The Journals of Gerontology: Series A

We have recently demonstrated that treatment of aged mice with a pan-ERR agonist reverses age-related increase in urinary albumin, decrease in podocyte density, impaired mitochondrial function, and inflammation. The contribution of individual isoforms of ERRs however has not been determined. Since the aging kidney showed a possible compensatory increased expression of ERR{gamma} in the podocytes, in the face of decreased ERR expression, in the present study we aimed to determine the role of ERR{gamma} in aging podocyte. To this end, we cross bred ERR{gamma} floxed mice with podocin-Cre mice to achieve a podocyte-specific ERR{gamma} deletion. While these mice at 3 months of age showed no effect on albuminuria compared to the wild type, when the mice were aged to 21 months of age, there was a significant increase in albuminuria and decrease in podocyte density. Furthermore, we found that the podocyte deletion of ERR{gamma} primarily targeted the expression of mitochondrial biogenesis regulator PGC-1, and mitochondrial fatty acid oxidation enzymes CPT1a and MCAD in the kidney. Electron Microscopy (EM) revealed thickened glomerular basement membrane and diffuse podocyte foot process effacement, as well as severe mitochondrial damage including cristae abnormalities, fragmentation, and changes indicative of altered fusion and fission dynamics. Fluorescence Lifetime Imaging Microscopy (FLIM) to determine NADH and FAD lifetimes indicate a metabolic shift from mitochondrial oxidative phosphorylation towards glycolysis, and decrease in mitochondrial redox capacity. Considering a significantly decreased expression of ERR in aging podocytes plus its traditional role in mitochondrial function, these studies using podocyte ERR{gamma} deletion suggested an overlapping mechanism for ERR/ERR{gamma} to act as modulators of age-related mitochondrial dysfunction and age-related kidney disease.

BackgroundPrediabetes is highly prevalent in older adults and is characterized by heterogeneous clinical trajectories, including regression to normoglycemia and progression to diabetes. While prediabetes has been associated with impaired physical function and frailty, the longitudinal impact of both a single diagnosis and dynamic glycemic transitions on functional outcomes remains unclear. We aimed to evaluate associations between baseline prediabetes and glycemic transitions over time with trajectories of functional capacity and frailty in older adults. MethodsWe conducted a pooled analysis of harmonized data from five nationally representative longitudinal aging cohorts (MHAS, HRS, CHARLS, ELSA, CRELES) within the Gateway to Global Aging Data, including adults aged [≥]50 years with [≥]1 HbA1c measurements. Prediabetes was defined per ADA criteria (HbA1c 5.7-6.4%). Functional outcomes included activities of daily living (ADL), instrumental ADL (IADL), and frailty assessed using Fried phenotype, FRAIL scale, and a deficit-accumulation Frailty Index (FI). Mixed-effects Poisson models estimated incidence rate ratios (IRRs) for baseline prediabetes, while generalized estimating equations assessed time-varying glycemic status and transition trajectories. Models were adjusted for age, sex, cohort, and time-varying covariates, with sensitivity analyses including BMI, smoking, and alcohol intake. FindingsAmong 18,571 participants (median follow-up 13.6 years), baseline prediabetes was associated with increased progression of functional deficits and frailty compared with normoglycemia, including higher FI values and accelerated FI progression. Prediabetes was associated with higher incidence of ADL, IADL, and multimorbidity deficits from early follow-up, although time-dependent changes in incidence rates were not significant. In time-varying analyses (n=7,840), both prediabetes and diabetes were associated with higher incidence of functional deficits compared with normoglycemia, with diabetes showing the strongest effects across all outcomes. Diabetes was associated with greater FI burden and accelerated progression, whereas prediabetes showed a smaller increase, with attenuation over time. Among individuals with baseline prediabetes, regression to normoglycemia occurred in 20.8% and was associated with increased incidence of ADL and frailty deficits. In contrast, progression to diabetes occurred in 24.3%, and was associated with lower risk of incident ADL and Fried frailty deficits compared to stable prediabetes. InterpretationPrediabetes is associated with increased risk of functional decline, frailty, and deficit accumulation in older adults, independent of progression to diabetes. Regression to normoglycemia was associated with higher risk of functional deterioration. These findings suggest that prediabetes reflects a state of metabolic vulnerability linked to biological aging rather than solely a precursor to diabetes and highlights a need to reframe its clinical significance in older populations. FundingThis research was supported by Instituto Nacional de Geriatria in Mexico. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to April 1, 2026, using the terms ("prediabetes") AND ("frailty" OR "functional decline" OR "activities of daily living" OR "mortality") AND ("older adults" OR "aging" OR "longitudinal" OR "cohort"). Existing evidence from predominantly single-country and cross-sectional studies suggests that prediabetes is associated with increased risk of frailty, disability, and adverse health outcomes in older adults. However, findings have been inconsistent, particularly regarding incident versus prevalent outcomes and the role of competing risks in aging populations. Importantly, few studies have used harmonized multinational longitudinal data, incorporated repeated measures of glycemic status, or evaluated multiple complementary frailty constructs. The impact of dynamic glycemic transitions, including regression to normoglycemia and progression to diabetes, on functional trajectories remains poorly understood. Added value of this studyThis study leverages harmonized longitudinal data from five nationally representative aging cohorts from Mexico, England, China, Costa Rica and the United States to examine both baseline prediabetes and time-varying glycemic status in relation to trajectories of functional decline and frailty. By integrating multiple validated measures of functional capacity and frailty, and applying longitudinal modeling strategies, we provide a comprehensive assessment of the relationship between prediabetes and age-related outcomes. We further characterize glycemic transition trajectories and show that regression to normoglycemia among older adults with prediabetes is associated with increased risk of frailty, while progression to diabetes does not uniformly confer additional risk beyond stable prediabetes. Implications of all the available evidenceOur results support a reconceptualization of prediabetes in older adults as a marker of systemic vulnerability rather than solely a precursor to diabetes. Glycemic status in later life appears to also reflect underlying physiological reserve, with dynamic changes potentially signaling deterioration rather than improvement. Our findings suggest a need to incorporate glycemic markers into geriatric risk stratification and to interpret their changes in the context of aging biology. Future research should focus on elucidating the mechanisms linking dysglycemia with frailty and functional decline, including the roles of sarcopenia, inflammation, and multimorbidity, and on evaluating interventions tailored to older populations across diverse global contexts.

