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

BackgroundSkeletal muscle energetics decline with age, and physical activity (PA) has been shown to counteract these declines in older adults. Yet, many studies were based on self-reported PA or structured exercise interventions. We examined the associations of objective daily PA and sedentary behavior (SB) with skeletal muscle energetics and also compared with self-reported PA and SB. We also explored the extent to which PA would attenuate the associations of age with muscle energetics. MethodsAmong the Study of Muscle, Mobility and Aging (SOMMA) enrolled older adults, 810 (mean age=76{+/-}5, 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maxOXPHOS) and in vivo by 31Phosphorus magnetic resonance spectroscopy (ATPmax). Objective PA was measured using the wrist-worn ActiGraph GT9X over 7-days to capture sedentary behavior (SB), light, and moderate-to-vigorous PA (MVPA). Self-reported SB, MVPA, and all exercise-related PA were assessed with The Community Healthy Activities Model Program for Seniors questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations between SB, PA and muscle energetics, and the attenuation of the age / muscle energetic association by PA. ResultsEvery 30 minutes more objective MVPA was associated with 0.65 pmol/s*mg higher maxOXPHOS and 0.012 mM/sec higher ATPmax, after adjustment for age, site/technician and sex. More time spent in objective light+MVPA was significantly associated with higher ATPmax, but not maxOXPHOS. In contrast, every 30 minutes spent in objective SB was associated with 0.43 pmol/s*mg lower maxOXPHOS and 0.004 mM/sec lower ATPmax. Only associations with ATPmax held after further adjusting for socioeconomic status, body mass index, lifestyle factors and multimorbidities. Self-reported MVPA and all exercise-related activities, but not SB, yielded similar associations with maxOXPHOS and ATPmax. Lastly, age was only significantly associated with muscle energetics in men. Adjusting for objective time spent in MVPA attenuated the age association with ATPmax by nearly 60% in men. ConclusionMore time spent in daily PA, especially MVPA, were associated with higher muscle energetics. Interventions that increase higher intensity activity might offer potential therapeutic interventions to slow the age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.

BackgroundKetone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on the inflammatory and metabolic aging pathways underpinning frailty in in vivo models. Ketone esters (KEs) are compounds that induce hyperketonemia without dietary changes and that may impact physical and cognitive function in young adults. The functional effects of KEs have not been studied in older adults. ObjectivesOur long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults. Here, we report the exploratory functional and quality-of-life outcome measures collected during a 12-week safety and tolerability study of KE (NCT05585762). DesignRandomized, placebo-controlled, double-blinded, parallel-group, pilot trial of 12-weeks of daily KE ingestion. SettingThe Clinical Research Unit at the Buck Institute for Research on Aging, California. Participants: Community-dwelling older adults ([≥] 65 years), independent in activities of daily living, with no unstable acute medical conditions (n = 30). InterventionSubjects were randomly allocated (1:1) to consume 25 g daily of either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil. MeasurementsLongitudinal change in physical function, cognitive function and quality of life were assessed as exploratory outcomes in n = 23 completers (n = 11 PLA, n = 12 KE). A composite functional outcome to describe the vigor-frailty continuum was calculated. Heart rate and activity was measured throughout the study using digital wearables. ResultsThere were no statistically significant longitudinal differences between groups in exploratory functional, activity-based or quality of life outcomes. ConclusionDaily ingestion of 25 g of KE did not affect exploratory functional or quality-of-life end points in this pilot cohort of healthy older adults. Future work will address these endpoints as primary and secondary outcomes in a larger trial of pre-frail older adults.

