Experimental Gerontology

Introduction: Stair walking challenges balance and coordination in older people. Bench-stepping training improves stair climbing speed in healthy older women. This study assessed whether bench-stepping also improves dynamic balance and movement complexity during stair walking. Methods: Stair walking data were obtained from a previous study involving 45 healthy older women (69y+/-4) that assessed the effects of a 12-week bench-stepping intervention with non-training controls. Centre-of-mass acceleration was measured during stair ascent and descent. Linear dynamics included time, acceleration magnitude, and harmonic ratios (HR; indicating symmetry). Movement complexity was quantified using nonlinear dynamics including sample entropy (SE), recurrence quantification analysis (RQA), and fractal dimension (FD). Results: For stair ascent, increased speed (p =0.018, R2partial =0.093,) was accompanied by proportional increases in acceleration magnitudes (p=<0.039, R2partial =0.078-0.101). SE decreased more in the intervention group (p=<0.012, R2partial =0.049-0.101), indicating more predictable dynamics. In contrast, for stair descent, no changes in speed or acceleration magnitudes were observed. However, SE (p =0.001, R2partial =0.082) and maximum RQA line length (p= 0.008, R2partial =0.057) of vertical acceleration increased significantly compared to controls, indicating lower predictability and more persistent recurring patterns. No significant changes were found for other outcomes. Exploratory factor analysis revealed distinct differences in motor behaviour between stair ascent and descent. Conclusion: Bench-stepping training induced measurable changes in stair walking dynamics. Specifically, sample entropy shows potential as a sensitive marker of altered motor complexity, particularly of vertical accelerations. Interestingly, the direction of changes in unpredictability differed between stair ascent and descent, suggesting different underlying control strategies.

Background: Coronary artery disease (CAD) increases the risk of cognitive impairment, dementia, and brain structural alterations. This heart-brain connection suggests that exercise-induced cardiovascular responses may influence brain regions vulnerable to Alzheimer's disease (AD), the most common cause of dementia. This study aimed to examine the effects of 12-weeks of either high-intensity interval training (HIIT) plus resistance training (RT) or HIIT alone on AD brain signatures in individuals with CAD, to explore moderating factors, and to assess associations between changes in AD brain signatures and cognition and physical fitness. Methods: This secondary analysis of a single-site, three-arm, single-blinded randomized controlled trial included 105 individuals with CAD (50-75 years; 21% female) randomly allocated to HIIT+RT, HIIT, or usual care (UC) groups. T1- and diffusion-weighted magnetic resonance imaging were acquired before and after the 12-week intervention. Primary outcomes were thickness/volume and gray matter mean diffusivity (GMMD) signatures, derived from seven cortical regions and the hippocampus. Moderators included age, sex, education, and baseline AD brain signatures. Results: For the thickness/volume signature, no between-group differences in changes were observed between HIIT+RT and UC (+0.13 standardized mean difference [SMD]; 95% CI, -0.07 to 0.33) or between HIIT and UC (-0.1 SMD; 95% CI, -0.3 to 0.1); however, a small but significant between-group difference in change was found between HIIT+RT and HIIT, in favor of HIIT+RT (+0.23 SMD; 95% CI, 0.03 to 0.42). For the GMMD signature, no significant between-group differences in changes were found between HIIT+RT and UC (+0.08 SMD; 95% CI, -0.18 to 0.34), HIIT and UC (+0.1 SMD; 95% CI, -0.16 to 0.36), or HIIT+RT and HIIT (-0.02 SMD; 95% CI, -0.28 to 0.23). No moderation effects were identified, and no associations were observed between changes in AD brain signatures and cognition or physical fitness. Conclusion: A 12-week HIIT+RT intervention was more effective than HIIT alone in increasing the thickness/volume signature in individuals with CAD, yet no differences were observed compared to UC and the interventions did not affect the GMMD signature. These findings suggest that the intra-session inclusion of RT with HIIT may enhance AD-related brain macrostructure in individuals with CAD more than just HIIT training.

