Experimental Gerontology

BackgroundSarcopenia is the progressive loss of skeletal muscle mass, strength, and function with age, driven by dysregulation in the rates of muscle protein synthesis (MPS) and breakdown (MPB). Although MPB contributes to net protein balance (NB), a primary contributor of sarcopenia is anabolic resistance, defined as the blunted MPS response to anabolic stimuli such as feeding. While candidate mechanisms of anabolic resistance have been identified, none singularly accounts for the observed reduction in MPS. Instead, multiple mechanisms likely act simultaneously and interactively to suppress MPS. Studying these interactions experimentally is challenging. Mathematical modeling is well suited to analyzing complex biological phenomena such as anabolic resistance. MethodsWe analyzed a previously developed kinetic model of leucine-mediated signaling and protein metabolism in human skeletal muscle to systematically investigate potential mechanisms contributing to anabolic resistance. Using global sensitivity analysis, we identified key controllers of MPS, MPB, and NB. We then simulated amino acid feeding in older adults, classified the responses as either anabolic sensitive or resistant, and compared the resulting parameter distributions of the two groups. We next performed targeted analysis to evaluate the effects of individual and combined putative mechanisms of anabolic resistance on muscle metabolism. Finally, we simulated therapeutic interventions aimed at restoring muscle metabolism. ResultsThe sensitivity analysis revealed that MPS and MPB are primarily controlled by their proximal signaling processes, while NB is largely driven by MPS dynamics. Exploratory simulations showed that several parameters and signaling protein concentrations, particularly those controlling MPS, differed significantly between anabolic sensitive and resistant groups. The targeted simulations indicated that multiple dysregulated mechanisms were required to account for the experimentally observed reductions in MPS in older adults. Therapy simulations showed that single-target interventions could largely restore MPS when isolated mechanisms were perturbed (e.g., increasing mTORC1 sensitivity, enhancing p70S6K levels), but a multifactorial approach was required to recover muscle metabolism when all anabolic resistance mechanisms were present. ConclusionThis study highlights the multifactorial nature of anabolic resistance and the implications for therapy. Specifically, the results motivate new hypotheses regarding the mechanisms most likely to be impaired and argue for multi-target therapeutic strategies to help restore muscle protein metabolism in aging.

Physical activity has been suggested to project again brain atrophy, but also to be a determinant of physical activity in older adults. However, research is needed to confirm this bidirectional relationship. Therefore, this research aimed to study the bidirectional relationship between physical activity and brain structure in older adults from the UK Biobank. A total of 3,027 (62.45 {+/-} 7.27 years old, 51.3% females) had physical activity and MRI data at baseline and follow-up. Physical activity was assessed through a self-reported questionnaire. T1-weighted MRI and diffusion tensor imaging were used to quantify brain volumes and white matter microstructure, respectively. Cross-lagged panel models were performed to estimate bidirectional associations, and linear mixed-effects models (LMM) to investigate the consistency of findings. Overall, our main findings suggest that higher hippocampal volume (Standardized Beta Coefficient ({beta})=0.075, pFDR<0.001), frontal volume ({beta}=0.043, pFDR=0.037), and global fractional anisotropy ({beta}=0.042, pFDR=0.028) were associated with more do-it-yourself (DIY) activities (e.g., watering the lawn or digging) levels at follow-up. In addition, strenuous sports at baseline were positively associated with hippocampal volume over time ({beta}=0.011, pFDR=0.108). Although this association did not survive/was not significant after adjustment for multiple comparisons, was confirmed by the LMM. In contrast, higher levels of walking for pleasure were negatively associated with white matter volume at follow-up ({beta}= -0.026, pFDR=0.008). In conclusion, there is a bidirectional association between physical activity and brain structure in healthy middle-aged and older adults. However, further research is needed to understand why physical activity subdomains are associated differently with brain structures and features during aging.

