Experimental Gerontology

The effects of older age on the oxidation of energy substrates (carbohydrates, fats) over 24 hr and during activities of daily living (ADL) may have substantial implications for metabolic health. To examine this issue, we evaluated age-related differences in substrate oxidation for 24 hr and periods of sleep, ADLs, and a 30-min treadmill walk (30MTW, 1.3m{middle dot}s^-1) in 17 young (29 {+/-} 5 yr, mean {+/-} SD, 6F) and 16 older (72 {+/-} 5, 8F) healthy active adults. Oxygen consumption (&VdotO2) and carbon dioxide production were measured using a 32,500 L room calorimeter to quantify substrate oxidation, which was normalized to body mass (kJ{middle dot}kg^-1) and total energy expenditure (%). Separately, &VdotO2peak was measured during an incremental treadmill test to exhaustion. &VdotO2peak (ml{middle dot}kg^-1{middle dot}min^-1) was lower in older adults compared with young adults. Older adults oxidized fewer carbohydrates than young over 24 hr (kJ{middle dot}kg^-1, %), sleep (kJ{middle dot}kg^-1), and ADLs (kJ{middle dot}kg^-1, %); and fat oxidation was greater in older than young over 24 hr (kJ{middle dot}kg^-1, %) and ADLs (kJ{middle dot}kg^-1, %). Carbohydrate oxidation did not differ by group during the 30MTW (kJ{middle dot}kg^-1, %), but fat oxidation was greater in older (kJ{middle dot}kg^-1) despite their walking at a greater relative intensity. These results indicate that older adults derived oxidative energy differently than young over 24 hr and during daily tasks. The lower carbohydrate and greater fat contribution to daily energy requirements may be meaningful in the development of metabolic disease in older adults.

Background: Associations of sleep duration and insomnia symptoms with cognitive decline are inconsistent, and whether they represent modifiable risk factors or early manifestations of neurodegeneration may depend on life stage. We examined how sleep-cognition associations vary with age (44 to >90 years). Methods: We studied 16,884 participants from three cohorts with harmonised measures. In the English Longitudinal Study of Ageing (ELSA: n=9,473, median age 64, range 50 to >=90), linear mixed-effects models examined age-specific differences in cognitive change (recall and fluency) associated with sleep duration, difficulty falling asleep, nocturnal awakenings, incorporating sleep-by-age-by-time interactions, with initial adjustment for sociodemographic factors and further adjustment for health and lifestyle factors. Sleep characteristics showing consistent age-dependent associations in ELSA were further evaluated in Whitehall II (n=5,580, median age 55, range 44 to 68) and the Rush Memory and Aging Project (MAP: n=1,831, median age 80, range 53 to 102). Findings: In ELSA, difficulty falling asleep >=1 time/week (vs <1 time/week) was associated with less favourable 5-year change in recall at age 50 (difference -0.12 SD, 95% CI -0.20 to -0.04), with the association attenuating and reversing towards more favourable change at older ages (p-interaction=0.009 [linear], 0.016 [quadratic]). These persisted after further adjustment for health and lifestyle factors. Short sleep (<=6 h) showed similar patterns that attenuated after further adjustment. Similar age gradients were observed for difficulty falling asleep in Whitehall II and MAP. There was no evidence of age modification on long sleep and nocturnal awakenings. Interpretation: The cognitive implications of sleep disturbances vary by life stage. In midlife, difficulty falling asleep was associated with faster cognitive decline, supporting its role as a modifiable risk factor. In advanced age, the reversal is consistent with diminished arousal capacity accompanying prodromal dementia. Funding: US National Institute on Aging

