (LBA) is a regional metric of brain aging that offers a spatially resolved alternative to global brain age, but whose genetic basis is unexplored. This study reports the first genome-wide association study of cortical LBA, as estimated by a deep neural network from the T 1 -weighted magnetic resonance images of 41,708 cognitively normal adults in the UK Biobank. We identified 1,212 single-nucleotide polymorphisms (SNPs) significantly associated with LBA in at least one brain region. Genes mapped to these SNPs are involved in developmental, metabolic, immune, and cytoskeletal pathways. Dimensionality reduction of SNP association profiles uncovered three clusters linked to morphogenetic, cytoskeletal, and immuno-epigenetic processes, helping to relate neuroanatomic, immunosenescent and epigenetic mechanisms of brain aging. Top variants are mapped to KCNK2 , NUAK1 , GMNC , MSL2 , and to other genes implicated in neurodevelopment and neurodegeneration. Spatial clustering of LBA-associated variants in default mode, limbic, and motor network regions parallel regional vulnerability to Alzheimer’s disease and frontotemporal dementia. These findings establish a polygenic architecture for regional brain aging and support LBA as a genetically informed phenotype for studying aging-related neurodegeneration. Our results suggest that cortical aging is not governed by isolated loci but by coordinated genetic programs—rooted in development, metabolism, and cellular structure—that confer lifelong patterns of regional brain vulnerability and resilience. This first genetic dissection of spatially specific brain aging reveals a polygenic landscape of coordinated genetic programs, developmentally encoded and metabolically maintained during senescence. This study reframes aging as an anatomically specific genetic process reflecting the varying structural vulnerabilities observed across neurodegenerative diseases.

Malnutrition as an independent risk factor for incident delirium in cohort of older adults receiving domiciliary care services - Benedicte Huseby Bøhn; Maria Krogseth; Nina Jøranson; Torgeir Bruun Wyller; Geir Selbæk; Gro Gujord Tangen (GeroScience, 2025)
Background Malnutrition and frailty frequently affect older adults receiving domiciliary care services, increasing their vulnerability to adverse events such as delirium. Despite this, the role of malnutrition as a risk factor for delirium in this population remains under-researched. The aim of this study was to examine the relationship between nutritional status and the development of delirium over a 2-year period among older adults who received domiciliary care services. Method In this 2-year prospective cohort study, we included 210 participants aged 65 years or older who received domiciliary care services at least once per week. Nutritional status was assessed using the Mini Nutritional Assessment at the time of inclusion, while delirium was assessed weekly, upon admission to hospital, and upon clinical indication according to DSM-5 criteria. Logistic regression analysis was used to examine the relationship between malnutrition and delirium. Results Of the sample, 116 (55.2%) were malnourished/at risk of malnutrition at the time of inclusion. Over a 2-year period, 42.4% developed delirium. The odds ratio for developing delirium was 2.00 (95% CI 1.08–3.72, P = 0.028), for the group with malnutrition/risk of malnutrition, adjusted for covariates. Conclusion Malnutrition is an independent risk factor for delirium in older adults receiving domiciliary care services. These findings highlight the importance of regular nutritional assessments and interventions to potentially reduce the risk of delirium in this vulnerable population.

Your brain doesn’t look a day past 70! Cross-sectional associations with brain-predicted age in the cognitively-intact oldest-old - Mark K. Britton; Hannah Hoogerwoerd; Joshua Juhasz; Keyanni Joy Johnson; Paul D. Stewart; Pradyumna K. Bharadwaj; Stacy S. Merritt; Cortney J. Jessup; Clinton B. Wright; G. Alex Hishaw; David A. Raichlen; Victor A. Del Bene; et al. (GeroScience, 2025)
The cognitively-intact oldest-old (85 +) may be the most-resilient members of their birth cohort; due to survivorship effects (e.g., depletion of susceptibles), risk factors associated with brain aging biomarkers in younger samples may not generalize to the cognitively-intact oldest-old. We evaluated associations between established aging-related risk factors and brain-predicted age difference (brainPAD) in a cross-sectional cognitively-intact oldest-old sample. Additionally, we evaluated brainPAD-cognition associations to characterize brain maintenance vs. cognitive reserve in our sample. Oldest-old adults (N = 206; 85–99 years; Montreal Cognitive Assessment > 22 or neurologist evaluation) underwent T1-weighted MRI; brainPAD was generated with brainageR, such that more-positive brainPAD reflected more-advanced brain aging. Sex, education, alcohol and smoking history, exercise history, BMI, cardiovascular and metabolic disease history, and anticholinergic medication burden were self-reported. Global cognitive z-score and coefficient of variation were derived from the UDS 3.0 cognitive battery; crystallized-fluid discrepancy was derived from the NIH Toolbox Cognitive Battery. Mean brainPAD was -7.99 (SD: 5.37; range: -24.50, 6.03). Women showed more-delayed brain aging than men (B = -2.9, 95% CI = -4.6, -1.1, p = 0.002). No other exposures were significantly associated with brainPAD. BrainPAD was not associated with any cognitive variable. These findings suggest that cognitively-intact oldest-old adults may be atypically-resistant to risk factors associated with aging in younger samples, consistent with survivorship effects in aging. Furthermore, brainPAD may have limited explanatory value for cognitive performance in cognitively-intact oldest-old adults, potentially due to high cognitive reserve. Overall, our findings highlight the impact of survivorship effects on brain aging research. Graphical Abstract

A multi-omics analysis of human fibroblasts overexpressing an Alu transposon reveals widespread disruptions in aging-associated pathways - Juan I. Bravo; Eyael Tewelde; Christina D. King; Joanna Bons; Samah Shah; Jacob Rose; Judith Campisi; Birgit Schilling; Bérénice A. Benayoun (GeroScience, 2025)

Healthy diet and slower biological aging as protective factors against microvascular complications in type 2 diabetes - Han Zhou; Shuai Ben; Qian Ma; RuiKang Yang; Jiao Xia; XiongYi Yang; Jing Li; JunYa Zhu; Qian Liu; Ya Zhao; Na Li; Kun Liu; et al. (GeroScience, 2025)

Cognitive training effects are shaped more by individual brain dynamics than age—evidence from younger and older women - Zsófia Anna Gaál; Petia Kojouharova; Boglárka Nagy; Gwen van der Wijk; István Czigler; Andrea B. Protzner (GeroScience, 2025)
Given the well-established structural and functional changes in the aging brain, it is widely assumed that cognitive aging is primarily driven by robust group-level differences between young and older adults. However, our individual-level EEG functional connectivity analysis challenges this notion. We investigated the impact of cognitive training on functional brain connectivity using task-switching paradigms in 39 younger (18–25 years) and 40 older (60–75 years) women. Participants were randomly assigned to either a training group, which completed eight individualized 1-h cognitive training sessions, or a no-contact control group. EEG was recorded at both pre- and post-training sessions across three task-switching paradigms (trained and near-transfer versions). Unique functional connectivity of different sources of variation was examined by calculating how much variance was shared across stable traits (e.g., individual, age, and common factors) or dynamic states (e.g., task and training effects). Our results revealed that age accounted for only a modest proportion of variance, whereas self-similarity was a dominant factor—particularly in older adults. Similarly, group-level training effects were small but strongly modulated by individual neural profiles, suggesting person-specific trajectories. Participants recruited distinct neural networks across tasks, and even within the same task engaged unique, individual-specific network configurations, reflecting personalized brain adaptations to cognitive demands. Importantly, older adults displayed a shift from common to individual network patterns, consistent with increased neural specialization and compensatory mechanisms. These findings underscore the importance of moving beyond group-level contrasts toward models that capture the complexity of individual brain dynamics in cognitive aging and training responsiveness.

Effect of fasting-mimicking diet on markers of autophagy and metabolic health in human subjects - Sara E. Espinoza; Sue Park; Gavin Connolly; Wenbo Qi; Ning Zhang; Manpreet Semwal; Yan Li; Marie Lauzon; Adam B. Salmon; William Hsu; Min Wei; Nicolas Musi (GeroScience, 2025)
We conducted a pilot randomized clinical trial to examine the effects of the fasting-mimicking diet (FMD) on autophagic flux and metabolic health markers in healthy humans. Thirty healthy participants were randomized to two oral formulations of FMD (ProLon and FMD2) or control for 8 days. Blood was collected at baseline, days 4 and 6 during intervention, and 48 h after completing FMD (Day 8). Effects on autophagic flux were measured in peripheral blood mononuclear cells (PBMC) using the ratio of LC3B-II/LC3B-I protein in samples treated with chloroquine (CQ) ex vivo. Metabolic outcomes measured included fasting plasma glucose, insulin, insulin growth factor-1, β-hydroxy-butyrate (BHB), and insulin resistance (HOMA-IR). One-way ANOVA or Kruskal-Wallis tests were used to determine significant differences between groups, both at individual time points and changes from baseline to subsequent time points. Participants were 49.1 ± 11.8 years. Significant between-group differences were observed in changes from baseline to the end of the 6-day dietary intervention for body weight, fasting glucose, BHB, HOMA-IR, and autophagic flux ( p < 0.05); however, differences were not significant across all time points. These results suggest that FMD may improve autophagic flux and markers of metabolic health. FMD may serve as a non-pharmaceutical intervention to modulate autophagy; however, further investigation with larger sample sizes is needed to confirm and extend these findings. This clinical trial was sponsored by L-Nutra Inc. and registered on ClinicalTrials.gov (NCT06115551). Graphical Abstract

Age-related change in skeletal muscle strength, size, and adiposity over 18 years in Caribbean men - Lauren S. Roe; Ryan K. Cvejkus; Victor W. Wheeler; Christopher L. Gordon; Tanya S. Kenkre; Joseph M. Zmuda; Iva Miljkovic (GeroScience, 2025)
Declines in muscle strength outpace declines in muscle mass with age, so factors like muscle adiposity (i.e., myosteatosis) may contribute to strength loss. We describe intermuscular adipose tissue (IMAT) and grip strength over 18 years among middle-aged and older African Caribbean men. We hypothesized that increases in IMAT precede the loss of muscle area and strength, and that increased IMAT is independently associated with strength decline. Men ( n = 339, 51.2 ± 5.5 years) were followed for 18.2 ± 0.9 years. Peripheral quantitative computed tomography at the calf determined IMAT (cm 2 ) and muscle area (cm 2 ) at baseline, follow-up visit 1 (FV1; 6.2 ± 0.4 years after baseline), and FV2 (12.0 ± 0.8 years after FV1). Grip strength (kg) was measured by handheld dynamometry at all visits. Generalized estimating equations determined associations between changes in IMAT and muscle area with time-varying grip strength. Grip strength decreased (mean ± SD, baseline: 51.33 ± 8.79, FV1: 47.02 ± 8.67, FV2: 40.12 ± 8.57), IMAT increased (median [quartile 1, quartile 3], baseline: 1.36 [0.73, 2.53], FV1: 1.74 [0.92, 3.14], FV2: 3.49 [2.06, 5.49]), and muscle area increased then decreased (baseline: 79.88 ± 12.33, FV1: 81.12 ± 13.88, FV2: 78.35 ± 12.72; all p < 0.05). A 1-cm 2 increase in IMAT from baseline to FV1 or FV2 was significantly associated with 0.18 kg (95% CI: −0.31, −0.06) decreased grip strength, independent of muscle area. The change in muscle area was not associated with grip strength declines ( β = 0.03, 95% CI: −0.03, 0.10). Despite initial muscle area increases, grip strength continuously decreased, and IMAT increased. Age-related increases in IMAT may contribute to the disconnect between declines in muscle strength and size. Graphical Abstract

Impairment in anticipatory cognitive brain processing in frail older adults - Luca Boccacci; Martina Scalia; Riccardo Borzuola; Valentina Camomilla; Chiara Fossati; Federica Galli; Andrea Macaluso; Fabio Pigozzi; Sabrina Pitzalis; Arnaldo Zelli; Francesco Di Russo (GeroScience, 2025)

Aerobic training conducted at different times of day in elderly patients with hypertension: a controlled trial - Luan M. Azevêdo; Natan D. da Silva Junior; Gustavo F. de Oliveira; Thais C. Marin; Sabrina A. A. Albino; Luiz A. R. Costa; Leandro C. Brito; Claudia L. M. Forjaz (GeroScience, 2025)

Longitudinal effects of cerebrovascular reactivity and cerebral pulsatility in cognitively intact older adults with APOE4: links with cognition - Zacharie Potvin-Jutras; Pierre-Luc Tremblay; Hanieh Mohammadi; Sylvia Villeneuve; R. Nathan Spreng; Claudine J. Gauthier; Sylvia Villeneuve; Judes Poirier; John C.S. Breitner; Jennifer Tremblay-Mercier; Jordana Remz; Jean-Michel Raoult; et al. (GeroScience, 2025)

The effect of anthocyanins and anthocyanin-rich foods on cognitive function: a meta-analysis of randomized controlled trials - Agnieszka Micek; Justyna Godos; Francesca Giampieri; Maurizio Battino; José L. Quiles; Daniele Del Rio; Pedro Mena; Giuseppe Caruso; Evelyn Frias-Toral; Irma Domínguez Azpíroz; Jianbo Xiao; Nicola Veronese; et al. (GeroScience, 2025)
The rising prevalence of cognitive disorders highlights the urgent need for effective prevention strategies and therapeutic interventions. While adherence to a balanced diet has been associated with a reduced risk of cognitive decline, emerging evidence underscores the potential role of plant-derived bioactive compounds, such as (poly)phenols, with anthocyanins receiving increasing attention. This meta-analysis aimed to evaluate the effect of anthocyanin-rich interventions on cognitive performance. A systematic search of randomized controlled trials (RCTs) assessing the effects of anthocyanin supplementation and cognitive outcomes identified 59 eligible studies. Overall, anthocyanin intervention significantly improved global cognition (standardized mean difference (SMD) = 0.46, 95% CI = 0.30 to 0.63, I 2 = 0.0%) compared with controls. Domain-specific analyses further revealed significant benefits for visuospatial processing/reasoning and attention (SMD = 0.37, 95% CI = 0.18 to 0.55, I 2 = 76.3%), processing and psychomotor speed (SMD = 0.19, 95% CI = 0.05 to 0.34, I 2 = 64.0%), verbal speed and fluency (SMD = 0.21, 95% CI = 0.03 to 0.39, I 2 = 30.5%), episodic memory (SMD = 0.30, 95% CI = 0.10 to 0.50, I 2 = 75.9%), and working memory (SMD = 0.24, 95% CI = 0.12 to 0.36, I 2 = 46.5%). Collectively, these findings suggest that anthocyanin supplementation may improve multiple cognitive domains. Although these results are promising, further well-designed RCTs are needed to validate these outcomes and consolidate the current evidence base.

A novel clinical biomarker-based Physiology Healthy Aging Index and risk of all-cause and cause-specific mortality: A 20-year prospective cohort study - Jieun Lyu; Ji-Yun Hwang; Joong-Yeon Lim; Yoon Jung Park (GeroScience, 2025)
Population aging is accelerating worldwide, with 16% projected to be aged ≥ 65 years by 2050. A practical index reflecting overall aging status is needed for population-based research, as existing indices often require specialised or cognitive assessments. We developed a Physiological Healthy Aging Index (PHAI) using accessible biomarkers and evaluated its association with mortality in Korean adults. A total of 6398 participants aged ≥ 40 years from the Korean Genome and Epidemiology Study (KoGES) Ansan-Ansung cohort followed up for an average duration of 16.5 years (2001–2022). The PHAI, based on systolic blood pressure, fasting blood glucose, serum creatinine, forced vital capacity, and C-reactive protein levels, was scored 0–10, with higher scores indicating healthier aging. Mortality risks across quartiles were estimated using Cox proportional hazard models. Long-term changes were classified as accelerated (decreased scores), stable (unchanged scores), or resilient (increased scores). During 105,597 person-years, 934 deaths occurred (778 age-related, 353 cancer-related, and 184 cardiovascular-related). Higher PHAI quartiles were linked with significantly lower mortality risk versus Q1. Fully adjusted hazard ratios (95% CIs) for all-cause mortality were 0.82 (0.69–0.98) for Q2, 0.50 (0.42–0.60) for Q3, and 0.51 (0.41–0.63) for Q4 ( P for trend < 0.001). Similar associations were observed for age-related mortality (HR 0.51, 95% CI 0.40–0.64 for Q4 vs. Q1), cancer (HR 0.66, 95% CI 0.48–0.92), and cardiovascular mortality (HR 0.24, 95% CI 0.13–0.44). Resilient agers had much lower all-cause mortality than accelerated agers (HR 0.21, 95% CI 0.16–0.28), with stable agers also at reduced risk (HR 0.65, 95% CI 0.54–0.77). Higher scores also correlated with a lower cognitive impairment risk. The PHAI is a simple, robust predictor of mortality outcomes, supporting its use as a practical tool for assessing physiological aging in public health and clinical settings. Graphical Abstract

The frailty mortality link in people with chronic diseases pertaining to 13 body organ systems: findings from the UK Biobank study - Justine Dastouet; Aurore Fayosse; Louis Jacob; Archana Singh-Manoux; Séverine Sabia; Benjamin Landré (GeroScience, 2025)
Frailty in older adults, particularly those with chronic diseases, has a robust association with risk of mortality, but whether this is the case in middle-aged adults is unclear. We examined the frailty-mortality association in middle-aged adults with chronic diseases and multimorbidity. Data on Fried’s frailty phenotype (robust, prefrail, frail) and 47 chronic diseases, mapped to 13 body organ systems, was available on 230,960 participants of the UK Biobank study (mean age 57.8, range 38.0–72.0). The mortality follow-up was 13.3 (± 2.1) years, and associations with mortality were examined using Cox regression, adjusted for socio-demographic factors and health behaviours. Compared to the robust group, frailty (HR, 2.32 (95% confidence intervals, 2.21; 2.43)) and prefrailty (1.35 (1.31; 1.39)) in those with diseases in any body organ system had a higher risk of mortality. Frailty was associated with a higher mortality risk for all 13 groups (all p < 0.01); estimates ranged from 2.25 (2.12; 2.39) for circulatory system diseases to 2.97 (2.60; 3.39) for the eye system. The same was the case for prefrailty; estimates ranged from 1.33 (1.23; 1.43) to 1.61 (1.03; 2.51). Between 19 and 34% of the mortality risk in the 13 disease groups could potentially be explained by frailty/prefrailty. Frailty ( p < 0.01) and prefrailty ( p < 0.01) had stronger associations with mortality in those with diseases affecting multiple organ systems. These findings highlight the importance of frailty in middle-aged adults with chronic diseases, suggesting that a third of the excess risk of mortality could potentially be addressed by improving frailty status.