Ageing is associated with a loss of skeletal muscle mass and function that negatively impacts the independence and quality of life of older individuals. Females demonstrate a distinct pattern of muscle ageing compared to males, potentially due to menopause where endogenous sex hormone production declines. This systematic review aims to investigate the current knowledge about the role of oestrogen in female skeletal muscle ageing. A systematic search of MEDLINE complete, Global Health, Embase, PubMed, SPORTDiscus, and CINHAL was conducted. Studies were considered eligible if they compared a state of oestrogen deficiency (e.g. postmenopausal females) or supplementation (e.g. oestrogen replacement therapy) to normal oestrogen conditions (e.g. premenopausal females or no supplementation). Outcome variables of interest included measures of skeletal muscle mass, function, damage/repair, and energy metabolism. Quality assessment was completed with the relevant Johanna Briggs critical appraisal tool, and data were synthesised in a narrative manner. Thirty-two studies were included in the review. Compared to premenopausal females, postmenopausal females display reduced muscle mass and strength, but the effect of menopause on markers of muscle damage and expression of the genes involved in metabolic signalling pathways remains unclear. Some studies suggest a beneficial effect of oestrogen replacement therapy on muscle size and strength, but evidence is largely conflicting and inconclusive, potentially due to large variations in the reporting and status of exposure and outcomes. The findings from this review points toward a potential negative effect of oestrogen deficiency in ageing skeletal muscle, but further mechanistic evidence is needed to clarify its role. Graphical abstract figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/23290199v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@97b4ecorg.highwire.dtl.DTLVardef@1e71a43org.highwire.dtl.DTLVardef@16d4a9corg.highwire.dtl.DTLVardef@3d7ac3_HPS_FORMAT_FIGEXP M_FIG C_FIG The role of oestrogen in female skeletal muscle ageing. {uparrow} = significant increase, {downarrow} = significant decrease, = = significantly different, ? = mixed evidence, p<0.05. ALM: appendicular lean mass; AMPK: adenosine monophosphate kinase; CSA: cross-sectional area; PGC-1: peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Created with BioRender.com.

Immune responses are highly variable from one individual to another, with this variability determined by factors such as age, sex, genetics and environment, which also affect physical and mental well-being. Systems immunology studies have been applied to human cohort studies to better understand these effects, but most are performed in Western populations of mostly European ancestry, neglecting the vast majority of human global diversity. To overcome this limitation, we established the Healthy Human Global Project - Hong Kong (HHGP-HK) cohort to allow the study of immune variability in a healthy Asian population. Taking inspiration from the established French Milieu Interieur study we adapted inclusion and exclusion criteria to identify healthy donors, and to facilitate cross comparison between the two cohorts we collected similar demographic, medical and lifestyle information. To study the effects of age and sex, donors were stratified for both ranging from 20-79 years. We report here significant age and sex effects on multiple clinical laboratory measures, many of which were consistently observed in the Milieu Interieur cohort. C-reactive protein and liver enzymes were two exceptions perhaps reflecting different environmental effects between the two cohorts. We applied biological aging, physiological, and mental health scores to our cohort which highlights the need to develop and adapt such scores for application to populations of non-European descent. We also included wearable fitness trackers from which we observed significant age and sex differences for sleep, physical activity, and heart rate variability. This unique cohort will enable the better understanding of factors that determine immune variability within Asian populations.

BackgroundTraining studies typically investigate the cumulative rather than the analytically challenging immediate effect of exercise on cognitive outcomes. MethodsWe investigated the dynamic interplay between single-session exercise intensity and time-locked cognition in older adults with suspected Alzheimers dementia (N = 17) undergoing a 24-week dual-task regime. We specified a state of the art hierarchical Bayesian continuous- time dynamic model with fully connected state variables to analyze the bidirectional effects between physical and cognitive performance over time. ResultsHigher physical performance was dynamically linked to improved memory recognition (-1.335, SD = 0.201, 95 BCI [-1.725, -0.954]). The effect was short-term, lasting up to five days (-0.368, SD = 0.05, 95 BCI [-0.479, -0.266]). Clinical scores supported the validity of the model and observed temporal dynamics. ConclusionHigher physical performance predicted improved memory recognition in a day- by-day manner, providing a proof-of-concept for the feasibility of linking exercise training and cognition in patients with Alzheimers dementia. HighlightsO_LIHierarchical Bayesian continuous-time dynamic modelling approach C_LIO_LI72 repeated physical exercise (PP) and cognitive (COG) performance measurements C_LIO_LIPP is dynamically linked to session-to-session variability of COG C_LIO_LIHigher PP improved COG in subsequent sessions in subjects with Alzheimers dementia C_LIO_LIShort-term effect: lasting up to four days after training session C_LI Research in ContextO_LISystematic review: Training-induced effects on cognitive outcomes in Alzheimers dementia and/or associated dynamic Bayesian modelling approaches were reviewed. Although studies showed exercise-induced cognitive improvements or maintenance, most of these studies fail to capture the dynamic nature of the change and interplay of physical (PP) and cognitive (COG) performance. C_LIO_LIInterpretation: Using a sophisticated hierarchical Bayesian continuous-time dynamic modelling approach, a fully connected state variable model was specified. PP is dynamically linked to COG, i.e. higher PP predicted improved COG in subsequent sessions. This effect was rather short term, lasting for up to five days. C_LIO_LIFuture direction: Our results support exercise-induced effects on cognition. The cognitive system was still able to fluctuate and change favourably even in a sample with Alzheimers dementia. Further studies using dynamic modelling are necessary to replicate findings and examine other contributors to cognitive volatility in dementia. C_LI