Importance: Long-term exposure to higher average air pollutant concentrations is associated with poorer cognitive health, but annual averages can obscure substantial differences in day-to-day exposure. Whether recurrent high pollution days are associated with long-term cognitive aging trajectories among people with similar overall air pollution exposure is unclear. Objective: To determine whether the annual number of days exceeding World Health Organization daily guideline values for nitrogen dioxide (NO2) and particulate matter (PM2.5 and PM10) is associated with subsequent cognitive decline after accounting for annual mean air pollutant exposure. Design: Prospective cohort study using data from waves 1-10 (2002-03 to 2021-23) of the English Longitudinal Study of Ageing. Setting: Population-based cohort of community-dwelling adults in England. Participants: 12,235 adults aged 50+ years at analytic baseline. Exposures: Number of days exceeding World Health Organization daily guideline values ('exceedance days') for NO2, PM2.5, and PM10, derived from residence-linked environmental estimates during the calendar year preceding the analytic baseline. Main Outcomes and Measures: Baseline cognitive performance and model-estimated 14-year cognitive decline (corresponding to the 75th percentile of follow-up duration) in episodic memory and verbal fluency. Results: Exceedance days were not associated with baseline memory or verbal fluency after adjustment for annual mean air pollutant exposure. More NO2 exceedance days were associated with faster cognitive decline: comparing the 75th percentile with the median of NO2 exceedance days, the difference in 14-year decline was -0.09 SD (95% CI, -0.17 to -0.01; p = 0.02) for memory and -0.10 SD (95% CI, -0.19 to 0.00; p = 0.04) for fluency. PM2.5 and PM10 exceedance days were not associated with cognitive decline. Conclusions and Relevance: In this cohort study of older adults, a higher number of NO2 exceedance days was associated with faster subsequent cognitive decline after adjustment for annual mean air pollutant exposure. This suggests that daily exposure to high NO2 concentrations may be related to accelerated cognitive aging even when offset by lower exposure on other days, potentially providing a new rationale for identifying and prioritizing areas with recurrent high NO2 exposure and the local emission sources contributing to it.

Study objectives: Aging is associated with increased sleep complaints and changes in sleep architecture, microstructure and rest-activity rhythms. Meditation-based interventions have shown benefits on subjective sleep quality, but their effects on objective sleep parameters remain largely underexplored. This study investigated the effects of an 18-month meditation intervention on sleep combining subjective (questionnaires) and objective (polysomnography and actigraphy) measures in older adults. Methods: A total of 120 cognitively unimpaired older adults ([&ge;]65 y) with minimal sleep complaint completed questionnaires, one week of actigraphy and in-home polysomnography at baseline, and again 18 months later. Following the baseline visit, participants were randomly assigned to one of 3 groups: meditation training, non-native language training (active control), or passive control. Group-by-visit interactions were examined using mixed-effects models for sleep questionnaires, actigraphy-derived metrics, sleep architecture and microstructure, including slow waves, spindles, and spectral power. Results: Compared to the passive control group only, meditation training was associated with greater ease of morning awakening (p=0.04). No significant intervention effects were observed for any other sleep parameter, including actigraphy- and polysomnography-derived measures. These findings remained unchanged after adjustment for depressive symptoms and trait anxiety. Conclusion: In cognitively unimpaired older adults, this 18-month meditation intervention yielded only limited improvements in subjective sleep assessment. Meditation may therefore have subtle effects on self-reported sleep quality in this healthy older population, although no effects on objective sleep measures were detected. Future studies should examine whether adapting the content, intensity, or timing of meditation practice and enrolling populations with clinically meaningful sleep disturbances or psychoaffective symptoms may yield greater benefits.

IntroductionFalls are a major cause of injury-related morbidity, mortality, and healthcare utilisation among older adults, with the greatest burden occurring in those aged [&ge;]80 years. Multicomponent exercise programmes that include balance and resistance exercises reduce falls, whereas the effect of resistance training delivered as a standalone fall-prevention intervention remains uncertain. Existing resistance-training trials have generally been small, underpowered for fall outcomes, and have produced inconsistent findings, despite reduced muscle strength being an important modifiable risk factor in the oldest old. The resistance training prescription used in these studies has not always aligned with recommendations for optimal strength adaptations in terms of intensity or progressive overload, which may explain this uncertain efficacy. Therefore, this study aims to determine whether 12 months of high-intensity progressive resistance training reduces fall rates in community-dwelling adults aged [&ge;]80 years with reduced muscle strength. Methods and analysisThis single-centre, randomised controlled trial conducted in Trondheim, Norway, includes 241 community-dwelling adults aged [&ge;]80 years with reduced muscle strength. Participants are randomly assigned (1:1) to either standard care with written physical activity guidance or a twice-weekly high-intensity progressive resistance training intervention for 12 months. The primary outcome is the rate of falls over 12 months. Secondary outcomes include time to first fall, fall-related injuries, muscular function, physical performance, balance, body composition, cardiometabolic health, cognition, and participant-reported outcomes. Cost-effectiveness is assessed from a healthcare perspective over the 12-month intervention period using costs and quality-adjusted life years. Analyses follow the intention-to-treat principle, using negative binomial regression for the primary outcome. The first participant was included on 30 March 2023, and the last participant was included on 29 September 2025. The 12-month intervention period is expected to be completed by September 2026. Ethics and disseminationThe study has received approval from the Regional Committee for Medical and Health Research Ethics in Norway (REK; reference number 462261). All participants provided written informed consent before participating. Findings will be shared via peer-reviewed publications, conference presentations, and communication with stakeholders and the public. Trial registration numberClinicalTrials.gov (NCT05691166), registered 11 January 2023. Available at: https://clinicaltrials.gov/study/NCT05691166

