The Journals of Gerontology: Series A

BackgroundIntrinsic capacity (IC) is a key marker of healthy ageing, which captures an individuals physical and mental capacities, measured across five domains: cognitive, locomotor, psychological, vitality, and sensory. Although genetic factors are known to influence both general IC and its individual domains, existing IC indices have been developed primarily using phenotypic data, without accounting for the underlying biological architecture across domains. In this study, we developed a multi-trait polygenic score (Mt-PGS) model for IC by integrating polygenic scores derived from a broad set of phenotypes spanning the five IC domains and examined its validity. MethodsUsing data from 13,085 participants of the Canadian Longitudinal Study on Aging (CLSA), we computed PGSs for 63 phenotypes related to IC domains. A supervised machine-learning model was applied to develop a mt-PGS model for IC and identify the optimal set of polygenic predictors. The validity of the mt-PGS IC score was evaluated by comparing it with a phenotype-based IC score and by examining its association with mortality. ResultsOur analysis identified PGSs for 33 phenotypes with non-zero coefficients, jointly explaining 2.23% of the variance in IC. Several of the strongest contributors were most closely aligned with vitality-related phenotypes in the literature (including body mass index, grip strength, fat-free mass, diastolic blood pressure, and chronic obstructive pulmonary disease), acknowledging cross-domain relevance, and that predictors from all five IC domains were represented. The mt-PGS IC score was consistent with the phenotype-based IC score, positively correlated with the phenotype-based IC score and was inversely associated with mortality (OR = 0.04; 95% CI: 0.005 - 0.379). ConclusionOur findings support the multisystem biological basis of IC, demonstrating that an mt-PGS model integrating diverse phenotypes is associated with the phenotype-based IC score. PGSs for the phenotypes frequently related to vitality in the literature were the strongest predictors, recognizing that several of these phenotypes may span multiple domains, and that all domains contributed to the model. If replicated across different ancestries and settings, these findings may serve as a foundation for future research for the potential integration of genetic information into IC frameworks.

Aging is associated with colon epithelial barrier integrity and upregulation of myelopoiesis in the bone marrow (BM). Alamandine (Ala) and MrgD are novel members of the renin angiotensin system (RAS). This study tested the hypothesis that Ala restores the colon epithelial barrier integrity in aging via modulating gut-BM axis. Mice of age 2-3 (Young) or 22-24 months (Old) were treated with saline or Ala by using Osmotic pumps. The intestinal permeability was evaluated by using FITC-dextran. Lgr5+Olfm4+ intestinal stem cells (ISCs), Wnt3a and {beta}-catenin were evaluated by immunohistochemistry or western blotting. Fecal microbiome was analyzed by 16S rRNA sequencing. Monocyte-macrophages were characterized by flow cytometry. Cecal or serum bacterial metabolites were analyzed. The pro-myelopoietic potential of cecal supernatants (CS) was tested in the Young-BM cells. MrgD was expressed in ISCs, which was decreased in the Old. Increased intestinal permeability in aging was reversed by Ala. In the colon organoids, Ala increased Wnt3a levels that were antagonized by the NF449, SQ22536 or 666-15. Ala restored phospho-CREB and active {beta}-catenin levels that were decreased in the Old colon-organoids. Ala increased the richness and {beta}-diversity of the aging microbiome and decreased Bacillota/Bacteroidota. Ala decreased the CD80+ and increased CX3CR+ cells in the Old colons. Old-CS induced myelopoiesis in vitro in BM cells with higher number of monocytes and pro-inflammatory macrophages which was not observed in the CS derived from Ala-treated Old mice. Ala is a promising pharmacological agent for reversing the leaky gut of aging by restoring homeostasis in the gut-BM axis.

Background: Prediabetes 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. Methods: We 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. Findings: Among 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. Interpretation: Prediabetes 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. Funding: This research was supported by Instituto Nacional de Geriatria in Mexico. Keywords: Prediabetes; Glycemic transitions; Frailty; Functional decline; Aging; Multimorbidity