RationaleCardiorespiratory fitness and mitochondrial energetics are associated with reduced walking speed in older adults. The impact of cardiorespiratory fitness and mitochondrial energetics on walking speed in older adults with diabetes has not been clearly defined. ObjectiveTo examine differences in cardiorespiratory fitness and skeletal muscle mitochondrial energetics between older adults with and without diabetes. We also assessed the contribution of cardiorespiratory fitness and skeletal muscle mitochondrial energetics to slower walking speed in older adults with diabetes. FindingsParticipants with diabetes had lower cardiorespiratory fitness and mitochondrial energetics when compared to those without diabetes, following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. 4-m and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated [~]20-70% of the difference in walk speed between older adults with and without diabetes. Further adjustments of BMI and co-morbidities further explained the group differences in walk speed. ConclusionsSkeletal muscle mitochondrial energetics and cardiorespiratory fitness contribute to slower walking speeds in older adults with diabetes. Cardiorespiratory fitness and mitochondrial energetics may be therapeutic targets to maintain or improve mobility in older adults with diabetes. ARTICLE HIGHLIGHTSWhy did we undertake this study? O_LITo determine if mitochondrial energetics and cardiorespiratory fitness contribute to slower walking speed in older adults with diabetes. C_LI What is the specific question(s) we wanted to answer? O_LIAre mitochondrial energetics and cardiorespiratory fitness in older adults with diabetes lower than those without diabetes? How does mitochondrial energetics and cardiorespiratory fitness impact walking speed in older adults with diabetes? C_LI What did we find? O_LIMitochondrial energetics and cardiorespiratory fitness were lower in older adults with diabetes compared to those without diabetes, and energetics, and cardiorespiratory fitness, contributed to slower walking speed in those with diabetes. C_LI What are the implications of our findings? O_LICardiorespiratory fitness and mitochondrial energetics may be key therapeutic targets to maintain or improve mobility in older adults with diabetes. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/23297992v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@100b234org.highwire.dtl.DTLVardef@b39e7eorg.highwire.dtl.DTLVardef@6a8c9dorg.highwire.dtl.DTLVardef@1359ecf_HPS_FORMAT_FIGEXP M_FIG C_FIG

ObjectiveExamine the association of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults. MethodsCross-sectional data from 829 older adults [&ge;]70 years was used. Total abdominal, subcutaneous, and visceral AT; and thigh muscle fat infiltration (MFI) was quantified by MRI. SM mitochondrial energetics were characterized using in vivo 31P-MRS (ATPmax) and ex vivo high-resolution respirometry (maximal oxidative phosphorylation (OXPHOS)). ActivPal was used to measure PA (step count). Linear regression models adjusted for covariates were applied, with sequential adjustment for BMI and PA. ResultsIndependent of BMI, total abdominal (standardized (Std.) {beta}=-0.21; R2=0.09) and visceral AT (Std. {beta}=-0.16; R2=0.09) were associated with ATPmax (p<0.01), but not after further adjustment for PA (p[&ge;]0.05). Visceral AT (Std. {beta}=-0.16; R2=0.25) and thigh MFI (Std. {beta}=-0.11; R2=0.24) were negatively associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA (p<0.05). Total abdominal AT (Std. {beta}=-0.19; R2=0.24) and visceral AT (Std. {beta}=-0.17; R2=0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p<0.05). ConclusionsSkeletal MFI and abdominal visceral, but not subcutaneous AT, are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT and in vivo mitochondrial bioenergetics are attenuated by PA.

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events "get under the skin" to influence physical wellbeing. Using data from the Study of Muscle, Mobility and Aging (n=879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (1) maximal adenosine triphosphate production (ATPmax) and (2) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing 1+ adverse childhood event. After adjustment, each additional event was associated with -0.07 SD (95% CI= - 0.12, -0.01) lower ATPmax. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism in understanding how early social stress influences health in later life.

BackgroundBody composition strongly influences clinical outcomes in older adults, yet body mass index (BMI) lacks discriminatory power, and standard tools such as bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry are not routinely accessible. Deep learning enables scalable, opportunistic assessment of body composition from chest radiographs (CXRs), one of the most widely available imaging modalities. Methods and FindingsUsing the Inception-V3 architecture, we developed a deep-learning model using 107,568 paired CXR and BIA records (2016-2018). The model was temporally validated on a separate dataset of 77,655 records (2014-2015). Our model predicted skeletal muscle mass (SMM) and fat mass (FM) with high accuracy (SMM: Pearson r = 0.967, MAE 1.40 kg; FM: r = 0.924, MAE 1.61 kg). In a cohort of 5,932 older adults (aged [&ge;]65years), a 1-SD increase in CXR-predicted skeletal muscle index (SMI) was associated with a significant reduction in 10-year all-cause mortality (Hazard Ratio [HR] 0.65 [95% CI 0.58-0.73] for men; 0.80 [0.67-0.97] for women). In an external validation of 925 geriatric clinic patients, predicted SMI also showed comparable associations with geriatric parameters, including lower odds of sarcopenia (per 1 SD increase: 0.29 [0.22-0.38] for men; 0.25 [0.18-0.34] for women) and frailty (0.62 [0.48-0.78] for men; 1.00 [0.81-1.23] for women). These associations were more robust than those of BMI. Key limitations include the retrospective, single-center design and the use of a relatively healthy screening population. ConclusionA deep learning model applied to routine CXRs enables accurate estimation of skeletal muscle and fat mass, demonstrating prognostic and functional relevance comparable to BIA measurements. This approach may serve as a practical, low-cost tool for risk stratification and long-term care planning, particularly in older adults.