. Abstract Objectives. Prior research has identified associations between sleep health and cognitive function. Our aim was to investigate multiple domains of sleep health and their associations with cognitive function in a diverse sample of older adults. Methods. These data are from an observational study in Chicago, USA, that enrolled adults aged 55 years and older without cognitive impairment at baseline and followed a subset for up to 2 years. Sleep was measured with 7 days of wrist actigraphy and we examined sleep duration (amount), sleep fragmentation (an index of restlessness and sleep quality), sleep start time and sleep regularity (based on the within-subject standard deviation of sleep start time). . Participants also completed tasks from the NIH Toolbox to estimate fluid cognition and the Trail Making Test (Trails B) to assess attention and processing speed. A subset of participants was examined at a follow-up visit that included only the NIH Toolbox assessment. Results. Our sample included 324 participants (63.6% women, 37.3% African American/Black, 13.6% Hispanic/Latino). Greater sleep fragmentation and less sleep regularity were associated with worse fluid cognition and Trails B scores (all p<.01). Longer sleep duration and earlier sleep start times were associated with better performance on Trails B. No sleep measures were associated with change in the fluid cognition score over an average of 1.9 years (n=133). Discussion. These findings support a cross-sectional association between cognitive function and multiple domains of sleep health, including duration, quality, timing and regularity, in a diverse sample of older adults.

Background Attentional control declines with normal aging, yet the role of modifiable lifestyle factors in accelerating this decline remains incompletely characterised in large, diverse populations. We examined associations between four modifiable risk factors (smoking intensity, alcohol binge drinking, social satisfaction and blood pressure) and sustained attention performance in 13,866 adults drawn from the All of Us Research Program. Methods Cognitive performance was assessed using the Gradual-Onset Continuous Performance Task (GradCPT). A composite cognitive efficiency score was derived via principal component analysis of four GradCPT metrics: d' (perceptual sensitivity), response criterion, median reaction time and reaction time variability. Associations between cognitive efficiency and each risk factor were examined using multiple linear regression adjusted for age, sex and race/ethnicity. Effect sizes were expressed as age-equivalent years of cognitive aging (age-equivalent years = regression coefficient for the risk factor divided by the regression coefficient for age) to aid clinical interpretation. Results GradCPT performance declined progressively with age (p < 0.001). Social satisfaction emerged as the strongest lifestyle predictor: low social satisfaction was associated with approximately 5.8 additional age-equivalent years of cognitive aging relative to high social satisfaction. Smoking showed a dose-response pattern, with heavy smokers (> 20 cigarettes/day) exhibiting an approximately 5-year age-equivalent deficit versus never-smokers. Stage 2 hypertension showed a modest, non-significant negative association. Binge drinking showed limited significant associations, likely complicated by survivor and abstainer biases. Bootstrapped analyses of combined exposures showed that combinations of risk factors, particularly those involving low social satisfaction, produced larger cognitive deficits than expected under an additive model. Conclusions These findings support an interactive rather than a purely additive model of lifestyle-related cognitive vulnerability and highlight the GradCPT as a subclinical measure of attention-based cognitive risk in non-clinical populations. Keywords Cognitive aging, Sustained attention, GradCPT, Modifiable risk factors, Social isolation, Smoking, Hypertension, All of Us Research Program