Smoothelin-like 1 (SMTNL1) is expressed in smooth and skeletal muscle tissues as well as a variety of steroid hormone-sensitive tissues. SMTNL1 can play a sex-dependent regulatory role in skeletal muscle metabolism in mice. Previous studies have documented appreciable changes in muscle morphology and metabolic function of young male mice with genetic deletion of Smtnl1. SMTNL1 can also impact the energy metabolism and insulin sensitivity of female mice during pregnancy. Therefore, we investigated the metabolic outcome of global SMTNL1 knockout (KO) in male and female mice with advancing age using a comprehensive lab animal monitoring system (CLAMS). With ageing, body weight gain was markedly higher with a concomitant increase in whole body adiposity as well as specific white adipose depots in the absence of SMTNL1. Moreover, this genotypic difference in whole body adiposity was greater in the female cohort. The deletion of SMTNL1 was also associated with delayed satiety in mice fed a high fat diet, which was more pronounced in the female mice. A significant genotypic difference was also revealed for the metabolic energy balance in 12 month old animals of both sexes. The KO animals were metabolically less efficient and displayed a preference for carbohydrate catabolism. However, reduced glucose tolerance was observed only in the female group with the deletion of SMTNL1. Taken together, the current findings establish a novel role for SMTNL1 in modulating adiposity and energy metabolism with ageing in a sex dimorphic way.

BackgroundThe increasing prevalence of depression and functional disability in older adults highlights the need for targeted interventions, with sleep as a potentially modifiable factor, yet the longitudinal effects and mediating role of sleep remain poorly understood. MethodsThis review and conceptual framework aimed to examine the pairwise bidirectional associations between sleep, depression, and functional disability and identify the longitudinal mediating role of sleep in the bidirectional relationship between depression and functional disability in older adults. The academic databases PsycArticles, PubMed, MEDLINE, Science Citation Index, Social Sciences Citation Index, ProQuest Dissertations and Theses Global, Cochrane, and Scopus were searched for research published in English between January 2000 and June 2024. Systematic review and cohort study designs were eligible. All included studies were assessed for quality using the Critical Appraisal Skill Programme checklist (CASP 2024). Results397,289 citations were identified, and 82 studies meeting the inclusion criteria were included. Cohort studies and reviews provide evidence that there is a dynamic reciprocal correlation between sleep, depression, and functional disability in the older population. We propose that sleep may increase the risk of depression and functional disability in the follow-up years, with sleep acting as a potential mediating factor between depression and functional disability. There was a selection bias in the study samples, as most studies focused on specific populations or regions. Moreover, some of the cohort studies included lacked sufficient follow-up time to observe long-term effects. ConclusionsThis review and conceptual framework highlight that sleep health can provide crucial insights for mitigating the adverse effects experienced by older adults due to depression and functional disability. For healthcare professionals and policymakers, it provides evidence about prioritizing sleep health as an accessible step to foster a healthy lifestyle. PROSPERO registration numberCRD42024556536. What is already known on this topicWith the increasing aging population, improving the physical and mental health of older adults has become a key social issue. Substantial epidemiological studies have confirmed the existence of bidirectional relationships between depression, sleep disorders, and functional disability in older adults, with all three variables influencing each other. However, the complex interaction mechanisms among these three variables remain unclear, and further research is needed to explore whether sleep plays a longitudinal mediating role between depression and functional disability. What this study addsThis study significantly enhances our understanding by providing robust evidence of the dynamic, bidirectional relationships among sleep, depression, and functional disability in older adults. Unlike previous research that primarily examined pairwise relationships, our study delves deeper by proposing a comprehensive conceptual framework. This framework underscores the potential mediating role of sleep, suggesting that sleep disturbances are not merely consequences of depression and functional disability but also active contributors to their interaction and progression. By elucidating these underlying mechanisms and potential pathways, our study sheds light on the complex interplay among these three variables, ultimately enhancing the quality of life for older adults. How this study might affect research, practice or policyThis study paves the way for deeper investigation into the causal mechanisms connecting sleep, depression, and functional disability. It highlights the critical importance of prioritizing resources for sleep-related research and interventions, recognizing their significant potential to enhance the well-being of an aging population. This holistic approach aims to foster a more comprehensive understanding and effective strategies for promoting healthy aging.