Frailty is a common consequence of aging that makes individuals increasingly susceptible to adverse health outcomes. Frailty screening can identify pre-frail and frail individuals to prescribe interventions or inform clinical decision making to prevent or slow additional frailty progression. Objective, scalable, and automated frailty assessments may expedite and improve clinical frailty screening. Here, we leveraged human pose estimation for video-based gait analysis in older adults who were non-frail, pre-frail, and frail. We focused on gait because slow walking speed is key diagnostic criteria of frailty, and many gait deviations are often observed in older adults with frailty. We collected videos of 68 older adults (25 non-frail, 25 pre-frail, 18 frail) walking at both self-selected and fast paces and used an established pose estimation-based gait analysis approach to measure and compare gait parameters across frailty statuses. Pose estimation-based step time measurements were strongly correlated with manual annotations (self-selected: R2=0.93, fast: R2=0.80) and showed tight Bland-Altman limits of agreement (self-selected: -0.082 to 0.052s, fast: -0.114 to 0.110s), establishing validity of this video-based gait analysis approach in older adults. We then identified a series of cross-sectional differences in spatiotemporal gait parameters among non-frail, pre-frail, and frail older adults, demonstrating that video-based gait analysis can be useful for measuring gait differences across frailty statuses. This study demonstrates the potential of video-based pose estimation for scalable gait tracking across frailty statuses in older adults.

BackgroundIndividuals with Mild Cognitive Impairment (MCI) have more gait variability under dual-task conditions than cognitively healthy adults. However, characteristics associated with this susceptibility of gait to dual-task stress are unknown. MethodsTesting was performed at baseline in the Study of Mental And Resistance Training (SMART). Ninety-three adults with MCI (age 70{+/-}6.8 years; 66.6% female) performed a single- and dual-task walk (cognitive distractor=letter fluency), in random order. Linear and non-linear gait variability were measured using force-sensitive insoles. Cognitive performance during dual-tasking was assessed by the number of correct words vocalized. Cognitive function, brain Magnetic Resonance Imaging (MRI), muscle strength, aerobic capacity, body composition, physical and psychosocial function were also assessed as potential correlates of gait dynamics. ResultsGait dynamics worsened during dual-tasking, with decrements in both stride time variability (p<0.001) and detrended fluctuation analysis (DFA) (p=0.001). Lower aerobic capacity and thinner posterior cingulate cortex were associated with greater decrements in DFA (p<0.05). Smaller hippocampal volume, worse psychological well-being and poorer static balance were associated with greater decrements in stride time variability (p<0.05). By contrast, cognitive performance did not change under dual-task conditions compared to seated testing (p=0.13). ConclusionsUnder dual-task conditions, participants with MCI preserved their cognitive performance at the expense of gait stability. Decrements in dual-tasking gait were associated with lower aerobic fitness, balance, psychological well-being, and brain volume in cognitively-relevant areas of the posterior cingulate and hippocampus, all potentially modifiable characteristics. Trials of targeted interventions are needed to determine the potential plasticity of gait variability in high-risk cohorts.