Purpose: The neural retina and retinal pigment epithelium/choroid (RPE/Cho) are metabolically coupled. Metabolic dysfunction of the RPE/Cho contributes to photoreceptor death in age-related macular degeneration (AMD). This study aimed to determine how aging, a major risk factor for AMD, alters the proteome and metabolic pathways in the retina and RPE/Cho. Methods: We performed quantitative proteomics on neural retina and RPE/Cho from young (8-week) and old (73-week) C57BL/6J mice. The differentially expressed proteins between old and young, as well as between the retina and RPE/Cho, were visualized using volcano plots and heatmaps, and functional analyses were assessed by Gene Ontology enrichment tools. Results: Aging altered the expression of 85 retinal proteins and 272 RPE/Cho, with 16 shared between tissues. In the aged retina, proteins associated with NADP(H) metabolism, neurodegeneration, and immunity were mostly upregulated, while proteins in lipid metabolism, transcription, and epigenetic regulation decreased. In the aged RPE/Cho, all 21 significantly altered lysosomal enzymes and transport proteins increased, together with complement components, and photoreceptor outer segment proteins. These changes accompanied increases in proteins associated with lipid metabolism and protection against lipid peroxidation, while several glutathione metabolism enzymes decreased. Seven shared proteins involved in lipid and NADP(H) metabolism, changed in opposite directions between retina and RPE/Cho. Comparison of the retinal and RPE/Cho proteomes identified 3073 differentially abundant proteins, of which 2452 maintained tissue-specific differences across both age groups, while approximately 17% showed age-dependent shifts in tissue enrichment. These shifts involved proteins associated with metabolism, extracellular matrix, visual function, lysosomal pathways, and innate immunity. Within the metabolic proteome, several glycolytic and fatty acid oxidation proteins showed greater relative enrichment in RPE/Cho with age, whereas glucose transporters and mitochondrial complexes shifted toward the retina. Conclusions: Overall, these findings show that aging differentially remodels the retina and RPE/Cho proteome, accompanied by altered metabolic specialization between the two tissues.

Background: Intramuscular fat and fibrous tissue deposition increase with ageing, disuse, and disease and contribute to impaired muscle function and reduced 'muscle quality'. Magnetic resonance imaging (MRI) and biopsy provide reference measures of muscle composition, but their cost, invasiveness, and limited accessibility restrict routine use. B-mode ultrasonography has emerged as a practical, low-cost alternative, with ultrasound-derived echo intensity widely interpreted as a surrogate measure (index) of intramuscular fat, fibrosis, and 'muscle quality'. However, such interpretation warrants further scrutiny. Aim: To quantify the relationship between ultrasound-derived echo intensity and reference measures of intramuscular fat and fibrous tissue and determine whether these relationships vary across muscles or according to anatomical and methodological factors. Methods: A systematic search of six databases was conducted (last search: August 2026). Human and animal studies reporting correlations between echo intensity and measures of intramuscular fat or fibrous tissue using MRI, histology, or chemical analysis were synthesised using multilevel random-effects meta-analysis with study-level cluster-robust inference. Correlations were Fisher z-transformed and back-transformed for interpretation. Exploratory analyses examined fat compartment, muscle, muscle architecture, health status, study model, and distance-correction procedures. Results: Twenty-eight studies met the eligibility criteria. For intramuscular fat, 204 effects from 23 independent studies yielded a weak-to-moderate pooled correlation with echo intensity (r=0.54, 95% CI: 0.45-0.61; 95% PI: - 0.02-0.84; P<0.01), with substantial heterogeneity (I^2=74.5%). The wide prediction interval suggests the true correlation could range from negligible to strong. No significant moderation effects were observed for study model (animal vs. human: r=0.46 vs. 0.55; P=0.26), health status (clinical vs. healthy: r=0.64 vs. 0.49; P=0.11), probe-to-muscle distance correction (corrected vs. raw echo intensity: r=0.57 vs. 0.53; P=0.25), or muscle architecture (non-pennate vs. pennate: r=0.63 vs. 0.53; P=0.56), although some categories contained few studies and effects. Model-based inference indicated significant moderation effect of lipid compartment (intramyocellular lipid vs. total intramuscular fat vs. extramyocellular lipid: r=0.10 vs. 0.57 vs. 0.49; P<0.001) but this effect was not significant under cluster-robust inference (P=0.50). For fibrous tissue, six effects from four studies yielded a weak, non-significant pooled correlation (r=0.34, 95% CI -0.39, 0.81], 95% PI [-0.85, 0.96]; P=0.24). Conclusions: Echo intensity is weakly-to-moderately associated with intramuscular fat, and this varied substantially across studies and muscles, whereas evidence for intramuscular fibrous tissue is limited and uncertain. These findings provide limited support for interpreting echo intensity as a surrogate measure or an index of intramuscular fat or fibrosis or, on this basis, as an index of 'muscle quality'.