Introduction Frailty is an ageing-related state associated with disability and mortality. Women often experience higher frailty but lower mortality than men, a pattern described as the male-female health-survival paradox. Evidence from low- and middle-income settings is limited. We examined sex differences in frailty trajectories and terminal decline in Mexico. Methods We analysed five waves (2001-2018) of the nationally representative Mexican Health and Aging Study (MHAS) including 12,440 adults ([&ge;]50 years at baseline). Frailty was measured using a 31-deficit frailty index (FI score; 0-1). We used survey-weighted linear mixed-effects models with time interactions, adjusted for sociodemographic, behavioural and health covariates to model sex differences in frailty trajectories. Terminal decline in FI was modelled among those who died using mixed-effects models on the time-to-death scale. Results A total of 12,440 adults aged 50 to 105 years were included, with a mean age of 62.1 years (SD 9.6); 5,698 men (45.8%) and 6,742 women (54.2%). Mean baseline FI was 0.17 (SD 0.12), higher in women than men (0.19 vs 0.16; P<0.001). After adjusting, women had a 0.014 higher mean FI than men at baseline (adjusted mean difference; 95%CI 0.008, 0.020), with difference widening over follow-up, increasing from 0.016 at 2 years to 0.029 at 17 years. Analysis of terminal decline found that accumulation of frailty accelerated in the years preceding death; with results suggesting that women reached death with higher frailty than men (difference 0.029; 95%CI 0.009, 0.048). Conclusion Women experienced higher and more rapidly increasing frailty compared to men and carried a greater frailty burden in the years preceding death. These findings underscore the importance of considering sex differences in frailty trajectories when developing healthy ageing strategies that address the life-course vulnerabilities disproportionately driving frailty accumulation in women in low- and middle-income countries.

Background: Elevated C-Reactive Protein (CRP), interleukin-6 (IL-6) and testosterone deficiency are associated with advanced age and chronic inflammatory diseases; while normal testosterone levels have been shown to decrease inflammation through several mechanisms. Cross-sectional studies have shown an inverse relationship between CRP, IL-6 and total testosterone (TT) levels, yet mixed findings have been reported when individual components of metabolic syndrome are considered. We evaluated the relationship between CRP, IL-6 and TT levels in men from 2004-2018 using the Baltimore Longitudinal Study of Aging to determine if low testosterone status is associated with a high inflammatory profile. Methods: Participants were selected from the Baltimore Longitudinal Study of Aging. Male participants with serum TT level measured during at least three visits were included in our cohort. Common measures of inflammatory disease such as CRP, High-Density Lipoprotein (HDL) and Triglyceride levels were collected via blood specimens. Comorbidity data were documented at each visit. Panel regression was used to analyze the relationship of a series of independent variables collected in pooled cross-sectional observations over time with a dependent variable for modeling. Results: A total of 347 patients were included in this study (median age = 70, IQR = 18, average follow up time = 6.7 +/- 3.2 years). Participants had a median CRP level of 1.0 mg/dL, median IL-6 level of 3.6, a median TT level of 446 ng/dL. On univariable analysis, increasing TT and HDL levels were associated with a decline in CRP, while high Body Mass Index (BMI), congestive heart failure (CHF), Diabetes, and increased serum triglycerides were associated with increased CRP. Age was not associated with CRP. On multivariable analysis, we found that increasing TT level was associated with a decline in CRP levels, independent of comorbidities (p = 0.018; Table 1). As expected, increased BMI was associated with a significant increase in CRP (p = 0.001, Table 1). Age, CHF, Diabetes, HDL, and Triglycerides were not significant predictors of CRP on multivariable analysis. Similarly, on multivariable analysis, increasing TT levels were independently associated with lower IL-6 levels. Higher HDL cholesterol levels were also associated with lower IL-6 levels, whereas increasing age was associated with higher IL-6 levels. BMI, CHF, diabetes, and triglycerides were not significant predictors of IL-6. Conclusions: Lower levels of serum total testosterone are associated with an increase in CRP in older men over time, independent of chronic inflammatory disease. Given the importance of CRP in pathogenesis of chronic disease, we highlight the potential benefits of using total testosterone as a biomarker of chronic inflammatory states.

Birds exhibit longer lifespans than similarly sized mammals, despite having higher mass-adjusted blood glucose levels. This makes them a valuable model for the comparative study of the metabolic and physiological aspects of aging. Circulating glucose contributes to multiple pathological processes, primarily through glycation reactions and the formation of advanced glycation end-products (AGEs), as well as by promoting oxidative stress. These mechanisms are interconnected by feedback loops and play a key role in the development of age-related pathologies. To explore the causal role of glycaemia in avian ageing, we conducted a one-year dietary supplementation experiment in captive zebra finches. Birds received either glucose- or methylglyoxal-enriched water. Previously, we observed that chronic glucose supplementation in zebra finches increased mortality, an effect that did not appear to be mediated by the associated increase in plasma protein glycation or AGE levels. Therefore, the mechanisms underlying increased mortality in the glucose group remained unclear. In the present study, we investigated how glucose and methylglyoxal supplementation affect blood oxidative status and red blood cell telomere dynamics and apoptosis. We found that methylglyoxal supplementation decreased the non-enzymatic antioxidant capacity (OXY) of plasma and increased DNA damage, while glucose supplementation had no significant effect on oxidative stress, although circulating glucose levels influenced oxidative status in a sex-dependent manner. Males exhibited a positive correlation between glucose levels and organic hydroperoxides and protein carbonyls. Additionally, we report, for the first time in birds, a seasonal variation in telomere length, which was more pronounced in glucose-supplemented individuals, yet seemed independent of oxidative status. Apoptosis probability increased with both treatments, particularly with the methylglyoxal supplementation. These results highlight that glucose and methylglyoxal trigger different glucotoxicity-related pathways, with distinct effects on bird health and aging. However, the relationship between glucose supplementation and mortality remains still unclear and warrants further investigation.

