Entropy may play an underappreciated role in human aging, such as in skeletal muscle functional declines. Histologically, muscle appears increasingly disorganized with aging, with greater fiber size variability and fiber-type grouping. We tested the hypothesis that entropy is associated with reduced physical performance and muscle function, independent of muscle mass. We quantified a homeostatic dysregulation index of muscle (HDIM) as a proxy for entropy of muscle fiber disorganization based on cross-sectional images of vastus lateralis biopsies from 299 adults age 70 or older. HDIM was derived from three traits: fiber area diversity, fiber-type heterogeneity, and the mean of the shortest path lengths through adjacent fiber networks. HDIM derived from muscle fibers was highly correlated with Shannon entropy, a different measure of entropy of muscle fiber traits. Higher HDIM derived from participants was associated with slower 400-m walk speed, lower peak VO2, muscle power, and decreased maximum rate of oxidative phosphorylation by mitochondria in muscle. These findings suggest that muscle fibers accumulate entropy with aging which contributes to decline in physical performance, muscle power, and mitochondrial energetics, advancing the entropy framework in aging research.

Introduction and Objective: Older adults with pre-diabetes (p-D) or type 2 diabetes (T2D) may be vulnerable to an accelerated loss of muscle mass and function due to poor recovery following physical inactivity. To test this paradigm, we conducted a 10-day bed rest study to characterize the recovery of muscle volume and function in older adults with p-D or T2D. Methods: Thirty-nine older adults with p-D or T2D (p-D/T2D 14M/13F, 65 ± 5.0 y) or who were metabolically healthy (CON, 6M/6F, 68 ± 2.9 y) completed a 10-day bed rest intervention, followed by 4 weeks of ambulatory recovery. Mid-thigh muscle volume was assessed by MRI. Knee extensor power and torque were determined by isokinetic dynamometry. Free living activity was quantified via actigraphy. Mitochondrial oxidative phosphorylation capacity (ATPmax) was assessed by 31P-MRS. All assessments were completed pre- and post-bed rest, and weekly during recovery with analyses performed via repeated measures ANCOVA controlling for baseline. Results: Bed rest decreased muscle volume similarly between groups (~2.3%), with volume returning to baseline levels after only 1 week of ambulatory recovery. However, knee extensor power (CON: 115.8 ± 41.6 vs p-D/T2D: 99.0 ± 43.1 watts, P<0.05) and torque (CON: 87.6 ± 26.6 vs p-D/T2D: 78.0 ± 30.6 N*m, P<0.05) remained significantly lower in the p-D/T2D group during ambulatory recovery. Physical activity levels returned to baseline after 1 week of ambulatory recovery for both groups. ATPmax decreased (~11.5%) and failed to return to baseline in both groups. Conclusion: Older adults with pre-diabetes/T2D had delayed recovery of muscle function after bed rest, despite recovery of muscle volume. Muscle mitochondrial energetics did not recover during ambulatory recovery for both groups. These data suggest that older adults with pre-diabetes or type 2 diabetes are uniquely vulnerable to inactivity induced muscle dysfunction and may require a targeted rehabilitation strategy to facilitate recovery of muscle function. Disclosure C. Elliehausen: None. S.V. Ramos: None. J. Hinkley: None. F. Yi: None. R. Pratley: Consultant; Current; Lilly USA LLC. Research Support; Current; National Institutes of Health, Novo Nordisk. Speaker's Bureau; Current; Novo Nordisk. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Novo Nordisk. Consultant; Current; Pfizer Inc., Recordati Rare Diseases Inc., Regeneron Pharmaceuticals Inc., Response Pharmaceuticals, Rona Therapeutics Ltd. Research Support; Current; Sanofi. Consultant; Current; Scholar Rock Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Sun Pharmaceutical Industries Ltd. Consultant; Current; Third Rock Ventures, Verdiva Bio Dev Limited. Research Support; Current; AstraZeneca AB, Boehringer Ingelheim International GmbH, Abbott Laboratories. Consultant; Current; Abbott Laboratories, AbbVie Inc. Other - Consulting; stock options; Current; Altanine, Inc. Consultant; Current; Amgen Inc., AstraZeneca Pharmaceuticals LP. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Bayer AG, Bayer HealthCare Pharmaceuticals Inc. Research Support; Current; Biomea Fusion. Consultant; Current; Boehringer Ingelheim Pharmaceuticals Inc., Carmot Therapeutics, Inc., Corcept Therapeutics. Research Support; Current; Dompé, Eli Lilly and Company. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Eli Lilly and Company. Research Support; Current; Endogenex Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Endogenex Inc. Consultant; Current; F. Hoffmann-La Roche Ltd. Research Support; Current; Fractyl Health, Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Gasherbrum Bio Inc., Genprex. Consultant; Current; Hanmi Pharm. Co., Ltd. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Intas Pharmaceuticals Ltd. Research Support; Current; Lexicon Pharmaceuticals, Inc. Consultant; Current; Lexicon Pharmaceuticals, Inc. Speaker's Bureau; Current; Lilly USA LLC. J.P. DeLany: None. B. Goodpaster: Advisory Panel; Ended; AbbVie Inc., Altimmune, Merck & Co., Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P.M. Coen: None. Funding National Institutes of Health (R01AG060153 to PMC)

Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA-gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70-79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA-gene interactions to uncover therapeutic targets for preserving muscle function with age.

BACKGROUND:Age-associated decline in mitochondrial oxidative capacity is associated with increased risk of disease, frailty, and disability. Oral nitrite and nitrate supplementation have been demonstrated to improve mitochondrial energetics and physical function in younger adults, but effects in older adults (age ≥70 years) remain unclear. METHODS:We conducted a randomized, placebo-controlled, double-blind, two-arm trial with a parallel group design to examine the effect of 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo in older (age ≥70 years) sedentary adults. Change in muscle mitochondrial respiration (complex I and II supported maximal oxidative phosphorylation [CI&II MaxOXPHOS]) was the primary outcome. Platelet bioenergetics, cardiorespiratory fitness, and other physical function measures were also assessed. RESULTS:Sixty-four adults (75.7 ± 5.7 years) completed the trial. Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration, nor improvements in exercise capacity and physical function. However, platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite. Notably, while nitrite levels increased 16- to 30-fold in plasma following an acute dose, levels increased only 1.6-fold in skeletal muscle. CONCLUSIONS:The divergent response of skeletal muscle versus platelet mitochondrial respiration in response to nitrite supplementation suggests tissue-specific pharmacokinetics and pharmacodynamics that likely impact the efficacy of nitrite supplementation. Results also suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness compared to the effects of nitrite/nitrate previously demonstrated in younger adults. Clinical Trial Registration Number: ClinicalTrials.gov NCT04405180.

Individuals with knee osteoarthritis (KOA) have skeletal muscle changes around the knee joint including reduced quadricep muscle mass and increased intermuscular adipose tissue (IMAT). We examined the cellular composition and transcriptional profiles using single-nuclei RNA sequencing in IMAT from 6 older women with KOA and knee pain and 5 older women without KOA or knee pain from the Study of Muscle, Mobility and Aging (SOMMA). From the resulting 21,436 nuclei, we identified 6 major cell types with unique transcriptional profiles, including progenitor cells, adipocytes, macrophages and other immune cells (T/B/NK cells), endothelial cells and smooth muscle cells/pericytes. Sub-clustering of the immune cell population revealed the presence of mast cells and B-cells with greater abundances in the KOA group. The adipocyte population was the most transcriptional diverse population between the KOA group and the group without KOA. Cell-cell communication network analysis highlighted that adipocytes had the most prominent signaling role of all cell types, independent of KOA status; however, signaling of the pro-inflammatory adipokine leptin was enriched in the KOA group. This study provides the first interrogation of the cellular diversity and transcriptional profiles of IMAT in individuals with KOA. Our findings suggest that IMAT may contribute to KOA disease burden potentially through pro-inflammatory signaling.