Background: Retirement is a major life transition that may influence cognitive aging. Retirement pathways are becoming increasingly diversified, yet evidence on how heterogeneous retirement trajectories relate to dementia risk remains limited. This study used sequence and cluster analysis to characterize thousands of transition-to-retirement trajectories, including retirement timing and work intensity, to estimate associations with dementia risk. Methods: We used data from 13,879 participants in the U.S. Health and Retirement Study. Our exposure was transition-to-retirement trajectories between ages 51 and 75 identified using sequence and cluster analysis. Our outcome was a validated algorithmically derived dementia probability measure. We estimated associations between trajectory clusters and dementia risk beginning at age 76 using generalized estimating equations, adjusting for sociodemographic characteristics. Inverse probability weights were used to account for attrition. Results: We identified ten distinct transition-to-retirement trajectories characterized by differences in timing of retirement, part-time work, disability, and labor force attachment. Compared with individuals retiring after full-time work in their early-to-mid 60s, dementia risk was similar among those retiring earlier or later from full-time work. In contrast, individuals with sustained part-time employment between ages 51 and 75 had lower odds of dementia (OR: 0.62, 95% CI: 0.48, 0.80), while trajectories characterized by prolonged disability were associated with higher odds of dementia (OR: 1.53, 95% CI: 1.22, 1.91). Conclusions: Retirement timing alone showed limited association with later-life dementia risk, whereas sustained part-time employment and disability-related trajectories were more strongly associated with dementia risk. These findings suggest that employment intensity and health-related exit from the labor force may be more relevant for dementia risk than retirement timing, and that gradual and flexible work-to-retirement transitions may benefit brain health. Background: Retirement is a major life transition that may influence cognitive aging. Retirement pathways are becoming increasingly diversified, yet evidence on how heterogeneous retirement trajectories relate to dementia risk remains limited. This study used sequence and cluster analysis to characterize thousands of transition-to-retirement trajectories, including retirement timing and work intensity, to estimate associations with dementia risk. Methods: We used data from 13,879 participants in the U.S. Health and Retirement Study. Our exposure was transition-to-retirement trajectories between ages 51 and 75 identified using sequence and cluster analysis. Our outcome was a validated algorithmically derived dementia probability measure. We estimated associations between trajectory clusters and dementia risk beginning at age 76 using generalized estimating equations, adjusting for sociodemographic characteristics. Inverse probability weights were used to account for attrition. Results: We identified ten distinct transition-to-retirement trajectories characterized by differences in timing of retirement, part-time work, disability, and labor force attachment. Compared with individuals retiring after full-time work in their early-to-mid 60s, dementia risk was similar among those retiring earlier or later from full-time work. In contrast, individuals with sustained part-time employment between ages 51 and 75 had lower odds of dementia (OR: 0.62, 95% CI: 0.48, 0.80), while trajectories characterized by prolonged disability were associated with higher odds of dementia (OR: 1.53, 95% CI: 1.22, 1.91). Conclusions: Retirement timing alone showed limited association with later-life dementia risk, whereas sustained part-time employment and disability-related trajectories were more strongly associated with dementia risk. These findings suggest that employment intensity and health-related exit from the labor force may be more relevant for dementia risk than retirement timing, and that gradual and flexible work-to-retirement transitions may benefit brain health.

Age-related skeletal muscle atrophy differs between upper and lower body muscles and may also differ between lower limb muscles, but these muscle-specific patterns remain poorly characterised. We acquired axial 3T magnetic resonance images from sex-balanced samples of thirty young (24+/-4 years) and thirty older adults (73+/-4 years). Muscle volume of seventeen lower limb muscles/compartments was quantified using manual segmentation and expressed as absolute volume, relative to body mass, and as a percentage of total muscle volume. Absolute muscle volume was lower in older adults in 13 out of 17 muscles compared to young, with substantial heterogeneity in the effect sizes (d=0.01-3.36). Age group * muscle interaction contrasts revealed muscle-specific age-related differences in volume. Three of the quadriceps muscles demonstrated greater age-related atrophy compared to several other muscles (e.g. vastus lateralis differing from 14 of the other 16 muscles; d[&ge;]1.54). Conversely, the anterior and deep posterior compartments of the shank and biceps femoris short head showed significantly smaller age-related atrophy than several other muscles. These interaction effects were exacerbated when expressed in relative terms. Consequently, three of four shank compartments, gluteus maximus and adductor magnus represented a greater proportion of total muscle volume in older adults, whereas the vastus lateralis, vastus intermedius, rectus femoris, semitendinosus, gracilis, and iliopsoas contributed a smaller proportion in older adults. These findings highlight the variability in age-related leg muscle atrophy in a large mixed sex cohort, resulting in a redistribution of muscle volume in the lower limb.