BACKGROUND: Aging is associated with a progressive decline in cognitive performance and functional autonomy, both closely related to frailty. Understanding the interrelation between these domains is essential to identify modifiable factors influencing cognitive impairment in older adults. OBJECTIVES: To evaluate the relationship between physical frailty, cognitive performance, and functional dependence, and to identify sociodemographic and clinical variables associated with cognitive impairment in community-dwelling older adults. DESIGN: Cross-sectional study. SETTING: FREEDOM-LNA cohort, a population-based study conducted by the University Hospital of Limoges, France. PARTICIPANTS: A total of 753 community-dwelling older adults aged [&ge;]75 years, or [&ge;]65 years with at least two comorbidities, were included. MEASUREMENTS: Cognitive function was assessed using the Mini Mental State Examination (MMSE), 5-word test (5WT), clock drawing test (CDT), and verbal fluency tests. Frailty was defined according to Frieds physical criteria, and functional independence was evaluated using ADL and IADL scales. Sociodemographic, clinical, and lifestyle factors were analyzed using multivariate models to identify predictors of cognitive impairment. RESULTS: Of the participants, 34.4% had a pathologic MMSE, 46.0% failed the CDT, 68.0% the verbal fluency test, and 17.0% the 5WT. Cognitive performance was significantly lower among frail compared to prefrail and robust individuals. Older adults with pathologic cognition were more frequently dependent in activities of daily living. Independent predictors of poor cognitive performance included non-modifiable factors (age, sex, education) and modifiable ones (low BMI, hypertension, alcohol consumption, smoking, and polypharmacy). CONCLUSIONS: Cognitive impairment was highly prevalent among frail older adults and was strongly associated with loss of independence. Interventions targeting modifiable risk factors such as low BMI, hypertension, alcohol consumption, and smoking may help preserve cognitive and functional abilities in aging populations. Interventions to improve BMI and reduce alcohol consumption, smoking, and hypertension may preserve cognition in older adults.

Objectives: Physical and cognitive aging do not occur uniformly, yet associations between specific physical function and cognitive domains in sedentary older adults remain unclear. This exploratory cross-sectional study examined associations between multiple physical function domains and cognitive outcomes in sedentary, community-dwelling, cognitively unimpaired older adults. Methods: Fifty-eight older adults (70.7{+/-}4.7 years; 84.5% Female) completed handgrip strength, 30-second chair stand, timed up and go (TUG), brisk walk, and 6-minute walk (6MWT) assessment. Cognitive outcomes included global cognition using the Montreal Cognitive Assessment (MoCA), and working memory, episodic memory, attentional inhibition, and cognitive flexibility using the NIH Toolbox. Linear regression models adjusted for age, sex, education, body mass index, and brachial pulse pressure. False discovery rate (FDR) correction was applied. Results: Greater 6MWT distance was associated with better episodic memory performance after FDR correction ({beta}=0.49, pa=0.028). Additional inverse associations were observed between TUG performance and global cognition ({beta}=-0.34, pa=0.166) and attentional inhibition ({beta}=-0.32, pa=0.180), and between gait speed and global cognition ({beta}=-0.33, pa=0.166) and episodic memory performance ({beta}=-0.32, pa=0.166), however, these did not survive FDR correction. Handgrip strength and chair stand performance were not associated with cognitive outcomes. Conclusions: These exploratory findings suggest that locomotor-based functional tasks may demonstrate stronger cognitive associations than strength measures in sedentary, cognitively unimpaired older adults. Tasks involving sustained locomotion and adaptive movement may place greater cognitive-motor demands, potentially increasing sensitivity to subtle cognitive variation. Larger longitudinal and multimodal studies are needed to determine whether these associations reflect reliable differential patterns across physical and cognitive domains.