BackgroundSlow gait speed is a risk factor for poor health outcomes among older adults and may be driven by decreased energy availability and increased fatigability. ObjectiveExamine walking energetics and perceived physical fatigability with gait speed among slower and faster walkers and understand whether fatigability statistically mediates the association between energetics and gait speed. MethodsPerceived physical fatigability was assessed using the Pittsburgh Fatigability Scale (PFS) Physical score (range 0-50, higher=greater). A three-phase cardiopulmonary exercise treadmill test collected peak oxygen consumption (VO2peak mL/kg/min), energetic cost of walking per distance travelled (ECW, mL/kg/meter), and cost-capacity ratios (VO2/VO2peak, %). Gait speed was determined by 4m walk; slower (<1.01m/s) vs faster ([&ge;]1.01m/s) walkers were classified using median 4m gait speed. Linear regressions and statistical mediation analyses were conducted. ResultsSlower walkers had lower VO2peak, higher ECW at preferred walking speed (PWS), and greater PFS Physical score compared to faster walkers (all p<0.05) (N=849). One standard-deviation higher increment of VO2peak, ECW at PWS, cost-capacity ratios at PWS and slow walking speed (SWS), and PFS Physical score were associated with 0.1m/s faster (VO2peak only) or 0.02-0.09m/s slower gait speed. PFS Physical score was a significant statistical mediator in the associations between VO2peak (15.2%), cost-capacity ratio (15.9%), and ECW at PWS (10.7%) with gait speed, and stronger among slower walkers. ConclusionsFitness and fatigability are associated with slower gait speed yet contributions may differ among slower and faster walkers. Future interventions may consider targeting fatigability among slower walkers and fitness among faster walkers.

BackgroundGait adaptability, defined as the ability to adjust walking performance to environmental challenges, likely reflects complex interactions among the central nervous system (CNS) and other physiological systems, however, the drivers of lower gait adaptability in older adults are poorly understood. MethodsWe applied a Bayesian network framework to quantify multisystem interactions contributing to percent change in gait speed (%GSC) on transition from even to uneven surface in 159 older adults (63% women). Neuroimaging measures include total gray matter and white matter hyperintensities, striatal dopaminergic neurotransmission, and resting state functional connectivity. Other measures were obtained for domains important for locomotor control: health history, lifestyle, psychological well-being, cognition, and musculoskeletal and peripheral nervous systems (neurological exam). The Bayesian network estimated direct and indirect dependencies among variables, and predictive accuracy of %GSC from the Bayesian network was compared with that of multivariable linear regression using 10-fold cross-validation. ResultsParticipants exhibited slower gait on uneven compared to even surfaces (mean %GSC = -6.32%). The Bayesian network outperformed linear regression in predicting %GSC and identified four direct paths to %GSC from: BMI, muscle strength, striato-cortical sensorimotor connectivity, and purpose in life. Indirect paths to %GSC showed interrelations among CNS and non-CNS variables, including striatal dopaminergic neurotransmission, total gray matter volume, medications, proprioception, and sex. ConclusionsGait adaptability in older adults is influenced by interactions among functional connectivity, body composition, muscle strength, and psychological well-being. Strengthening both neural and physical systems through targeted interventions may mitigate declines in gait instability and preserve mobility with aging.

Frailty is a clinical syndrome in older adults characterized by heightened vulnerability to adverse outcomes, yet it remains under-assessed in routine practice due to time-intensive evaluation methods. Wearable accelerometers offer a promising approach for passive, continuous frailty monitoring. We analyzed data from 151 community-dwelling older adults ([&ge;]65 years) in the FACE Aging Study who wore hip accelerometers for seven days. Machine learning models were developed to classify baseline frailty status using an adapted frailty phenotype and predict 12-month frailty decline. Features derived from accelerometry data included sleep patterns, activity levels, sedentary behavior, and circadian rhythms. Multiple algorithms were compared, including deep neural networks (ResNet), gradient boosting machines (LightGBM, XGBoost, CatBoost), and multilayer perceptrons (MLPs). For baseline frailty classification, LightGBM achieved the highest performance with an F1 score of 0.898, precision of 0.815, perfect recall (1.000), and AUROC of 0.887. For predicting 12-month frailty decline, multilayer perceptron performed best with an F1 score of 0.812, precision of 0.891, and recall of 0.746. Key predictive features included low overall activity, high sedentary behavior, fragmented activity patterns, and poor sleep quality, which aligned with established frailty phenotypes. One week of free-living hip accelerometry data can accurately identify current frailty status and predict short-term frailty progression in older adults. These findings support the feasibility of developing automated, scalable frailty screening tools that could enable proactive interventions and transform geriatric care from reactive to preventive approaches. External validation in larger, diverse populations is needed to confirm generalizability.