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

BackgroundThe risk of chronic diseases and multimorbidity increases with age, yet, individuals of the same age can strongly differ in healthspan, ranging from early manifestation of age-related disease to robust health into very old age. Plasma biomarkers, including metabolites and proteins, can capture intrinsic health status, thereby providing insights into the nature of this variation. These biomarkers have been widely explored to understand chronic and early disease risk but less so for disease resilience in mid- and late-life survival (i.e. after 90 years), or for multigenerational longevity. MethodsWe quantified 326 plasma proteins using data-independent mass spectrometry in two generations of the Leiden Longevity Study cohort: F1 nonagenarian siblings (late-life; age [≥]89; N=852) and F2 offspring and their partners (mid-life; age 30-80; N=2,282). Baseline plasma protein levels were tested for association with mid- and late-life survival, with up to 22 years of follow-up, and cardiometabolic healthspan, with up to 16 years of follow-up. By comparing F2 offspring and partners, we tested for plasma proteins associating with familial longevity. FindingsFour proteins: GSN, F2, CRTAC1, and HP, consistently associated with increased mid- and late-life survival, prolonged cardiometabolic healthspan, and familial longevity; representing overall resilience. Moreover, six proteins: APCS, C7, FCN2, HPR, GSN, and PIGR, associated with mortality independent of MetaboHealth, a well-established metabolomics-based mortality score. InterpretationWe identified GSN, F2, CRTAC1, and HP as promising candidate indicators of healthy aging and resilience, meriting further study. FundingZonMw, LUF, BBMRI-NL, VOILA, Jorg Bernards-Stiftung, Koln Fortune, and CECAD Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAs the population ages, implementing biomarkers that are able to distinguish vulnerable individuals from highly resilient ones may help to alleviate the burden on our healthcare system. Several studies have shown that plasma-derived proteins change with chronological age and can be used to discern those at risk of disease or early mortality. However, most plasma proteome studies to date have focused either on cross-sectional analyses, short follow-up periods, and/or cohorts with a narrow age range, often centered around mid-life. These studies therefore do not capture the biological factors that contribute to survival up to high ages (longevity), disease resilience and sustained health. In addition, it remains unclear whether the proteins and underlying mechanisms associated with increased survival are consistent across mid and late-life. Added value of this studyThis study set out to investigate the potential of plasma proteins as markers for healthy aging and resilience, and examines the extent to which these associations are consistent across generations. Using the family-based Leiden Longevity Study cohort, including long-lived nonagenarian siblings, their middle-aged offspring, and their partners, we leveraged a unique design to study survival, mid-life health, and multigenerational longevity. We show that prospective (longevity) survival is associated with both age-dependent and age-independent protein effects. Most age-independent proteins displaying consistent associations across life stages. In addition, relative protein level differences were detectable on average ten years before the onset of cardiometabolic disease in mid-life, indicating signatures of future resilience or vulnerability. Four proteins (GSN, CRTAC1, F2, and HP) show consistent association with survival-related outcomes and are proposed as candidate markers of healthy aging. We further observe favorable differences in these proteins in families enriched for longevity, which is indicative of lower disease risk. These identified proteins implicate inflammatory and osteoarthritis related processes. Furthermore, we demonstrate that proteins capture survival domains distinct from those reflected by metabolomic measures, demonstrating the complementary value of plasma proteomics. Implications of all the available evidenceThese findings highlight candidate protein biomarkers of healthy aging and resilience, which may provide improved insight into the mechanisms underlying healthy aging. They also facilitate the development of more sensitive indicators of health, whose implementation may enable earlier and more effective interventions in both population health and clinical care.

IntroductionUnderstanding the links between metabolism, ageing and age-related phenotypes may clarify the role of ageing in disease onset and improve risk prediction. MethodsWe conducted a cross-cohort assessment of biological age using broad-spectrum LC-MS metabolomics in 2,295 participants, aged 20-89, from the UK Airwave study (N=960) and The Irish Longitudinal Study of Ageing (N=1,335). ResultsN2,N2-dimethylguanosine, C-glycosyltryptophan, bile acid glucuronides, and zeta-carotene were associated with chronological age, frailty, and mortality. We developed a metabolomic clock that was highly predictive of chronological age (r = 0.92) in test samples. Metabolomic age acceleration was strongly correlated between study visits (r > 0.6). Each standard deviation higher metabolomic age acceleration ([~]5 years) was associated with 43% higher mortality risk, 27% higher risk of mild cognitive impairment, and 10% increased risk of a higher frailty score in fully adjusted models. DiscussionOur metabolomic clock provides a reproducible marker of generalised age-related disease risk.

