The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences

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

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

Objectives. The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA). Methods. Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL [≤] 1, n = 326) and two nested case groups: (a) KL [≥] 2 (n = 197), (b) KL [≥] 3 (n = 112). Results. Compared with controls, there were 27 and 41 genes associated (FDR [≤] 0.05) with KL [≥] 2 and KL [≥] 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL [≥] 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL [≥] 2 and KL [≥] 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism. Conclusions. Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.

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.

Background: This study investigates whether proteomic aging clocks (PACs) are associated with cerebral small vessel disease (CSVD). Methods: We included participants from two US community-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Study. These analyses leveraged PACs that were developed in ARIC using proteomics measured by SomaScan in midlife (Visit 2; mean age 56 y; n=1,486) and late-life (Visit 5; mean age 76 y; n=1,496), trained on chronological age. Proteomic age acceleration (PAA) was calculated as residuals from regressing PACs on chronological age. 3T brain MRI data were collected in late-life. We examined associations of PAA with log-transformed white matter hyperintensity (WMH) volume using linear regression and with the presence of microbleeds, and subcortical, lacunar, and cortical infarcts using logistic regression. Associations of PACs with WMH volume and microbleeds were tested in MESA using proteins measured at Exam 1 (mean age 57 y; n=932) and Exam 5 (mean age 66 y; n=934). All associations were quantified per 5-year increase in PAA. All models were adjusted for demographics and cardiovascular risk factors. Results: In ARIC, higher midlife PAA was associated with greater WMH volume (percent difference: 25% [95% CI: 13%, 39%]) and higher odds of subcortical infarcts (OR: 1.24 [1.02, 1.51]). Late-life PAA was associated with all CSVD markers: WMH volume (percent difference: 20% [8%, 34%]), cerebral microbleeds (OR: 1.40 [1.15, 1.69]), subcortical (OR: 1.80 [1.47, 2.22]), lacunar (OR: 1.80 [1.46, 2.23]), and cortical infarcts (OR: 1.39 [1.07, 1.82]). In MESA, higher late-life PAA was associated with greater WMH volume (28% [3%, 58%]) but not with microbleeds. Conclusion: Accelerated proteomic aging is associated with a higher prevalence of MRI markers of CSVD, most predominantly in late-life. Understanding this relationship may help stratify those at higher risk of CSVD at an early stage.

While bone mineral density (BMD) remains the clinical standard for assessing age-related fracture risk, accumulating evidence indicates that bone quality, including matrix properties and microarchitecture, contributes to fracture susceptibility in ways not captured by BMD alone. As matrix-targeted therapeutics emerge, preclinical models that exhibit translationally relevant bone quality changes are needed. Here, we evaluated the Fischer 344 x Brown Norway (F344xBN) F1 rat, a strain characterized by hybrid vigor and non-pathological aging, as a model for studying matrix-related mechanisms of skeletal aging. Femurs from male and female rats aged 7, 15, and 22 months were analyzed to quantify age- and sex-dependent changes in bone microarchitecture, fracture resistance, and matrix properties. Microcomputed tomography analyses revealed sexually dimorphic aging trajectories. From 7 to 22 months, females exhibited moderate declines in trabecular microarchitecture and no change in cortical porosity, whereas males showed pronounced trabecular deterioration and increased cortical porosity. Whole-bone flexural testing demonstrated age-related declines in material properties that were not attributable to changes in geometry, while females maintained geometry-scaled bone strength. Both sexes exhibited reduced bone toughness with age. Raman spectroscopy identified matrix-level alterations in males by 15 months, whereas systemic markers of bone turnover remained unchanged across age or sex. Together, these findings indicate that males exhibit combined tissue-scale and whole-bone deterioration by midlife, while females exhibit declining fracture resistance preceding substantial cortical bone loss or overt matrix deterioration. These results support the F344xBN F1 rat as a translational model for investigating matrix-driven skeletal aging. Lay summaryF344 x BN F1 hybrid rats provide a healthy, matrix-driven skeletal aging model. This strain exhibits distinct aging trajectories dependent on sex. Strength and toughness decrease in both sexes by midlife. Fracture resistance declines in females prior to substantial bone loss.

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.