BackgroundPhysical performance tests are predictive of mortality and have been proposed for screening for certain health conditions (e.g., sarcopenia); however, the diagnostic screening and prognostic value of physical performance tests has primarily been studied in age-limited or disease-specific cohorts. In this study, we sought to identify the most salient characteristics associated with three lower quarter balance and strength tests in a deeply phenotyped cohort of community-dwelling adults. MethodsWe applied a stacked elastic net approach on detailed data on sociodemographic, health and health-related behaviors, and biomarker data from the first visit of the Project Baseline Health Study (N=2502) to determine which variables were most associated with three physical performance measures: single-legged balance test (SLBT), sitting-rising test (SRT), and 30-second chair-stand test (30CST). Analyses were stratified by age (<65 and [&ge;]65). ResultsFemale sex, Black or African American race, lower educational attainment, and health conditions such as non-alcoholic fatty liver disease and cardiovascular conditions (e.g., hypertension) were consistently associated with worse performance across all three tests. Several other health conditions were associated with either better or worse test performance, depending on age group and test. C-reactive protein was the only laboratory value associated with performance across age and test groups with some consistency. ConclusionsOur results highlighted previously identified and several novel salient factors associated with performance on the SLBT, SRT, and 30CST. Future research should discern and validate the value of these tests as affordable, noninvasive biomarkers of prevalent and/or future disease in the community.

BackgroundFrailty is a common geriatric syndrome characterized by increased vulnerability to stressors, reduced physiological reserves and heightened vulnerability and. It is also associated with adverse health outcomes. Given its complex phenotypes and underlying pathophysiology, there is a pressing need for robust, multidimensional biomarkers of frailty to advance personalized care. The objective of this study was to identify serum metabolomics signatures associated with different frailty phenotypes and related features. MethodsWe analyzed Nuclear Magnetic Resonance (NMR) metabolomics signatures in 901 subjects, 47.5% of them males (average age 68.34 {+/-} 3.51 years) from the Berlin Aging Study II, categorized as non-frail, pre-frail, or frail based on Frieds criteria at baseline (T0) and follow-up (T1, on average 7 years later). Linear models were used to assess associations between metabolite levels, frailty phenotypes, and frailty-related parameters. ResultsAt baseline (T0), only 1% of the population was classified as frail, increasing to 4.8% at T1 (p-value<0.0001). In contrast, in terms of frailty progression during follow-up 323 subjects (35.8%) transitioned from non-frail to pre-frail, pre-frail to frail, or directly from non-frail to frail. In the overall population no significant differences were found in the relative quantifications of the 82 identified metabolites for any of the tested study outcomes. In contrast, 27 and 30 metabolites were negatively associated with handgrip strength at T0 and T1, respectively (p-value<0.05), and one metabolite (L-tyrosine, p-value=0.0297) positively associated with fat mass in men. In women, dimethylsulfone was positively associated with the percentage of evolution in the hand grip strength between T0 and T1 (p-value=0.0442), and glycerol was positively associated with appendicular lean mass at T0 (p-value=0.0049). Additionally, 22 metabolites were positively correlated with nutritional status at T0 in men (p-value<0.05): many of these were linked to carbohydrate (e.g., maltose, fructose, glucose, galactitol, mannose, lactate, acetylcarnitine) and amino acid metabolism (e.g., valine, tyrosine, isoleucine, alpha-hydroxybutyrate). ConclusionsWe may conclude that while serum metabolome revealed a weak association with frailty, significant associations were observed (particularly in men) between metabolomics signatures and frailty-related features such as muscle strength and nutritional status. These findings point to insulin sensitivity as a central feature, with early markers of impaired insulin sensitivity potentially impacting muscle health.

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.