Background: It is well-established that males have a higher mortality risk than females. Immune cells and their function are known to undergo characteristic changes during aging, and immune cells are known to have sex differences. Immune cells and their function have been linked to mortality risk, but no studies have investigated to what degree, if at all, Immune Cell Biomarkers (ICBs) contribute to the known differences in mortality risk by sex. Methods: Using participant data from the Health and Retirement Study (n = 8,822), we applied multivariable linear regressions adjusting for age, cytomegalovirus (CMV) serostatus, sex, and race/ethnicity to identify differences by sex in 48 immune cell biomarker (ICB, e.g. T cells, B cells, Monocytes, etc.) percentages and counts (measured in 2016). We studied how the associations between ICBs and mortality risk differ by sex using stratified Cox Proportional Hazard (CPH) models. We estimated how inclusion of sex explained the relationship between ICBs and all-cause mortality, and conversely, how inclusion of individual and all ICBs combined explain the relationship between sex and all-cause mortality using multivariable modeling approaches. Results: Differences in ICBs by sex range between 2-38% (39/48 statistically significant). 9 ICBs were significantly associated with mortality risk in the entire sample. While different ICBs were significantly associated with mortality risk in the stratified analyses, particularly with respect to monocyte, B cell, and NK cell populations, adjusting for sex modestly influenced the hazard ratios of the ICBs (sex: 8 ICBs, percent change <5.4%). Furthermore, individual and cumulative contributions of ICBs in explaining the differences in mortality risk by sex were not significant.

The VACS 2.0 Frailty Index was developed using the VA health records system to identify frailty and predict mortality in older Veterans that were living with HIV. Systemic inflammatory indices have been associated with frailty, but little is known about the association between frailty and immunosenescence. We aim to investigate the potential link between soluble inflammatory indices, T cell expression of exhaustion and senescence markers, and frailty as measured by the VACS 2.0 index. We analyzed a one-time blood draw for plasma levels of inflammatory indices, T cell subsets and expression of exhaustion and senescence markers, and calculated VACS 2.0 index scores in a cohort of 30 older (>65 years) Veteran participants. We found that VACS 2.0 scores correlated with the number of prescribed medications in the older Veterans. Soluble TNF receptor levels strongly correlated with VACS 2.0 frailty scores. How these soluble TNF receptors are generated and whether they mechanistically contribute to frailty warrants further investigation.