Comparing rehabilitation with and without neuromuscular electrical stimulation in hospitalized older adults: Cognitive, functional, and acceptability outcomes from a pragmatic pilot study - Evrim Gökçe; Gilles Loggia; Alyzée Henry; Antoine Gauthier; Antoine Langeard (GeroScience, 2025)

The immuno-neurological axis: association between autoimmune diseases and dementia risk - Wanhyung Lee; Xiaoxue Ma; Seunghyun Lee (GeroScience, 2025)

Multimorbidity, frailty and polypharmacy in European and Asian patients with atrial fibrillation: a comparison of two regional prospective observational registries - Davide Antonio Mei; Marco Proietti; Giulio Francesco Romiti; Tommaso Bucci; Bernadette Corica; Alena Shantsila; Hung-Fat Tse; Giuseppe Boriani; Tze-Fan Chao; Gregory Y. H. Lip (GeroScience, 2025)
Multimorbidity, frailty, and polypharmacy are associated with worse outcomes in patients with atrial fibrillation (AF), leading to ‘clinically complex’ patient phenotypes. Possible differences between European and Asian patients regarding these aspects have not been studied. We studied AF patients derived from two large prospective observational AF registries, conducted in Europe and Asia. Multimorbidity and polypharmacy were defined according to the number of comorbidities and drugs at baseline. Frailty was defined according to a 40-items frailty index (FI). Prescription of OAC was assessed at baseline. The primary outcome was the composite of all-cause death and major adverse cardiovascular events. European patients had a higher burden of multimorbidity, frailty, and polypharmacy domains compared with Asians. Asian patients with these domains were less likely to be prescribed OAC than Europeans, especially those who were frail. After adjustments, being frail was associated with lower OAC prescription, with Asians less likely prescribed than Europeans (OR 0.34, 95% CI 0.25–0.45 vs. OR 0.47, 95% CI 0.40–0.55, p int = 0.037). Adjusted Cox regression found that multimorbidity, frailty, and polypharmacy domains were associated with a higher risk of the composite outcome. On subgroup analysis, frail Asian patients had a higher risk of the composite outcome (p int = 0.007) than Europeans. Multimorbidity, frailty and polypharmacy have different epidemiological characteristics amongst European and Asian AF patients. Being frail was associated with a higher likelihood of not being prescribed OAC, particularly in Asian patients. The adverse impact of ‘clinically complex’ patient phenotypes on risks of adverse outcomes was greater in Asian patients than in Europeans. Graphical Abstract

Diurnal dynamics of multilayer brain networks predict cognitive trajectories in aging - Kenza Bennis; Anna Canal-Garcia; Joana B. Pereira; Giovanni Volpe; Francis Eustache; Christophe Phillips; Christine Bastin; Fabienne Collette; Gilles Vandewalle; Thomas Hinault (GeroScience, 2025)

Oral functional limitation and risk of frailty onset in older adults: a sex-stratified 4-Year cohort study with competing risk analysis - Kyung-Yi Do; Chang Won Won; Miji Kim; Joong-Yeon Lim (GeroScience, 2025)
Background Oral functional decline may contribute to frailty in older adults by affecting nutrition, physical performance, and psychosocial well-being. However, longitudinal evidence using rigorous analytic approaches, including competing risk analysis, remains limited. This study examined the association between self-reported oral functional limitation and frailty onset over 4 years, with attention to sex differences. Methods We used 4-year prospective data from the Korean Frailty and Aging Cohort Study, comprising 1558 community-dwelling older adults aged 70–84 years at baseline (2016). After excluding participants with missing data and baseline frailty, 1348 robust individuals were analyzed. Oral function was assessed using two self-reported items on chewing and pronunciation difficulties. Frailty was defined using the validated Korean Frailty Index. Cox proportional hazards and Fine–Gray competing risk models were applied to evaluate the risk of frailty onset, stratified by sex. Interaction analyses were performed for major comorbidities. Results Oral functional limitation was significantly associated with increased frailty risk (Cox-adjusted HR, 1.74; 95% CI, 1.20–2.53; Fine–Gray-adjusted SHR, 1.70; 95% CI, 1.17–2.46). This association was significant among women (HR, 2.44; 95% CI, 1.52–3.92; SHR, 2.36; 95% CI, 1.46–3.80), but not among men (HR, 0.87; 95% CI, 0.44–1.73; SHR, 0.86; 95% CI, 0.44–1.68). No significant interactions were observed with cardiovascular disease or osteoporosis. Conclusion Self-reported oral functional limitation was significantly associated with frailty onset over 4 years, particularly among women. Incorporating oral function assessment into geriatric screening and community health programs may facilitate early identification of risk and the implementation of preventive strategies for frailty.

Mesenchymal cell-derived extracellular vesicles ameliorate age-related deficits in working memory and in vivo MRI measures of white matter structure and function in rhesus monkeys - Evan C. Mackie; Chia-Hsin Cheng; Maya N. Alibrio; Christine Rutledge; Hongqi Xin; Michael Chopp; Ryan P. McCann; Douglas L. Rosene; Qiong Yang; Ella Zeldich; Maria Medalla; Bang-Bon Koo; et al. (GeroScience, 2025)
Aging humans and non-human primates both exhibit a similar pattern of cognitive decline beginning in middle age that is characterized by progressive impairments in rule learning, executive function, and working and recognition memory—functions often associated with dysfunction of prefrontal and medial temporal lobe regions. The heterogeneity and inter-subject variability in aging and age-related cognitive impairments present challenges for developing effective therapeutics and can be attributed to differing degrees of cortical white matter (WM) damage and alterations to local and long-range prefrontal and temporal networks. A promising therapeutic that has been shown to be efficacious in mitigating WM damage and improving cognitive function in rodent models is mesenchymal cell-derived extracellular vesicles (MSC-EVs). In the present study, late middle-aged rhesus monkeys were systemically administered monkey-derived MSC-EVs every 2 weeks for 18 months. We demonstrate that MSC-EV treatment improves spatial working memory and decreases the frequency of perseverative responses with largely no effects on recognition memory. These cognitive improvements were associated with increases in MRI diffusion measures of WM structural integrity over time as well as preservation of inter-network functional connectivity as measured by resting-state functional MRI. These findings suggest that MSC-EV treatment can slow or reverse age-related cognitive decline while strengthening WM integrity and improving functional connectivity in late middle-aged rhesus monkeys.

Intervertebral disc degeneration is accelerated by GH overexpression but attenuated by GH antagonism - Abhijit Sukul; Siqi Ren; Anna E. Miller; Huanhuan Liu; Olanrewaju Akande; Simon Y. Tang; Patrick O’Connor; John J. Kopchick; Shouan Zhu (GeroScience, 2025)
Background Intervertebral disc degeneration (IVDD) is a leading contributor to lower back pain, yet its underlying mechanisms remain poorly defined. While insulin-like growth factor 1 (IGF-1) has been implicated in disc homeostasis, the specific contributions of growth hormone (GH)—a key upstream regulator of IGF-1 that also acts and independently influences skeletal tissues—have not been thoroughly investigated in the context of IVDD. Methods We utilized transgenic mouse models with altered GH signaling, including bovine GH (bGH)-expressing and GH receptor antagonist (GHA) mice, to investigate how GH excess or GH antagonism influences disc structure, degeneration, and to identify potential molecular pathways involved in disc maintenance and degradation. Disc histology was evaluated using Safranin-O/Fast Green staining and quantitative scoring across the nucleus pulposus (NP), annulus fibrosus (AF), and endplate (EP) compartments. Bulk RNA sequencing was conducted on intervertebral discs harvested from 12-month-old bovine GH-overexpressing (bGH) and wild-type (WT) mice to identify transcriptional changes associated with GH overexpression. Results bGH mice developed visible IVDD as early as 3 months of age, with degenerative features across all disc compartments. At 15 months, bGH males exhibited more severe degeneration than females, including greater proteoglycan loss, disc height reduction, and fibrotic remodeling. In contrast, 2-year-old GHA mice were protected from age-related disc degeneration, maintaining disc integrity and low histological scores. Transcriptomic analysis revealed sex-specific upregulation of inflammatory and catabolic pathways in bGH discs, including TNF, IL-17, and NOD-like receptor signaling, alongside downregulation of anabolic and ECM maintenance pathways such as PI3K-Akt and mTOR. Notably, these effects were more pronounced in males than females. Conclusion Abundance of GH accelerates IVDD through sex-dependent activation of inflammatory and matrix-degrading pathways, while GH antagonism confers protection against age associated disc degeneration. These findings identify GH as a critical regulator of disc homeostasis and a potential therapeutic target for mitigating IVDD and associated low back pain. Graphical Abstract

Prevalence and clinical implications of Rapid eye movement sleep behavior disorder in Alzheimer’s disease and Lewy body dementia - Jiaxin Yang; Wanting Xue; Huihui Zhang; Chao Tang (GeroScience, 2025)

Multiparametric profiling of plasma cell-free nucleic acids in nonagenarians and centenarians highlights age-related differences associated with longevity - Nicolas P. Tessier; Lise M. Hardy; Florence Mauger; Antoine Daunay; Christian Daviaud; Caroline Horgues; Hélène Blanché; Mourad Sahbatou; Jean-François Deleuze; Alexandre How-Kit (GeroScience, 2025)

Visual cortical responses in age-related hearing loss show evidence for compensatory neuroplasticity - Patricia V. Aguiar; Michelle R. Williams; Brandon T. Paul (GeroScience, 2025)
Sensory loss is prevalent in older adults and is associated with changes to brain structure and function. In early life, the brain compensates for sensory loss by upregulating intact senses, such as in deafness where neural sensitivity for vision increases and visual peripheral perception improves. However, it is unclear if similar neuroplastic compensation occurs in older adults with sensory loss, which would show the aging brain’s adaptability and inform sensory rehabilitation strategies. We tested for evidence of compensatory visual neuroplasticity in adults ( N = 66) aged 53 to 80 with typical hearing or hearing loss, and if this neuroplasticity differed for visual stimuli that were or were not relevant to speech perception. Participants viewed speech-like or non-speech stimuli as we recorded cortical activity with the 64-channel electroencephalogram (EEG). Participants with more hearing loss tended to have longer cortical P1 and N1 latencies in the visual evoked potential. However, the later cortical P2 response latency decreased with more hearing loss in agreement with compensatory plasticity. Effects were independent of numerical age. Latency effects in hearing loss were more pronounced for the speech-like stimulus compared to the non-speech stimulus, but P2 responses for the non-speech stimulus showed greater cross-modal recruitment of the temporal cortex. Findings show for the first time that compensatory plasticity operates on later cortical P2 responses in older adults, is not explained by numerical age, and differs for speech and non-speech events. However, P1 and N1 responses in networks coding for visual speech may be sensitive to sensory decline.

Dementia risk across distinct metabolic profiles in the UK Biobank - Amanda L. Lumsden; Anwar Mulugeta; Elina Hyppönen (GeroScience, 2025)
Sub-optimal metabolism is linked to dementia risk, yet metabolic traits rarely occur in isolation. Using data from 308,019 UK Biobank participants, we examined associations of six diverse metabolic subgroups (I–VI) – previously derived via a self-organising map (SOM) that captures patterns of co-occurring metabolic biomarker traits in the population – and 39 individual biomarkers, with incident all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD). Biomarker associations were assessed using both linear and nonlinear (restricted cubic spline) models. After adjusting for age, sex, socioeconomic, and lifestyle factors, subgroup analyses showed that participants in the two leanest and two most adipose subgroups had higher risk of dementia outcomes compared to others. Subgroups with high adiposity exhibited elevated VaD risk, which was linked to hypertension, hyperglycaemia, and liver stress (Subgroup II); inflammation, microalbuminuria, and low apolipoprotein A1 (III). For AD, the risk was elevated in the lean subgroups (IV, V), characterised by low body mass index (BMI), triglycerides, and urate, and high sex-hormone binding globulin; as well as for adipose Subgroup II. APOE -ε4 allele count had limited influence on dementia associations with metabolic subgroups and biomarkers. This marked metabolic heterogeneity in dementia risk suggests that metabolic profiling could inform targeted prevention strategies. Interpretation of these findings is supported by previously reported MRI profiles of the metabolic subgroups, providing biological context.

Plasma biomarkers of alzheimer’s disease and related dementias are associated with cognitive change in community-dwelling older individuals in Australia and the US - Zimu Wu; Michelle M. Mielke; Anne M. Murray; Katherine Webb; Robyn L. Woods; Alice Owen; Suzanne G. Orchard; Trevor T.-J. Chong; Kerry M. Sheets; Joanne Ryan (GeroScience, 2025)

Longevity-driven hepatic transcriptional programs mediate resilience to diet-induced liver injury in Ames dwarf mice - Jaspreet Kaur Osan; Sharlene Rakoczy; Heidi L. Pecoraro; Holly M. Brown-Borg (GeroScience, 2025)
The liver plays a central role in regulating systemic metabolism, and its function declines with age, contributing to increased susceptibility to metabolic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic lipid accumulation and inflammation, is an early manifestation of liver dysfunction strongly associated with aging, insulin resistance, and high-fat diet (HFD) consumption. Ames Dwarf mice, which are growth hormone (GH)-deficient and long-lived, retain insulin sensitivity and exhibit resistance to age-related metabolic decline, making them an ideal model to study hepatic protection mechanisms. In this study, male and female Ames Dwarf and wildtype (WT) mice were fed either a standard diet or HFD for 12 weeks. WT males developed classical features of MASLD, including hepatic steatosis, hepatocyte ballooning, and elevated levels of inflammatory cytokines (IL-1β, MCP-1, IL-2, and IL-4). In contrast, Ames Dwarf mice exhibited minimal liver pathology, reduced lipid accumulation, and limited cytokine induction. Transcriptomic profiling revealed that WT mice upregulated genes involved in inflammation and proliferation, while Ames Dwarf mice showed activation of protective metabolic pathways (PPAR and AMPK) and suppression of lipogenic and fibrotic gene programs. Notably, female Ames Dwarf mice displayed the strongest resistance to HFD-induced changes, with minimal transcriptomic alterations. These findings suggest that disrupted GH signaling in Ames Dwarf mice leads to a reprogrammed hepatic response that preserves metabolic health and protects against MASLD, highlighting potential links between aging, GH signaling, and liver resilience.

Cortical spreading depolarizations in stroke: Mechanisms, neuroprotective interventions, and monitoring techniques - Andrea Díaz-Pérez; Nerea Alvarez de Eulate; Eduard Masvidal-Codina; Xavi Illa; Xavier Navarro; Anton Guimerà-Brunet; Francesc Jiménez-Altayó; Clara Penas (GeroScience, 2025)
Cortical spreading depolarization (CSD) is a pathophysiological event critically implicated in ischemic stroke and other brain disorders. It consists of slowly propagating waves of massive neuronal and glial depolarization in cerebral gray matter, accompanied by spreading depression of cortical activity. CSD disrupts ion homeostasis, alters cerebral blood flow, and contributes to neuronal death in vulnerable tissue. This comprehensive review summarizes both classic and recent studies on CSD mechanisms and their role in brain damage progression after stroke. We also review potential neuroprotective strategies to mitigate CSD-induced damage and discuss available technologies for detecting CSD. Advancing our understanding of CSD mechanisms, combined with targeted neuroprotective strategies and improved monitoring techniques, holds promise for reducing stroke-related brain injury and guiding personalized recovery approaches.

Angiotensin II, miR-34a, and AGTRAP crosstalk in arterial smooth muscle cells - Maria Cristina Florio; Sara Sileno; Liqun Jiang; Marco D’Agostino; Sunayana Begum Syed; Laura Monteonofrio; Mirko Baranzini; Chiara Prampolini; Federica Macrì; Manuel Casaburo; Nadia Fanotti; Stefania Castiglione; et al. (GeroScience, 2025)
Arterial aging is associated with enhanced angiotensin II (Ang II) signaling via Ang II type 1 receptor (AT1R) and with microRNA-34a (miR-34a) increased expression. AT1R-associated protein (ATRAP/Agtrap) binds to AT1R, promotes its internalization, and inhibits Ang II signaling. This study addresses the hypothesis that miR-34a targets ATRAP/Agtrap and enhances Ang II pro-inflammatory signaling via AT1R in arterial vascular smooth muscle cells (VSMC). Our results show that miR-34a exhibits an age-associated increase in Rhesus monkey’s common carotid artery and rat aorta. Further, AGTRAP protein expression is lower in old rat VSMC and in old mice aorta. Ang II enhances miR-34a in old rat VSMC and human aortic smooth muscle cells (HASMC), and inhibits AGTRAP and sirtuin 1 (SIRT1) mRNA/protein expression. In miR-34a-overexpressing HASMC, AGTRAP and SIRT1 mRNA/protein decrease, and these effects are rescued by AGTRAP forced expression. Moreover, miR-34a directly targets AGTRAP and AGTRAP downmodulation further enhances miR-34a expression decreasing SIRT1 in HASMC. Finally, Ang II and miR-34a induce the upregulation of pro-inflammatory genes, interleukin (IL)-6, cyclooxygenase 2 (COX2), monocyte chemoattractant protein-1 (MCP-1), and milk fat globule-epidermal growth factor 8 (MFGE8) in HASMC, and this effect is abolished by AGTRAP forced expression. In conclusion, Ang II upregulates miR-34a, activating a negative feedback loop on AGTRAP that reinforces Ang II signaling. The age-associated AGTRAP downmodulation in central arteries and VSMC underlies a potential miR-34a/AGTRAP role in vascular aging.