Computational models can be used to study the mechanistic phenomena of disease. Current mechanistic computer simulation models mainly focus on (patho)physiology in humans. However, often data and experimental findings from preclinical studies are used as input to develop such models. Biological processes underlying age-related chronic diseases are studied in animal models. The translation of these observations to clinical applications is not trivial. As part of a group of international scientists working in the COST Action network MouseAGE, we argue that in order to boost the translation of pre-clinical research we need to develop accurate in silico counterparts of the in vivo animal models. The Digital Mouse is proposed as framework to support the development of evidence-based medicine, for example to develop geroprotectors, which are drugs that target fundamental mechanisms of ageing. HighlightsO_LIComputational modelling of human (patho)physiology is advancing rapidly, often using and extrapolating experimental findings from preclinical disease models. C_LIO_LIThe lack of in silico models to support in vivo modelling in mice is a missing link in current approaches to study complex, chronic diseases. C_LIO_LIThe development of mechanistic computational models to simulate disease in mice can boost the discovery of novel therapeutic interventions. C_LIO_LIThe Digital Mouse is proposed as a framework to implement this ambition. The development of a Digital Mouse Frailty Index (DM:FI) to study aging and age-related diseases is provided as an example. C_LI

Musculoskeletal function declines with aging, resulting in an increased incidence of trips and falls. Both bone and muscle experience age-related losses in tissue mass that alter their mechanical interactions in a well characterized manner, but changes in the biochemical interactions between bone and muscle with aging are not well understood. Of note, insulin-like growth factor 1 (IGF-1), a potent growth factor for bone and muscle, can be negatively altered with aging and may help explain losses in these tissues. We recently developed a co-culture system for simultaneous growth of bone mesenchymal stem cells (MSCs) and muscle satellite cells (SCs) to investigate the biochemical crosstalk between the two cell types. Here, we utilized an aging rat model to study cellular changes between young and old rat MSCs and SCs, in particular whether 1) young MSCs and SCs have increased proliferation and differentiation compared to old MSCs and SCs; 2) young cells have increased IGF-1 and collagen expression as a measure of crosstalk compared to old cells; and 3) young cells can mitigate the aging phenotype of old cells in co-culture. Rat MSCs and SCs were either mono- or co-cultured in Transwell(R) plates, grown to confluence, and allowed to differentiate for 14 days. Across the 14 days, cell proliferation was measured, with differentiation and crosstalk measurements evaluated at 14 days. The results suggest that in both young and old, proliferation is greater in mono-cultures compared to co-cultures, yet age and cell type did not have a significant effect. Differentiation did not differ between young and old cells, yet MSCs and SCs demonstrated the greatest amount of differentiation in co-culture. Finally, age, cell type, and culture type did not have a significant effect on collagen or IGF-1 expression. These results suggest co-culture may have a controlling effect, with the two cell types acting together to promote differentiation more than in mono-cultures, yet this response was not altered by age. In general, results for old cells had higher variability, suggesting a wider variety in the aging phenotypes demonstrated in these animals. This study was the first to use this rat aging model to investigate changes between bone and skeletal muscle cells, however further investigations are required to determine what signaling changes occur in response to age. Determining these signaling changes could lead to new targets for mitigating the progression of aging.

Clustering effects, such as those introduced by housing animals in shared cages, are often overlooked in preclinical lifespan studies, despite their potential to distort variance estimates and inflate Type I error rates, leading to misleading conclusions. This methodological oversight reduces statistical rigor and may undermine the reliability of findings. To address this gap, the current study examines the impact of accounting for clustering and nesting effects on lifespan analyses by comparing the results of statistical models which both account for and ignore these effects. Using 2019 data from the Interventions Testing Program (ITP), a large-scale initiative evaluating the effects of compounds on lifespan in UM-HET3 mice as a case study, we illustrate how different modeling approaches influence statistical estimates and conclusions. Clustering and nesting effects were addressed using linear mixed effects, and Cox frailty models, both of which explicitly account for cage-level dependencies and different levels of data nesting. Comparisons were made between unadjusted lifespan analyses and those incorporating clustering and nesting adjustments. The results of this case study indicate that properly adjusting for clustering and nesting effects can change the conclusions drawn from statistical significance tests as compared to unadjusted model approaches, and so it remains best practice to properly account for clustering and nesting to reduce the potential for inflated Type I error rates. These findings highlight the importance of accounting for clustering and nesting in preclinical research to ensure valid and robust statistical inference. By demonstrating the practical application of clustering adjustments, this work underscores the broader implications for improving reproducibility and rigor in lifespan studies and other experimental designs.