Many overgrowth syndromes are associated with increased risk of tumorigenesis and malignancies. Our group recently identified a frameshift variant in histone reader SPIN4 located on the X chromosome to be a new genetic cause for human overgrowth. In the current study, we investigated the prevalence of malignancies, along with body weight, body length, body composition and bone mineral density, in Spin4 knockout mice at 18 months of age. We found that male mice lacking Spin4 have increased number of tumors and increased body length, while body weight, body composition and bone mineral density were comparable with wild-type mice. We also analyzed publicly available expression data in various types of human cancers and looked for increased or decreased expression of genes that are implicated in overgrowth syndromes and act through epigenetic mechanisms. We found that the expression of SPIN4, EZH2, and DNMT3A to be elevated in many human cancers compared to the corresponding non-malignant tissue samples. Taken together, our current findings confirm that loss of SPIN4 causes overgrowth in mice (in terms of body length) and is associated with increased prevalence in neoplasia; but does not appear to affect adiposity or bone density.

BACKGROUNDLittle is known about whether epigenetic age acceleration (EAA) clocks are capable of predicting exceptional longevity with or without preserved cognitive function. METHODSWe examined 5844 women from the Womens Health Initiative Memory Study. Fifteen epigenetic clocks were measured at baseline (1996-1999). Longevity outcomes were defined as: 1) survival to age 90 with preserved cognition (n=1726, 29.5%); or 2) survival to age 90 with cognitive impairment (n=956, 16.4%); vs. 3) death before age 90 (n=2611, 44.7%). Logistic regression models examined associations between the 15 clocks and survival to age 90 (vs. death before age 90), adjusting for covariates. Multinomial logistic regression models examined associations with survival to age 90 without cognitive impairment and survival to age 90 with cognitive impairment (each vs. death before age 90), also adjusting for covariates. FINDINGSEach standard deviation increase in EAA for the first-generation clocks was associated with 7%-18% reduced odds of survival to age 90 vs. earlier death. Stronger associations were observed for second- and third-generation clocks, including AgeAccelGrim2 (OR=0.66; 95% CI 0.61-0.71), PCGrimAge (OR=0.64; 95% CI 0.59-0.69), PCPhenoAge (OR=0.73; 95% CI 0.68-0.78) and DunedinPACE (OR= 0.77; 95% CI 0.72-0.82). None of the clocks was more strongly associated with survival to age 90 with preserved cognition than with survival to age 90 with cognitive impairment, relative to death before age 90. INTERPRETATIONAll epigenetic clocks were associated with exceptional longevity, but none were associated with cognitive healthspan. Developing clocks that can differentiate long survival with and without preserved cognitive function is critical.

BackgroundVestibular complaints are common in older adults and are linked to imbalance and falls. Some older adults show impaired vestibular perception despite preserved peripheral-reflex ("vestibular agnosia"). Yet it remains unclear if vestibular agnosia is independently linked to imbalance and falls in otherwise healthy older adults. We therefore investigated the prevalence of vestibular agnosia in community-dwelling older adults, and examined its association to balance and prospective falls. MethodsVestibular perceptual thresholds were measured during yaw-plane rotational chair testing. Postural sway and instrumented Timed-Up-and-Go were assessed using wearable sensors, and falls were recorded prospectively over six-month. Vestibular agnosia was identified using K-means clustering. Multivariable regressions examined associations between perceptual thresholds and balance outcomes; logistic and negative binomial regressions evaluated associations with prospective falls. ResultsAmong 166 participants (75.4 years; 81.9% female), 18.7% were classified as having vestibular agnosia. These individuals had worse cognition and somatosensation. Elevated (i.e. worse) vestibular perceptual thresholds were independently associated with greater sway velocity when standing on foam with eyes-open (adjusted {beta}=0.002, p=0.03). Associations with other balance outcomes were attenuated after adjustment. Vestibular perceptual thresholds were not associated with prospective falls (odds of [≥]1 fall: adjusted OR=0.99, p=0.65; fall counts: adjusted IRR=1.02, p=0.35). ConclusionsApproximately one-fifth of healthy older adults exhibit vestibular agnosia. While elevated perceptual thresholds are independently associated with poorer balance, they did not predict falls. Vestibular perceptual testing provides complementary insight into age-related balance impairment, although its utility in fall-risk prediction requires further investigation. Key PointsO_LIApproximately one-fifth of healthy older adults had vestibular agnosia (impaired vestibular perception despite intact peripheral function) C_LIO_LIOlder adults with vestibular agnosia have poorer cognition, reduced lower limb somatosensation, and higher anxiety. C_LIO_LIHigher (i.e. worse) vestibular perceptual thresholds were independently associated with greater sway velocity when standing on foam (eyes open). C_LIO_LIHigher vestibular perceptual thresholds were only associated with slower TUG performance and greater eyes-closed foam sway in unadjusted models. C_LIO_LIVestibular perceptual thresholds did not predict prospective falls over 6 months. C_LI

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.