Introduction: This study aimed to characterize the neurochemical profile of Alzheimer s disease (AD) continuum stages using proton magnetic resonance spectroscopy (1H-MRS) data for brain metabolites and macromolecules. We used Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) to classify diagnostic groups and assess feature importance. Methods: Our dataset consisted of 7 T short-echo time 1H-MRS spectra of the posterior cingulate cortex/precuneus of individuals diagnosed with AD (n = 27) or Mild Cognitive Impairment (MCI, n = 27) and Healthy Controls (HC, n = 31). Classification used 100-round Monte Carlo cross-validation based on metabolite concentrations and macromolecular peak intensities. Variable importance in projection (VIP) was assessed across classification models to identify the most relevant neurochemical features. The resulting metabolite rankings were compared with previous literature to evaluate their biological plausibility. Results: Classification was strongest for AD versus HC (AUC=0.88) and lower for comparisons involving MCI. Metabolites contributing most strongly to classification included myo-inositol, ascorbate, and choline-containing compounds, consistent with previous studies on AD-related neurochemical alterations. In addition, specific macromolecular components were identified as relevant features, suggesting a potential contribution of MM signals to the characterization of AD-related neurochemistry. Discussion: These findings support the use of short-echo-time 1H-MRS as a complementary tool for characterizing neurochemical changes in the AD continuum, with potential applications in disease characterization and monitoring, warranting validation in larger cohorts.

BackgroundAlcohol use disorder (AUD) is an established contributor to neurocognitive impairment and a major modifiable risk factor for dementia. However, the extent to which lifetime AUD interacts with aging to accelerate subtle cognitive trajectories prior to overt clinical dementia remains unclear. ObjectiveTo investigate whether a lifetime history of DSM-5 AUD and correlated indices of alcohol consumption are associated with accelerated age-related cognitive decline in middle-aged and older adults. MethodsParticipants (N = 1,421) were drawn from the Collaborative Study on the Genetics of Alcoholism (COGA) prospective longitudinal study. Lifetime AUD status (defined as 2 or more DSM-5 criteria endorsed at peak drinking) and drinking patterns were derived from the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Cognitive performance across multiple domains was evaluated using the NIH Toolbox Cognition Battery to yield Total, Fluid, and Crystallized Composite Scores. Linear mixed-effects models examined main effects of AUD and age, as well as an AUD-by-age interaction, controlling for testing site. ResultsAt the time of cognitive assessment, the overall sample had a mean age of 52.5 years (SD = 14.5) with a mean longitudinal observation period of 25.0 years (SD = 4.7). The sample was 60% female, 40% male, 7% Hispanic, 23% non-Hispanic Black, 68% non-Hispanic White, 2% other race/ethnicity. 64% met lifetime criteria for AUD (n = 908). While baseline mean cognitive composite scores were similar between those with and without AUD, lifetime AUD was significantly associated with steeper age-related decline for both the Total Composite score (interaction estimate = -0.092, 95% CI [-0.173, -0.010], p = 0.03) and Fluid Composite score (interaction estimate = -0.13, 95% CI [-0.220, -0.040], p = 0.005). No significant AUD-by-age interaction was observed for Crystallized Composite scores (interaction estimate = -0.026, 95% CI [-0.092, 0.041], p = 0.449). Based on model projections, the AUD-associated cognitive deficit on Total Composite scores was equivalent to 7.1 additional years of cognitive aging at age 60 (95% CI [-0.5, 14.7]) and 13.8 additional years at age 75 (95% CI [0.2, 27.3]). Measures of current (past-year) drinking status and current drinks per week showed no significant interaction with age. ConclusionsA lifetime history of AUD acts as a catalyst for cognitive aging, significantly steepening the trajectory of age-related decline in total and fluid cognitive functioning well before the onset of clinical dementia. Cross-sectional measures of current drinking failed to capture these effects, demonstrating that evaluating cumulative lifetime drinking history is important for assessing alcohol-related cognitive decline.

Weekly training volume is the primary driver of resistance-training hypertrophy, but the independent role of frequency can be isolated only when weekly volume is equated. We quantified the effect of training frequency on hypertrophy across one to three volume-equated sessions per muscle per week. Following PRISMA 2020, five databases were searched to October 2026 for trials of at least six weeks that equated weekly volume between per-muscle frequencies and measured muscle size. One change-score standardized mean difference per trial (Hedges g; negative favoring higher frequency) was pooled with a random-effects model, and certainty was rated with GRADE. Sixteen trials (380 participants) were pooled. The frequency effect was trivial and non-significant (g = -0.02; 95% CI -0.21 to 0.16; I-squared = 0%; prediction interval -0.23 to 0.18); the interval admits at most a small effect favoring the higher frequency. Contrast-specific estimates were similarly trivial, and no moderator was significant, although the moderator analyses could detect only large effects. Certainty was low to very low. Within this range, the data give no basis for preferring one, two or three sessions at a fixed weekly volume. Most trials measured muscle thickness, which does not track whole-muscle growth reliably.