ObjectivesExamine the effect of aerobic exercise on structural brain age and explore potential mediators. MethodsIn a single-blind, 12-month randomized clinical trial, 130 healthy participants aged 26-58 years were randomized into a moderator-to-vigorous intensity aerobic exercise group or a usual-care control group. The exercise group attended 2 supervised 60-minute sessions per week in a laboratory setting plus home-based exercise to achieve 150 minutes of exercise per week. Brain-predicted age difference (brain-PAD) and cardiorespiratory fitness (CRF) were assessed at baseline and 12 months. Intention-to-treat (ITT) and completers analyses were performed. ResultsThe 130 participants (67.7% female) had a mean (SD) age of 41.28 (9.93) years. At baseline, higher CRF (VO2peak) was associated with smaller brain-PAD ({beta}=-0.309, p=0.012). After the intervention, the exercise group showed a decrease in brain-PAD (estimated mean difference (EMD) =-0.60; 95% CI: -1.15 to -0.04; p=0.034) compared to the control group (EMD=0.35; 95% CI: -0.21 to 0.92; p=0.22); timexgroup interaction (between-group difference (BGD)= -0.95; 95% CI: -1.72 to -0.17; p=0.019). VO2peak improved in the exercise group (EMD=1.60; 95% CI: 0.29 to 2.90; p=0.017) compared to the control group (EMD=-0.78; 95% CI: -2.17 to 0.60; p=0.26); timexgroup interaction (BGD=2.38; 95% CI: 0.52 to 4.25; p=0.015). Body composition, blood pressure, and brain-derived neurotrophic factor levels were unaffected. None of the proposed pathways statistically mediated the effect of exercise on brain-PAD. The results from completers were similar. ConclusionEngaging in 12 months of moderate-to-vigorous exercise reduced brain-PAD in early-to-midlife adults. The pathways by which these effects occur remain unknown. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSMidlife risk factors influence brain aging, with physical activity conferring protective benefits, yet evidence for the effect of exercise on midlife brain age and underlying mechanisms remains limited. What this study addsParticipation in a 12-month aerobic exercise intervention significantly reduced a neuroimaging marker of brain age. Higher cardiorespiratory fitness was also associated with younger brain age. How this study might affect research, practice or policyFindings of this study complement the scarce literature examining the effects of exercise on early-to-midlife brain health and confirm the neuroprotective effects of aerobic exercise against accelerated brain aging in early-to-midlife adults.

BackgroundIntrinsic capacity (IC) is a composite measure, computed from five domains: cognition, psychological well-being, locomotion, vitality, and sensory. IC reflects the overall physiological reserve and functional capacity of an individual, making it a key indicator of healthy ageing. The substantial interindividual variability in IC is likely influenced by genetic (polygenic) as well as socioeconomic status and lifestyle factors. However, the interaction effect of these factors is yet to be explored. ObjectiveThis study examined (1) associations of IC with socio-economic and lifestyle factors and the polygenic scores for IC (PGS-IC) when stratified by age, and (3) the interaction effects of the PGS-IC and socio-economic or lifestyle factors on IC. MethodsOur study included 13,112 participants from the Canadian Longitudinal Study on Aging (CLSA) comprehensive cohort with complete IC variables and genetic data. Composite lifestyle scores, including the Physical Activity Scale for the Elderly (PASE), Prospective Urban Rural Epidemiological study (PURE) diet, and Mediterranean diet scores, were generated following established guidelines. Associations of IC with the socioeconomic and lifestyle factors were assessed using linear regression models adjusted for age and sex. The IC scores and the PGS-IC were developed in CLSA in our previous work, and this study tested age-stratified associations of PGS-IC with IC, and interaction effects of the PGS-IC and socioeconomic or lifestyle factors on IC using linear regression models adjusted for age, sex, and the top five genetic principal components. Statistical significance was defined as a false discovery rate (FDR) adjusted P < 0.05. ResultsThe mean age was 61 (standard deviation 9.6) years, and 50.8% were females. Higher IC was associated with higher education (B = 0.255, 95% CI: 0.180, 0.329), higher income (B = 0.392, CI: 0.322, 0.461), physical activity (PASE score: B = 0.001, CI: 0.0004, 0.001), and healthier diets (PURE diet score: B = 0.024, CI: 0.021, 0.027; Mediterranean diet score: B = 0.018, CI: 0.016, 0.021). IC was lower in previous (B = -0.093, CI: -0.121, -0.064) and current smokers (B = -0.407, CI: -0.459, -0.355) compared to never smokers. Likewise, short (<7h: B = -0.133, CI: -0.161, -0.105) and long (>9h: B = -0.258, CI: -0.392, -0.124) sleep durations were negatively associated with IC compared to those who had optimal sleep. The PGS-IC was positively associated with IC, particularly in younger adults. Significant interaction effects were observed with Mediterranean diet (B = -0.003, CI:-0.006 -, -0.0002) in whole sample, education in younger adults (B = -0.109, CI: -0.211 -, -0.007), and sleep (younger adults: long sleep, B = 0.198, CI:0.023, 0.373; older adults: short sleep, B = -0.095, CI: -0.153 -, -0.036). ConclusionNovel findings confirming the interaction effects of PGS-IC with socioeconomic and lifestyle factors suggest that there is a complex interplay between genetics and the environment in shaping IC and healthy ageing.