Biomarkers of aging, particularly DNA methylation-based clocks, have shown promise as tools to assess whether interventions may impact the rate of biological aging. Among possible interventions physical exercise has shown protective effects against many age-associated diseases, while time-restricted feeding (TRF), has shown metabolic benefits in preclinical models. The combined effect of exercise and TRF on aging biomarkers remains largely unexplored. In this 52-week four-armed, randomized, controlled trial (clinicaltrials.gov: NCT07207044) 240 healthy adults aged 65 and over will be allocated to four groups: combined cardio and strength training (EXE), TRF, combined EXE and TRF, or control. Participants will undergo assessments at baseline, 3, 6, and 12 months, with follow-ups at 2, 5, and 10 years. The primary outcome measure is DNA-methylation age with secondary measures including RNA-sequencing, metabolomics, inflammatory marker, microbiome analysis, cognitive and physical measures. By deeply phenotyping participants the Fasting And eXercise (FAXAge) study will provide novel insights into whether TRF, EXE, or a combination can slow or reverse biological aging in older adults.

Chronic pain has been identified as a risk factor for cognitive decline in later life. However, most studies measure pain at a single time point and none have investigated whether variations in pain severity are associated with changes in cognitive function over time. This project aimed to assess the relationship between individual-level change in pain severity and decline in cognitive function over time. We used data from the English Longitudinal Study of Ageing (ELSA), a cohort of nationally representative middle aged and older adults. Pain severity was measured at each wave using a 4-point scale (none, mild, moderate and severe) and cognitive function was assessed using 3 objective tests. We applied latent growth curve modelling, a method for longitudinal analysis, to 19,376 ELSA participants data collected over 11 waves, spanning more than 20 years, to examine the relationship between initial level and change of both pain and cognitive function. Adjusting for age and sex, worsening chronic pain severity was associated with accelerated decline in a general measure of cognitive function ({beta} = -0.053, p = 0.039). However, when additionally adjusting for ethnicity, socioeconomic status and comorbid chronic conditions, this association was attenuated to non-significance ({beta} = -0.025, p = 0.365). Greater initial pain severity was associated with steeper decline in cognitive function even in the fully adjusted model ({beta} = -0.104, p < 0.001). Our study suggests that baseline level of pain severity but not worsening pain severity is associated with steeper decline in cognitive function over time. SUMMARYAge- and sex-adjusted analyses find that higher baseline and worsening pain severity predict faster cognitive decline; only baseline pain remains significant after full adjustment.

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.

The aim of this study was to investigate the effects of cognitive dual-tasking on low-frequency oscillations during quiet standing in older adults. Thirty-two older adults (age 71{+/-}8 yrs) were categorized into high- and low-risk fall groups. Both groups performed three trials each of the following tasks: 1) quiet standing with eyes open - on a force plate; 2) quiet standing with eyes open and verbal memory encoding task - on a force plate; and 3) quiet sitting with eyes open and verbal memory encoding task - not on a force plate. We found that: A) older adults at high fall risk exhibit greater postural sway when compared with older adults at low fall risk, B) most of the absolute and normalized wavelet power from 0-4 Hz is concentrated within the 0-1 Hz frequency band across all directions, and C) the absolute change in wavelet power in the 0-1 Hz band from single to dual-task is associated with increased total COP sway displacement irrespective of fall risk group. Based on these findings, it is concluded that nonlinear postural sway measures provide valuable insights into age-associated changes in fall risk and dual-task performance. Focusing on low-frequency oscillations, particularly in the 0-1 Hz band, could enable the earlier identification of individuals at high risk of falls and a better understanding of how the dual-tasking paradigm challenges the aging population.

Gait variability is a critical functional indicator of dynamic balance and neurocognitive decline in health. Its translation into clinical practice is, however, challenged by a lack of age-related normative trajectories and reference values under real-world ecological settings. Furthermore, the conventional metrics used to estimate gait variability (Coefficient of Variation, CV; Standard Deviation, SD) have a fundamental methodological flaw: the inherent sensitivity of conventional metrics to the statistical outliers and environmental noise in real-world walking. In this study, we mitigate this factor by applying a robust statistical framework to quantify gait variability. Analysing a large-scale cohort of community-dwelling older adults (n=2,193), we first demonstrate that freeliving gait data follows a heavy-tailed distribution, necessitating the use of robust estimators like the Robust Coefficient of Variation (RCVMAD) and Median Absolute Deviation (MAD). Leveraging these metrics, we established the normative trajectory and reference values of real-world gait variability across the ageing lifespan, revealing a distinct, age-dependent increase in spatio-temporal fluctuations, indicating a decline in rhythmicity and steadiness with age. We further demonstrated the clinical utility of these robust metrics: RCVMAD consistently yielded larger effect sizes than conventional CV in discriminating between fallers and non-fallers across all gait parameters. Furthermore, we illustrate the potential of long-term unsupervised monitoring to capture intrinsic variability during real-world walking. Validated for consistency and reliability, this robust framework provides the necessary ecological validity to transform gait variability into a standardised, rapid clinical metric for assessing functional decline at an early timepoint.