Introduction: Mild Cognitive Impairment (MCI) is defined as a decline in one or more cognitive domains worse than expected for age and encompasses several subtypes depending on the cognitive(s) function(s) impaired. Older adults presenting amnestic MCI combined with one or several other impaired domains are the highest at risk of dementia. Yet, no consensual screening method for MCI in community-dwelling older adults has been established. The aim of this study was to identify cognitive aging profiles using multivariate analysis based on three neuropsychological assessments and to characterize profiles consistent with different probable MCI subtypes. Methods: A total of 161 community-dwelling older adults from the 13EVAL cluster-randomized controlled trial performed the Montreal Cognitive Assessment including the Memory Index Score, the Trail Making Test and the Victoria Stroop Test. Hierarchical clustering on principal components was conducted based on four cognitive domains (global cognition, memory, inhibition and cognitive flexibility) and age. Inter-groups comparisons were performed using one-way ANOVA. Individual performances were compared to normative standard for each assessment to characterize each group. Results: Three clusters were identified that differed significantly in age (F2,158=78.56, p<.001, 2p=.50), global cognition (F2,158=96.07, p<.001, 2p=.55), memory (F2,158=81.48, p<.001, 2p=.51), cognitive flexibility (F2,158=52.25, p<.001, 2p=.40) and inhibition (F2,158=12.14, p<.001, 2p=.13). Inter-groups comparisons and comparisons to normative values led to the characterization of Cluster 1 as normal cognition, Cluster 2 as probable executive MCI and Cluster 3 as probable amnestic and executive MCI. Conclusions: Individuals with cognitive profiles consistent with probable executive MCI were identified using simple assessments of global cognition, memory and executive functions in a community-dwelling older population. As participants were not clinically diagnosed, further prospective studies are needed to determine the screening performance of this approach.

Abstract Background: The influence of taurine on biological ageing remains unclear, particularly whether it acts as a causal driver or a functional biomarker. We aimed to disentangle the distinct roles of plasma taurine relative abundance, dietary taurine supply, and genetic metabolic capacity on all-cause mortality and unhealthy ageing. Methods: This prospective study used data from the Korean Genome and Epidemiology Study (2001~2022). A subcohort of 2,321 participants (mean age 56.5 years; 51.4% female) with complete metabolomic, dietary, and genomic data was analyzed. Three independent pathways were evaluated: (1) plasma taurine/total amino acid (AA) ratio, (2) dietary taurine to protein ratio, and (3) a weighted genetic risk score (GRS) from 21 SNPs in taurine biosynthesis and transport genes. Primary outcomes were all-cause mortality and unhealthy ageing (Physiological Healthy Ageing Index [PHAI] score [&le;] 25th percentile). Results: A higher plasma taurine/total AA ratio was consistently associated with improved ageing outcomes. Participants in the highest quartile showed 29% lower all-cause mortality (Hazard Ratio [HR], 0.71; 95% Confidence Interval [CI], 0.52-0.98; P for trend = .04) and lower risk of PHAI-based unhealthy ageing (HR, 0.77; 95% CI, 0.59-1.00; P for trend = .04) versus the lowest quartile. Dietary taurine-to-protein ratio was not associated with mortality (P for trend = .70), nor was the GRS (P for trend = .74). Conclusions: The protective association of taurine was linked to its relative abundance within the systemic amino acid pool, rather than dietary intake or genetic predisposition, supporting taurine as a functional biomarker of metabolic efficiency rather than a deterministic causal driver of ageing.

Background: Epigenetic clocks are markers of biological aging that may vary in their sensitivity to environmental stressors and lifestyle modifiers. To evaluate the utility of these biomarkers as sensors of the human exposome, we investigated how they respond to two powerful and opposing exposures: smoking, a source of oxidative stress, and the antioxidant-rich Mediterranean diet. Objectives: We assessed the sensitivity of eleven epigenetic clocks to diet and smoking and evaluated whether Mediterranean diet adherence modifies associations between smoking and epigenetic aging. Methods: We analysed 928 participants (mean age 41 years, 59% male) from the Airwave Health Monitoring Study. Linear regression models assessed associations between Mediterranean Diet Score (MDS) and epigenetic age acceleration (EAA), alongside smoking status and blood cotinine. Interaction terms between smoking status and MDS were included to detect dietary attenuation of smoking-related EAA. Models were adjusted for demographic, socioeconomic, lifestyle, and psychological covariates. Results: Higher MDS was associated with lower EAA for GrimAge ({beta} = -0.07 SD; 95% CI: -0.13, -0.01) and Bernabeu ({beta} = -0.08 SD; 95% CI: -0.14, -0.02) after false discovery rate correction. Smoking was strongly associated with increased EAA, particularly for GrimAge, Bernabeu, and DunedinPACE. Among current smokers, effect sizes were greater in those with lower dietary adherence (e.g. GrimAge: 1.79 SD, 95% CI: 1.54, 2.04) compared with those with higher adherence (1.35 SD, 95% CI: 1.01, 1.68; P_interaction < 0.001). Similar attenuation patterns were observed for Bernabeu. Higher intake of fruits, vegetables, and whole grains contributed most to the attenuation of smoking-related EAA. Conclusions: Our findings indicate that certain epigenetic clocks effectively capture the tension between harmful and protective exposures within the exposome. Rather than suggesting that diet neutralises the risks of tobacco, these results demonstrate that specific clocks are sensitive enough to monitor how lifestyle factors modify molecular responses to environmental toxins. This highlights the value of second-generation clocks in quantifying biological resilience.