BackgroundThe impact of common cardiovascular medications on sarcopenia in older persons is unclear. The aim of this population-based cohort study was to investigate the relationship between long-term intake of statins and renin-angiotensin-system inhibitors (RASi), i.e. angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), and established muscle mass and function parameters. MethodsCommunity dwelling older adults (n=1,083, 52% women, 68.3 {+/-} 3.5 years at baseline) from the Berlin Aging Study II (BASE-II) with a mean follow-up of 7.4 {+/-} 1.5 years were analyzed. Users of statins or RASi were compared to non-users. Appendicular lean mass (ALM) was measured via dual-energy X-ray absorptiometry and related to body mass index (ALM/BMI) and height2 (SMI). Hand grip strength (HGS) was assessed and related to arm muscle mass. The Timed "Up and Go" and Tinetti mobility test were used to evaluate physical performance. Adjusted linear regressions of drug use on muscle mass, strength, and function were conducted. ResultsIn linear regression analysis, statin use was neither associated with any of the muscle mass nor with function parameters. In contrast, RASi users had significantly lower ALM/BMI ({beta}= -0.036, p=0.004). When stratified by sex, the use of RASi was significantly associated with lower ALM/BMI in women ({beta}= -0.033, p=0.029) but not in men ({beta}= -0.037, p=0.072). ConclusionAlthough statins have been associated with adverse muscle events, their use in older adults was not significantly associated with muscle mass or function parameters. In contrast, use of RASi was associated with a lower muscle mass phenotype. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/25332603v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@3f6e5aorg.highwire.dtl.DTLVardef@660b27org.highwire.dtl.DTLVardef@16655a7org.highwire.dtl.DTLVardef@1814dd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

ObjectiveEnzyme Acetylcholinesterase is a potential marker for ageing, disease onset, progression and therapy. Physical activity and storage time affect the variable range, quality data prevalence and variability. The study aims to examine the effect of one and two months of storage time on protein concentration, acetylcholinesterase activity and inhibitor efficacy in subjects subjected to 3 months of physical activity. MethodThe value of AChE activity was measured spectrophotometrically by Elman et al. (1961). The obtained results were processed by the statistical program SPSS v 23.0. ResultsGroup of 32 healthy subjects showed a significant difference (P<0.01) for protein concentration and acetylcholinesterase activity in Plasma, inhibitor Eserine efficacy in Plasma and Whole blood before and after physical activity. Based on Age, a significant difference is present for Height (P<0.01), Muscle mass (P<0.01) and protein concentration (P<0.05) in Whole blood after physical activity and storage time. A statistically significant difference between Gender exists for Age (P<0.01), Height (P<0.01), Weight (P<0.05), Muscle mass (P<0.05), protein concentration (P<0.05) in whole blood and acetylcholinesterase activity (P<0.05) in Plasma after physical activity. ConclusionsPreliminary and descriptive data indicate no difference in acetylcholinesterase activity between Age groups. Physical activity and storage time influence the change of protein concentration, enzyme activity and inhibitor Eserine efficacy in healthy elderly subjects. Future studies should compare disease and healthy participants.

Markers of oxidative stress are widely used as biomarkers of health, ageing, and physiological stress. However, their reliability as biomarkers remains uncertain due to high intraindividual variation, obscuring associations with environmental conditions, lifestyle, frailty, and physiological indicators of health such as telomere length. Whilst numerous longitudinal studies exist, individual repeatability of oxidative stress measurements is rarely reported. This study presents the first meta-analysis assessing individual repeatability of oxidative stress markers, comprising 123 repeatability estimates from 22 studies. We found that oxidative stress exhibits low individual repeatability (Intraclass correlation = 0.164), regardless of marker type, taxa, sex, study design, or environment. We also found that different markers of oxidative stress were often poorly correlated, which could be due to their low repeatability. This flags serious limitations regarding the utility of oxidative stress measurements as health biomarkers. To illustrate this point, we simulated causal effects of oxidative stress on telomere length to reveal statistical power limitations on the detection of a relationship between oxidative stress and telomere length when individual repeatability is low. Our simulations reveal that substantially larger samples sizes are required than those typically used in this field. On a more positive note, we also show that increasing the number of repeated samples can improve statistical power. Such longitudinal studies would create valuable opportunities for untangling the causes of intraindividual variation in oxidative stress, elucidating the functional consequences of oxidative stress for health and ageing.