Aging can alter macrophage functions through changes in intracellular processing, mitochondrial activity, and chronic inflammatory activation; however, whether aging-associated macrophage deregulation contributes to tumor-associated multinucleated syncytial formation remains poorly understood. Here, we investigated the role of aging macrophages in promoting tumor-like multinucleated syncytia and explored the underlying metabolic mechanisms. Immunohistochemical analyses of metastatic tissue sections from patients with prostate, breast, and lung cancers demonstrated enrichment of CD68+/panCK+ multinucleated tumor-like osteoclast syncytia in elderly patients. Using ex vivo co-culture systems, aged bone marrow-derived macrophages exhibited significantly increased propensity to generate multinucleated syncytia containing proliferative Ki67-positive cancer-associated nuclei. These syncytia displayed attenuated mitochondrial oxidative phosphorylation (OXPHOS) programs characterized by reduced oxygen consumption rates and decreased expression of mitochondrial respiratory proteins, such as ATP5a and SDHB. Pharmacologic inhibition of STAT6 further enhanced syncytial formation and suppressed OXPHOS-associated programs, whereas treatment with the EP2 antagonist C52 partially restored mitochondrial gene expression and reduced syncytial formation. Together, these findings identify a previously unrecognized aging-associated mechanism linking macrophage deregulation, attenuated STAT6-associated mitochondrial programs, and tumor-like multinucleated syncytial formation.

BackgroundAgeing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking. Methods and AnalysisThis trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70+. Participants will be randomised to one of three arms (Metformin MR 1500mg, Fisetin 100mg or Spermidine 15mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-{beta}-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition. Ethics and DisseminationEthical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary. Trial RegistrationREPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839. Trial Registration Data Set O_TBL View this table: org.highwire.dtl.DTLVardef@1db6074org.highwire.dtl.DTLVardef@1997837org.highwire.dtl.DTLVardef@a39a11org.highwire.dtl.DTLVardef@d7e6eforg.highwire.dtl.DTLVardef@7a5b7f_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1C_FLOATNO O_TABLECAPTIONTrial Registration Data Set C_TABLECAPTION C_TBL

Autophagy is a hallmark of aging, but autophagy-related proteins have not been exclusively targeted to attenuate the progressive decline in physical function associated with aging. Here, we combined Tat-Beclin1, an autophagy agonist, and endurance training to determine whether Tat-Beclin1 enhances exercise adaptation in old male mice. Tat-Beclin1 was administered intraperitoneally (TB group, 15 mg/kg, 2x/week) as a standalone therapy, or in combination with endurance training (TB+Exe group, 70% of maximal running speed 3x/week) for 1 month in 23-month-old male C57BL/6J mice. Control groups were age-matched cage controls and exercise-only groups. Animals were assessed for grip strength, endurance capacity on a treadmill, and balance and coordination on a rotarod. Gastrocnemius/plantaris (G/P) and tibialis anterior muscles were harvested for western blotting, myofiber typing, and proteomic profiling (G/P only). TB+Exe led to significant increases in grip strength, endurance capacity, and balance and coordination performance beyond those observed in the TB and Exe groups alone. Autophagy markers, including Beclin1, the LC3B-II/I ratio, and p62, did not differ among groups. A proteomic analysis of the G/P muscle revealed that TB upregulated biological processes involved in muscle contraction and adaptation, whereas TB+Exe increased mitochondrial bioenergetic processes and, surprisingly, upregulated acute inflammatory responses, including proteins such as haptoglobin and orosomucoid-1. We conclude that combining Tat-Beclin1 and endurance training may represent a new approach to attenuate aging-related decline in physical function. New & NoteworthyWe show evidence that combining Tat-Beclin1 and endurance training (TB+Exe) resulted in greater improvements in physical function in 24-month-old male mice than either standalone therapy. We also show that TB+Exe upregulates traditional exercise-like biological processes and unexpectedly upregulates acute-inflammatory proteins (e.g., orosomucoid-1), which are thought to improve physical function in preclinical studies. Our study suggests that TB may be a new drug enhancing physical function, especially when combined with endurance training in old male mice.