Background: Frailty is a prominent risk factor for dementia. Early detection of at-risk individuals may enable intervention to prevent or slow dementia pathology. Blood-based biomarker discovery could offer a path for early detection of frailty and cognitive decline. Methods: Older adults at risk of dementia underwent comprehensive multi-disciplinary assessment at the Healthy Brain Ageing (HBA) clinic, including geriatric, neurophysiological and mood evaluations, in addition to providing a fasted blood sample. Clinical data were used to calculate a deficit accumulation frailty index (FI) score. Additional cohorts attended either one (n=118) or two (n=73) subsequent visits over an average period of 4 years. Untargeted metabolomics was performed on plasma samples, and metabolites were clustered by similarity. Linear regression was used to assess association of clusters with FI. Finally, change in plasma abundance over time was assessed. Results: At assessment, participants had a mean (SD) age of 68.10 (8.07) years; 72.2% were female. Hierarchical clustering identified 10 clusters of metabolites, of which 6 were significantly associated with FI (p<0.05) at baseline and contained similar classes of metabolite. Differential abundance analysis found unique temporal regulation of metabolite abundance in each cluster, but across clusters severity of frailty impacted direction of change in plasma abundance over time. Conclusions: Frailty index was associated with carboxylic acids and derivatives, fatty acyls and organooxygen compounds across multiple clusters, and a large number of lipids were linked to frailty score, potentially implicating dysregulation of energy metabolism in the pathophysiology of frailty and forming a panel of predictive biomarkers of at risk patients.

Individuals with Down syndrome (DS) exhibit accelerated biological aging and unique patterns in disease prevalence. However, empirical characterizations of relative risk and age at onset of disease in this population are not common. Here we aimed to quantify the difference in risk and timing of age-related conditions between individuals with DS when compared to typically developing (TD) matched controls. We used semiparametric Cox proportional hazards models and Restricted Mean Event-Free Age (RMEA) to estimate differences in risk and approximate average age at onset of cataracts, cognitive decline, death, menopause, and osteoporosis. Individuals with DS were at higher risk of all age-related conditions or events and experienced these events at younger ages, excluding menopause. We observed a 24.5-fold higher risk of cognitive decline in individuals with DS (p<0.001), and between a 2- and 4-fold higher risk of the other age-related events or conditions (p<0.01). Cognitive decline and death occurred more than 14 years earlier in individuals with DS and were more likely to co-occur (p<0.001) compared to in TD individuals. These findings have important implications for tailored screening and prevention efforts in aging individuals with DS, as this population experiences a distinct cadence of age-related events.

OBJECTIVE: Research on neighborhood context and cognitive health often relies on composite indices that collapse neighborhood socioeconomic status (SES) and aspects of the built environment into a single score. This study examined the extent to which neighborhood SES and built environment were associated with late-life cognitive impairment. METHOD: Participants were 281 predominantly Black older adults who completed the Self-Administered Gerocognitive Exam (SAGE), a brief cognitive screening measure. Participants also provided their home address to obtain four neighborhood metrics: Two composite measures of neighborhood disadvantage, the Environmental Justice Index (EJI) and the EJI Social-Environmental Rank, as well as the EJI Social Vulnerability Rank as a measure of neighborhood SES, and the EJI Environmental Burden Rank to measure exposure to hazardous aspects of the built environment. RESULTS: Lower neighborhood SES was associated with higher odds of cognitive impairment. In contrast, greater environmental burden was associated with lower odds of impairment, with years of education as a moderator; the association was strongest among individuals with high levels of education. The two composite scores were not associated with cognitive impairment. CONCLUSION: Composite measures of neighborhood features may obscure distinct pathways of their effects on cognition.