Purpose Postprandial sedentary behavior is associated with negative health effects and constitutes a large part of daily life in modern society. This study investigated how the timing of physical activity after eating influences glucose levels, cerebral and muscle oxygenation, cognitive performance, and well-being during subsequent sitting. Methods In a four-armed randomized crossover trial, healthy adults consumed four standardized meals separated by 48-hour washout periods. Each meal was followed by 2 hours of sitting combined, in random order, with one of four interventions: (1) sitting only, (2) 15 minutes of moderate intensity cycling immediately after eating, (3) 15 minutes of cycling 20 minutes after eating, or (4) three workload-matched five-minute cycling bouts during sitting. Interstitial glucose (continuous glucose monitoring), cerebral and muscle oxygenation (Functional near infrared spectroscopy), cognitive performance (Stroop test), heart rate, blood pressure, and subjective ratings were assessed every 30 minutes. Data were analyzed using repeated-measures ANOVA. Results Twenty participants (mean age 27.1{+/-}10.3 years, 12 females) completed the study. Cycling immediately after eating reduced mean glucose levels during postprandial sitting, while both 15-minute cycling bouts increased cerebral oxygenation. All active conditions enhanced muscle oxygenation. Heart rate and arousal increased with delayed cycling and active breaks. No effects were observed for blood pressure, cognitive performance, focus, or well-being. Conclusion A short bout of physical activity immediately after eating reduces postprandial hyperglycemia and improves brain oxygenation during sitting, whereas delayed activity and brief breaks increase physiological activation without cognitive or perceptual benefits.

Purpose: The Swedish Evaluation Through Follow-up study of Learning Later in Life (UGU-LIFE) was established to study the factors that shape lifelong learning and advance evidence-based means to facilitate learning in older age. Participants: UGU-LIFE builds on the Evaluation Through Follow-up (Utvardering Genom Uppfoljning, UGU, in Swedish) study, which consists of nationally representative samples of Swedish birth cohorts. The two oldest cohorts, born 1948 (N = 11,945) and 1953 (N = 9,927), were assessed at age 13 years and invited for follow-up assessments as part of UGU-LIFE in 2025 (age 72/77 years; N = 5,738). Findings to date: Data collection in childhood included a survey (on school and family conditions), cognitive tests, and school administrative data. The follow-up assessment in late adulthood included a survey (on personal and contextual factors), cognitive tests, learning tasks, and saliva sampling for DNA extraction. In addition, registry data was collected from Statistics Sweden (census), the National Board of Health and Welfare (medical records), and the Swedish National Archives (military conscription). Analysis of selectivity at follow-up showed higher retention rate among individuals with higher education and better cognitive ability in childhood, which was only partially explained by selectivity in survival. Future plans: Data collected in UGU-LIFE will be used to describe the predictors of lifelong learning, the factors that influence learning gains and engagement in learning in older age, and the mechanistic pathways through which these factors affect learning in older age. Work to add birth records and geocoding to the data is ongoing. A subsample of participants will be invited to take part in an in-depth data collection of learning an ecologically relevant task over several days. The findings will be used to design and test interventions aiming to facilitate learning in older age.