BackgroundThe Eatwell Guide represents the UKs principal healthy eating model and understanding whether adherence to UK dietary recommendations can attenuate age-related functional decline is essential to inform healthy ageing strategies. MethodsIn up to 157,457 participants from the UK Biobank, we explored cross-sectional and prospective associations between adherence to the Eatwell Guide and markers of physical function (grip strength, fat-free mass percentage, self-reported walking pace, and falls). Eatwell Guide adherence scores were derived from 24-hour dietary recall data (Oxford WebQ), and quantified using a graded, food-based scoring system. Differences between population subgroups including by age, sex, physical activity, and protein intake level were explored. ResultsHigher Eatwell Guide adherence was cross-sectionally associated with higher grip strength, greater fat-free mass percentage, higher odds of brisk walking pace, and lower odds of falls (all p<0.001). Prospectively, greater adherence was associated with attenuated fat-free mass decline ({beta}=0.02, SE=0.001, p<0.001) and slower grip strength decline ({beta}=0.01, SE=0.002, p<0.01). Higher adherence was also prospectively associated with greater odds of brisk walking pace (OR=1.02, 95% CI: 1.017-1.021, p<0.01), though this advantage attenuated over follow-up (EWG*Time: OR=0.998, 95% CI: 0.997-0.999, p=0.002). Higher adherence was prospectively associated with lower falls risk (OR=0.996, 95% CI: 0.995-0.998, p<0.001), with this protective association remaining stable over time (EWG*Time: p=0.89). ConclusionsHigher Eatwell Guide adherence was associated with preserved muscle mass, modest attenuation of grip strength decline over time, and a reduced risk of falls, supporting its relevance for musculoskeletal health and physical function in ageing populations.

Cardiovascular and cerebrovascular risk factors (CVRFs)--including hypertension, diabetes, heart disease, and stroke--are prevalent chronic conditions in older adults and major determinants of late-life cognitive decline. These conditions involve chronic inflammatory and metabolic processes that may accelerate biological aging, reflecting multisystem physiological decline beyond chronological age. We examined associations among CVRFs, accelerated biological aging, and cognitive performance and assessed whether biological aging mediates the association between CVRFs and cognitive performance overall and across race/ethnicity and sex. We analyzed data from 2,384 U.S. adults aged 60 years and older in the National Health and Nutrition Examination Survey 2011-2014. CVRFs were defined using clinical measurements and self-reported diagnoses. Biological aging was quantified using the PhenoAge algorithm derived from blood-based clinical biomarkers. Cognitive performance was assessed using composite scores of memory, executive function, and processing speed. Weighted linear regression and causal mediation analyses were conducted overall and stratified by race/ethnicity and sex. All CVRFs were associated with accelerated biological aging, with diabetes demonstrating the strongest association (0.76 SD higher PhenoAge acceleration; 95% CI: 0.67-0.85). CVRFs were associated with lower cognitive performance, with stroke showing the largest association ({beta} = -0.317; 95% CI: -0.471 to -0.165). Accelerated biological aging mediated these associations, accounting for 88.5% of the diabetes association and 13.7%-27.2% for other CVRFs. Associations and mediation effects varied across racial/ethnic and sex groups, with mediation more consistent among Non-Hispanic Whites and females. Accelerated biological aging represents an important link between cardiometabolic risk to cognitive performance in older adults.

BackgroundSkeletal muscle aging exhibits substantial heterogeneity, with some individuals maintaining robust function into advanced age while others develop sarcopenia and frailty. Whether molecular signatures distinguishing these trajectories reflect biological aging or modifiable factors, such as physical activity, remains unclear. MethodsAn integrated discovery-validation study was conducted on skeletal muscle transcriptomes. Discovery analysis used the GSE144304 dataset comprising vastus lateralis biopsies from young adults (n=26, aged 18-30 years), fit elderly (n=30, aged 65-80 years with preserved function), and frail elderly (n=24, aged 65-80 years stratified by grip strength). Top 10 most significantly altered genes were validated across five independent transcriptomic studies (n=184 total) strategically selected to represent distinct activity contexts: activity-controlled aging, sedentary aging, mixed-activity aging, disease-impaired aging, and exercise intervention. Expression of two established atrogenes were examined (FBXO32/Atrogin-1 and TRIM63/MuRF-1) as benchmarks. ResultsDiscovery analysis identified 10 genes with profound age-related changes (adjusted p < 10-{superscript 2}{superscript 1}, |log2FC| > 1.3). Cross-dataset validation revealed striking activity-dependence: genes downregulated with aging in sedentary populations (MYORG, STRADB) showed maintained or increased expression in active elderly individuals (80% validation rate, r = 0.75-0.82 with activity level). In contrast, established atrogenes showed poor replication (25-50%) and context-dependent patterns. C4ORF54 expression strongly correlated with grip strength (r = 0.68, p < 0.001), with age effects disappearing after phenotype adjustment, indicating purely phenotype-mediated expression. Critically, sedentary versus active aging datasets showed opposing transcriptional patterns (r = -0.68), demonstrating that activity confounds conventional age-based signatures. ConclusionsMolecular signatures distinguishing fit from frail aging predominantly reflect physical activity levels rather than inevitable biological processes. MYORG and STRADB emerge as activity-responsive biomarkers of muscle health, while C4ORF54 serves as an indicator of functional capacity. These findings challenge conventional atrogene paradigms and suggest that exercise-responsive AMPK signaling pathways represent immediately translatable therapeutic targets for preserving muscle function in older adults.