Distinct patterns of endothelial response to endotoxin in aged mice as compared to young mice - Joanna Suraj-Prażmowska; Magdalena Sternak; Anna Kurpińska; Anna Bar; Izabela Czyżyńska-Cichoń; Kelly Ascencao; Ewa Niedzielska-Andres; Elżbieta Buczek; Łukasz Mateuszuk; Agnieszka Karaś; Maria Walczak; Csaba Szabo; et al. (GeroScience, 2025)
Aging exacerbates organ injury in endotoxemia, but it is not clear whether endotoxemia is associated with a specific, age-related profile of the endothelial response. Therefore, the aim of the study was to assess the pattern of endothelial response to lipopolysaccharide (LPS) in aged mice (18-month-old) as compared to young mice (3-month-old). Our analysis was based on functional endothelial responses measured in vivo by magnetic resonance imaging (MRI) and on a comprehensive panel of biomarkers of endothelial dysfunction measured by micro-flow liquid chromatography tandem mass spectrometry (microLC-MS/MS). In aged mice, the systemic inflammatory response (serum amyloid A, IL-1β, IL-2, eotaxin), kidney injury (urea), liver injury (ALT), and endothelial dysfunction induced by a relatively low dose of LPS (3 mg/kg) were all more pronounced as compared with young mice. Interestingly, in aged mice, LPS induced a different pattern of endothelial response compared to young mice, as evidenced by glycocalyx injury biomarkers (SDC-1, ESM-1), the endothelial permeability biomarkers (Angpt-2, sTie-2) and various hemostasis-related factors (sTM, TAFI, THBS-1). In contrast, biomarkers of endothelial inflammation (sVCAM-1, sICAM-1, sE-selectin, sP-selectin) and classical hemostasis biomarkers (PAI-1, t-PA, von Willebrand factor) displayed comparable responses to LPS in aged and young mice. In conclusion, aging does not indiscriminately potentiate LPS-induced inflammatory mediator generation in the current model of endotoxemia induced by a relatively low dose of LPS, but selectively alters the endothelial response in terms of glycocalyx injury, endothelial permeability, and hemostasis. Graphical Abstract

Workplace health promotion for healthy aging: a randomized controlled trial within the Semmelweis–EUniWell Workplace Health Promotion Model Program comparing email-based and face-to-face motivational interviewing to increase step count - Wei Yi Hung; Dorottya Árva; Noémi Mózes; David Major; Kata Pártos; András Terebessy; Ferenc Horváth; Ágnes Fehér; Mónika Fekete; Norbert Dósa; Péter Varga; Andrea Lehoczki; et al. (GeroScience, 2025)

GDF-15 plasma levels are elevated in mobility-limited older adults with frailty and sarcopenia—results from the BIOFRAIL study - Pernille Hansen; Hanne Nygaard; Louis Praeger-Jahnsen; Martin Schultz; Flemming Dela; Per Aagaard; Jesper Ryg; Charlotte Suetta (GeroScience, 2025)
Growth differentiation factor 15 (GDF-15) has been proposed as a potential biomarker for the geriatric syndromes of frailty and sarcopenia. This study investigated plasma GDF-15 as a biomarker associated with sarcopenia and frailty in a cohort of mobility-limited older adults. Patients (≥ 65 years) were recruited from a geriatric outpatient clinic for fall assessment. Frailty was identified using the Clinical Frailty Scale with a cut-off ≥ 5. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People 2. Plasma GDF-15 was analyzed using electrochemiluminescence assays (Meso Scale Discovery, Rockville, MD, USA). Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic accuracy of GDF-15 for identifying frailty and sarcopenia. The optimum GDF-15 cut-off for frailty was determined using Youden’s Index. A total of 429 patients (age 79.6 ± 6.2 years, 64% female) were included. Of these, 16% had sarcopenia and 25% had frailty. Median GDF-15 levels in patients with/without sarcopenia and with/without frailty were 1916 pg/mL vs. 1569 pg/mL (p = 0.035), and 2252 pg/mL vs. 1438 pg/mL (p < 0.001), respectively. The area under the curve (AUC) for frailty was 0.681 (95% CI: 0.623–0.739) with an optimal cut-off of 2047 pg/mL. For sarcopenia, AUC was 0.577 (95% CI: 0.501–0.653). GDF-15 plasma levels appear to be elevated in mobility-limited older adults with frailty and sarcopenia. The diagnostic accuracy of GDF-15 for frailty appears of moderate magnitude, suggesting a potential clinical role of this biomarker in identifying frailty in mobility-limited older adults. In contrast, the diagnostic accuracy of GDF-15 for sarcopenia was poor. ClinicalTrials.gov Identifier: NCT05795556.

Necroptosis induced by MLKL overexpression in liver triggers cellular senescence and leads to chronic inflammation and fibrosis - Ramasamy Selvarani; Sunho Lee; Mani Saminathan; Puvarajan Boovalingam; Kavitha Kurup; Kevin Pham; Roman F. Wolf; Willard M. Freeman; Archana Unnikrishnan; Arlan Richardson (GeroScience, 2025)
Cellular senescence and necroptosis are two cell fates, which trigger an inflammatory response and increase with age, that have been proposed to play a role in inflammaging. In this study, we performed the first study to directly test the possible interaction between necroptosis and cellular senescence. Using a novel Mlkl -KI mouse model, we were able to specifically induce (~ 4-fold) the overexpression of MLKL, the necroptotic executioner, in hepatocytes (h Mlkl -KI mice). The overexpression of MLKL led to increased necroptosis and cell damage/death in liver, as shown by increased levels of MLKL-oligomers, TUNEL staining, and Ki-67 staining in the livers, as well as increased ALT activity and HMGB1 levels in the plasma. The increase in necroptosis was paralleled by an increase in cellular senescence. We observed increased levels of p16 INK4A and p21 Clip1/Waf1 as well as SASP-factors. As expected, inflammation, as measured by the levels of proinflammatory factors and mononuclear cell clusters, was increased in the h Mlkl -KI mice. Transcriptomic analysis revealed that MLKL overexpression altered the expression of genes involved in cellular senescence, inflammation, and drug metabolism. The increase in inflammation, necroptosis, and cellular senescence in the livers of 6-month-old h Mlkl -KI mice was associated with an increase in liver fibrosis. The data from our study suggest that necroptosis has the potential of inducing inflammation through two pathways: (1) the initial inflammatory storm triggered by DAMPs released from necroptotic, dying cells and (2) SASP-factors produced by senescent cells that were induced by necroptosis. Graphical abstract

A ketogenic diet improves memory in females in the APOE4 mouse model of Alzheimer’s disease - Jacopo Di Lucente; Jennifer M. Rutkowsky; Alfredo Errico Provenzano; Giuseppe Persico; Zeyu Zhou; Lee-Way Jin; Jon J. Ramsey; Claire B. Montgomery; Kyoungmi Kim; Marco Giorgio; Izumi Maezawa; Gino A. Cortopassi (GeroScience, 2025)
The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for Alzheimer’s disease (AD), increasing AD risk about fourfold in ~ 34 million American and ~ 75 million European females. APOE4 carriers exhibit cerebral metabolic deficits decades before clinical onset. We previously demonstrated that ketogenic diet (KD), a low-carbohydrate, high-fat diet promoting ketone metabolism, confers cognitive benefits in aged C57BL/6 mice, and in the PS1/APP mouse model of early-onset AD. Here, we evaluated the effects of KD in a humanized APOE4 AD mouse model. KD significantly improved composite cognitive performance and spatial working memory, with pronounced effects in females. Synaptic plasticity, measured via long-term potentiation (LTP), was likewise enhanced exclusively in females. Transcriptomic and protein analyses revealed KD-induced activation of CREB pathway, marked by increased phosphorylation of ERK and CREB in female brains. Moreover, KD selectively reduced pro-inflammatory cytokine levels in females. These findings demonstrate sex-specific neuroprotective effects of KD in APOE4 mice and suggest its potential therapeutic role in mitigating AD risk in APOE4-positive women. Graphical Abstract

Cognition and brain network connectivity in timed up & go performance - Benxamin Varela-López; Santiago Galdo-Álvarez; Alba Felpete; Christian Habeck; Yaakov Stern; David Facal (GeroScience, 2025)

Colorectal cancer screening, incidence, and mortality among aging veterans in the U.S. Department of Veterans Affairs healthcare system by housing status - Hind A. Beydoun; Shilpa S. Murthy; Caroline G. Falker; Jack Tsai (GeroScience, 2025)

Effects of aging on transmission from Ia afferents to α-motoneurons and presynaptic mechanisms across muscle lengths and contraction types - Yohan Betus; Julian Colard; Marc Jubeau; Anne-Sophie Boureau; Guillaume Chapelet; Christophe Cornu; Thomas Cattagni (GeroScience, 2025)

Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice - Ramkumar Thiyagarajan; Rupadevi Muthaiah; Bhavana Sreevelu; Owen P. Treanor; Yonas Redae; Reem Berman; Anna L. Davis; Nanda Yellapu; Spencer R. Rosario; Lee D. Chaves; Kenneth L. Seldeen; Bruce R. Troen (GeroScience, 2025)
Cognitive impairment affects 1 in 6 individuals over 60, with over 75 million projected by 2030. Age-related changes in microglial function and declining nicotinamide adenine dinucleotide (NAD + ) levels may contribute to cognitive decline. Although nicotinamide riboside (NR) supplementation can restore NAD + levels in aged mice, its effects on microglial phenotype and cognition during normal aging remain unclear. We assessed cognitive function, neuroinflammation, and microglial gene expression in 6-month (Young) and 22-month (Aged) mice, along with aged mice supplemented with NR (Aged + NR; 400 mg/kg body weight) for 8 weeks. Aged mice exhibited impaired cognition and increased gene expression related to neuroinflammation. NR supplementation improved or prevented the decline in nest-building ability, Y-maze spontaneous alternation, and novel object recognition, which are reflective of instrumental activities of daily living, spatial working memory, and recognition memory. NR supplementation diminished microglial (IBA1) and astrocytic (GFAP) activation, resembling the young phenotype. Gene expression profiling revealed reduced microglial activation, inflammatory pathways, and chemokine production in Aged + NR mice, along with upregulation of genes associated with learning, memory, and gliogenesis. NR lowered transcriptional signatures from age-dependent (ADEM) and disease-associated (DAM) microglia and enhanced homeostatic state profiles. Metabolic pathway analysis of microglial transcripts indicated that NR suppressed age-induced increases in fatty acid metabolism. This was supported by immunostaining, which showed reduced lipoprotein lipase (LPL), a DAM marker, in the cortex and hippocampus. Overall, NR appeared to mitigate age-related cognitive decline by shifting microglial gene expression and metabolism toward a younger phenotype, suggesting potential therapeutic relevance for healthy brain aging.

Causal risk factors for stroke, delirium, and mortality after elective and urgent open aortic arch surgery for older adults - Mirthe M. van Diepen; Ioan Gabriel Bucur; Ralf W. J. Weijs; Robin H. Heijmen; Tom Claassen; Jurgen A. H. R. Claassen (GeroScience, 2025)

Redefining the concept of erythrocyte senescence: is eryptosis fundamentally different from erythrocyte senescence - Anton Tkachenko; Ondrej Havranek; Florian Lang; Karl S. Lang; Thomas Wieder (GeroScience, 2025)

Unveiling the importance of SIRT5 for cardiac health and disease in an era of increasing longevity - Arkadiusz Grzeczka; Szymon Graczyk; Pawel Kordowitzki (GeroScience, 2025)
As the world’s population ages, strategies to promote healthy longevity are critical. SIRT5, belonging to the sirtuin family, plays a key role in regulating cellular metabolism and mitochondrial homeostasis by removing post-translational modifications such as succinylation, malonylation, and glutarylisation from lysine residues of proteins. Herein, we discuss the multifunctionality of SIRT5, its impact on heart function, and its involvement as a target in geroscience for the pathogenesis of cardiovascular diseases, including heart failure, diabetic cardiomyopathy, cardiac hypertrophy, and ischemia-reperfusion injury. Research indicates that SIRT5 modulates metabolic pathways, oxidative stress response, and apoptosis, making it a potential therapeutic target for extending the health span and lifespan. However, its role is complex and context-dependent, exhibiting protective and harmful effects in various pathological conditions.

Glycemic status-dependent proteomic signatures of biological aging for health risk prediction - Jiang Li; Jie Li; Xiaoqin Xu; Yuefeng Yu; Wenqi Shen; Ying Sun; Yanqi Fu; Xiao Tan; Ningjian Wang; Yingli Lu; Bin Wang (GeroScience, 2025)

Metabolic syndrome and risk of dementia and cognitive decline: a systematic review and meta-analysis of prospective cohort studies from 6,753,197 participants - Qi Wang; Luyi Zhang; Ruiqi Xu; Kexin Meng; Lutong Pan; Xiaoyu Zhang; Long Ge; Dongshan Zhu (GeroScience, 2025)

Associations of BDNF methylation and rs6265 genotype with cognitive response to a six-month aerobic exercise intervention in women with early-stage breast cancer: results from the EPICC Trial - Myeong-ga Cho; Susan M. Sereika; Meredith Cummings; Lucia King; Kirk I. Erickson; Catherine M. Bender; Yvette P. Conley (GeroScience, 2025)

Long term cognitive outcome of prodromal and mild dementia with Lewy bodies: a cohort study - Frédéric Blanc; Benjamin Cretin; Candice Muller; Anne Botzung; Lea Sanna; Olivier Bousiges; Alix Ravier; Benoît Schorr; Pierre Anthony; Nathalie Philippi; Catherine Demuynck; Erik Sauleau (GeroScience, 2025)

Age-related changes in synapse ultrastructure and neuroprotective effect of dietary curcumin in the lateral prefrontal cortex layer 3 of the rhesus monkey - Carmen Freire-Cobo; Maria Medalla; Merina Varghese; William G. M. Janssen; Jennifer I. Luebke; Patrick R. Hof (GeroScience, 2025)

Age–period–cohort analysis of multimorbidity prevalence among Chinese older adults: from 2002 to 2022 - Yebo Yu; Wei Pan; Hewei Min; Siyu Dong; Zhen Huang; Yi Zeng; Xuxi Zhang; Xinying Sun (GeroScience, 2025)

Association of tongue, handgrip, and pinch strength with blood-based phosphorylated-tau 181 in cognitively healthy older adults - Getachew Yideg Yitbarek; Jane Alty; Eddy Roccati; Katherine Lawler; Lynette R. Goldberg (GeroScience, 2025)

Associations between biological age acceleration and hospitalization burden of community-acquired pneumonia: a cohort study - Biying Wang; Chen Qian; Liping Yi; Youyi Zhang; Hongjie Yu; Xiaohua Liu; Yonggen Jiang; Tao Zhang; Genming Zhao (GeroScience, 2025)

A scalable step count-based predictor of biological age: development and validation of MoveIt! Age in community-dwelling adults and geriatric rehabilitation inpatients - Jessica K. Lu; Weilan Wang; Lihuan Guan; Jeroen van der Velde; Joris Hoeks; Patrick Schrauwen; Gajja S. Salomons; Riekelt H. Houtkooper; Andrea B. Maier; Georges E. Janssens (GeroScience, 2025)

The association between uric acid and incident cardiovascular events amongst healthy, community-dwelling older adults - Amily Lo; Amanda J. Rickard; Nazmul Karim; Cammie Tran; Joanne Ryan; John J. McNeil; Swarna Vishwanath; Zhen Zhou (GeroScience, 2025)

Targeting the HMGB1-IL32 pathway to alleviate T cell exhaustion in epithelial ovarian cancer - Ankita Murmu; Balázs Győrffy (GeroScience, 2025)

Machine learning models for predicting postoperative delirium in non-cardiac surgery patients — systematic review and meta-analysis - Oishika Das; Linda Y. Tang; Esther S. Oh; Jose Suarez; Nicholas Theodore; Tej D. Azad (GeroScience, 2025)

Targeted clearance of senescent cells alleviates alcohol-associated liver disease by restoring cellular function and immune balance - Tian Tian; Yuhua Xue; Zhewei Song; Brady Jin-Smith; Joshua Barkin; Melak Ottallah; Mahfuza Mannan; Arina Zhirkova; Daohong Zhou; Liya Pi (GeroScience, 2025)
The liver is one of the organs most affected by alcohol consumption, and its interaction with aging is particularly significant. Chronic alcohol consumption accelerates liver aging through mechanisms such as oxidative stress, inflammation, fibrosis, and impaired regeneration. It is still unknown whether senescent cell clearance orchestrates innate and adaptive immune responses during the alcohol-induced old liver damage process. To investigate this, we used INK-ATTAC transgenic mice treat with AP20187 (AP) to eliminate p16 Ink4a -positive senescent cells in chronic-plus-binge ethanol feeding model. Senescent cell clearance alleviates age-related liver oxidative stress and lipid accumulation in long-term (8wks)-plus-binges mice. Importantly, AP clears senescent cells, promoting M1/M2 macrophage polarization and reducing the expression of senescence-associated secretory phenotype (SASP) factors. In addition, senescent cell clearance mitigates liver injury by reducing CD8 + T cells, myeloid-derived suppressor cells (MDSCs), and neutrophil infiltration, as well as ameliorating immuno-senescence and T cell exhaustion. These findings demonstrate that the clearance of senescent cells influences immune response and contributes to inhibiting immune senescence. This work sheds light on senolytic interventions’ being a potential therapeutic avenue for alleviating age-associated pathologies in alcohol related liver disease (ALD) and has the potential for clinical translation.

Increased quadriceps intermuscular adipose tissue in chronic liver disease is associated with an altered muscle transcriptome compared with healthy age matched controls - J. I. Quinlan; T. Nicholson; C. Bell; A. Dhaliwal; F. R. Williams; S. L. Allen; S. Choudhary; A. V. Rowlands; A. M. Elsharkawy; M. J. Armstrong; C. A. Greig; J. M. Lord; et al. (GeroScience, 2025)
Muscle fat infiltration (i.e., myosteatosis) is an important index of muscle health and pathology in disease states, such as chronic liver disease (CLD). However, it is unknown whether myosteatosis differs due to anatomical location. Further, the mechanistic implications of divergent intermuscular adipose tissue (IMAT) deposition remain unknown in patients with CLD. Thirty-three patients with CLD (55.0 ± 10.5 years) and 17 healthy controls (HC) (49.6 ± 15.4 years) were recruited. Quadriceps IMAT was estimated between 20 and 80% of muscle length and psoas IMAT at L3 via MRI. Body composition, muscle strength, and habitual activity were assessed. Fasted vastus lateralis muscle biopsies were collected and subjected to RNA sequencing analysis. ClinicalTrials.gov identifier: NCT04734496. IMAT was greater in CLD compared with HC in both quadriceps and psoas ( P < 0.0001). Quadriceps IMAT positively correlated with BMI ( r = 0.62), body fat ( r = 0.65), age ( r = 0.36), and negatively correlated with maximal knee extensor strength ( r = −0.45) and habitual physical activity ( r = −0.50) in CLD and HC. One hundred sixty-nine differentially expressed genes (DEGs) were identified in low IMAT CLD vs. HC, and 178 DEGs were identified in high IMAT CLD vs. HC. CLD patients with high and low IMAT exhibited defined expression profiles, with only 39 DEGs (representing 12.7%) in common. Pathway analysis of DEGs revealed enrichment of atrophic and pro-inflammatory pathways in the high IMAT group. IMAT is greater in patients with CLD compared to HC, irrespective of anatomical location, and is associated with reductions in muscle function and may be exacerbated by physical inactivity. IMAT appears to alter the muscle transcriptome in COLD, potentially exacerbating muscle loss. Graphical Abstract

Early loss of astrocyte p38α MAPK reduces hippocampal neuroinflammation, enhances synaptic strength, and increases non-synaptic mitochondrial uncoupling in female mice during non-pathological aging - Caleb S. Bailey; John C. Gant; Hilaree N. Frazier; Josh M. Morganti; Meggie C. Coleman; Verda A. Davis; Hemendra J. Vekaria; Patrick G. Sullivan; Christopher M. Norris; Linda J. Van Eldik; David J. Braun (GeroScience, 2025)
The p38 mitogen-activated protein kinase has a well-characterized role in modulation of inflammatory processes throughout the body. In the central nervous system, p38 is primarily studied within neurons and microglia, most commonly in the context of neurological insult. The present study was designed to determine its function in astrocytes during non-pathological aging. We generated a conditional knockout model in which a tamoxifen-inducible Aldh1l1 promoter drives Cre recombinase expression in mice with exon 1 of the p38α gene flanked by loxP sites. Knockout of astrocyte p38α was achieved via tamoxifen administration in young sexually mature mice at 3–4 months old. Animals were subsequently aged to 21–24 months prior to performing electrophysiological, immunohistochemical, and biochemical analyses. We found that early loss of astrocyte p38α was associated with a reduction in hippocampal neuroinflammation and concomitant enhancement of synaptic strength in aged female mice. In subsequent experiments in younger animals, the knockout reduced peripheral GFAP levels and increased non-synaptic mitochondrial uncoupling. These findings indicate that astrocyte p38α has wide-ranging effects on brain metabolism, inflammation, and synaptic function during the course of normal aging, including release of GFAP from the central nervous system to the periphery. Follow-up studies exploring the role of astrocyte p38α in various age-associated neuropathological contexts are warranted.