Background. Maximal oxygen uptake (VO2max) is a leading marker of cardiorespiratory fitness and a strong predictor of all-cause mortality. Cardiopulmonary exercise testing (CPET) is the reference method but is resource-intensive, so consumer wearables estimate VO2max from passively collected signals; these estimates compress the fitness range, returning near-correct group averages while ranking individuals poorly. No peer-reviewed validation of a smart-ring VO2max estimate against CPET has been reported, and none in a South Asian cohort. Objective. To validate the Ultrahuman Ring AIR VO2max estimate against laboratory CPET, benchmark it against published prediction equations, and assess its generalization and construct validity. Methods. In a single-site paired ring-CPET cohort (N = 101; mean CPET peak VO2 43.3 mL{middle dot}kg-{superscript 1}{middle dot}min-{superscript 1}, SD 9.9), peak oxygen uptake was measured by treadmill or cycle-ergometer CPET, and the Ultrahuman Ring AIR estimate was computed from passively collected signals using a transparent ensemble based on published equations. Ensemble weights and calibration were selected on an 85-subject development set by an automated search minimizing a composite 5-fold cross-validated error criterion; the locked estimate was evaluated on a 16-subject held-out test set. The calibrated coefficients are proprietary. Agreement was quantified with mean absolute error (MAE), bias, Pearson r, regression slope and Lin's concordance correlation coefficient (CCC; bootstrap 95% CIs), and Bland-Altman limits of agreement. Separately, in 181,133 de-identified Ring users (no CPET reference), construct validity was assessed against ring-measured sleep, continuous glucose monitoring (n = 2,597), and a venous blood panel (n up to 15,203), adjusted for age, sex, and BMI, with lipoprotein(a) as a pre-specified negative control. Reporting followed TRIPOD and STARD. Results. With a self-reported fitness level provided, the estimate agreed with CPET peak VO2 at MAE 4.68 mL{middle dot}kg-{superscript 1}{middle dot}min-{superscript 1} (95% CI 3.93 to 5.49), Pearson r 0.79, CCC 0.79, and slope 0.71. The five published equations were worse on every metric (MAE 6.2 to 10.6, CCC 0.28 to 0.56, slope 0.32 to 0.42), each compressing the fitness range. On the held-out test set (n = 16), agreement held (r 0.84, slope 0.81, MAE essentially unchanged). Without the fitness input, full-cohort MAE was 5.16, still ahead of every published equation. At population scale, higher estimated fitness tracked a healthier profile on measurements the estimate does not use: better ring-measured sleep; higher continuous-glucose time in target range (79.6% versus 61.5%, top versus bottom decile; n = 222 and 399 of 2,597 users); and lower triglycerides, fasting glucose, and HOMA-IR (n up to 15,203 assayed per marker). These associations held after adjustment for age, sex, and BMI, whereas the pre-specified negative control lipoprotein(a) did not separate the deciles. Conclusions. The Ultrahuman Ring AIR VO2max estimate agreed with laboratory CPET substantially better than published prediction equations, held its agreement on held-out subjects, and ordered a large population along independent cardiometabolic gradients consistent with true fitness.

Growing evidence supports a critical role for the gut-brain axis in regulating metabolic health, inflammation,and cognitive function during aging. Age-associated gut dysbiosis has been linked to metabolic dysfunction and cognitive decline, with females exhibiting increased susceptibility to these age-related impairments. Diet is a major determinant of gut microbiome composition and function. Previous studies from our laboratory demonstrated that dietary protein restriction (DPR) induces fibroblast growth factor 21 (FGF21), improves metabolic health, and extends lifespan in male mice. However, the effects of DPR on the gut microbiome and associated health outcomes in aged female mice remain poorly understood. Female mice were assigned at 16 months of age to either a normal-protein (NP) or low-protein (LP) diet for 26 weeks. Metabolic assessments included food intake, fasting glucose concentrations, and glucose tolerance testing. Senescence-associated markers in mesenteric white adipose tissue (mWAT), fecal microbiome composition, and behavioral outcomes were evaluated to determine relationships among dietary protein intake, microbial communities, metabolic health, and cognitive function. Low-protein diet significantly improved metabolic health in aged female mice, as evidenced by improved glucose regulation. Microbiome analyses revealed increased abundance of Akkermansia at 17 months and Faecalibaculum in LP-fed animals at 22 months of age. More so, functional profiling and gene set enrichment analyses indicated enrichment of microbial pathways associated with membrane integrity and metal ion binding. Lastly, LP-fed female mice displayed improved memory performance at 22 months of age compared with age-matched NP-fed controls. Collectively, these findings demonstrate that DPR remodels the gut microbiome and improves metabolic and cognitive health in aged female mice. The observed microbial adaptations may contribute to the beneficial effects of DPR on aging related physiology, highlighting the gut microbiome as a potential mediator of dietary interventions that promote healthy aging.