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 Poor physical function has been associated with higher cardiovascular disease (CVD) risk. However, the association between physical function and atrial fibrillation (AF) remains understudied. The comprehensive investigation of the association between physical function and incident AF risk could highlight a novel target for AF prevention. Methods A total of 4,803 participants without diagnosed AF from the Atherosclerosis Risk in Communities (ARIC) Study cohort with physical function assessed in 2011-2013 were studied. Physical function was measured using Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength. Hospital discharge codes and death certificates were used to ascertain incident AF through 2022, and through 2020 for participants from Jackson. Cox regression was used to assess the association between physical function and incident AF risk, adjusting for multiple covariates. Z-score transformations were performed to identify the physical function measure most strongly associated with incident AF risk, and SPPB component analysis was performed to identify the most influential SPPB component. Results Mean age of the study participants was 75.1 {+/-} 5.0 years, with 41.2% being male participants and 22.2% being black participants. During a median follow-up of 9.2 years, there were 809 incident AF events. SPPB (HR: 0.93, 95% CI: 0.90-0.96, per 1-point increase) and grip strength (HR: 0.87, 95% CI: 0.78-0.96, per 10kg increase) were inversely associated with incident AF risk, while 4-meter walk time (HR: 1.08, 95% CI: 1.03-1.13, per 1-second increase) was positively associated with incident AF risk. SPPB had the strongest association with incident AF risk. Within SPPB, only the chair stand component was significantly associated with incident AF risk. Conclusions The findings suggest that better physical function is associated with reduced incident AF risk, with higher SPPB having the strongest association. Given the modifiable nature of physical function, these findings highlight a potential novel target for AF prevention in aging populations.

Plasma biomarkers of Alzheimers pathology have been studied in relation to cognitive decline and dementia, but no prior study has examined their associations with longevity or healthspan. In this cohort study of older women (N=2,576), we examined plasma biomarkers measured at baseline when women were cognitively unimpaired. We found that plasma biomarkers were associated with both exceptional longevity and healthspan, defined as survival to age 90 without cognitive impairment. Elevated levels of plasma p-tau217 (OR, 0.58; 95% CI, 0.50-0.68), p-tau181 (OR, 0.81; 95% CI, 0.71 - 0.93), NfL (OR, 0.70; 95% CI, 0.60 - 0.82) and GFAP (OR, 0.78; 95% CI, 0.68 - 0.90) were all associated with reduced odds of healthspan; findings survived adjustment for multiple comparisons. These findings suggest that plasma biomarkers may not only reflect ADRD pathology but also systemic aging processes that underlie lifespan and healthspan, underscoring their potential value as novel biomarkers of aging.

{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.

ObjectivesGrowth Mindset and Grit have been proposed as key psychological resources for resilience and adaptation, yet their manifestation and social distribution in later life remain underexplored. This study examines the structure, distribution, and correlates of Growth Mindset and Grit in older adulthood using proxy indicators in the English Longitudinal Study of Ageing (ELSA). MethodsProxy indicators reflecting learning behaviour, personality traits, affect, and beliefs were used to derive three components of Growth Mindset (education-, personality-, and belief-based) and two components of Grit (affective- and personality-based). Multinomial logistic regression models examined associations with age, socioeconomic position, health, and cognitive functioning. ResultsDistinct distributional patterns emerged across components. Education-based Growth Mindset was concentrated in lower categories, whereas personality-, belief-, and affect-based components showed greater variability. Older age was associated with lower Growth Mindset, particularly in education- and belief-based domains, while associations with Grit were more nuanced, including a lower likelihood of low affect-based Grit among older adults. Higher educational attainment, employment, wealth, and better memory performance were associated with more favourable profiles across selected domains. Living alone and limiting longstanding illness were consistently associated with less favourable profiles. ConclusionsGrowth Mindset and Grit appear to function as multidimensional and socially patterned psychological resources in later life. Belief-, personality-, and affect-based components capture meaningful variation even when formal learning declines, underscoring the importance of distinguishing opportunity-constrained indicators from dispositional domains in ageing research.