Role of age in the association of chronic conditions and multimorbidity with incident ADL disability: multicohort analyses of 108,810 adults - Benjamin Landré; Aurore Fayosse; Louis Jacob; Mikaela Bloomberg; Ian Danilevicz; Frank van der Heide; Séverine Sabia; Archana Singh-Manoux (GeroScience, 2025)
Chronic conditions and multimorbidity are increasingly prevalent in ageing populations, and their impact on disability remains poorly understood. This study investigated the association of chronic conditions and multimorbidity at ages 50, 60, 70, and 80 years with the subsequent onset of disability. Data from 108,810 participants (54% women, mean age 61.2 ± 9.8 at baseline) from the Health and Retirement Study, the English Longitudinal Study of Ageing, and the Survey of Health, Ageing, and Retirement in Europe were used. The number of chronic conditions was determined from a list of eight conditions. Cox regression was used to examine the incidence of disability in activities of daily living (ADL). ADL disability per 1000 person-years was 14.2 (13.7, 14.7) at age 50, 22.4 (21.9, 22.9) at age 60, 34.3 (33.4, 35.1) at age 70, and 67.6 (65.6, 69.6) at age 80. Having one chronic condition at age 50 was associated with a hazard ratio (HR) for ADL disability of 1.50 (1.42, 1.58) and 1.22 (1.13, 1.42) at age 80. For individuals with three or more chronic conditions, the HRs were 3.05 (2.79, 3.33) at age 50 and 1.74 (1.61, 1.87) at age 80. Analysis of population attributable fraction suggests that between 5.0 and 29.4% of incident disability, depending on the intervention scenarios and age at onset of chronic diseases, could be reduced by acting on chronic diseases. Chronic conditions and multimorbidity demonstrated a strong association with the onset of ADL disability, highlighting the need for early intervention to mitigate future disability risks.

Nighttime dexmedetomidine modifies the association between neurofilament light chain and delirium severity after major cardiac surgery: a secondary analysis of the MINDDS trial - Tina B. McKay; Matthew Smith; Ariel Mueller; Haobo Li; Pooja H. Patel; Isaac G. Freedman; Jason Z. Qu; Oluwaseun Akeju (GeroScience, 2025)

Mitochondrial dysfunction drives age-related degeneration of the thoracic aorta - Arjune S. Dhanekula; Benjamin R. Harrison; Gavin Pharaoh; Aurora Mattson-Hughes; Stefano Tarantini; Rudolph Stuppard; Scott C. DeRoo; Christopher R. Burke; Billiana Hwang; Jay D. Pal; Michael S. Mulligan; David J. Marcinek (GeroScience, 2025)

Age-related changes in adrenergic regulation of contractility and redox status of glycolytic and oxidative skeletal muscles - Julia G. Odnoshivkina; Guzel V. Sibgatullina; Svetlana A. Dmitrieva; Anastasia A. Ponomareva; Venera F. Khuzakhmetova; Ellya A. Bukharaeva; Alexey M. Petrov (GeroScience, 2025)

HomeCoRe for telerehabilitation in mild or major neurocognitive disorders: a non-inferiority randomized controlled trial - Sara Bernini; Alice Valcarenghi; Silvia Panzarasa; Silvana Quaglini; Alfredo Costa; Matteo Cotta Ramusino; Marta Picascia; Marica Barbieri; Cristina Tassorelli; Tomaso Vecchi; Sara Bottiroli (GeroScience, 2025)
This randomized controlled trial (RCT) assessed the non-inferiority of HomeCoRe, a home-based version of the CoRe (Cognitive Rehabilitation) software, compared to its in-clinic counterpart in older adults with mild or major neurocognitive disorders. Seventy-seven participants were randomized to receive a 6-week cognitive training with either HomeCoRe ( n = 40) or CoRe ( n = 37). Global cognition, specific cognitive domains, and well-being were assessed at baseline and after training. Participant-centered outcomes were also examined, including Weighted Scores, which offer a composite measure capturing both individual session performance and overall rehabilitation progress. Results showed that HomeCoRe was non-inferior to CoRe in improving cognition. Both groups showed significant gains in working memory ( p HomeCoRe = 0.03; p CoRe = 0.005) and logical-executive functions ( p HomeCoRe = 0.003; p CoRe = 0.002), while only HomeCoRe was found to improve global cognition ( p = 0.01). Weighted Scores significantly increased in both groups ( p HomeCoRe = 0.001; p CoRe < 0.001). No significant differences emerged in mood or mental health outcomes. This study provides important evidence on how the mode of delivery can influence cognitive rehabilitation outcomes, representing one of the first RCTs to assess the same intervention delivered both in-person and remotely. The demonstration of HomeCoRe’s non-inferiority highlights the potential of this promising alternative to in-clinic rehabilitation, promoting accessibility, engagement, and autonomy. Clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT04889560 (registration date: May 17, 2021).

Single-cell transcriptomic analysis reveals immune remodeling in bone marrow during aged sepsis - Yijia Lin; Zhiying Zhou; Mingkun Yang; Yingzheng Weng; Zhouxin Yang; Jing Yan (GeroScience, 2025)

An integrated multi-algorithm analysis to decipher senescence and metabolic characteristics in nucleus pulposus cells during disc degeneration - Zhuangyao Liao; Ming Li; Ziyu Chen; Zhi Yao; Yuluan Wu; Zhen Tan; Junyu Qian; Chunyuan Yang; Lin Huang; Lixiang Xue; Deli Wang (GeroScience, 2025)
Accumulating evidence has suggested that intervertebral disc degeneration (IVDD) serves as a health problem deserving attention from worldwide, owing to the low back pain and even disability it causes. Cellular senescence, an irreversible process of terminal cell cycle arrest, plays an essential role in the degeneration of nucleus pulposus (NP) cells and IVDD with an unknown underlying mechanism. Here, we have explored the senescence signature in IVDD through high dimensional weighted gene co-expression network analysis (hdWGCNA) algorithm in two single cell datasets (PRJCA014236 and GSE244889) to construct a novel signature called NP_Senescence, which accurately identifies the patients with IVDD. The efficacy and accuracy were validated in various external datasets, including two expression array datasets (GSE70362 and GSE34095) and one single cell dataset (GSE230809). Additionally, the accuracy of the specific model was also verified with the senescent cell identification (SenCID) algorithm. IVDD patients with a high NP_Senescence score exhibited the characteristics of compensated activation of hyaluronic acid monomers synthesis and abnormal status of DNA damage repair through single-cell Flux Estimation Analysis (scFEA) algorithm. Furthermore, the NP_Senescence was negatively associated with the level of AMP and Glucose-1-phosphate, while positively associated with the level of β-alanine and UDP-glucuronic acid. In conclusion, we constructed a novel disc-specific scoring model NP_Senescence by comprehensively analyzing the senescence-related genes of IVDD, which can be used for patient early diagnosis and treatment, as well as the identification of metabolic characteristics.

Loss of molecular resilience as the ultimate outcome of aging biology - Felipe Sierra; Viviana Perez (GeroScience, 2025)

Life-extending interventions do not necessarily result in compression of morbidity: a case example offering a robust statistical approach - Deependra K. Thapa; Wasiuddin Najam; Erik S. Parker; Xi Rita Wang; Daniel L. Smith; Ufuk Beyaztas; James F. Nelson; Steven N. Austad; Gary A. Churchill; David B. Allison (GeroScience, 2025)
Despite extensive research on life-extending interventions, rigorous statistical techniques to determine their impact on compression of morbidity (CoM) are rarely used. We present a case example of an analytical method for examining the effect of life-extending dietary interventions on CoM by comparing the rates of decline in vitality and survival toward the end of life. Using data from previous experimental studies in mice, we calculated the average rate of vitality decline by fitting exponential decay models to individual vitality trajectories and compared this rate with the rate of survival decline estimated from Cox proportional hazards model. The results showed that, surprisingly, the life-extending interventions failed to compress morbidity. Instead, the models suggested a potential expansion of morbidity with the interventions, particularly for chronic caloric restriction, as evidenced by a greater difference between the rates of vitality decline and survival decline in the intervention group than in the control group. The results further showed age-dependent effects, with interventions likely to demonstrate CoM at very old ages. These findings challenge the assumption that lifespan extension necessarily compresses morbidity, highlighting the need to consider lifespan, healthspan, and CoM as endpoints when evaluating anti-aging interventions. We do not claim that life-extending interventions categorically fail to achieve CoM; rather, we demonstrate how a rigorous statistical approach can be applied to test the CoM hypothesis. Our framework offers a valuable tool for future studies, and further refining this method will be crucial to determine under which circumstances lifespan extension leads to CoM. The potential to choose from multiple analyses of CoM calls for leadership in the geroscience community both to standardize the nomenclature so that different CoM analysis approaches can be communicated clearly and to establish a “default” CoM analysis for everyone to use in addition to their analyses of choice, thus facilitating comparisons and meta-analyses across studies.

Widespread neuronal hemokinin-1 expression in motor regions and its protective role in age-related impairment - Dávid Vince Simon; Katalin Rozmer; Eszter Kepe; Norbert Tóth; Krisztina Pohóczky; Orsolya Salamonné Mihály; Bibiána Török; Éva Renner; Miklós Palkovits; Zsuzsanna Helyes; Éva Borbély (GeroScience, 2025)
Hemokinin-1 (HK-1) regulates several processes in the central and peripheral nervous systems, including musculoskeletal functions; however, its involvement in age-related motor coordination and muscle strength remains unknown. Therefore, these were investigated here with HK-1-deficient mice together with the expression patterns in the mouse and human motor coordination centers. Tac4 gene expression, encoding HK-1, was detected by RNAscope, and its age-dependent changes in the cerebellum and soleus muscle were analyzed by qPCR. The rotarod and static rod tests were used to measure motor coordination, while the horizontal bar and grid tests assessed muscle strength in 3–4 (young), 12 (middle-aged), and 18-month-old (old) C57BL/6 wildtype (WT) and HK-1-deficient male and female mice. HK-1 mRNA was abundant in motor cortices, basal ganglia, and cerebellum, showing a significant increase with age. Motor coordination gradually declined with aging in WT mice of both sexes. This age-dependent reduction in motor coordination was significantly enhanced by HK-1 deficiency in middle-aged males but not females. Additionally, muscle strength was also remarkably worse in old WT mice, with a significantly greater decline in males. HK-1 deletion resulted in improved muscle strength in middle-aged male mice, but interestingly worsened function in the old groups of both sexes. HK-1 exerts age- and sex-dependent effects on motor coordination with a predominantly protective action on aging-induced decline in males. This might be explained by its high expression in all motor regions of the brain. Meanwhile, its function in regulating muscle strength is more complex, with a protective role only evident in old age.

Heavy alcohol use exacerbates skeletal myopathy in peripheral artery disease - Panagiotis Koutakis; Emma Fletcher; Evlampia Papoutsi; William T. Bohannon; Iraklis I. Pipinos; Dimitrios Miserlis; Pal Pacher (GeroScience, 2025)
Peripheral artery disease (PAD) is an age-associated vascular condition that contributes to progressive skeletal muscle dysfunction, marked by oxidative stress, mitochondrial abnormalities, and muscle atrophy. Chronic alcohol misuse independently induces similar myopathic changes. Whether alcohol use disorder (AUD) worsens PAD-related skeletal muscle pathology in humans remains unknown. We analyzed gastrocnemius biopsies from PAD patients with heavy alcohol misuse (PAD-AUD), PAD patients without heavy alcohol misuse (PAD-LA), and non-PAD controls with low-to-no alcohol consumption (CON). Markers of oxidative stress, mitochondrial respiration and myofiber morphometrics were compared across groups. Lower extremity function—including walking distance and ankle plantar flexor strength—was also evaluated. Markers of muscle oxidative stress (4-hydroxynonenal (4-HNE), protein carbonyls, and acetaldehyde), mitochondriopathy and myofiber morphometric damage, were significantly elevated in PAD-LA patients relative to CON. Functional outcomes, including walking ability and muscle strength, were correspondingly reduced in PAD. Notably, these pathological and functional impairments were further exacerbated in PAD-AUD. Interestingly, levels of the alcohol-detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) were unchanged in PAD-AUD muscle but were significantly upregulated in PAD-LA. Although traditionally recognized for metabolizing alcohol-derived aldehydes, ALDH2 also facilitates the clearance of endogenous reactive aldehydes generated by mitochondrial oxidative stress, including 4-HNE and protein carbonyls. In PAD-LA patients, elevated ALDH2 levels coincided with reduced oxidative stress and mitochondriopathy, whereas PAD-AUD patients exhibited no ALDH2 upregulation and intramuscular pathology was enhanced. These findings implicate ALDH2 dysfunction as a contributing factor to muscle degeneration in PAD-AUD and support its potential as a therapeutic target for attenuating oxidative stress in PAD. Graphical abstract

Greater prefrontal cortical activation is associated with higher balance confidence in older adults - Jin-Young Min; Baek-Yong Choi; Seung-Woo Ryoo; Seok-Yoon Son; Sang-Won Ha; Jihyun Cha; Hanseung Nam; JongKwan Choi; Kyoung-Bok Min (GeroScience, 2025)
Fear of falling (FoF) is a prevalent and consequential concern among older adults, often associated with impaired mobility, cognitive decline, and reduced quality of life. Traditionally conceptualized as a psychological response to prior falls, FoF is increasingly recognized as a neurobehavioral phenomenon reflecting dysregulated cognitive-motor integration. In particular, the prefrontal cortex (PFC)—responsible for executive control, attentional regulation, and anticipatory motor planning—has emerged as a key neural substrate underlying FoF. This study investigated the association between PFC activation and balance confidence, a continuous correlate of FoF, in 308 community-dwelling older adults aged ≥ 60 years. Prefrontal oxygenated hemoglobin (HbO) was measured using functional near-infrared spectroscopy (fNIRS) during a verbal fluency task, a standardized cognitive paradigm eliciting PFC engagement without motor interference. Balance confidence was assessed using the validated Korean version of the Activities-specific Balance Confidence (ABC) scale. Subgroup analyses stratified by fall history, age, sex, and educational attainment were conducted to explore heterogeneity by known vulnerability factors. Higher regional HbO levels were significantly associated with higher ABC scores, reflecting greater balance confidence and lower FoF. This association was most pronounced in the right lateral and lower PFC regions (e.g., Right Lateral: β = 1.41, p = 0.0062; Lower Right: β = 1.41, p = 0.0007), and remained robust after adjusting for demographic and clinical covariates. Subgroup analyses revealed stronger associations among individuals with a history of falling, aged ≥ 75 years, women, and those with lower education. For example, in participants with prior falls, Right Hemisphere HbO was strongly correlated with ABC scores (β = 2.06, p = 0.020), suggesting greater cortical recruitment in response to heightened threat perception. We found that greater PFC activation was associated with higher balance confidence in older adults, particularly in those at elevated risk of falling. This relationship may reflect adaptive cortical engagement supporting postural assurance in vulnerable populations.

Subjective memory and 5-year all-cause mortality in subjective cognitive decline, non-amnestic mild cognitive impairment, and amnestic mild cognitive impairment - Paula A. Grässler; Johann Lehrner (GeroScience, 2025)
Cognitive decline is becoming increasingly prevalent, and dementia diseases are currently the seventh leading cause of death worldwide—the trend is rising. Consequently, it is imperative to identify influencing factors on the mortality of cognitively impaired patients. So, the main aim of this study was to determine the impact of subjective memory on 5-year mortality in Subjective Cognitive Decline (SCD), non-amnestic Mild Cognitive Impairment (naMCI), and amnestic Mild Cognitive Impairment (aMCI). A Cox proportional hazard model was applied to assess whether subjective memory performance (FAI) predicts mortality across SCD, naMCI, and aMCI. It was based on a university-based single-center retrospective data analysis with n = 1004 adjusted patient records from the Department of Neurology of the Medical University of Vienna over the observation period 2000–2022. Covariates such as sociodemographic factors (age, gender, years of schooling), depression (BDI-II), and neuropsychological performance (NTBV) were included blockwise. Study findings suggest that subjective memory performance could not be identified as an explanatory value for mortality in the study population, p ’s ≥ .181. Rather, increasing age (HR 1.083, p < .001) and male gender (inverted HR 1.517, p = .004) were identified as relative risk factors. Also, four NTBV dimensions emerged as significant factors: decreased attention (HR 1.417, p < .001), diminished executive function (HR 1.283, p < .001), reduced objective memory (inverted HR 1.253, p = .001), and a declined language (inverted HR 1.166, p = .026) can be assumed to be relative risks for higher mortality.