Introduction: Brain-predicted age, estimated from structural MRI data, is a machine-learning biomarker of biological brain aging. Greater brain age gap (BAG) indicates advanced brain aging and is associated with cognitive decline and mortality. Cardiometabolic risk factors, including elevated blood glucose, body mass index (BMI), blood pressure, and cholesterol, increase risk of cognitive impairment and dementia in aging. Their relationship with BAG in severe obesity remains poorly characterized despite increased prevalence of cardiometabolic risk factors among this population. Methods: T1-weighted MRI data from 97 adults (BMI 35-73) were used to calculate BAG using ENIGMA and Pyment brain age models. Associations between BAG and HbA1c, BMI, hypertension, and hyperlipidemia were examined using multiple linear regression and MM-estimation robust regression, adjusting for age, sex, and race. Post hoc analyses stratified models by clinical HbA1c cutoffs (normoglycemic, prediabetic, diabetic). Results: Higher HbA1c was associated with greater BAGENIGMA (B = 1.58, p = .014) and BAGPyment (B = 0.93, p = .013) in linear regression models. In robust models, HbA1c remained significantly associated with BAGENIGMA (B = 1.70, p = .002) but not BAGPyment (B = 0.71, p = .13). BMI, hypertension, and hyperlipidemia were not associated with BAG in either linear or robust models. HbA1c was associated with greater BAGENIGMA (B = 2.15, p = .01) and BAGPyment (B =1.21, p = .04) in those at or above prediabetic levels and with BAGENIGMA (B = 2.49, p = .047) in those with diabetes. Conclusions: Elevated HbA1c is associated with accelerated brain aging in individuals with severe obesity. BAG was not associated with BMI, hypertension, and hyperlipidemia, which may reflect the restricted BMI range inherent to the sample with severe obesity.

Mitochondrial diseases (MDs) are genetically and phenotypically diverse and can be difficult to diagnose. Prevalence estimates derive largely from diagnosed cases and may underestimate population MD risk. Population-based studies are limited in scope and number but indicate MD variants are common. As genomic sequencing advances have made comprehensive population-based evaluation feasible, we sought to evaluate nuclear MD variation in a population cohort to understand variant prevalence and differences in MD risk estimates We identified disease-associated nuclear gene variants in 270 nuclear MD genes across 2,845 healthy older individuals in the Medical Genome Reference Bank. From Pathogenic or Likely Pathogenic Variants (PLPVs) we estimated autosomal recessive (AR) and autosomal dominant (AD) MD risk for individual genes and all nuclear variant-associated MDs. We identified 554 PLPV alleles representing 357 unique variants in 145 genes. Combined AR MD risk was estimated at 25.8 per 100,000 (95% CI 18.7 to 32.9), or 1 in 3,880 individuals. SPG7 (12.65 per 100,000; 95% CI 7.52-20.6) and POLG (4.23 per 100,000; 95% CI 2.10-8.01) contributed the greatest single gene AR MD risks and OPA1 variants posed the greatest AD MD risk. We observed a high rate of MD-associated nuclear gene variation in this healthy older cohort. The estimated lifetime AR MD risk was higher than commonly quoted prevalence estimates for all MDs, and the presence of common AD variants suggests variant penetrance may be lower than previously understood. These data help contextualise population MD risk and may inform clinical counselling and care.