The ability to recall learned movements and rapidly adapt to environmental changes, known as locomotor savings, is crucial for mobility in community-dwelling older adults. However, the influence of aging on locomotor savings and the underlying mechanisms remains poorly understood. Attentional compensation is a particularly relevant mechanism because the control of automatic motor behaviors like walking tend to recruit more attentional/executive resources with aging. We hypothesize that locomotor savings is diminished with age and relies on attentional rather than automatic control of walking. To test this, we compared savings of a novel walking pattern learned on a split-belt treadmill, where each leg moves at a different speed, across multiple days in 21 older and 21 younger adults. Attentional control of walking was assessed by overground dual-task walking while prefrontal cortex (PFC) activity was recorded using functional near-infrared spectroscopy (fNIRS). We found that older adults exhibited less locomotor savings than younger adults after practice. Older adults also relied more on attentional resources during dual-task walking. Importantly, greater locomotor savings was associated with higher attentional control of walking in older adults, suggesting that the use of attentional resources during challenging walking facilitates the recall of previously learned movements. These results indicate that cognitive compensation strategies utilizing attentional resources are important neural mechanisms modulating locomotor savings. Understanding the role of cognitive compensation in locomotor savings may inform rehabilitation design to enhance mobility in older adults ensuring movement corrections practiced in clinical settings are saved for long-term benefit in daily life. Significance StatementSuccessfully navigating everyday environments requires adapting and recalling learned walking patterns, a process known as locomotor savings. We found that older adults showed locomotor savings across multiple days following structured practice, but to a lesser extent than younger adults. With aging, walking becomes less automatic and more reliant on attentional control, which is traditionally considered detrimental. Interestingly, we found that greater attentional control during walking was linked to better locomotor savings in older adults. These results suggest that attentional compensation during walking may support motor memory retrieval and adaptability in healthy aging, highlighting a potentially beneficial role of cognitive control in maintaining mobility during aging.

BackgroundFrailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that geroscience interventions, which target mechanisms of aging, could ameliorate frailty. Metabolites such as ketone bodies are candidate geroscience interventions, having pleiotropic effects on inflammo-metabolic aging mechanisms. Ketone esters (KEs) induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate geroscience mechanisms and clinical outcomes relevant to frailty in older adults. ObjectivesThe primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a generalizable population of older adults ([&ge;] 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures. MethodsCommunity-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n=30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12. ConclusionThis study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of geroscience-related endpoints. This data will inform design of larger trials to rigorously test KE effects on geroscience mechanisms and clinical outcomes relevant to frailty.

BackgroundThe rising prevalence of Alzheimers disease (AD) and related neurodegenerative disorders highlights the need for non-pharmacological strategies to preserve cognitive health. Brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and irisin are biomarkers associated with cognitive resilience and metabolic health. ObjectiveTo assess the impact of a multimodal lifestyle intervention on serum BDNF, VEGF, and irisin levels in an aging population, aiming to explore how modifiable lifestyle factors influence biomarkers linked to neurodegeneration risk. MethodsIn a randomised controlled trial, participants were assigned to a 12-week lifestyle intervention group (n=42, 32 female; mean age 67.1{+/-}7.6 years) or a control group (n=41, 34 female; mean age 62.7{+/-}8.6 years). The intervention included structured physical exercise, dietary modifications, sleep hygiene, and mindfulness practices. Serum BDNF, VEGF, and irisin levels were measured at baseline (T1), post-intervention (T2), and six months post-intervention (T3). Linear mixed models assessed biomarker changes over time and between groups. ResultsIrisin levels increased significantly post-intervention (T2) in the intervention group (p < 0.001) in comparison to the control group and were maintained at T3 (p = 0.003). The intervention group also exhibited a significant attenuation of BDNF decline at T3 compared to the control group (p = 0.007). VEGF levels remained stable across all time points (p > 0.05). Collectively, these changes suggest that the intervention resulted in positive metabolic and neuroprotective effects. ConclusionA structured lifestyle intervention can significantly elevate BDNF and irisin levels, supporting non-pharmacological strategies to enhance brain health and potentially reduce neurodegeneration risk in older adults.