BackgroundAging and disuse are two of the most clinically relevant conditions associated with the loss of skeletal muscle mass, yet the ultrastructural adaptations that drive these losses remain poorly defined. In particular, it is unclear whether radial atrophy of muscle fibers is driven by a reduction in the size of the existing myofibrils, and/or the loss of myofibrils. Accordingly, the objective of this study was to define the macro-to-ultrastructural adaptations that mediate aging- and disuse-induced loss of muscle mass. MethodsSkeletal muscle structure was assessed at the macroscopic, microscopic, and ultrastructural levels in humans and mice. In humans, magnetic resonance imaging was used to quantify knee extensor muscle volume and cross-sectional area (CSA) in young (19 - 40 years) and old (65 - 84 years) adults, and vastus lateralis biopsies were analyzed for microscopic and ultrastructural adaptations using immunohistochemistry and fluorescence imaging of myofibrils with image deconvolution (FIM-ID). Parallel studies were performed in young (4 months) and aged (24 months) mice, along with the use of unilateral hindlimb immobilization to model disuse. ResultsAging led to a robust loss of skeletal muscle mass that was mediated by coordinated macro-to-ultrastructural adaptations. In humans, aging reduced knee extensor muscle volume (34%, P < 0.005) and CSA (32%, P < 0.001) in a sex-independent manner, and these effects were associated with radial atrophy of SERCA1-positive fibers (23%, P < 0.05). Ultrastructural analyses revealed that the radial atrophy was driven by a reduction in the number of myofibrils per fiber (23%, P < 0.05) without changes in myofibril CSA. In mice, aging produced similar macro-to-ultrastructural adaptations in various flexor muscles; however, radial atrophy of the highly glycolytic/Type IIb fibers, which are not present in human limb muscles, was also associated with a decrease in the CSA of the myofibrils (9%, P < 0.005). We also determined that disuse led to radial atrophy of SERCA1-positive fibers (24%, P < 0.001), and this was mediated by a decrease in both the number (22%, P < 0.005) and size of the myofibrils (4%, P < 0.05). Notably, the results also revealed that the magnitude of the disuse-induced adaptations was significantly blunted with aging. ConclusionThis study identifies the loss of myofibrils as a central and conserved mediator of the radial atrophy of muscle fibers that occurs in response to disuse and aging, while also highlighting smaller context-dependent contributions that can arise from changes in myofibril size.

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.

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

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.

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.

Background: Epigenetic clocks based on DNA methylation (DNAm) have emerged as promising biomarkers of biological aging, yet their associations with cognitive performance remain inconsistent. This study investigates the relationship between epigenetic age acceleration and cognitive performance in older adults using 14 DNAm clocks from five generations of development. Methods: We analyzed data from the Berlin Aging Study II (BASE-II) using genome-wide DNAm profiles and cognitive assessments ascertained at baseline (T0) and two follow-up time points (T1, T2) in up to 1,014 individuals. DNAm-based age and age acceleration estimates were calculated using Biolearn and MethylCIPHER. Analyses focused on cross-sectional and longitudinal associations between DNAm clock estimates and cognitive performance, including sex-specific effects and comparisons with frailty as non-cognitive positive control. Results: Among all tested DNAm clocks, DunedinPACE (a third-generation clock) showed the strongest and most consistent associations with cognitive performance. In addition, the fifth-generation SystemsAge framework also demonstrated robust associations with cross-sectional and longitudinal cognitive outcomes. In contrast, second-generation clocks (GrimAge [v2], PhenoAge) showed occasional nominal associations, while first-generation clocks (Horvath [v1], Hannum) and the causally-informed, fourth-generation clocks (e.g. YingCausAge, YingDamAge) showed no noteworthy signals. Likewise, telomere length estimated from DNAm was not strongly associated with cognitive performance in this dataset. Conclusions: Our findings highlight DunedinPACE as a particularly informative biomarker for various aspects of cognitive aging, while other DNAm aging measures showed no consistent associations. Future work should further refine domain-specific epigenetic biomarkers to improve biological aging assessments and achieve a more reliable early detection of cognitive decline.

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.