Longitudinal changes in epigenetic measures over 2 years: methodological implications - Rikuta Hamaya; Sidong Li; Brian H. Chen; Alexandre C. Pereira; Nichole Rigby; Haidong Zhu; Kerry L. Ivey; Pamela M. Rist; JoAnn E. Manson; Yanbin Dong; Howard D. Sesso (GeroScience, 2025)

Longitudinal transitions in sedentary behavior and physical activity in relation to all-cause and cause-specific mortality among postmenopausal women - Zhong-Yue Liu; Guo-Chong Chen; Michael J. LaMonte; Victor Kamensky; Kelly R. Evenson; Aladdin H. Shadyab; Juhua Luo; Matthew Allison; Robert A. Wild; Scott B. Going; Charles B. Eaton; Katie L. Stone; et al. (GeroScience, 2025)

Low intrinsic capacity is associated with risk of developing mild cognitive impairment in the English Longitudinal Study of Ageing (ELSA) - Rosa Birchenough; Ingrid Buller-Peralta; Alejandra Marroig; Graciela Muniz-Terrera (GeroScience, 2025)
Intrinsic capacity (IC) is a composite that includes five different domains related to a person’s capacities: sensory, locomotion, vitality, psychological and cognitive. IC represents part of a global effort to promote healthy ageing, one aspect of which is healthy cognitive functioning. This study aimed to elucidate the association of IC and cognitive decline in older adults. Using data from the English Longitudinal Study of Ageing (ELSA, wave 6), IC composite was derived through z-score and item-response theory (IRT) methods in a sample of cognitively normal older adults ( n = 731, aged 70.1 ± 6.77 years). Global cognition (GC) was derived by categorizing Mini-mental State Examination scores obtained in the same population 4–5 years later (ELSA-HCAP, 2018). After algorithm selection, GC categories were regressed on IC scores, demographic and lifestyle covariates. The IRT algorithm showed better model fit and strong associations with age, sex and education. Lower IC was associated with higher likelihood of developing mild cognitive impairment (MCI) 4 to 5 years after IC assessment. Increased age and lower education were also strong predictors of GC, whereas no significant effects were found for sex, physical activity, or number of comorbidities in the fully adjusted model. Although bivariate regressions showed that reduced moderate or vigorous physical activity and increased number of comorbidities are associated with higher odds of developing later MCI, the lack of associations between these covariates and GC in the fully adjusted model suggests a possible mediation effect on IC. No study had previously explored the association of IC on later cognitive impairment. Results agree with previous evidence associating low IC to females, older ages and lower education. Further research to reveal possible underlying mechanisms explaining this association is needed to improve our understanding and relevance of IC for healthy ageing.

The effects of ageing on fatigue and endurance of the spinal extensor muscles: a systematic review and meta-analysis - Martina Parrella; Michail Arvanitidis; Andrea Macaluso; Deborah Falla (GeroScience, 2025)
The endurance capacity of the spinal extensor muscles plays a key role in maintaining spinal function. This systematic review and meta-analysis aims to synthesise current evidence on how ageing influences fatigue of the spinal extensor muscles, addressing the inconsistent findings reported across existing studies. Medline, EMBASE, PubMed, Web of Science and CINAHL Plus databases were searched from their inception to 28 June 2025. Cross-sectional studies assessing fatigue of the spinal extensor muscles of healthy older adults (>60 years) versus younger adults were included. Methodological quality was evaluated using the Appraisal Tool for Cross-Sectional Studies and the GRADE approach was applied to assess the certainty of evidence. Results were synthesised using both narrative and quantitative approaches. A random-effects meta-analysis was conducted for endurance time. The PRISMA guidelines were followed for reporting. Of the 1253 records screened, 13 studies were included, with 9 contributing to the meta-analysis. The meta-analysis, supported by moderate certainty of evidence, revealed a significant reduction in endurance time of the back extensor muscles during sustained isometric contractions in older adults compared to younger controls (MD = −41.31; 95% CI: −64.04; −18.57). The remaining outcomes were synthesised narratively: electromyograph (EMG) related measures showed mixed findings, likely due to methodological variability across studies, while force decline and Borg ratings were reported in only a few studies. This systematic review revealed that the endurance time of the back extensor muscles is reduced during isometric tasks in older adults. However, inconsistent EMG findings limit our understanding of the neuromuscular mechanisms underlying this decline.

Open problems in ageing science: a roadmap for biogerontology - Angelo Talay; Aleksey V. Belikov; Paul Ka Po To; Hamid H. Alfatemi; Uri Alon; Joris Deelen; Collin Y. Ewald; David Gems; Vera Gorbunova; Jan Gruber; Sara Hägg; John Hemming; et al. (GeroScience, 2025)

Germline regulation of the intestinal mitochondrial unfolded protein response - Anna C. Foulger; Nathaniel A. Jordan; Alyssa Castle; Dipa Bhaumik; Julie K. Andersen; Gordon J. Lithgow; Suzanne Angeli (GeroScience, 2025)
The disposable soma theory posits that there is a trade-off between reproduction and somatic maintenance. In support of this theory, we previously identified that pharmacological inhibition of the germline has widespread protective cell non-autonomous effects on cellular protein homeostasis in the model organism Caenorhabditis elegans . However, the cell non-autonomous effects of the germline on mitochondrial protein homeostasis are not well defined. Here, we use pharmacological or genetic inhibition of the germline to determine its effects on intestinal mitochondrial protein homeostasis as measured by the mitochondrial unfolded protein response (UPR mt ). We find that pharmacological inhibition of germline proliferation by 5-fluoro-2-deoxyuridine (FUdR), a DNA synthesis inhibitor, potently inhibits activation of the intestinal UPR mt as well as reverses lifespan effects induced by mitochondrial dysfunction. We find similar results with the genetic mutant ( glp-1 ), which lacks germline proliferation. To further identify the reproductive processes required to regulate the intestinal UPR mt , we examined the genetic mutant fem-1 , which contains an intact gonad with oocytes but lacks sperm. Like glp-1 mutants, fem-1 mutants do not activate the intestinal UPR mt due to mitochondrial dysfunction caused by loss of OXPHOS subunits. Restoring reproduction in fem-1 mutants by mating them with wild type males is sufficient to reactivate the intestinal UPR mt . Furthermore, loss of the FOXO transcription factor daf-16 is sufficient to reactivate the intestinal UPR mt in fem-1 mutants and partially in glp-1 mutants. These findings suggest that FOXO/ daf-16 acts to limit UPR mt activation in the intestine. These findings also suggest that late-stage reproductive signals that include the maturation of oocytes and fertilization may play a critical role in cell non-autonomous intestinal UPR mt activation.

Characterizing motoric cognitive risk syndrome beyond traditional criteria - Kai Cheng; Sodiq Fakorede; Bruce Troen; Kenneth Seldeen; Lydia Pemberton; Shelley Bhattacharya; Tobia Zanotto; Jacob Sosnoff; Hannes Devos (GeroScience, 2025)

Association of muscle mass and strength with blood-based epigenetic aging among middle-aged and older adults in the United States - Hye-Ji Seo; Yoosoo Chang; Seungho Ryu; Kyeezu Kim (GeroScience, 2025)

The combined association between sleep duration and insomnia symptoms with dementia and cognitive deficits: a multivariable-adjusted and genetic liability study - Jasmijn F. Stroo; Jeroen de Bresser; Susan Redline; Diana van Heemst; Raymond Noordam (GeroScience, 2025)

Angiotensin II induces sex-specific ventricular remodeling in aging C57Bl/6 mice - Ninh Khuong; Manish Mishra; Shubham Banga; Susan E. Howlett (GeroScience, 2025)
Renin-angiotensin system (RAS) activation in heart failure (HF) increases circulating angiotensin II (AII). This increases blood pressure (BP) and promotes adverse ventricular remodeling that makes HF worse. Although human HF increases with age and differs between the sexes, preclinical studies have used young, mostly male animals. We investigated sex differences in AII-induced cardiac remodeling in aging C57BL/6 mice. Mice (≈16 months) were infused with AII (3 mg/kg/day; 6 weeks; osmotic minipumps). BP (tail cuff), ventricular structure/function (echocardiography), M1 (Cd80/Mcp-1/Cd68), and M2 (Mrc1) macrophage markers and profibrotic markers (transforming growth factor beta (Tgfb1), collagen 1 (Col1a1), collagen 3 (Col3a1); qPCR/Western blot) were measured. AII treatment increased BP and heart weight/tibia length in both sexes. Interestingly, AII increased wall thickness in females but reduced it and caused left ventricular (LV) dilation in males only. AII increased E/A ratios in males and isovolumic relaxation time in both sexes, indicative of diastolic dysfunction. However, isovolumic contraction time (IVCT) increased (12.0 ± 0.7 vs. 24.3 ± 3.0 ms; p = 0.0001) and ejection fraction (EF) declined in males (68.9 ± 1.9 vs. 46.1 ± 4.5; p = 0.0001), which indicates marked systolic dysfunction. By contrast, IVCT was unaffected, and EF declined but remained well above 50% in females (68.1 ± 1.3 vs. 55.9 ± 2.0; p = 0.01). mRNA for macrophage markers (Cd80, Mrc1), Tgfb1, Col1a1, and Col3a1, plus collagen 1 protein increased in treated male ventricles. By contrast, AII increased collagen 3 protein in females compared to treated males. Thus, AII promotes inflammatory/profibrotic signaling, which contributes to fibrosis and impairs systolic function in aging males. Older females appear resistant to these effects. Graphical Abstract

Classification accuracies of plasma ptau217 vs. ptau217/Aβ1-42 for brain Aβ pathology in cognitively normal older adults - Marcos Olvera-Rojas; Patricio Solis-Urra; Beatriz Fernandez-Gamez; Andrea Coca-Pulido; Eva M. Triviño-Ibáñez; Xuemei Zeng; Lauren E. Oberlin; Juan Domingo Gispert; Kirk I. Erickson; Manuel Gómez-Río; Thomas K. Karikari; Francisco B. Ortega; et al. (GeroScience, 2025)

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans - Juri Kim; Naibedya Dutta; Gilberto Garcia; Ryo Higuchi-Sanabria (GeroScience, 2025)
Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signaling pathways, including the mitochondrial unfolded protein response (UPR mt ). Activation of UPR mt restores the function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans , mitohormesis can be accomplished by electron transport chain inhibition, a decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPR mt . However, not all methods that activate UPR mt promote longevity. These and other studies have started to question whether UPR mt is directly correlated with longevity. Here, we attempt to address this controversy by unraveling the complex molecular regulation of longevity of the nematode under different mitochondrial stressors that induce mitochondrial stress by performing RNA sequencing to profile transcriptome changes. Using this comprehensive and unbiased approach, we aim to determine whether specific transcriptomic changes can reveal a correlation between UPR mt and longevity. Altogether, this study will provide mechanistic insights on mitohormesis and how it correlates with the lifespan of C. elegans .

Clinical outcomes of antihypertensive medication use in people with dementia: a systematic review and meta-analysis - Firehiwot Amare; Corinne Mirkazemi; Gregory M Peterson; Woldesellassie M Bezabhe (GeroScience, 2025)

Evaluating effects of aging on dog olfactory performance - Lane I. Montgomery; Sarah Krichbaum; Jeffrey S. Katz; Lucia Lazarowski (GeroScience, 2025)
Aging is a dynamic process across a dog’s lifespan, with age-related changes impacting how dogs function in their companion and working roles. However, the impact of aging on key sensory modalities, such as olfaction, is not well understood. The current study aimed to characterize age-related changes in canine olfactory abilities via an adaptation of the Natural Detection Task. Data were collected on 65 dogs aged 5 years or older, with 44 dogs completing all components of the task. We found age-related decrements in olfactory performance, but only under certain conditions and with differential effects as a function of training level. Age also affected whether dogs completed the entirety of the task, indicative of non-olfactory (e.g., physical or motivational) factors. Additionally, dogs completed the Cylinder Reversal Task (CRT) to determine whether olfactory changes were correlated with cognitive changes. We found no age-related changes in CRT performance and no significant associations between cognitive and olfactory task performance. These findings indicate that dogs’ olfactory capabilities decrease with age but, critically, training experience may have protective effects against age-related declines, and effects may only be apparent under certain conditions. Future studies should continue to consider olfaction when studying aging impacts upon the dog.

Gut microbiome signatures predict cognitive impairment in older cancer survivors - Brandi C. Miller; Jayden A. Haggler; Diptaraj S. Chaudhari; Rohit Shukla; Vivek Kumar; Sidharth P. Mishra; Michal M. Masternak; Peter Holland; Corinne Labyak; Adam Golden; Mariana Dangiolo; Andrea Y. Arikawa; et al. (GeroScience, 2025)
Cancer treatments are improving, and the population of cancer survivors is steadily increasing. However, many survivors experience long-term side effects, including chemobrain and other age-related geriatric disorders like cognitive impairment (CI), severely impacting their quality of life. Emerging studies suggest that the gut microbiome plays a central role in cognitive health. However, the long-term effects of cancer treatments on the microbiome, and how these changes impact cognitive health in survivors, remain largely unknown. Shotgun metagenomic data from 150 older adults (≥ 60 years old, including 49 cancer survivors and 101 controls) from the Microbiome in Aging Gut and Brain (MiaGB) consortium revealed that Tyzzerella , Eggerthella lenta , and Bacteroides vulgatus were specific markers of the cancer survivor gut and could differentiate cancer survivorship in this cohort. Microbiome signatures were distinct in cancer survivors with CI compared to those without and differed from those seen in non-cancer individuals with CI. Bacterial taxa including Streptococcus thermophilus and Firmicutes bacterium CAG 114 were significantly reduced in cancer survivors and strongly associated with CI. Importantly, metabolic pathway analysis revealed that microbial neurotransmitter synthesis was significantly depleted in the gut of cancer survivors, suggesting a mechanistic link to CI. Our results suggest that microbiome signatures predict cancer survivorship and the risk of CI in older adults, potentially by depleting neurotransmitter synthesis in the gut. These findings aid in establishing the role of the microbiome in predicting cancer survivorship and CI risk, which is valuable in the development of novel therapies to support the growing population of cancer survivors. Graphical Abstract

Arterial stiffness is associated with prefrontal cortex integrity in ageing - Rachael Yu; Nicole Espinosa; Shawn Kong; Hamish Mundell; Johannes C. Michaelian; Sharon L. Naismith (GeroScience, 2025)

Standardization to personalization: geroscience-driven future for preoperative optimization in spine surgery - DuJiang Yang; Jiexiang Yang; GuoYou Wang (GeroScience, 2025)

Dystrophin and dystrophin association protein expression decreases with age in vascular smooth muscle - Katherine M. Kaplan; Yueyue Xiong; Audrey Lucerne; Kathleen G. Morgan (GeroScience, 2025)
As humans age, the aorta stiffens, diminishing its essential shock absorber function. This increased stiffness transmits higher pressures to downstream vessels in the kidney, brain, and heart, contributing to hypertension and end-organ damage. Although multiple mechanisms involving extracellular matrix (ECM) remodeling and vascular smooth muscle cell (VSMC) contributions to aortic stiffness have been described, additional molecular players likely remain uncharacterized. Dystrophin (DYS) and the dystrophin-associated proteins (DAPs) are cytoskeletal stabilizers known for protecting skeletal muscle cells from contraction-induced damage but are poorly characterized in VSMCs. Loss of DYS has been linked to myocardial stiffness and carotid artery abnormalities. Here, we investigated the function of DYS in biomechanical properties of the mouse aorta. We demonstrated by immunofluorescence that DYS and DAPs are expressed and colocalize in freshly dissociated murine VSMCs. The mdx model, a known dystrophin knockout mouse model, was used to investigate the consequences of lack of dystrophin expression on aortic geometry and biomechanics. In mdx mice, we observed decreased aortic wall thickness but no significant difference in diameter compared to wild-type (WT) mice. This significant difference in aortic geometry is directly related to ex vivo stress and stiffness. We measured aortic stiffness by high-frequency small-amplitude sinusoidal length perturbation and determined dystrophin is essential to maintain normal stiffness and stress at baseline. This suggests that extracellular matrix components in the mdx aorta are contributing to the increased stress and stiffness at baseline. We also determined that DYS is not required to maintain normal stress and stiffness due to the contractile response to depolarization by high K + or alpha-agonist, phenylephrine-induced contraction. Finally, we revealed by Western blot that DYS and alpha-sarcoglycan, a DAP, expression is decreased in aged vascular smooth muscle. Previous studies show that matrix metalloproteinase-2 (MMP2) can degrade DYS in cardiac tissue and that MMP2 activity increases with age in vascular tissue. While we did not directly assess MMP2 in this study, we propose its role as a hypothesis for future exploration. In summary, this study identifies a novel role for DYS in maintaining aortic mechanical integrity and presents evidence that aging diminishes DYS and DAP protein expression in VSMCs.

Functional disability screening in the elderly: a machine learning approach with ELSI-Brazil data - Dalton Breno Costa; Carmen Moret-Tatay; João Carlos Néto; Tatiana Quarti Irigaray (GeroScience, 2025)

Elevated plasma GFAP levels in MCI link APOE ε4 allele with impaired gait speed - Ryota Sakurai; Hiroyuki Suzuki; Yoshinori Fujiwara; Kazuaki Uchida; Kosuke Fujita; Akinori Nakamura; Takashi Sakurai; Hidenori Arai (GeroScience, 2025)

Association between sedentary time and intrinsic capacity among community-dwelling older adults: evidence from a prospective BLINDSCE cohort - Siqi Cheng; Shaoyuan Lei; Chengbei Hou; Jiafan Qin; Xinyan Du; Xiaolin Yue; Yansu Guo (GeroScience, 2025)

Leukocyte telomere length and risk of heart failure with preserved ejection fraction in high-risk Chinese patients with hypertension under 65 years - Alian Zhang; Zhengde Tang; Alex Chia Yu Chang; Jun Gu; Junfeng Zhang; Yang Zhuo; Huili Zhang (GeroScience, 2025)

Age differences in spontaneous cerebrovascular reactivity at rest - Allison C. Engstrom; Shubir Dutt; John Paul M. Alitin; Arunima Kapoor; Trevor Lohman; Isabel J. Sible; Anisa J. Marshall; Fatemah Shenasa; Jillian L. Joyce; Aimée Gaubert; Farrah Ferrer; Amy Nguyen; et al. (GeroScience, 2025)
Deficits in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) may indicate vulnerability to vascular dysfunction and cognitive impairment. Prior findings on age-related change in CVR are mixed, and no studies to date have investigated age group differences in spontaneous CVR (sCVR) at rest. The present study compared whole brain and regional sCVR at rest between 24 healthy younger adults (ages 18–34) and 163 cognitively unimpaired older adults (ages 55–87). Relative to younger adults, older adults had deficits in both whole brain and regional sCVR at rest. Among the regions examined, medial temporal lobe areas showed the largest age differences in sCVR at rest. Age differences in sCVR and CBF variability were larger than age differences in mean CBF. Results show age-related deficits in sCVR are present even in cognitively unimpaired older adults, suggesting sCVR may be indicative of cerebrovascular aging. Further research should investigate sCVR as a means for early detection of age-related vascular dysfunction that may predate irreversible vascular brain injury.