Background: Sleep problems are common in older people and have been associated with increased fall risk, but the mechanisms underlying this relationship remain unclear. Gait quality reflects balance control and neurological function and may provide insight into pathways linking sleep health and falls. Methods: Data from 758 community-dwelling older people ([&ge;]65 years; mean age 75.8 years, 69.3% women) were analysed. Sleep problems were assessed at baseline using a self-reported item (Patient Health Questionnaire-9, question 3). Daily-life gait quality and habitual walking speed were derived from one week of wearable sensor monitoring. Falls and injurious falls were prospectively recorded over 12 months. Associations between sleep problems, gait quality, and fall incidence were examined using regression models adjusted for demographic, pain and cognitive factors, and use of sleeping medication. Results: Sleep problems were reported by 43.9% of participants. Sleep problems were not associated with habitual walking speed, but were associated with lower gait quality in daily life (adjusted {beta} = -0.15, 95% CI -0.27 to -0.03). Participants reporting sleep problems had higher incidence rates of total falls (adjusted IRR = 1.42, 95% CI 1.07 to 1.90) and injurious falls (adjusted IRR = 1.50, 95% CI 1.07 to 2.10). Conclusions: Self-reported sleep problems were associated with impaired real-world gait quality and substantially higher rates of falls and injurious falls in older people. These findings suggest that sleep problems may increase fall risk by altering balance control rather than by reducing walking speed. Sleep should be considered when managing fall risk, and fall risk should be considered in older people with sleep complaints.

Age-related cognitive decline (ARCD) is driven by conserved biological mechanisms of aging, yet no gerotherapeutic directly targets these processes in the brain. Glycyl-L-histidyl-L-lysine complexed with copper (GHK-Cu) is an endogenous peptide with regenerative and anti-inflammatory properties that declines with age. Whether its effects on cognitive aging depend on delivery route or exposure duration remains unclear. Aged C57BL/6J mice (20-21 months) received GHK-Cu (15 mg/kg) via short-term intraperitoneal (IP; 5 days) or longer-term intranasal (IN; 8 weeks) administration. Hippocampal-dependent escape learning was assessed using a spatial navigation task. Molecular effects were evaluated using hippocampal immunohistochemistry and bulk RNA sequencing. Differential gene expression was analyzed using DESeq2 with false discovery rate (FDR) correction, and pathway-level changes were assessed via gene set enrichment analysis (GSEA). IN GHK-Cu improved escape latency across Trials 2-4 in both sexes (P < 0.05), whereas IP dosing produced a transient improvement in males during Trial 2 (P < 0.05) without sustained effects or improvement in females. IN treatment increased synaptophysin in females (P < 0.001) and decreased GFAP in both sexes (P < 0.01), while IP treatment reduced TGF-{beta}, GFAP, and MCP-1 in males (P < 0.05) and decreased p21 in females (P < 0.0001). Transcriptomic analysis revealed distinct molecular programs. IN GHK-Cu induced coordinated suppression of oxidative phosphorylation (male NES -5.44, female NES -4.20; FDR < 0.0001) and MYC target pathways (female NES -4.31, FDR < 0.0001), with additional attenuation of PI3K-AKT-mTOR signaling in females (NES -3.15, FDR = 0.062). In contrast, IP treatment activated oxidative phosphorylation (female NES 4.97, FDR < 0.001), DNA repair (NES 5.58, FDR < 0.001), and MYC targets (NES 4.34, FDR = 0.002), indicating engagement of acute stress-response and repair pathways. GHK-Cu improves hippocampal-dependent learning in aged mice through distinct biological modes: IP exposure activates repair and stress-response pathways, whereas IN delivery induces sustained suppression of growth and mitochondrial metabolic signaling associated with aging biology. These findings demonstrate that functional cognitive improvement can arise from divergent molecular states and identify administrative route and exposure duration as key determinants of gerotherapeutic response.