Features of urbanicity have been linked to poor psychiatric health in adulthood, but little is known about their relationship with biological age and cognition earlier in life. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we tested associations between the built environment and epigenetic ages (EpiAgeAltum, EpiAgeHorvath, EpiAgePACE) (n=2,452), brain age (n=751), and cognition (n=12,199). Analyses were replicated in Generation R and triangulated in the Millennium Cohort Study. The built environment was not associated with epigenetic ages ({beta}Altum range = 0.013-0.015, p range = .466-.689; {beta}Horvath range = -0.011-0.023, p range = .182-.728; {beta}PACE range = -0.045-0.013, p range = .131-.524) or brain age ({beta} range = 0.022-0.028, p range = .337-.429). A negative association with cognition was observed in Generation R. We provide no consistent evidence that childhood built environment exposure relates to biological age and cognition in adolescence, suggesting these relationships may emerge in later life.

Dietary supplements are increasingly being adopted by physically active individuals to support exercise performance and recovery. This randomised, double-blind, placebo-controlled trial evaluated the ergogenic potential of SpinoleRG, an HPLC-PDA-standardised combination of Amaranthus tricolor L. and Spinacia oleracea L. in healthy, recreationally active adults over 12 weeks. Participants received a total of 1,600 mg of the extract or a placebo daily before exercise. Primary endpoints included cardiopulmonary exercise testing, muscle strength, and endurance. Secondary endpoints included treadmill-based time to exhaustion (TTE), body composition, repetitions to failure, biochemical markers, delayed onset muscle soreness (DOMS), and vitals. Routine investigations and safety monitoring were also conducted. Four participants per group were withdrawn due to non-compliance and 64 participants completed the study. Compared to the placebo, the test group showed a significant increase in the ventilatory threshold, but not in VO2 max or maximal ventilation. They also showed significantly improved one-repetition maximum strength, fatigue indices, TTE, repetitions to failure, plasma nitrite, blood lactate, creatine kinase, lactate dehydrogenase, and DOMS outcomes. Vital signs or routine parameters were not impacted meaningfully. Three minor adverse events across both groups were observed, considered unrelated to the interventions and fully resolved. Overall, the findings support the tolerability and ergogenic potential of the extract.

Background: Mitochondrial dysfunction is a hallmark of ageing and is implicated in the pathogenesis of sarcopenia. Genetically confirmed mitochondrial disease provides a biologically definitive model of impaired oxidative phosphorylation against which novel functional assessments can be validated. We investigated whether a brief, submaximal, non-ischaemic intermittent isometric handgrip exercise protocol combined with Near Infra-Red Spectroscopy (NIRS) could detect distinct muscle oxygenation signatures in mitochondrial disease and sarcopenia. Methods: Adults with genetically confirmed mitochondrial disease (n=10, 7 female) and group-matched controls (n=19, 11 female), underwent assessment of maximal grip force, handgrip relaxation kinetics and a 3-minute intermittent submaximal isometric handgrip test (40% maximal voluntary contraction, 1Hz contraction/relaxation) with continuous force recording at 2000Hz and simultaneous NIRS. Findings were compared with 23 community-dwelling older adults from the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse cohort (n=23, 13 female) including seven with probable or confirmed sarcopenia according to European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. Results: Participants with mitochondrial disease demonstrated an attenuated reduction in tissue saturation index (TSI) during exercise compared with controls (TSI % {middle dot} s150-180s: -59.9 {+/-} 94.5 vs -175.1 {+/-} 128.4; p=0.02). Total haemoglobin (THb) responses did not differ between groups (p=0.10). In contrast, participants with probable or confirmed sarcopenia showed exaggerated reduction in TSI compared with non-sarcopenic participants (TSI % {middle dot} s150-180s: -256.5 {+/-} 146.0 vs -121.2 {+/-} 95.2; p=0.05), while THb responses remained similar. The association between sarcopenia and TSI differed by sex (interaction coefficient -240, p=0.016), with greater TSI reductions observed in males with sarcopenia. Differences in TSI between mitochondrial disease and control groups were independent of age and sex. No statistically significant associations were observed between THb responses and age, sex or force production. Conclusions: A brief, non-ischaemic handgrip exercise protocol combined with NIRS identified divergent muscle oxygenation responses in mitochondrial disease and sarcopenia. The attenuated TSI response observed in genetically confirmed mitochondrial disease is consistent with impaired oxygen utilisation secondary to defective oxidative phosphorylation, whereas the exaggerated TSI reduction observed in sarcopenia suggests a distinct physiological mechanism, potentially involving impaired oxygen delivery, reduced muscle efficiency, or both. This portable and non-invasive approach has significant potential as a physiological biomarker for mechanistic studies and clinical trials in ageing and neuromuscular disease. More broadly, our findings demonstrate how biologically defined rare diseases can provide a powerful framework for interpreting mechanisms in common heterogeneous age-related conditions.