ObjectiveTo evaluate the effectiveness of iso-inertial resistance training on eccentric power compared to gravitational training in physically active middle-older adults. MethodsParallel-group, randomised controlled trial at Espai Esport Wellness Center (Granollers, Spain). Forty-four physically active adults (>57 years of age) were randomised to iso-inertial (n=21) or gravitational (n=23) training groups (R software; 1:1 ratio). Participants had to complete a 6-week training program (2 sessions/week) consisting of three exercises (forward lunge, side lunge, forward lunge with row). Primary outcome: power in the eccentric phase of each exercise evaluated with both iso-inertial and gravitational devices. Secondary outcomes: concentric power, physical performance, risk of falls. Only outcome evaluators were blinded. We used multivariate linear regression models to analyse the effect of interventions. ResultsIso-inertial training showed better eccentric power gains than gravitational training for iso-inertial system evaluation, although the difference was only statistically significant for the side lunge. Forward lunge: between-group difference 3.99 W (95% CI: -3.99 to 11.33, p: 0.28); side lunge: difference 8.50 W (95% CI: 2.13 to 14.87; p: 0.01); forward lunge with row: difference 14.07 W (95% CI: -2.07 -to 30.20, p: 0.09). We observed no differences for the gravitational system evaluation nor for concentric power, physical performance, and risk of falls. The two groups improved remarkably from baseline for all outcomes. ConclusionsIso-inertial resistance training might lead to better eccentric power gains than gravitational training. Both approaches seem equally effective in improving concentric power and physical performance, and reducing the risk of falls. Trial registrationClinicalTrials.gov (NCT06160089). O_TEXTBOXWHAT IS ALREADY KNOWN ON THIS TOPIC- Physical exercise in middle-older adults is an effective strategy to promote health and improve quality of life. - Resistance training using iso-inertial devices generates an advantage in hypertrophy, electromyographic activity or balance compared to cable-resistance training in middle-older adults. - The power at which an action is performed is considered a predictor of functional capacity, as it is associated with the execution of activities of daily living such as climbing stairs, getting up from a chair or walking. WHAT THIS STUDY ADDS- The iso-inertial training system improves muscle power in the eccentric phase compared to the gravitational system, although the difference is only statistically significant for the side lunge exercise. - Iso-inertial and gravitational resistance training are equally effective in improving concentric power, and physical performance and reducing the risk of falls. - Using iso-inertial devices is recommended to evaluate power in the eccentric phase, as they may capture better the eccentric demands than gravitational devices. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY- Using iso-inertial devices for resistance training in middle-older adults seems a promising way to improve the power in the eccentric phase of an action. - Improving eccentric power in older adults is crucial due to its transfer to daily life activities. - Regardless of the training system, clinicians should prescribe resistance training programs to middle-older adults as these programs remarkably increase power and physical performance and reduce the risk of falls. C_TEXTBOX

The mechanisms responsible for increased walking metabolic cost among older adults are poorly understood. We recently proposed a theoretical premise by which age-related reductions in Achilles tendon stiffness (kAT) can disrupt the neuromechanics of calf muscle behavior and contribute to faster rates of oxygen consumption during walking. The purpose of this study was to objectively evaluate this premise. We quantified kAT at a range of matched activations prescribed using electromyographic biofeedback and walking metabolic cost in a group of 15 younger (age: 23{+/-}4 yrs) and 15 older adults (age: 72{+/-}5 yrs). Older adults averaged 44% less kAT than younger adults at matched triceps surae activations (p=0.046). This effect appeared to arise not only from altered tendon length-tension relations with age, but also from differences in the operating region of those length-tension relations between younger and older adults. Older adults also walked with a 17% higher net metabolic power than younger adults (p=0.017). In addition, we discovered empirical evidence that lesser kAT exacts a metabolic penalty and was positively correlated with higher net metabolic power during walking (r=-0.365, p=0.048). These results pave the way for interventions focused on restoring ankle muscle-tendon unit structural stiffness to improve walking energetics in aging.