Revisiting the relationship between cardiorespiratory fitness and biological aging: insights from DunedinPACE analysis - Takuji Kawamura; Nobuhiro Nakamura; Hiroki Tabata; Ryoko Kawakami; Chiyoko Usui; Tomoko Ito; Keishi Soga; Yasuyuki Taki; Zsolt Radak; Suguru Torii; Katsuhiko Suzuki; Kaori Ishii; et al. (GeroScience, 2025)
DunedinPACE quantifies the pace of biological aging. No study has examined its association with cardiorespiratory fitness (CRF). Additionally, the physiologically relevant CRF thresholds associated with slow aging remain unclear. The purpose of this study was to investigate the association between CRF and the pace of epigenetic aging, as measured by DunedinPACE, and to identify a CRF threshold indicative of slower biological aging. Here, we analyzed data of 144 older men (aged 65–72 years) enrolled in the WASEDA’S Health Study to examine the association of CRF (VO₂/kg at peak and ventilatory threshold (VT)), physical fitness, anthropometric parameters, and nutritional intake with epigenetic aging. Epigenetic aging was assessed using DunedinPACE derived from blood DNA methylation profiles. We performed Pearson’s and partial correlation analyses adjusted for age, smoking status, and drinking status, followed by receiver operating characteristic (ROC) curve analyses with bootstrapped optimal cutoff determination. In the unadjusted analyses, VO₂/kg at peak ( r = − 0.17, p = 0.041) and VT ( r = − 0.17, p = 0.046) were inversely associated with DunedinPACE, and VO₂/kg at peak showed a significant association even in the adjusted models ( r = − 0.16, p = 0.046). The ROC curve analysis revealed a potential threshold of VO₂/kg at peak (26.2 mL/kg/min) for differentiating individuals with slower biological aging, supported by bootstrap distributions of optimal cutoff points and Youden’s index. This study suggests that higher CRF is associated with a slower pace of epigenetic aging, as measured using DunedinPACE. The identified VO₂peak threshold may provide a biomarker-based fitness target to support healthy aging in older adults.

Association between blood nicotinamide adenine dinucleotide levels and blood laboratory parameters at baseline and after nicotinamide mononucleotide supplementation in middle-aged healthy individuals: post hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial - Ajla H. Kuerec; Weilan Wang; Keona D. M. Fokke; Lin Yi; Zhigang Lin; Aditi Vaidya; Sohal Pendse; Sornaraja Thasma; Niranjan Andhalkar; Ganesh Avhad; Vidyadhar Kumbhar; Andrea B. Maier (GeroScience, 2025)

Associations of changes in social isolation and loneliness with all-cause mortality among older adults: a prospective cohort study - Qing-Mei Huang; Si-Tong Wei; Zhi-Hao Li; Yue-Bin Lv; Xiao-Ming Shi; Chen Mao (GeroScience, 2025)

Elevated alpha-1 antitrypsin and C-reactive protein: association on all-cause and cause-specific mortality in older adults - Cammie Tran; Hans G. Schneider; Que T. Lam; Johannes T. Neumann; Flavia Cicuttini; Chenglong Yu; Zhen Zhou; Mark R. Nelson; Andrew M. Tonkin; Daniel Clayton-Chubb; Sultana Monira Hussain; Peter D. Fransquet; et al. (GeroScience, 2025)

Irradiation-induced brain senescence accelerates cardiac aging via systemic mechanisms: insights from transcriptomic profiling - Rafal Gulej; Roland Patai; Tamas Kiss; Siva Sai Chandragiri; Shoba Ekambaram; Raghavendra Yelahanka Nagaraja; Dorina Nagy; Kiana Vali Kordestan; Tamas Lakat; Stefano Tarantini; Peter Mukli; Anna Ungvari; et al. (GeroScience, 2025)
Aging is characterized by a coordinated functional decline across multiple organs. While cell-autonomous mechanisms contribute to local aging phenotypes, the systemic synchronicity of aging suggests a major role for cell non-autonomous drivers. Emerging evidence implicates the hypothalamus—a central regulator of neuroendocrine and homeostatic functions—as a potential source of circulating pro-geronic signals. A hallmark of brain aging is the accumulation of senescent cells, particularly in microglia and brain microvascular endothelial cells, including within the hypothalamus, which contributes to a heightened state of neuroinflammation and altered systemic signaling. Here, we tested the hypothesis that brain senescence and its associated inflammatory milieu promote peripheral aging by reshaping the systemic environment. To model this, we employed targeted whole-brain irradiation (WBI) in young mice—a well-established method to induce widespread brain cellular senescence and neuroinflammation, mimicking changes seen in natural aging. Two months after WBI, we performed transcriptomic profiling of the heart to evaluate remote, cell non-autonomous effects. Cardiac RNA sequencing revealed a striking overlap in gene expression changes between WBI-treated young mice and naturally aged controls. Notably, several gene sets associated with fundamental cellular and molecular mechanisms of aging were concordantly dysregulated in both groups, with strong enrichment for pathways related to mitochondrial metabolism, immune activation, interferon signaling, and extracellular matrix remodeling. These findings demonstrate that localized brain senescence is sufficient to induce aging-like transcriptomic remodeling in peripheral organs, likely mediated by circulating factors. Our findings establish brain senescence as a key orchestrator of systemic aging—a mechanism that may contribute to accelerated aging trajectories in individuals with lifestyle-associated increased brain senescence and neuroinflammation, as well as in cancer survivors exposed to senescence-inducing treatments such as whole-brain irradiation.

Novel evidence of age-related cortical and subcortical constraints in cross-education - Ummatul Siddique; Ashlyn K. Frazer; Jamie Tallent; Oliver Hayman; Justin Andrushko; Matt S. Stock; Joshua Carr; Yonas Akalu; Mohamad Rostami; Sergio Uribe; Simon Walker; Dawson J. Kidgell (GeroScience, 2025)
Cross-education (CE), the phenomenon whereby unilateral strength training induces neuromuscular adaptations in the contralateral limb, is underpinned by distributed cortical and subcortical plasticity. This study evaluated acute neural responses to a single bout of metronome-paced unilateral strength training in younger (n = 17; 27 ± 6 years) and older adults (n = 18; 67 ± 5 years). Neurophysiological assessments included corticospinal excitability and inhibition via transcranial magnetic stimulation (TMS), intracortical inhibition through short-interval intracortical inhibition (SICI), and reticulospinal drive using the StartReact paradigm. Following training, younger adults exhibited a significant reduction in the responsiveness of intracortical inhibitory interneurons, reflected as a release of SICI (pre: 58.05, 95% CI 48.83–67.27; post: 68.88, 95% CI 59.69–78.06; p < 0.01), consistent with diminished GABA- A -mediated synaptic efficacy. In contrast, older adults showed no changes (pre: 65.73, 98% CI 57.00–74.46; post: 60.71, 95% CI 52.03–69.39; p = 0.13), indicating no significant modulation of GABA- A -mediated inhibitory circuits with ageing. No changes in corticospinal excitability were observed in either group. StartReact responses remained stable across timepoints, implying insufficient acute engagement of the reticulospinal tract. Notably, younger adults exhibited a decline in rate of force development (RFD; pre: 912.70, 95% CI 821.97–1003.44 N/s; post: 791.02, 95% CI 700.29–881.75 N/s; p < 0.05), potentially reflecting central fatigue, while older adults displayed no significant change. These findings reveal age-dependent asymmetries in the neural mechanisms underpinning CE, with older adults exhibiting a lack of adaptive modulation in intracortical and subcortical systems. The absence of reticulospinal adaptation underscores the need for sustained or higher-intensity training stimuli to elicit subcortical plasticity. These results inform the development of targeted, age-sensitive neuromuscular rehabilitation strategies. Graphical Abstract

Nα-p-tosyl-L-lysine chloromethyl ketone and Nα-p-tosyl-L-phenylalanine chloromethyl ketone are potent inhibitors of β-amyloid-induced lamin fragmentation - Md. Selim Hossain; Vijay Sankar Ramasamy; Md. Aminul Haque; Il-Seon Park (GeroScience, 2025)

Neuromechanistic causes of timber falls in older adults with mild cognitive impairment: Is response initiation or motor execution the problem? - Jessica Pitts; Shuaijie Wang; Tanvi Bhatt (GeroScience, 2025)
Older adults with mild cognitive impairment (OAwMCI) show reactive balance deficits compared to cognitively intact older adults (CIOA), which could increase the likelihood of ‘Timber’ falls (i.e., backward falls caused by extremely delayed reactive stepping). This study investigated potential neuromechanistic causes of Timber falls in OAwMCI, including delayed muscle onset latencies and/or altered muscle synergies during reactive stepping. 36 OAwMCI, 38 CIOA, and 20 young adults were exposed to a large anterior stance perturbation, with electromyography collected from the biceps femoris (BF), vastus lateralis (VL), medial gastrocnemius (MG), and tibialis anterior (TA). Timber falls were identified by falling (> 30% weight in harness) without initiating stepping within 430 ms (perturbation duration). Timber falls only occurred in OAwMCI, who were subcategorized into MCI: Timber (36%) or MCI: Step (intact stepping, 64%). MCI: Timber had higher fall rate, lower reactive stability, shorter step length, and longer step initiation time compared to groups with intact stepping ( p < 0.05 ), and delayed onsets of stepping limb muscles and the stance limb MG ( p ≤ 0.03 ). MCI: Timber also showed many structural differences in muscle synergies (M1-6), such as recruiting a unique synergy (M4) which might affect coordination of the stepping limb MG, and failing to recruit M6, which might be involved in taking a long recovery step (stepping limb VL). These results suggest that reactive balance deficits in OAwMCI may be related to problems with both initiating and executing reactive stepping, possibly due to neural pathology and sensorimotor processing deficits which delay response initiation and/or affect motor command execution.

Methylation patterns associated with TTV load in geriatric hospitalized patients: an exploratory functional analysis - Carlo Fortunato; Pietro Giorgio Spezia; Federica Novazzi; Gretta Veronica Badillo Pazmay; Laura Cianfruglia; Francesca Drago Ferrante; Davide Gentilini; Luciano Calzari; Paolo Antonio Grossi; Nicasio Mancini; Luigi Rosa; Mirko Di Rosa; et al. (GeroScience, 2025)
Torque Teno Virus (TTV) is a widespread commensal virus within the human virome, characterized by a high prevalence in human population and an unclear pathogenic role. Over the past three decades, TTV has garnered increasing attention due to its ability to establish lifelong chronic viremia, which intriguingly fluctuates among individuals in relation to immune competence status, with a typical peak after an organ transplantation, followed by a plateau and a slow decrease. The regulatory mechanisms underlying TTV infection remain elusive, and factors influencing its interactions with the immune system have yet to be identified. To explore this complex interplay, we analyzed DNA methylation patterns associated with TTV load in older adult hospitalized patients (mean age: 83.15 ± 7.49) from the PROMOTERA cohort. In this study, we present for the first time the identification of differentially methylated probes (DMPs) correlated to TTV load in our cohort. The statistically significant DMPs were located in genes involved in immune regulation and lipid metabolism. To further characterize these findings, we performed an exploratory enrichment analysis by applying several p -value thresholds, which yielded multiple gene lists derived from the sets of significant probes. Genes associated with this epigenetic signature were found to enrich functional pathways related to immune activation, leukocyte differentiation, and cytokine production, while additional significantly enriched gene sets were involved in cell–cell adhesion and cell migration processes. Since our analysis followed an exploratory approach, these results should be interpreted as hypothesis-generating and warrant further investigation. Graphical Abstract

Comparative evaluation of relative fat mass and body mass index in predicting cardiometabolic multimorbidity in older adults: results from the English Longitudinal Study of Ageing - Setor K. Kunutsor; Sae Young Jae; Richard S. Dey; Jari A. Laukkanen (GeroScience, 2025)
Relative fat mass (RFM) is a more accurate measure of body fat percentage than body mass index (BMI). However, its association with cardiometabolic multimorbidity (CMM) and its predictive value have not been examined. This study evaluated and compared the associations and predictive utility of RFM and BMI for CMM. We analyzed data from 3,348 adults (mean age 64 years; 45.1% male) in the English Longitudinal Study of Ageing who were free of hypertension, coronary heart disease, diabetes, and stroke at wave 4 (2008–2009). RFM was derived from height and waist circumference. CMM was defined at wave 10 (2021–2023) as the presence of two or more of hypertension, cardiovascular disease, diabetes, or stroke. Odds ratios (ORs) with 95% confidence intervals (CIs) and measures of discrimination were estimated. Over 12–15 years of follow-up, 197 participants developed CMM. Restricted cubic spline models showed linear dose–response relationships for both RFM and BMI ( p for nonlinearity > .05). Higher RFM was strongly associated with CMM (per 1-SD increase: OR 1.66, 95% CI 1.29–2.15; top vs bottom tertile: OR 2.70, 95% CI 1.46–4.99). Associations for BMI were weaker (per 1-SD increase: OR 1.28, 95% CI 1.12–1.47; top vs bottom tertile: OR 1.88, 95% CI 1.24–2.85). Adding RFM to a conventional risk model modestly increased discrimination (ΔC-index = 0.0088, p = .29) and significantly improved model fit (-2 log likelihood, p < .001). Corresponding values for BMI were ΔC-index = 0.0049 ( p = .46) and -2 log likelihood ( p < .001). The C-index gain from RFM was 0.0039 greater than BMI ( p = .39). In an older UK population, RFM was a stronger indicator and predictor of CMM risk than BMI.

Frailty elements, direct oral anticoagulants and mortality risk in atrial fibrillation patients aged ≥ 80 or ≥ 90 years from the nationwide Italian START registry: a propensity score matching analysis - Danilo Menichelli; Emilia Antonucci; Daniela Poli; Francesco Baratta; Angela Sciacqua; Giuseppe Armentaro; Gianluca Gazzaniga; Federica Moscucci; Gualtiero Palareti; Alessio Farcomeni; Evaristo Ettorre; Giovambattista Desideri; et al. (GeroScience, 2025)
This study aims to investigate the use of direct oral anticoagulants (DOACs) in elderly frail patients with atrial fibrillation (AF). In 4244 patients aged ≥ 80 years and 533 aged ≥ 90 years from the nationwide START registry, we examined factors associated with DOACs use (vs warfarin) and its association with all-cause and cardiovascular (CV) death, CV events (CVEs) and bleeding. Propensity score-matching (PSM) analysis was also performed. Mean age was 84.8 years, 54.9% were women and 64% received DOACs. Frailty elements as tendency to falls (odds ratio [OR] 0.66, p = 0.030), living alone (OR 0.74, p = 0.027) and lack of familial/social support (OR 0.74, p < 0.001) were inversely associated with DOACs use, while wheelchair use was directly associated (OR 1.57, p = 0.014). During a mean of 686 ± 538 days follow-up, 492 all-cause deaths, 110 CV deaths, 548 CVEs and 221 bleedings occurred. Multivariable Cox regression and Fine–Gray analyses showed that DOAC use inversely associated with all-cause mortality (hazard ratio [HR] 0.35, p < 0.001), CV death (subdistribution HR [sHR] 0.43, p < 0.001), CVEs (sHR 0.46, p < 0.001) but not with bleeding. These associations were confirmed after PSM and persisted between sexes, in patients with Charlson Comorbidities Index > 5 or aged ≥ 90 years. At 24 months, the number needed to treat (NNT) for all-cause, CV death and CVEs were 11.0, 40.2 and 13.4. In patients aged ≥ 90 years, NNTs were 4.2, 4.5 and 12.0. In very elderly AF patients, DOACs prescription is influenced by frailty elements. DOACs inversely associated with mortality and CVEs risk independently from age, sex and comorbidities burden. Graphical Abstract

Association of chronic pain and analgesic use with the risks of Parkinson’s and Alzheimer’s disease - Fatemeh Vazirian; Jing Tian; Jane Alty; Dawn Aitken; Michele L. Callisaya; Anna King; James C. Vickers; Flavia Cicuttini; Graeme Jones; Feng Pan (GeroScience, 2025)

Age and associated hypertension impair hippocampal circuitry function and memory - Marcia H. Ratner; Kayla M. Nist; Richard D. Wainford; David H. Farb (GeroScience, 2025)
Chronic hypertension with aging induces significant alterations in the structure and function of brain parenchyma and memory dysfunction. While therapeutic control of hypertension reduces risk, the functional changes in neural circuitry that underlie memory deficits are unknown. Identifying possible early onset changes in the hippocampal trisynaptic circuit (HTC) may reveal opportunities for therapeutic intervention. A large-scale clinical study revealed a direct relationship between reduced prospective memory score and reduced hippocampal functional connectivity in subjects with a history of chronic hypertension. Here, we report a potential mechanistic linkage between hypertension/aging and hippocampal neural circuitry dysfunction. We used chronically implanted multi-electrode silicon probes in awake freely behaving rats to monitor synchronous high frequency oscillations (at 140–200 Hz or the “ripple band”) in the HTC CA1 subregion. This hippocampal subregion is known to participate in memory consolidation, in part via HTC ripples. The nootropic drug, α5IA, that inhibits α5GABA-A receptors, was administered orally, under conditions for target engagement, and ripple amplitude measured within subject in awake resting Sprague–Dawley (SD) rats. Significant HTC and memory dysfunction was observed in aged-hypertensive SD rats. The results reveal an hypertension/age-associated anomaly in ripple band activity in SD males, characterized by reductions in mean peak ripple amplitude and in the ability of α5IA to potentiate peak ripple amplitude, without effect upon ripple frequency or duration. Thus, the population of large peak amplitude sharp wave ripples is reduced and becomes insensitive to potentiation by α5IA. Having identified a specific change in peak ripple amplitude that is resistant to potentiation by α5IA, a nootropic probe-drug, this finding could lead to nuanced circuitry level approach for the treatment of memory dysfunction with aging and hypertension.