Background: It is an everyday observation that people of the same chronological age differ with respect to their physical and mental capacity. However, assessing these differences in biological age remains challenging. Methods: Here, we aggregate 89 age-associated variables from the Berlin Aging Study II (BASE-II, n=1,631) to generate MultiAge, a new marker of biological age that summarizes information from ten domains reflecting organ health and global biological age. We then used methylation data obtained from an Illumina MethylationEPIC array and supervised machine learning to translate MultiAge into a DNA methylation signature, MultiAgeEpi (309 CpGs), which was subsequently validated in four independent external validation cohorts (KORA FF4, KORA Age, SHIP-TREND, BiDirect, total n=4,339). MultiAgeEpi results were compared with previously published epigenetic clocks (GrimAge, DunedinPACE, SystemsAge). Results: We report that MultiAgeEpi showed similar, and in several cases, stronger associations with age-associated outcomes such as diabetes, metabolic syndrome, multimorbidity, frailty and mortality (q < 0.05) compared to the other clocks. Conclusions: MultiAge and MultiAgeEpi thus provide a comprehensive assessment of biological age through aggregation of numerous age-associated variables and the use of the high-resolution methylomics data makes transfer of this marker to other cohorts possible.

{Delta}133p53 is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We recently reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes and extends lifespan in progeria model mice (heterozygous LmnaG609G/+). The anti-aging effect of {Delta}133p53 was attributed in part to reduced levels of the proinflammatory cytokine IL-6. To comprehensively profile {Delta}133p53-induced changes in cytokines and chemokines, we in this study performed a Luminex-based multiplex quantitative assay of mouse sera collected from transgenic {Delta}133p53-expressing LmnaG609G/+ mice and non-expressing controls. This assay not only confirmed the {Delta}133p53-mediated repression of IL-6 but also showed that {Delta}133p53 reduced the levels of CXCL1 (also known as KC), IL-1, and CXCL10 (also known as IP-10). Among these factors, we further characterized CXCL10, which has not previously been associated with progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) {Delta}133p53-expressing LmnaG609G/+ mice showed reduced Cxcl10 expression, compared with age-matched non-expressing controls, in the liver, spleen, and brain, major organs known to produce CXCL10. In naturally aged wild-type mice (2-year-old), Cxcl10 expression was also significantly repressed by transgenic {Delta}133p53 in the spleen and brain. Analysis of gene expression datasets from human tissues demonstrated an inverse association between CXCL10 and {Delta}133p53 levels, suggesting physiological relevance to human aging. This study defines CXCL10 as a proinflammatory chemokine elevated in both accelerated and natural aging and as a potential target of the anti-inflammatory activity of {Delta}133p53.

Burn trauma disproportionately impacts older adults, yet existing burn severity models emphasize age, total body surface area (TBSA), and inhalation injury without accounting for geriatric-specific vulnerabilities such as frailty. We conducted a retrospective cohort study of 326 geriatric patients admitted with burn injuries between 2020 and 2024 to evaluate how TBSA, burn location, inhalation injury, renal insufficiency, comorbidities, and functional dependence in activities of daily living (ADLs) and instrumental activities of daily living (IADLs) affect in- hospital mortality and discharge disposition. Based on multivariable logistic regression and chi- square analyses, TBSA, as expected, emerged as the strongest predictor across models. Each 1% increase in TBSA was associated with a 7% increase in the odds of in-hospital mortality (p=0.006) and a 12 to 19% increase in odds of post-acute care placement (p<0.001). Inhalation injury and renal insufficiency were also independently associated with increased odds of both mortality and post-acute care disposition, whereas respiratory comorbidity predicted mortality alone. Functional status demonstrated outcome-specific prognostic value: ADL dependence predicted mortality, while IADL dependence predicted discharge disposition. Patients with some ADL dependence had five-fold higher odds of in-hospital mortality (p=0.011), while some (OR=2.48, p= 0.039) and full IADL dependence (OR=2.61, p=0.025) were associated with higher odds of post-acute care placement. Integrating structured functional assessments that distinguish basic from instrumental limitations alongside established burn severity metrics may enhance prognostication and guide individualized care planning for older adults with burn injuries.