Abstract Background: Sarcopenia is associated with anabolic resistance, a blunted muscle protein synthesis response to protein ingestion. Here, we hypothesized that anabolic resistance may be associated with a delayed postprandial decline in circulating plasma amino acids following protein ingestion. We therefore wanted to investigate whether an oral protein tolerance test (OPTT) combined with untargeted plasma metabolomics can detect age-related or sarcopenia-related differences in amino acid time courses consistent with altered postprandial amino acid handling, which could potentially reflect reduced anabolic sensitivity. Moreover, we investigated whether metabolites other than amino acids reacted to the OPTT. Methods: Twelve young healthy adults (controls: 22-28 years) and 12 older adults with clinically diagnosed probable or confirmed sarcopenia (70-91 years) ingested 20 g of whey protein after an overnight fast. We collected venous blood at baseline, 1 h, and 2 h post-ingestion and analyzed the samples by untargeted LC-HRMS plasma metabolomics. Linear mixed-effects models were fitted for 2,968 metabolic features with Benjamini-Hochberg FDR correction. For each category (branched-chain amino acid, essential amino acid [EAA], total amino acid) we summed the within-subject log2 fold changes (FC); fold changes (FC) of the constituent amino acids. This composite is reported as the summed log2FC. Results: 201 metabolites were structurally annotated including 58 amino acid-related metabolites and 97 lipids. Fourteen of 17 proteinogenic amino acids increased significantly after protein ingestion (FDR<0.05). In young controls, essential amino acids rose more steeply at 1 h than in sarcopenic individuals (+10.06 +/- 1.05 vs. +7.84 +/- 1.58 summed log2FC) and declined more between 1 and 2 h (-4.93 +/- 1.29 vs. -0.20 +/- 2.27 summed log2FC). Leucine exemplified this pattern best, rising 1.74 log2FC in controls and declining to 0.96 at 2 h, while remaining elevated at 1.61 log2FC in the sarcopenic group at 2 h (p=0.009). Beyond amino acids, whey protein lowered circulating free fatty acids in both groups (FA 18:2, FA 18:1, FA 16:0; all FDR<0.05). Medium- and long-chain acylcarnitines (Car 8:0, Car14:2) declined postprandially in controls but remained elevated in sarcopenic individuals (p<0.05), suggesting altered postprandial lipid metabolism. Conclusion: In this proof-of-concept study, an OPTT showed that plasma EAAs declined more slowly from their postprandial peak in older adults with sarcopenia than in young adults, consistent with altered postprandial amino acid handling that may reflect anabolic resistance. Whey protein ingestion additionally modulates lipid and acylcarnitine metabolism in an age-dependent manner, suggesting broader alterations in postprandial metabolic regulation in older adults with sarcopenia.

Sleep deprivation is associated with impaired endurance performance and an increased risk of running-related injury. Previous research has identified alterations in running biomechanics following a single night of sleep deprivation under laboratory conditions. However, whether these biomechanical changes can be detected using wearable technology remains unknown. Twenty-one recreationally active runners completed submaximal treadmill running under both normal sleep and total sleep deprivation conditions in a randomized crossover design. Biomechanical features were extracted simultaneously using a full-body motion capture system and a trunk-mounted wearable sensor. Five machine learning classifiers were evaluated in two classification tasks: a within-subject task using paired recordings from the same individual, and a between-subject task performed without individual baseline data. Within-subject classification consistently exceeded chance level for both measurement systems, with best accuracies of 85% for the wearable sensor (Logistic Regression) and 83% for the motion capture system (Random Forest). These findings indicate that sleep deprivation produces a systematic and individually consistent biomechanical signature during running. In contrast, between-subject classification failed across nearly all models and systems, with accuracies remaining close to chance level ([~]50%), demonstrating that inter-individual variability obscures the sleep-deprivation signal in the absence of personalized baseline data. Both systems converged on temporal organization, loading-related variables, and stride-to-stride variability as the most discriminative feature domains. Contrary to expectations, the laboratory motion capture system did not outperform the wearable sensor. Together, these findings demonstrate that individualized, baseline-referenced monitoring is essential for detecting sleep-deprivation-related changes in running gait, and suggest that a single trunk-mounted wearable sensor may provide a practical solution for real-world monitoring when paired recordings are available.

Background: Cognitive function is crucial for healthy aging, and its impairment reduces quality of life and increases healthcare and societal burden. Social vulnerability, shaped by factors like income, education, and access to healthcare, has been associated with cognitive health, but reliance on community-level assessments may limit understanding of risk at the individual level. Objectives, Design, Setting, Participants: We examined the cross-sectional association between a proposed individual-level Social Vulnerability Index (iSVI) and cognitive function among 5,989 participants aged [&ge;]60 years in the US National Health and Nutrition Examination Survey (NHANES) 1999-2002 and 2011-2014 cycles. Measurements: Cognitive performance was measured using the Digit Symbol Substitution Test (DSST). iSVI was constructed by summing six risk indicators (income, education, health insurance, employment, housing tenure, and food security). Health insurance and employment were scored on a three-level scale (0/0.5/1); other indicators were binary (0/1). Survey-weighted linear regression estimated associations between iSVI and DSST scores, adjusting for age, sex, race and Hispanic origin, and survey cycle. Estimates were benchmarked against adjusted associations between age and DSST. Results: Higher iSVI was associated with poorer cognition, with each one-unit increase corresponding to a 5.30-point lower DSST score (95% CI: -5.71, -4.89). This difference was comparable to nearly 5 years of age-related difference in DSST performance, as each additional year of age was associated with a 1.08-point lower DSST score (95% CI: -1.14, -1.03). Conclusions: Increased iSVI was associated with lower cognitive function in older adults, highlighting individual-level social vulnerability as a key intervention opportunity to prevent cognitive impairment.