BackgroundAge-related muscle dysfunction is a major contributor to disability, frailty, and poor clinical outcomes in older adults. Muscle mass and strength provide limited insight into the multifactorial nature of muscular decline. Skeletal Muscle Function Deficit (SMFD) framework integrates multiple domains muscle mass, quality, strength, and power to capture a broader spectrum of age-related muscle dysfunction. ObjectiveTo develop and validate a composite SMFD score and evaluate its association with key geriatric outcomes in older adults. MethodsThis study used data from the InCHIANTI longitudinal cohort (1998-2018), including 1,035 participants and 3,196 total assessments. The SMFD score (range 0-20) was computed by assigning quintile-based values of muscle area, density, strength, and lower limb power. Associations with disability in basic and instrumental activities of daily living (BADL/IADL), frailty phenotype, poor physical performance (SPPB <7), hospitalization, falls number, and major chronic diseases were analyzed using mixed-effects models, adjusting for age, sex, fat area, and multimorbidity. ResultsThe SMFD score declined significantly over time and was independently associated with lower risk of BADL (OR 0.57), IADL (OR 0.70), frailty (OR 0.72), poor performance (OR 0.68), hospitalization (OR 0.96), and falls number (OR 0.96). Higher SMFD scores were also inversely associated with the prevalence and incidence of Parkinsons disease, stroke, and hip osteoarthritis. ConclusionsThe SMFD score is a valid, multidimensional measure that predicts adverse outcomes in older adults more effectively than traditional sarcopenia, dynapenia, and powerpenia. It holds promise for use in clinical assessment, risk stratification, and targeted interventions.

ObjectiveTo investigate the association of objective long sleep duration (LS) and insomnia with objective short sleep duration (ISSD) with mortality in older persons. MethodsIn 3,054 men (average age 76.4{+/-}5.5; mean follow-up=12.1 years) and 3,048 women (average age 83.6{+/-}4.8; mean follow-up=5.4 years), Cox proportional hazards models examined the association of LS (actigraphy-estimated sleep duration>8h) and ISSD (insomnia [difficulty initiating or maintaining sleep and/or sleep medication use [&ge;]3/week] and concurrent actigraphy-estimated sleep duration<6h) with mortality. Other phenotypes (insomnia with normal sleep duration [INSD; insomnia and sleep duration 6-8h]; asymptomatic short sleep [AS; no insomnia and sleep duration<6h]) were also examined. Participants with normal sleep (NS; no insomnia and sleep duration 6-8h) served as the reference group. Models were adjusted for demographics and comorbidities. ResultsIn unadjusted models, LS was associated with increased mortality in men and women when compared with NS. In women only, LS was associated with higher mortality after adjustment for demographics and comorbidity compared with NS (HR 1.30 [1.07, 1.59]). In demographic-adjusted models and across cohorts, ISSD was significantly associated with an increased hazard of mortality compared with NS (HR 1.25 [1.10, 1.43] for men; 1.36 [1.11, 1.67] for women). This association was not significant in either cohort after adjusting for comorbidity. Persons with INSD or AS did not have increased mortality risk compared with NS. ConclusionLS and ISSD are at-risk phenotypes in older persons. Associations with mortality may be mediated by chronic diseases. Future work should examine whether sleep improvements decrease mortality in older persons. STATEMENT OF SIGNIFICANCEPrior studies have reported inconsistent results on the association between insomnia with objective short sleep duration (ISSD) and mortality in older persons. While long sleep duration (LS) has been associated with mortality, self-reported assessments may be subject to bias. Through analysis of two large cohorts of community-dwelling older men and women with objective sleep measurements and robust longitudinal data, we found ISSD and LS to be associated with all-cause mortality. After controlling for the presence of chronic conditions, however, only LS in women was significantly associated with mortality. Our findings suggest that underlying comorbidities mediate the risk of ISSD and LS in older persons and that objective measures may be needed to differentiate risk among older persons with insomnia symptoms.

Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs each targeting different but overlapping processes. In order to determine if combining drugs previously shown to improve lifespan would have greater impact than any individuyal drug, a diet containing rapamycin at 14 ppm, acarbose at 1000 ppm, and phenylbutyrate at 1000 ppm was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice fed the cocktail diet showed a strain and gender-dependent phenotype consistent with healthy aging including decreased body fat and blood glucose, improved cognition, and increased grip strength and walking ability compared to mice fed individual drug or control diets. A cocktail diet containing [1/2] dosing of each compound was overall less effective than the full dose. The composite age-related lesion score of heart, lungs, liver and kidney was decreased in mice fed the cocktail diet compared to mice fed individual drug or control diets suggesting an interactive advantage of the three drugs. Senescence and inflammatory cytokine levels in kidneys from mice fed the cocktail diet were lower than in kidneys from mice fed control diet, and consistent with low expression levels in kidneys from young untreated mice, suggesting the cocktail diet delayed aging partly by senolytic and anti-inflammatory effects.