BackgroundObesity and metabolic disease drive premature aging and reduced lifespan. While metabolic interventions like calorie restriction, protein restriction, and time restricted feeding have been shown to improved lifespan, they are either not effective or sustainable for most humans. Bariatric surgery is the most efficacious metabolic intervention available and is associated with increased lifespan. However, whether its longevity benefits derive solely from weight reduction or reflect surgery-specific metabolic reprogramming remains unknown. MethodsWe employed a lean mouse model of sleeve gastrectomy (SG) in which young, lean male C57BL/6J mice underwent SG or sham operation while maintained on low-fat chow, then were challenged with high-fat diet (HFD) in midlife. We assessed glucose metabolism, body composition, energy expenditure, hepatic histology, adipose tissue inflammation, and cecal microbiome composition. ResultsDespite identical weight and food intake on low-fat chow, SG mice demonstrated improved glucose tolerance and insulin sensitivity prior to HFD challenge. Upon HFD exposure, SG animals exhibited enhanced metabolic flexibility with greater capacity for fat oxidation, increased energy expenditure, attenuated weight gain, and reduced adiposity compared to sham controls. SG further reduced hepatic lipid accumulation and attenuated visceral adipose tissue inflammation, marked by decreased pro-inflammatory cytokine expression and reduced macrophage infiltration. These metabolic benefits occurred independently of caloric intake. Cecal microbiome profiling revealed surgery-specific remodeling characterized by Lactobacillus enrichment and reductions in Verrucomicrobia and Clostridia -- a pattern distinct from caloric restriction and consistent with prior SG studies. ConclusionsEarly-life SG confers durable, weight-loss-independent protection against midlife metabolic deterioration. Gut microbiome remodeling, particularly enrichment of Lactobacillus species, represents a candidate mediating mechanism and a potential therapeutic target for aging and metabolic disease.

BackgroundVitamins are important modulators of intestinal health and may affect the gut-brain axis through microbial metabolites such as short-chain fatty acids (SCFAs). However, the neurocognitive effects of colon-delivered vitamins in older adults remain unexplored - a critical gap given the gut-brain axiss emerging role in cognitive aging. ObjectiveWe investigated the effect of a colon-delivered multivitamin (CDMV) supplement on intestinal health and neurocognitive outcomes in older adults at risk of cognitive decline. MethodsWithin the double-blind randomized placebo-controlled trial COMBI (ClinicalTrials.govID: NCT05675007), we included 75 older adults (60-75 years) at risk of cognitive decline based on lifestyle-related factors. Participants consumed a colon-delivered capsule with vitamins B2, B3, B6, B9, C and D3, or a placebo, daily for six weeks. Pre- and post-intervention, we employed neuroimaging, feces- and blood collection. Primary outcomes were fecal SCFA concentrations, working memory (WM)-related fMRI responses, and WM performance measured with the n-back task. ResultsAfter adjusting for baseline values, we found no significant between-group differences in total fecal SCFA levels (p=0.30) and WM performance (p=0.50). Post-intervention WM-related fMRI responses in the hippocampus (p=0.01; p{superscript 2}=0.09) and dorsolateral prefrontal cortex (dlPFC) (p=0.06; p{superscript 2}=0.04), driven by the right dlPFC (p=0.02), were higher in the CDMV group compared to placebo. Independent of intervention group, post-pre increases in fecal SCFA levels were significantly correlated to increases in dlPFC fMRI responses ({rho}=0.31; p=0.02) and WM performance ({rho}=0.43; p=0.001). ConclusionsOur findings suggest that CDMV supplementation increases WM-related responses of the dlPFC and hippocampus in older adults, but this effect was not accompanied by changes in fecal SCFA levels or WM performance. The positive correlation of within-subject changes in fecal SCFAs with changes in WM dlPFC responses and performance across intervention groups provides human evidence for gut-brain communication in cognitive aging beyond cross-sectional associations.

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.

BackgroundOlder adults exhibit hallmark changes in gait mechanics that may contribute to mobility loss. These changes are suggested to be precipitated by decreased mechanical output from the ankle plantar flexor muscles. However, the extent of age-related changes within individual triceps surae muscles and the consequences for plantar flexor specific torque (torque per unit muscle) and walking mechanics remains unclear. The study aims were to quantify age-related differences in triceps surae muscle cross-sectional area (CSA), fat fraction and peak absolute and specific plantar flexion torque, and to evaluate their relationships with positive hip and ankle work distribution during walking. MethodsEleven younger (36.2 +/-3.4 years, 5 female) and 12 older (73.3+/-2.8 years, 6 female) adults completed dynamometry, magnetic resonance fat-water imaging of the shank, and overground gait analysis at a prescribed (1.2 m/s) and fast walking speed. ResultsOlder adults had a smaller fat-free muscle CSA for the soleus and medial gastrocnemius, resulting in {bsim}25% smaller triceps surae CSA. There was no difference by age in fat fraction for any muscle. Peak plantar flexor torque was lower in older and proportional to the differences in cross-sectional area, thus specific torque did not differ by age. Older adults generated greater positive hip work at both speeds and less positive ankle work at the fast speed leading to a greater redistribution ratio compared to younger. However, no significant correlations were found between the redistribution ratio and triceps surae muscle morphology or plantar flexion absolute or specific torque in older adults. ConclusionsThese results suggest that triceps surae muscle morphology and function may not be a primary source of age-related changes in gait mechanics in healthy older adults.