Healthspan, the period of life where organisms are without frailty and/or disease, is a major focus of biogerontological research. To understand late-life decline and increased mortality risk, short-lived organisms such as nematode worms are commonly used. Pristionchus nematodes are established models for evolutionary developmental genetics research and show promise as systems for comparative and experimental study of ageing. To support this, we developed phenotypic ageing profiles for the evo-devo model Pristionchus pacificus and its little-studied congener Pristionchus fissidentatus. We find that various life history traits differ between P. pacificus and P. fissidentatus (lifespan, brood size, and reproductive period), demonstrating their utility for studying divergent ageing trajectories. Further, several traits are consistently impacted by age, including intestinal barrier function, body size, and locomotory ability. Additionally, in P. pacificus, rupture avoidance, cuticle integrity, and feeding rate decline with age, indicating dysregulation across many tissue types. Several age-linked patterns resemble those documented for Caenorhabditis elegans despite considerable evolutionary distance, suggesting conserved senescent processes across the Rhabditida family of nematodes. This work highlights similarities and differences in the impact of ageing in two Pristionchus nematodes and supports their development as models for evolutionary genetic study of senescence.

Objectives: We tested how multi-level socioeconomic disadvantage relates to biological aging and systemic inflammation in women and men from the population-based Canadian Longitudinal Study on Aging (CLSA). Methods: We examined cross-sectional data from 8,516 CLSA participants with baseline measures on systemic inflammatory biomarkers (C-reactive protein, interleukin-6, and tumoral necrosis factor-) and biological aging (metabolomic and six DNA methylation [DNAm] age estimates). Plasma samples underwent metabolomic profiling by Metabolon, Inc. Metabolomic age was estimated separately in males and females using sex-stratified models based on age-correlated metabolite levels. DNAm data generated using the Illumina Infinium MethylationEPIC v1.0 array were used to estimate DNAm age across six established models, including Horvath, Hannum, PhenoAge, GrimAge, GrimAge2, and DunedinPACE. We used log-transformed metabolite levels to calculate metabolomic age by sex. We linked education, income, material and social deprivation to biomarkers of systemic inflammation and biological aging stratified by sex using generalized linear models. Multivariable models were adjusted by age, major behavioral risk factors, and chronic conditions. Results: Participants were aged on average of 62.6 years of age, and approximately 50% were females. In multivariable linear adjusted models, we found that in comparison to those earning [&ge;]$100K a year, women earning less <$20K were on average 1.14 (95%CI: 0.46, 1.82) year older with respect to metabolomic age; those earning [&ge;]$20K & <$50K were on average 0.90 (95%CI: 0.26, 1.53) years older; and those earning [&ge;]$50K & <$100K were on average 0.70 (95%CI: 0.05, 1.34) years older. We did not observe this dose response among men. A similar dose-response association was observed for interleukin-6 in both men and women. Discussion: These findings suggest that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes, including metabolomic aging.

Background Literature investigating mediation of the association between child abuse and dementia has largely considered composite adverse childhood experience scores rather than individual adverse experiences, despite evidence that different experiences have different impacts on dementia risk. Additionally, prior studies consider mediators in isolation, despite known associations between mediators which may impact indirect pathways from child abuse to dementia. Objectives To investigate whether potentially modifiable health and lifestyle factors mediate the association between child abuse and dementia. Methods We used data from the English Longitudinal Study of Ageing to investigate associations between child abuse and dementia (N:5,448). Indirect pathways through four mediator categories (education, health behaviours, mental health and cardiovascular health) were examined. We used regression modelling to estimate associations between child abuse, mediators and dementia, and causal mediation analysis using the g-formula to estimate the joint indirect effect through the mediators. Results Individuals who experienced child abuse had, on average, an 80% higher hazard of dementia, compared to those who did not (RTE HR:1.80, 95% CI:1.21-2.39). Mental health mediators showed strong associations with both child abuse and dementia. Evidence for other mediators was weaker. Education, health behaviours, mental health and cardiovascular health mediated approximately 18% of the association. Sensitivity analysis revealed that almost all this mediation occurred through mental health. Conclusions Child abuse was associated with higher risk of dementia. Joint mediation analysis suggested that education, health behaviours, cardiovascular health, and mental health accounted for a relatively small proportion of the observed association, with most mediation occurring through mental health. Future research must focus on other potential pathways from child abuse to dementia, including biological and social mechanisms.