BackgroundThe aging population faces numerous health challenges, with sedentary behavior and decreased physical activity being paramount. We explore the physical behaviour of older adults in the GOTO combined lifestyle intervention study and its related immuno-metabolic health effects. MethodsThe research utilized accelerometers and machine learning to assess physical activity behaviours during a 13-week program of increased physical activity and decreased calorie intake. Subsequently, the association of variation in physical behaviour with immuno-metabolic health parameters is investigated cross-sectionally at baseline and longitudinally using sex-stratified linear regression and linear mixed regression respectively. ResultsParticipants exhibited physical behaviors similar to their age-matched peers from the UK-Biobank. Interestingly, gender-based differences were evident, with men and women showing distinct daily physical behavioural patterns. At baseline, a positive correlation was found between higher physical behavior and a healthier immune-metabolic profile, particularly in men. The longitudinal changes depict an overall boost in activity levels, predominantly among women. While increasing general activity and engaging in intense exercises proved advantageous for physical health, the immune-metabolic health benefits were more pronounced in men. ConclusionThe short-term GOTO intervention underscores the significance of regular physical activity in promoting healthy aging even in middle to older age. Gender differences in behavior and health benefits deserve much more attention though. Our results advocate the broader implementation of such programs and emphasize the utility of technology, like accelerometers and machine learning, in both monitoring and promoting active lifestyles among older adults.

Older adults have difficulty maintaining balance when faced with postural disturbances, a task that is influenced by the stiffness of the triceps surae and Achilles tendon. Age-related changes in Achilles tendon stiffness have been reported at matched levels of effort, but measures typically have not been made at matched loads, which is important due to age-dependent changes in strength. Moreover, age-dependent changes in muscle stiffness have yet to be tested. Here, we investigate how age alters muscle and tendon stiffness and their influence on ankle stiffness. We hypothesized that age-related changes in muscle and tendon contribute to reduced ankle stiffness in older adults and evaluated this hypothesis when either load or effort were matched. We used B-mode ultrasound with joint-level perturbations to quantify ankle, muscle, and tendon stiffness across a range of loads and efforts in seventeen healthy younger and older adults. At matched loads, there was no significant difference in ankle, muscle, or tendon stiffness between groups (all p>0.13). However, at matched effort, older adults exhibited a significant decrease in ankle (27%; p=0.008), muscle (37%; p=0.02), and tendon stiffness (22%; p=0.03) at 30% of maximum effort. This is consistent with our finding that older adults were 36% weaker than younger adults in plantarflexion (p=0.004). Together these results indicate that, at the loads tested in this study, there are no age-dependent changes in the mechanical properties of muscle or tendon, only differences in strength that result in altered ankle, muscle, and tendon stiffness at matched levels of effort. NO_SCPLOWEWC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWANDC_SCPLOW NO_SCPLOWOTEWORTHYC_SCPLOWWe provide the first simultaneous estimates of ankle, muscle, and tendon stiffness in younger and older adults. In contrast to earlier conclusions, we found that muscle and tendon mechanical properties are unaffected by age when compared at matched loads. However, due to age-related decreases in strength, mechanical properties do differ at matched efforts. As such, it is important to assess the relevance of the comparisons being made relative to the functional tasks under consideration.

DNA methylation-based age estimators (DNAm aging clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between objectively measured physical fitness, including cardiorespiratory fitness, and DNAm aging clocks are largely unknown. We investigated the relationships between physical fitness and the age-adjusted value from the residuals of the regression of DNAm aging clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of physical fitness variables to DNAmAgeAccel in the presence of other lifestyle factors. DNA samples from 144 Japanese men aged 65-72 years were used to calculate first- (i.e., DNAmHorvath and DNAmHannum) and second- (i.e., DNAmPhenoAge, DNAmGrimAge and DNAmFitAge) generation DNAm aging clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrients intake, smoking, alcohol consumption, disease status, sleep status, and chronotype. The peak oxygen uptake (VO2peak) per kg body weight had a significant negative correlation with GrimAgeAccel (r = -0.222, p = 0.008). A comparison of the tertile groups showed that the GrimAgeAccel of the highest VO2peak group was decelerated by 1.6 years compared to the lowest group (p = 0.035). Multiple regression analysis suggested that rather than physical fitness, serum triglycerides, carbohydrate intake, and smoking status, were significantly associated with DNAmAgeAccel. In conclusion, the contribution of cardiorespiratory fitness to DNAmAgeAccel was relatively low compared to lifestyle factors such as smoking. However, this study reveals a negative relationship between cardiorespiratory fitness and DNAmAgeAccel in older men.