Eye-tracking-based tablet application for enhanced cognitive assessment: a clinical trial for software as a medical device (SaMD) - Yoichi Takami; Tetsuro Miki; Yasushi Takeya; Hiromi Rakugi; Ryuichi Morishita; Shuko Takeda (GeroScience, 2025)
Efficient screening tools for cognitive decline and dementia are in high demand. We previously reported on a novel cognitive assessment tool using eye-tracking technology and its utility in dementia screening. In this study, we developed a tablet version of the eye-tracking-based cognitive assessment (ETCA) app and conducted a clinical trial to verify its clinical utility as software as a medical device (SaMD). Participants with and without dementia were enrolled between December 1, 2020, and July 31, 2021. They used the ETCA app and completed the most widely applied screening test, the Mini-Mental State Examination (MMSE), on the same day. The primary outcome was the correlation between the ETCA and MMSE scores. The key secondary outcomes were the administration time for the ETCA, questionnaire-based assessments of test-related burdens, and correlations of the subscores. Performance for detecting dementia was evaluated exploratorily. Analyses of the full analysis set population revealed a strong positive correlation in total scores between the tests (r = 0.831; 95% CI, 0.743–0.891; p < 0.0001). The median ETCA administration time was 254.0 s, and more than 70% of participants reported experiencing less or a similar test-related burden with the ECTA app, compared to the MMSE. Significant correlations were observed for all subscores. The ETCA achieved an area under the curve of 0.864 in detecting participants with dementia. These results verified the clinical utility of the tablet-based ETCA app as a rapid cognitive assessment tool. Based on the results, the ETCA app has obtained regulatory approval as SaMD.

The effect of aging on post-translational modifications of wild-type human SOD1 and the A5V ALS mutant - Gabriel Freitas de Souza; Rayne Stfhany Silva Magalhães; José Raphael Monteiro-Neto; Michele Martins; Cristian Follmer; Magno Junqueira; Elis Cristina Araujo Eleutherio (GeroScience, 2025)

Weight loss aggravates obesity-induced hypothalamic inflammation in mid-aged mice - Alon Zemer; Yulia Haim; Alexandra Tsitrina; Vered Chalifa-Caspi; Habib Muallem; Yair Pincu; G. William Wong; Uri Yoel; Alon Monsonego; Assaf Rudich (GeroScience, 2025)
While neuroinflammation is an established response to both weight gain and aging, the hypothalamic neuroinflammatory early response to weight loss (WL) remains unknown, particularly in mid-age. Here, we questioned whether WL-induced rapid restoration of normoglycemia is mediated by the resolution of hypothalamic microgliosis in mid-aged mice. Mid-aged (1 year) mice were fed normal chow (NC) or a high-fat diet (HFD, 8 weeks), and WL was induced by a 2-week switch back to NC. Key findings were compared to young (7 weeks) mice. Mid-aged WL mice lost within 2 weeks 54% of their excess body weight, somewhat less than young mice (68%). Whole-hypothalamus RNA sequencing revealed ~ 4 times more differentially expressed genes (DEGs) in mid-aged than in young mice (2419 vs. 670, respectively). Nevertheless, in both ages, WL did not reverse but rather aggravated the transcriptomic response to HFD in ~ 80% of DEGs, uncovering downregulated metabolic (oxidative phosphorylation, thermogenesis) and neurodegenerative pathways, particularly in mid-age. Consistently, in the arcuate nucleus (ARC), HFD-induced increase in microglial number and volume further increased in weight-losing mid-aged mice. Consistently, only in mid-aged mice, WL further increased HFD-induced mean single-microglial volume in ARC, corresponding to increased pNFκB-(p-p65) nuclear staining. Despite aggravated hypothalamic and microglial changes, mid-aged mice fully normalized impaired glucose tolerance by early WL. Adipose tissue inflammation was not resolved in mid-aged WL mice, and adipose tissue crown-like-structure density correlated with ARC microglial cell volume (Rho(ρ) = 0.691, p = 0.001). In conclusion, in mid-aged mice, obesity-induced hypothalamic and microglial changes were aggravated during the early response to WL. The resolution of these obesity-induced changes is not required for the normalization of glucose intolerance.

Religious group differences in non-communicable disease risk factors in India: A cross-sectional study of adults aged 45 and older - Ravi Sadhu; Rockli Kim; S. V. Subramanian; Goodarz Danaei (GeroScience, 2025)

Association of inflammatory biomarkers with physical and cognitive frailty in a Spanish population of older adults - Carlota Lema-Arranz; Ali Hemadeh; Natalia Fernández-Bertólez; Nuria Cibeira; Rocío López-López; Solange Costa; José Carlos Millán-Calenti; Laura Lorenzo-López; Vanessa Valdiglesias; Blanca Laffon (GeroScience, 2025)
Frailty is a multifactorial geriatric syndrome characterized by increased vulnerability to stressors and associated with a higher risk of adverse health outcomes. Chronic low-grade inflammation has been proposed as a key pathophysiological mechanism underlying physical frailty, although its role in cognitive frailty remains undefined. In this cross-sectional study, we assessed the relationship between frailty status, both physical and cognitive, and plasma concentrations of six inflammatory biomarkers—C-reactive protein (CRP), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), soluble TNF-α receptor type II (sTNF-RII), high-temperature requirement serine protease A1 (HTRA1), and growth differentiation factor 15 (GDF15)—in a cohort of Spanish older adults ( N = 150, ≥ 65 years old), classified according to Fried’s frailty phenotype and frailty index. The results showed notable differences between frailty phenotype and frailty index, and highlighted CRP, TNF-α, sTNF-RII, and GDF15 as key biomarkers significantly associated with physical frailty status, with CRP and TNF-α also discriminating pre-frail individuals. sTNF-RII stood out for its high predictive capacity, while GDF15 added value as an indicator of sustained cellular stress. Regarding cognitive frailty, CRP, TNF-α, and GDF15 displayed significant associations with this condition. sTNF-RII and HTRA1, scarcely studied in this context, showed promising and significant associations (specific for cognitive frailty in the case of HTRA1) that justify their inclusion in future research aimed at better understanding the inflammatory mechanisms involved in cognitive frailty. Graphical Abstract

Mortality, functional outcome, and bleeding risk after early versus delayed thrombectomy - Zoltan Ungvari; János Tibor Fekete; Mónika Fekete; Andrea Lehoczki; Rafal Gulej; Farzaneh Sorond; Eric Liotta; Calin I. Prodan; Peter Toth; Csaba Kiss; Anna Ungvari; Balázs Győrffy (GeroScience, 2025)
Endovascular thrombectomy (EVT) is an established treatment for acute ischemic stroke, due to large vessel occlusion (LVO), but the optimal time window for intervention remains a subject of ongoing debate. We aimed to assess the impact of treatment timing on mortality, functional outcomes, and safety by comparing early (≤ 6 h) versus late (> 6–24 h) EVT. We conducted a systematic review and meta-analysis to evaluate the effect of time to intervention on outcomes of endovascular thrombectomy (EVT) in acute ischemic stroke. Four databases (PubMed, Web of Science, Cochrane Library, and EMBASE) were searched for studies published between 2000 and 2024. Eligible randomized controlled trials and cohort studies reported on 90-day mortality, functional outcome (modified Rankin Scale, mRS), or symptomatic intracranial hemorrhage (sICH), stratified by treatment timing (≤ 6 h vs. > 6–24 h from symptom onset). Pooled incidence rates, incidence rate differences (IRD), and incidence rate ratios (IRR) were calculated using random-effects models. Eighteen studies met inclusion criteria. The pooled incidence of symptomatic intracranial hemorrhage (sICH) was 0.19 events per person-year (95% CI: 0.12–0.26) in the early group and 0.23 events per person-year (95% CI: 0.11–0.35) in the late group, with no significant difference between groups (incidence rate difference [IRD] − 0.028; p = 0.33, incidence rate ratio [IRR] 0.88; p = 0.33). For mortality, early EVT showed a significantly lower incidence rate of 0.66 events per person-year (95% CI: 0.51–0.82) compared to 0.77 events per person-year (95% CI: 0.63–0.91) in the late EVT group (IRD − 0.148; p = 0.0012, IRR 0.81; p = 0.0014). Functional independence was more frequent in the early group (1.72; 95% CI: 1.42–2.01) than in the late group (1.45; 95% CI: 0.91–1.98) (IRD 0.32; p < 0.0001, IRR 1.22; p < 0.0001). Heterogeneity was moderate to high across outcomes. The timing of endovascular thrombectomy significantly influences clinical outcomes in acute ischemic stroke. Our analysis shows that early intervention (within 6 h) is associated with a significantly lower mortality rate and a higher likelihood of achieving functional independence at 90 days compared to late intervention (beyond 6 up to 24 h). The incidence of symptomatic intracranial hemorrhage did not differ significantly between the groups, suggesting that late treatment does not increase safety risks. These findings underscore the importance of minimizing treatment delays, while also supporting the continued use of EVT in selected patients beyond the 6-h window.

Sex specific gut bacterial community structure: implications for frailty risk in people with HIV - Aline Zaparte; John W. Lammons; Christopher M. Taylor; Meng Luo; Hui-Yi Lin; Robert W. Siggins; Patricia E. Molina; David A. Welsh (GeroScience, 2025)

The ganglioside GD3 and its synthase (ST8SIA1) as novel senescence markers associated with osteoarthritis - Christina Fissoun; Georges Maroun; Raissa Silva; Margot Milano; Benoit Guibert; Louis Dagneaux; Rosanna Ferreira-Lopez; Thérèse Commes; Eric Gilson; Christian Jorgensen; Julien Cherfils-Vicini; Yves-Marie Pers; et al. (GeroScience, 2025)

Estimation of biological age and age-related outcomes with easily accessible parameters in Chinese - Yi Li; Bingqi Ye; Jialu Yang; Zekai Lei; LeLe Yuan; Meisi Kong; Yan Liu; Min Xia (GeroScience, 2025)

Sulforaphane improves exercise-induced NRF2 signaling in older adults: an in vivo-ex vivo approach - Dominick J. Rodriguez; Ethan L. Ostrom; Connor Chassman; Jay Robertson; Vincent Pan; Robert Buscaglia; Aimee L. Eggler; Tinna Traustadóttir (GeroScience, 2025)

Age, glucose tolerance, and cognitive performance in female vervet monkeys - Brett M. Frye; Trinity G. Davis; Haiying Chen; Thomas C. Register; Suzanne Craft; Mark G. Baxter; Carol A. Shively (GeroScience, 2025)

Increase of brain Aβ peptides and secretase activity during normal aging in rodent and human - Jose A. Godoy-Lugo; Max A. Thorwald; Elizabeth Head; Ashley L. Gomm; Can Zhang; Rudolph E. Tanzi; Caleb E. Finch (GeroScience, 2025)
Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration.

Efficiency of DNA repair mechanisms of domestic dog primary fibroblasts isolated from small and large breeds of different ages in response to double stranded breaks (DSB) - Ana Gabriela Jiménez; Sophia Cucinotta (GeroScience, 2025)

Probiotics reduce the severity of DSS-induced colitis in aged mice by enhancing intestinal barrier function and modulating gut microbiota - Ai-Ling Liu; Hong Lv; Hong-Ying Wang; Hong Yang; Yue Li; Yan-Fang Jia; Jia-Ming Qian (GeroScience, 2025)

Ferroptosis-related stress during aging and its relevance to disease - Pamela Maher; David Soriano-Castell; Nawab John Dar; Salvador Soriano; Antonio Currais (GeroScience, 2025)

Recent advances in treating age-related macular degeneration and diabetic retinopathy: Current therapies and emerging novel approaches - Réka Antal; Zoltán Benyó; Zoltán Zsolt Nagy; Illés Kovács; János Tibor Fekete; Balázs Győrffy; Krisztián A. Kovács (GeroScience, 2025)
The incidence of retinopathies is expected to increase globally as our population ages and diabetes becomes more prevalent. Neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR) are major causes of severe vision loss. These ophthalmological conditions are associated with neovascularization caused by excessive vascular endothelial growth factor (VEGF) secretion. This review focuses on the milestones achieved during the last few decades in treating retinopathies, presents a meta-analysis of key human clinical trials, and finally describes various novel therapies, some of which could potentially eliminate the need for intravitreal injections of anti-VEGF in the future. According to data from clinical trials and everyday medical practice, treatments targeting VEGF are efficient; however, they can cause various systemic (such as stroke) and ocular adverse events. The most frequently experienced adverse reactions (such as endophthalmitis or retinal detachment) are related to the injection process itself. These complications warrant the efforts invested in developing novel approaches, including gene therapy-based products and inhibitors of VEGF receptors. We discuss here the strengths and drawbacks of gene therapy and highlight the potential of small-molecule tyrosine kinase inhibitors (TKIs) as alternative anti-neovascularization agents. TKIs have recently been tested via numerous administration routes, including simple oral dosing of oral formulations in addition to intravitreal implants, which allow for a slow release, intravitreal depots, and suprachoroidal injections. All of which have shown different safety and efficacy profiles. We conclude that gene therapy products, especially TKIs, have the potential to become inhibitors of ocular neovascularization in the upcoming years. Graphical Abstract

Machine learning assessment of cognitive reserve using functional near-infrared spectroscopy in older adults with cognitive frailty - Wanrui Wei; Shuaifang Wei; Wei Han; Kairong Wang; Huan Zhang; Gabriella Engstrom; Azita Emami; Zheng Li (GeroScience, 2025)

Dysfunction of cerebrospinal fluid circulation and neurovascular decoupling in end-stage renal disease patients with mild cognitive impairment - Zhaoyao Luo; Lurui Bo; Xinyi Zhu; Qiange Zhu; Huijie Yuan; Wen Gu; Peng Li; Yihao Peng; Xiang Chen; Ming Zhang; Shaohui Ma; Junya Mu (GeroScience, 2025)
End-stage renal disease (ESRD) patients frequently experience mild cognitive impairment (MCI), which significantly affects their quality of life. Although dysfunctions in cerebrospinal fluid (CSF) circulation and neurovascular coupling (NVC) have been implicated in cognitive impairment, their interrelationship remains unclear. This study aimed to investigate the association between CSF circulation dysfunction and NVC disruption in ESRD patients with MCI. We enrolled 68 ESRD patients with MCI and 65 healthy controls (HCs). CSF circulation was assessed using choroid plexus volume (CPV), the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and perivascular space volume fraction (PVSVF). NVC was evaluated using coupling metrics between cerebral blood flow (CBF) and resting-state functional magnetic resonance imaging (MRI) indicators: amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo). Cognitive performance was measured using a battery of neuropsychological tests. Compared to HCs, ESRD patients showed significantly increased CPV ( P < 0.001) and enlarged PVSVF ( P < 0.05), along with a decreased DTI-ALPS index ( P < 0.01). Global and regional NVC metrics were significantly reduced in ESRD patients ( P < 0.001). Moreover, regional NVC metrics were negatively correlated with CPV. Mediation analysis further revealed that CBF-ReHo coupling in the left cingulate gyrus pregenual area 32 mediated the relationship between elevated LCPV and cognitive decline. These findings suggest that CSF circulation dysfunction and impaired NVC are interrelated in ESRD-MCI. Disruption of CSF circulation may contribute to cognitive decline by impairing NVC, highlighting both as potential targets for early diagnosis and intervention in ESRD-related cognitive impairment.

GHSR suppression in neurons protects against aging-associated metabolic and cognitive impairments - Hongying Wang; Chia-Shan Wu; Danilo Landrock; Ariel Nevarez; Shanrun Liu; Anna Thalacker-Mercer; Yanfeng Zhang; Jamie I. Baum; Sunja Kim; Bingzhong Xue; Yuxiang Sun (GeroScience, 2025)
Aging is accompanied by progressive declines in metabolic and cognitive functions. Growth hormone secretagogue receptor (GHSR), a receptor for the gut hormone ghrelin, is highly expressed in neurons and plays a crucial role in metabolic regulation. We previously reported that aged global GHSR-ablated mice are lean and insulin-sensitive, and that neuronal GHSR-deleted mice ( Syn1‐cre;Ghsr f/f ) completely prevent diet‐induced obesity. However, the role of neuronal GHSR in metabolic and cognitive aging has not been elucidated. The current study aims to determine the roles of neuronal GHSR in aging metabolism and cognitive dysfunction. Syn1‐cre;Ghsr f/f mice were subjected to cold stress, glucose- and insulin-tolerance tests, behavioral tests, and tissue analysis. Aging is accompanied by glycemic dysregulation and insulin resistance; old Syn1‐cre;Ghsr f/f mice showed improved glucose tolerance and insulin sensitivity. Aging is associated with thermogenic impairment and cognitive decline; old Syn1‐cre;Ghsr f/f mice showed better cold resistance and retained better recognition memory. Noticeably, there were increased expression of thermogenic makers (PGC1α and UCP1) and elevated sympathetic innervation markers (tyrosine hydroxylase and synaptophysin) in brown adipose tissue of old Syn1‐cre;Ghsr f/f mice. Lastly, old Syn1‐cre;Ghsr f/f mice exhibited decreased pro-inflammatory cytokines and increased neural plasticity-related markers (brain-derived neurotrophic factor, synaptophysin, and tyrosine hydroxylase) in metabolic and cognitive-relevant brain regions such as hypothalamus, cortex, and hippocampus. In conclusion, neuronal inhibition of GHSR promotes a healthy aging phenotype showing improved energy metabolism and cognitive function, which is likely contributed to the improved thermogenesis and insulin sensitivity, reduced inflammation, and restored neuronal plasticity.

Combined creatine and HMB co-supplementation improves functional strength independent of muscle mass in physically active older adults: a randomized crossover trial - Rafael Ramos-Hernández; Álvaro Miguel-Ortega; María Martínez-Ferrán; Diego Fernández-Lázaro; Natalia Busto; Juan Mielgo-Ayuso (GeroScience, 2025)
Sarcopenia is a major contributor to frailty and functional decline among older adults. Combining exercise with nutritional strategies such as creatine monohydrate (CRE) and β-hydroxy-β-methylbutyrate (HMB) supplementation may help to preserve strength and independence. To evaluate the effects of 6-week CRE + HMB supplementation combined with an integral physical conditioning (IPC) program on functional strength and body composition in physically active older adults. In a randomized, double-blind, placebo-controlled crossover trial, 30 older adults (20 men, 10 women; ≥ 60 years) completed two 6-week intervention periods (CRE + HMB or placebo) separated by a 3-week washout. The IPC program performed in both conditions consisted of four supervised weekly sessions combining strength, power, multicomponent circuits, high-intensity interval and moderate intensity continuous training), performed at 40–100% training heart rate (THR) and 20–90% one-repetition maximum (1RM) and structured as warm-up, main part and cooldown. Functional strength and body composition (bioelectrical impedance analysis) were assessed pre- and post-intervention, respectively. Significant time × group interactions were observed for fat mass, fat-free mass, total muscle mass, skeletal muscle mass, appendicular skeletal muscle mass, muscle mass index, skeletal muscle index and ALM/BMI (all p < 0.05). The CRE + HMB group showed reductions in fat mass and body fat percentage, with slight numerical increases in muscle parameters, whereas the placebo group exhibited opposite trends. However, within-group changes were not statistically significant. In contrast, CRE + HMB significantly improved multiple functional strength outcomes, including leg/back strength, arm flexion strength, upper-body endurance (dumbbell flexion, push-ups, isometric hold) and core endurance (crunches). Regression analyses suggested that these improvements were largely independent of changes in muscle mass, supporting a potential neuromuscular mechanism. Six weeks of CRE + HMB supplementation combined with IPC enhanced functional strength and endurance in active older adults, largely independent of changes in muscle mass. This combined approach represents a promising strategy for preserving functional capacity and promoting healthy ageing.