BackgroundOlder adulthood is often accompanied by declines in auditory processing and cognitive functioning, increasing the risk of reduced autonomy and quality of life. Multidomain lifestyle interventions have shown potential to counteract these changes, and choir-based activities represent a promising approach by simultaneously engaging auditory, cognitive, physical, and social domains. However, evidence regarding their feasibility and neurophysiological impact in community-dwelling older adults, particularly those without formal musical training, remains scarce. MethodsThis 9-month quasi-experimental feasibility study involved 54 community-dwelling older adults (mean age = 72.9 years) with no formal musical background. Participants self-selected into a choir-based intervention group, an active control group engaging in non-musical leisure activities, or a passive control group; however, some participants in the control groups were selected from the waiting list for the choir. Assessments were conducted at baseline and follow-up and included measures of global cognition, cognitive reserve, psychological well-being (Flourishing Scale), multidimensional frailty (Selfy-MPI), music perception, pure-tone audiometry, and auditory evoked potentials recorded using a standardized clinical oddball paradigm. ResultsThe choir-based intervention was feasible in a community setting. At the neurophysiological level, choir participation was associated with a bilateral, significant shortening of the N2-P3 inter-peak latency, indicating faster auditory-cortical processing. Additionally, through explorative analyses multidimensional frailty, as assessed by the Selfy-MPI, showed a significant reduction in individuals engaging in a higher number of activities, irrespective of group allocation. Similarly, psychological well-being revealed a decrease in flourishing scores in the passive control group relative to the choir group. No changes were observed in audiometric thresholds or music perception measures. ConclusionChoir-based multidomain participation is a feasible intervention for community-dwelling older adults without formal musical training and is associated with selective benefits in cognitive reserve, psychological well-being, auditory-cortical processing speed, and multidimensional frailty. These findings provide a foundation for a larger randomized controlled trial aimed at clarifying the cognitive, psychosocial, and neural mechanisms underlying choir-based interventions in ageing. Trial RegistrationThe upcoming trial has been prospectively registered on ClinicalTrials.gov (ID: NCT06767410; registration date: January 9, 2025).

Sarcopenia is a geriatric condition characterized by the loss of muscle strength, muscle mass, and physical performance, yet its neural mechanisms remain insufficiently understood. This study aimed to identify cortical indicators of motor and cognitive functioning in individuals with sarcopenia using functional near-infrared spectroscopy (fNIRS), along with electromyography (EMG) and hand dynamometer measurements. 30 sarcopenia patients (age 67.33 {+/-} 7.48, F/M: 22/8) and 38 healthy controls (age 65.37 {+/-} 4.18, F/M: 29/9) participated in three experimental sessions designed to probe different neural systems: a Hand Grip task to assess motor function, an N-Back task to evaluate working memory, and an Oddball task to measure attention and inhibitory control. fNIRS measurements were carried out during all experimental sessions, while EMG and force output were extracted from the Hand Grip task. Group differences and neural-behavioral relationships were examined using t-tests, correlations, and repeated measures analyses. Participants with sarcopenia demonstrated significantly reduced EMG activity and force production. Although motor cortex responses during the Hand Grip task were similar between groups, the N-Back task revealed lower activation in the precentral, middle frontal, and superior frontal regions in the sarcopenia group. In contrast, the Oddball task showed increased right-hemisphere activation in sarcopenic individuals, suggesting compensatory recruitment. Significant correlations between cortical activity, grip strength, and Chair Stand Test performance indicated shared neural pathways linking motor and cognitive function. These findings highlight altered neural processing in sarcopenia and emphasize the importance of integrating neuroimaging with clinical measures to advance early detection and targeted intervention strategies. HighlightsO_LIfNIRS assessed motor and cognitive cortical activity in sarcopenia. C_LIO_LISarcopenia showed lower EMG amplitude and grip force output. C_LIO_LINo group difference in motor cortex activation during hand grip. C_LIO_LIN-back revealed lower frontal and precentral activation in sarcopenia. C_LIO_LIOddball showed higher right-hemisphere activation in sarcopenia. C_LI