Objectives: Cardiovascular disease (CVD) is a leading cause of mortality and disability in older populations. This study aimed to identify CVD risk factors in community-dwelling older adults and to examine whether frailty-related factors (sarcopenia and nutritional status) interact with chronic kidney disease (CKD). Methods: This cross-sectional study included 307 community-dwelling Japanese adults aged [&ge;]65 years between September 2024 and March 2025. CVD history was assessed based on self-reported physician diagnoses obtained through a structured questionnaire. Lifestyle-related factors included hypertension, diabetes, dyslipidemia, and body mass index (BMI). Frailty-related factors included sarcopenia (Asian Working Group for Sarcopenia 2019 criteria), nutritional status (Mini Nutritional Assessment-Short Form), and physical activity (International Physical Activity Questionnaire-Short Form). CKD was defined using the estimated glomerular filtration rate (eGFR): non-CKD ([&ge;]60 mL/min/1.73 m2) and CKD (<60 mL/min/1.73 m2). Multivariable logistic regression identified independent correlates of CVD, and interactions between CKD and frailty-related factors were tested. Results: The prevalence of CVD was 17.9%. Independent correlates included CKD (aOR 5.0), hypertension (aOR 4.0), male sex (aOR 3.1), undernutrition (aOR 2.7), sarcopenia (aOR 2.7), and low physical activity (aOR 2.5). No significant interactions were observed between CKD and sarcopenia (p = 0.70) or nutritional status (p = 0.40). Conclusions: CKD, sarcopenia, undernutrition, and low physical activity were independently associated with CVD, with no interaction between CKD and frailty factors. These findings suggest that integrated management addressing both renal function and frailty-related factors may be important for CVD prevention in older adults.

Birds provide a unique model for ageing research, as they exhibit higher mass-adjusted metabolic rates and blood glucose levels than other vertebrate groups, yet demonstrate greater longevity and slower senescence compared to mammals of similar body size. This challenges the "pace of life syndrome" hypothesis, which predicts that high metabolic rates and elevated glucose should correlate with shorter lifespans. While the effects of glucose, glycation, and advanced glycation end-products (AGEs) on ageing are well-documented in humans and the conventional models used in biomedical research, their impact on avian physiology and ageing remains poorly understood. Some evidence suggests that birds possess adaptations mitigating the potential detrimental effects of glucose levels, which are much higher than those of all other vertebrate groups. However, previous studies indicate that elevated glucose predicts reduced lifespan, and protein glycation--varying with age--can influence survival and some fitness-related traits. This implies that glycation or AGE accumulation may have relevant effects on avian longevity. In this study, we experimentally investigated how one year of dietary supplementation with glucose or methylglyoxal affects survival and ageing markers (metabolic rate, flying performance, and beak coloration) in captive zebra finches (Taeniopygia guttata). Our results reveal a significant increase in mortality exclusively in glucose-supplemented birds. Although glucose treatment elevated albumin glycation rate and AGE formation--the latter also observed with methylglyoxal supplementation--these variables did not directly explain the increased mortality in glucose-treated birds, which was absent in methylglyoxal-treated individuals despite similar AGE accumulation. Additionally, we observed some effects on the assessed senescence markers, with an age-related constraint on seasonal metabolic adjustment, and a treatment-influenced age decline in secondary sexual traits expression. These findings support the use of these markers as proxies for senescence in zebra finches. We also discuss alternative mechanisms, independent of the glycation cascade, which may contribute to mortality. A seasonal decline in flight performance, particularly during peak mortality periods, suggests a broader deterioration of health. Thus, although we demonstrate glucose supplementation to be more deleterious than methylglyoxal, the underlying mechanisms for the observed increase in mortality induced by the treatment remain unresolved.

Frailty is a multi-system syndrome causing increased susceptibility to health insults in older adults. Immune system dysregulation and inflammaging have emerged as mechanisms that may affect multiple organ systems in the frailty syndrome. This present study seeks to define the immune state in community-dwelling adults suffering from frailty. We evaluated a subgroup of 169 individuals enrolled in the Gut-brain Alzheimers disease Inflammation and Neurocognitive Study (GAINS). Participants in the GAINS study were scored for frailty using the Clinical Frail Scale. A panel of 27 inflammatory cytokines was analyzed from the serum of each participant. Frailty was present in 33 (19.5%) of the cohort, and was correlated with age, malnutrition, and cognitive assessments. Statistical analysis adjusting for clinical covariates revealed higher serum levels of IL-2, IL-10, and IL-17 in frail patients. Using machine learning classification, we developed a predictive model of frailty with strong discriminative performance (AUC 0.78). Individual element analysis via Shapley Additive Explanations (SHAP) revealed that inflammatory markers had the greatest influence on the model, and IL-7 was the single most important element in the prediction of frailty. Together, our data demonstrate a novel pattern in which T-cell regulatory inflammatory molecules as mediators of frailty, implicating cellular immunity as a potential mechanism of dysfunctional aging.