Probing buccal-customized epigenetic clocks to investigate socioeconomic and health disparities - Qiao Wu; Marta Bosanac; Maxim N. Shokhirev; Laurel Raffington (GeroScience, 2025)
Epigenetic clocks are emerging as promising tools for examining social and health disparities. These measures are typically developed using blood DNA methylation (DNAm) data. Cheek swabs, being less invasive than blood collection, can be used to assay buccal DNAm. This study examines how buccal-originated epigenetic clocks relate to socioeconomic status (SES) and health, and compares these associations to those of blood-originated clocks applied to buccal DNAm in the German SOEP cohort (N = 1,128, aged 0–72, 57% female). We found that, unlike second- and third-generation blood-originated clocks (PCPhenoAge, PCGrimAge, and DunedinPACE), a first-generation buccal-derived clock (PedBE acceleration) and a novel second-generation buccal-derived clock trained on age, lifestyle, and health factors (CheekAge acceleration) were not significantly correlated with SES. All clocks were associated with health, and those associations were similar in magnitude across buccal- and blood-originated clocks. Our findings suggest that PedBE and CheekAge acceleration did not show stronger associations with SES and health compared to blood-originated clocks. The finding that PedBE acceleration, which is trained on chronological age in 0–20-year-olds, was associated with self-reported health and had the strongest association with multimorbidity (without cancer) is consistent with the notion that the methylome captures health-relevant processes early in ontogeny. Future studies should include multiple tissue types to further evaluate whether buccal DNAm is sensitive to socioeconomic health disparities. The development of buccal clocks may benefit from further training on aging-related biomarkers and mortality, as well as longitudinal changes in biomarkers beginning early in ontogeny.

Psycho-socio-economic factors and cardiorenal multimorbidity in middle to older-aged adults: cross-sectional results from the Canadian Longitudinal Study on Aging - Setor K. Kunutsor; Reyhaneh Rikhtehgaran; Anita Soni (GeroScience, 2025)
Psycho-socio-economic factors (PSEFs) such as income, education, housing, and social support are known to influence health outcomes, yet their relationship with cardiorenal multimorbidity (CRM) remains poorly understood. This study aimed to estimate the prevalence of CRM and examine its associations with PSEFs in a large, nationally representative Canadian sample. We analyzed baseline data from 19,370 participants (mean age: 60 years; 49.8% men) in the Canadian Longitudinal Study on Aging, a prospective cohort of community-dwelling adults aged 45–85 years recruited between 2010 and 2015. CRM was defined as the co-existence of at least one cardiovascular disease and kidney disease. PSEFs assessed included household income, education, homeownership, marital status, employment status, and psychosocial variables. Survey-weighted multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for prevalent CRM. The overall prevalence of CRM was 0.83% (160 individuals), equivalent to 3.90 per 1000 individuals (95% CI 2.81–5.41). Prevalence increased with age and was higher among men than women (4.57 vs. 3.35 per 1000) and slightly higher in rural than urban areas (4.47 vs. 3.84 per 1000). Homeownership was associated with significantly lower odds of CRM (OR = 0.56; 95% CI 0.33–0.94). A household income of $50 K–99 K was associated with lower odds of CRM (OR = 0.63; 95% CI 0.39–1.00). No other PSEFs showed clear associations with prevalent CRM. CRM is relatively uncommon but shows variation by age, sex, and geography. Among the PSEFs assessed, homeownership and, to a lesser extent, moderate income were associated with reduced odds of prevalent CRM. These findings highlight the potential role of housing and economic stability in mitigating CRM risk. Longitudinal studies are needed to assess the impact of PSEFs on the development and progression of CRM over time.

Age differences in what-if thinking from midlife onwards: Prefrontal contribution and implications for emotional health in late life - Riccardo M. Galli; Friederike Thams; Bernd Löwe; Bastian Cheng; Götz Thomalla; Max Bieder; Elina L. Petersen; Christian Büchel; Stefanie Brassen (GeroScience, 2025)

When Melodies Cue Memories: Electrophysiological Correlates of Autobiographically Salient Music Listening in Older Adults - Veronica Vuong; Mary J. O’Neil; Andrew Dimitrijevic; Bradley R. Buchsbaum; Michael H. Thaut; Claude Alain (GeroScience, 2025)
Autobiographical memory is essential for older adults, providing a foundation for self-identity. Although healthy aging is accompanied by changes in memory retrieval, musical memory remains relatively unaffected, suggesting music may serve as a cue for autobiographical memory recall. Autobiographically salient (ABS) music (i.e., deeply encoded songs associated with significant people, places, and events) is posited to engage distinct memory processes from familiar (FAM) music (i.e., songs that are recognized but lack personal significance). We tested this in 36 older adults (70.6 $$±$$ ± 6.6 years, 20 females) who listened to music varying by personal significance, including ABS, FAM, and unfamiliar (UFAM) music. In Experiment 1, participants pressed a button as soon as they identified the excerpt as ABS, FAM, or UFAM. In Experiment 2, we measured event-related potentials and time-frequency responses while participants listened to the same stimuli and rated familiarity and memory following each excerpt. Reaction times were fastest for ABS, followed by FAM, then UFAM music. We observed a sustained evoked response from 2238 to 5000 ms post-stimulus onset that was least negative in amplitude for ABS, relative to FAM and UFAM music, over right frontal-central regions. We also observed less beta power suppression for ABS than FAM music between 1300 and 5000 ms over bilateral frontal-central-parietal areas. Our behavioral and neurophysiological findings show that ABS music elicits faster and distinct memory-related neural activity throughout the excerpts compared to FAM music. These results emphasize that music is a powerful cue for activating memory processes, which varies by personal significance.

Pharmacokinetic analysis of intermittent rapamycin administration in early-stage Alzheimer's Disease - Helen Annervik Wallgren; Miia Kivipelto; Pontus Plavén-Sigray; Jonas E. Svensson (GeroScience, 2025)
Rapamycin, an mTOR inhibitor used clinically for immunosuppression, shows promise for repurposing in age-related disorders, including Alzheimer's disease (AD). While the pharmacokinetics of daily rapamycin are well-characterized in transplant populations, limited data exist on intermittent dosing regimens in patients with neurodegenerative conditions. This open-label pilot study investigated the pharmacokinetic properties of weekly oral rapamycin in 13 patients with early-stage AD. Participants received 7 mg weekly (11 patients) or reduced doses (2 mg and 4 mg; 2 patients) for 26 weeks. Blood concentrations were measured at four timepoints (pre-dose/Cmin, and 1-, 3-, and 48-h post-dose) during week 13. Moderate interindividual variability was observed across timepoints (coefficient of variation was 0.28–0.40), with the 48-h sample showing the lowest variability (CoV = 0.28) and strongest correlation with Cmin from the previous dosing (r = 0.72). Estimate of terminal half-life (68.9 ± 13.6 h) aligned with previous studies. Blood concentrations at Cmin were below immunosuppressive levels in all participants. Our findings suggest that weekly rapamycin administration in AD patients results in acceptable pharmacokinetic variability, supporting fixed-dose regimens in future trials. The 48-h post-dose measurement appears optimal for monitoring blood concentrations. Additionally, our investigation into cerebrospinal fluid rapamycin quantification revealed methodological challenges due to analytical sensitivity limitations. The foremost limitation of this study was the sparse blood sampling schedule, with Cmin collected from the previous dosing occasion which prevented a complete AUC-calculation. ClinicalTrials.gov (NCT06022068) and EudraCT (2023–000127–36).

Immune cells and inflammatory proteins are differentially associated with subsequent DNA methylation biological aging measures in the Framingham Heart Study Offspring Cohort - Lia Rotti; Joanne M. Murabito; Jiachen Chen; Yumeng Cao; Ahmed A. Y. Ragab; Chunyu Liu; Mengyao Wang; Margaret F. Doyle; Kathryn L. Lunetta (GeroScience, 2025)

Association of accelerated phenotypic aging, lifestyle and genetic risk with progression of cardiometabolic multimorbidity: a multi-state model analysis - Yunxin Shi; Hongxian Wu; Lulu Pan; Yahang Liu; Chen Huang; Yongfu Yu; Guoyou Qin; Leqi He (GeroScience, 2025)

Reference values for handgrip strength in Europe: analysis of individual participant data from 27 countries - Jozo Grgic; Vanessa Kristina Wazny; Andrea B. Maier; Brad J. Schoenfeld; Zeljko Pedisic (GeroScience, 2025)
We aimed to determine reference values for handgrip strength in Europe. Data from the Survey of Health, Ageing and Retirement in Europe were used, involving adults aged 50 + years. Reference values were expressed as weighted percentiles for absolute (kg) and relative (kg/m 2 ) handgrip strength. For women, the highest absolute handgrip strength was observed among the 50–54-year-olds (standing: 5th percentile [P5] = 19 kg; 50th percentile [P50] = 29 kg; 95th percentile [P95] = 39 kg, sitting: P5 = 20 kg; P50 = 29 kg; P95 = 40 kg) and the lowest among the ≥ 90-year-olds (standing: P5 = 9 kg; P50 = 17 kg; P95 = 26 kg, sitting: P5 = 6 kg; P50 = 14 kg; P95 = 24 kg). For men, the highest absolute handgrip strength was observed among the 50–54-year-olds (standing: P5 = 30 kg; P50 = 46 kg; P95 = 62 kg, sitting: P5 = 29 kg; P50 = 46 kg; P95 = 60 kg) and the lowest among the ≥ 90-year-olds (standing: P5 = 12 kg; P50 = 27 kg; P95 = 39 kg, sitting: P5 = 10 kg; P50 = 25 kg; P95 = 37 kg). Compared with women, men had higher handgrip strength. Handgrip strength was generally higher in Northern and Western Europe compared with Southern and Central/Eastern Europe, and in the standing position compared with the sitting position. Similar patterns were found for relative handgrip strength. The reference values determined in this study can facilitate benchmarking for clinical, population health, and research purposes.

Effects of whole-body vibration on cognitive function: a systematic review and meta-analysis - Ji-Woo Seok; Jaeuk U. Kim; Jung-Dae Kim (GeroScience, 2025)
Whole-body vibration exercise (WBV) is a low-intensity intervention for improving cognitive function, particularly among individuals who are older or have physical limitations. However, quantitative evidence regarding its effectiveness is limited. This meta-analysis aimed to quantify the effects of WBV on cognitive function and explore major moderating variables and differences across cognitive domains. Sixteen randomized controlled trials (RCTs) were included, yielding 37 effect sizes (Hedges' g) related to cognitive outcomes. Effect sizes were estimated for overall cognitive function and four subdomains: global cognition, executive function, attention, and memory. A meta-regression analysis was conducted to assess the influence of potential moderators, including vibration frequency, intensity, posture, and intervention duration. WBV had a small but statistically significant positive effect on overall cognitive function (Hedges' g = 0.375, 95% CI = [0.263, 0.486], p < .001). Effect sizes were greatest for global cognition (g = 0.55), followed by executive function (g = 0.41), attention (g = 0.28), and memory (g = 0.28). Meta-regression analysis revealed that most of the moderating variables were not significant. The total intervention dose was the only significant moderator (p = .041). This meta-analysis revealed that WBV is associated with meaningful improvements in cognitive function and that the benefits may be greater among populations with cognitive impairment. WBV may be clinically applicable as a low-intensity, accessible cognitive intervention for older adults and individuals with physical limitations. Future research should investigate the relationships between cognitive domain-specific responses and physiological indicators and develop tailored intervention strategies based on age and cognitive status. Registration: PROSPERO CRD420251067063.

Low protein-induced-FGF-21 signaling remodels adipose tissue on reduced markers of senescence during aging - Jose G. Godoy-Lugo; Khristina E. Young; Prerana Vaddi; Yvann Batamack; Jolaiya Aldridge; Sun Ok Fernandez-Kim; Diana C. Albarado; Susan J. Burke; Jacqueline M. Stephens; Christopher D. Morrison; Cristal M. Hill (GeroScience, 2025)
Cellular senescence and metabolic impairment occur during aging, with adipose tissue decline playing a key role in this process. Furthermore, the detriments of aging on adipose tissue function are further exacerbated by obesity. Dietary protein restriction (DPR), without reducing calorie intake, protects against age-related metabolic decline and extends lifespan through the metabolic hormone FGF21. Here, we demonstrate that protein restriction significantly decreases pro-oncogenic and senescence-related markers in adipose tissue, including SASP, Cdkn1a Cdkn1a , and SA-βgal staining. Additionally, mice fed a low-protein diet during diet-induced obesity demonstrated significant decreases in tumorigenic and cell cycle markers compared with mice fed a control protein and high-fat diet, suggesting that a low-protein diet decreases the burden of cellular senescence on adipose tissue in aged mice and aged obese mice. Conversely, mice lacking FGF21 failed to exhibit the benefits of protein restriction on markers of senescence in white and brown adipose tissue. These data demonstrate that protein restriction exerts distinct beneficial effects on white and brown adipose tissue remodeling on senescence and other markers associated with improvements in lifespan and particularly health span. Given the negative impact of cellular senescence on adipose tissue, protein restriction offers a potential dietary intervention to prevent the detriments of cellular senescence on adipose tissue function during obesity and aging.

Surface-based morphometry reveals divergent aging trajectories in veterans with and without traumatic brain injury - Michelle C. Eliason; Amrutha Bindu Nagella; Cristian Cuadra; David S. Wack; Ghazala T. Saleem; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; John Q. Trojanowki; Arthur W. Toga; et al. (GeroScience, 2025)

Toward new clinical evaluation models for skin longevity: the need for predictive and accelerated approaches - Diala Haykal; Frédéric Flament; Rawad Abdayem; Dong Hun Lee (GeroScience, 2025)

rTMS modulates early AD progression via synergistic brain network reorganization and peripheral biomarker dynamics - Tian Wang; Miaomiao Guo; Hao Wu; Shuai Liu; Yong Ji; Pan Wang; Guizhi Xu (GeroScience, 2025)

Senescence-associated gene signatures predict survival in lung cancer: a multi-cohort analysis - Zoltán Ungvári; Otília Menyhart; Alberto Ocana; Mónika Fekete; Andrea Lehoczki; Balázs Győrffy (GeroScience, 2025)
Lung cancer is a leading cause of cancer-related mortality worldwide and is predominantly diagnosed in older adults, underscoring the need to explore aging-related biological mechanisms that influence disease progression and prognosis. Cellular senescence, a hallmark of aging, plays a dual role in cancer by contributing to both tumor suppression and tumor promotion through its influence on tumor growth, modulation of the tumor microenvironment, the senescence-associated secretory phenotype (SASP), and response to therapy. In this study, we evaluated the prognostic significance of senescence-related gene expression in lung cancer using three independent gene signatures, including the SenMayo gene set and two additional curated lists. Transcriptomic and clinical data from publicly available datasets were analyzed using Cox regression, Kaplan–Meier survival analysis, and multivariate modeling. All three senescence signatures were significantly associated with overall survival, with the SenMayo signature showing the most robust and consistent prognostic power. Notably, higher expression of senescence-associated genes was associated with improved survival in the overall lung cancer cohort and in lung adenocarcinoma, while a more heterogeneous pattern emerged in squamous cell carcinoma. Although hazard ratios varied among the gene sets, their broadly concordant associations with clinical outcomes highlight the biological relevance and context dependence of senescence in lung cancer. These findings suggest that senescence-associated gene expression may serve as a valuable prognostic biomarker and offer mechanistic insights into tumor behavior. Our results contribute to the growing body of gero-oncology research and emphasize the need for tumor-specific exploration of aging-related processes in cancer.

Cognitive function, physical function, and mental health in older adults amid reduced primary and specialist healthcare service use during COVID-19: the HUNT study - Tanja Louise Ibsen; Ekaterina Zotcheva; Sverre Bergh; Debby Gerritsen; Gill Livingston; Hilde Lurås; Svenn-Erik Mamelund; Anne Marie Mork Rokstad; Bjørn Heine Strand; Richard C. Oude Voshaar; Geir Selbæk (GeroScience, 2025)
COVID-19 containment measures reduced older adults’ healthcare access, with uncertain long-term effects on cognitive, physical, and mental health. To investigate whether reductions in primary and specialist healthcare service use during the pandemic were associated with changes in cognitive, physical, and mental health in community-dwelling older adults, with attention to sex differences. Data from the Norwegian Trøndelag Health Study collected before (HUNT4 70 + , 2017–2019) and after the pandemic (HUNT AiT, 2021–2023) included 5387 participants (53% women) aged 70 + . Propensity score matching, accounting for baseline confounders, was used to examine associations between reduced healthcare service use and cognitive, physical, and mental health changes from pre- to post-pandemic. Reduced contact with general practitioners was associated with greater cognitive decline among women (MoCa-change − 0.32 [95% CI − 0.62, − 0.32]). No differences were observed in physical or mental health. Reductions in other primary care services (e.g., in-home nursing, practical assistance) were associated with greater decline in cognitive function (MoCa-change − 0.94 [− 1.53, − 0.36]), particularly among men (MoCa-change − 2.12 [− 3.13, − 1.11]). Men also had a decline in physical function (SPPB-change − 1.06 [− 1.79, − 0.33]). No differences in mental health were observed. Reductions in specialist healthcare services were unrelated to health changes in the overall sample but linked to improved physical function in women (SPPB-change 0.32 [0.11, 0.53]). Although associations between reduced healthcare service use during the pandemic and cognitive, physical, and mental health were limited, findings highlight the importance of sustaining access to primary care for older adults during public health crises. Trial registration The study is pre-registered at ClinicalTrials.gov 02.02.2021, with the identification number NCT 04792086.

Standardizing Preoperative Care for Elective Spine Surgery: The University of Oklahoma Elective Spine Surgery Protocol - Lonnie Smith; David Barkyoumb; William C. Kaiser; Fauziyya Muhammad; Tara Sukut; Ishan Purani; Chao Li; DO; Karl Balsara; Hakeem J. Shakir; M. Burhan Janjua; John F. Burke; et al. (GeroScience, 2025)