Regular physical activity represents one of the greatest mechanisms for maintaining human health, yet the underlying molecular transducers of these benefits remain incompletely understood. Multi-omic assays now provide new opportunities to study the coordinated molecular responses of body tissues to different exercise modalities. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this need by creating a molecular map of the response to physical activity. Described here is the first human cohort of MoTrPAC: sedentary adults enrolled prior to study suspension during the COVID-19 pandemic (N=175) randomized to either endurance or resistance exercise, or non-exercise control. From these participants, we detail their global acute molecular response in skeletal muscle, adipose tissue, and blood, integrated at multiple levels: tissue, exercise modality, timepoint, and omic category. These analyses characterize key molecular pathways, identify central regulators, and implicate novel candidate exerkines in mediating multi-organ exercise effects.

Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear. We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women). Striatal DA was measured using (+)-a-[11C] dihydrotetrabenazine (DTBZ) PET imaging for the limbic, sensorimotor, and executive control subregions. Mitochondrial capacity to produce ATP (ATPmax, mM ATP/s) was measured in vivo using 31P magnetic resonance spectroscopy after repeated voluntary muscle contractions. Ex-vivo respirometry assays from biopsies of resting muscle captured complementary aspects of mitochondrial function under optimal conditions. In multivariable linear regression models, [11C]DTBZ in the limbic striatum, but not other subregions, was positively associated with greater ATPmax in vivo, independent of demographics, muscle volume, leg power, white matter hyperintensities, gray matter atrophy, moderate-to-vigorous physical activity and diabetes (β = 0.275, standard error 0.108, p=0.019). [11C]DTBZ was not associated with the ex-vivo mitochondrial respiration markers (p>0.2). The role of striatal limbic DA and the energetic capacity of skeletal muscles should be further investigated in older adults.

Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA–gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70–79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA–gene interactions to uncover therapeutic targets for preserving muscle function with age.

The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to systematically characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response of human skeletal muscle to acute endurance (EE) and resistance (RE) exercise. Distinct temporal responses were observed, with changes in ATAC-seq, phosphoproteome, and metabolome occurring before changes in the transcriptome and proteome. These distinct temporal multi-omic dynamics were used to identify transcriptional regulatory hubs converging around MEF2A and NFIC regulation of autophagy, angiogenesis and metabolism. Further, early RE-specific phosphoproteome signatures counteracted epigenetic modifications and downregulated transcripts involved in protein turnover. Additional findings include suppression of HIPK2/3 kinase signatures linked to the acute exercise regulation of sarcomeric proteins TTN, NEB, ANKRD2 and LMOD2. Our data demonstrate distinct temporal regulation across the multi-omic landscape of human skeletal muscle, with EE and RE eliciting common and unique molecular signatures.

Older adults with pre-diabetes (p-D) or type 2 diabetes (T2D) may be vulnerable to an accelerated loss of muscle mass and function1 due to poor recovery following physical inactivity (1,2,3). To test this paradigm, we conducted a 10-day bed rest study to characterize the recovery of muscle volume and function in older adults with p-D or T2D. Thirty-nine older adults with p-D or T2D (p-D/T2D 14M/13F, 65 ± 5.0 y) or who were metabolically healthy (CON, 6M/6F, 68 ± 2.9 y) completed a 10-day bed rest intervention, followed by 4 weeks of ambulatory recovery. Mid- thigh muscle volume was assessed by MRI. Knee extensor power and torque were determined by isokinetic dynamometry. Free living activity was quantified via actigraphy. Mitochondrial oxidative phosphorylation capacity (ATPmax) was assessed by 31P-MRS. All assessments were completed pre- and post-bed rest, and weekly during recovery with analyses performed via repeated measures ANCOVA controlling for baseline. Bed rest decreased muscle volume similarly between groups (~2.3%), with volume returning to baseline levels after only 1 week of ambulatory recovery. However, knee extensor power (CON: 115.8 ±41.6 vs p-D/T2D: 99.0 ± 43.1 watts, P

BACKGROUND:D3-creatine (D3Cr) dilution provides an accurate estimate of total body skeletal muscle mass, yet few studies have examined its relationship with function and performance across the lifespan, particularly before age 70. We modelled the association of age with D₃Cr muscle mass across adulthood and compared it with age-related differences in muscle function and performance. METHODS:Adults aged 30-69 years (n = 69; 33 men) and 70+ (n = 826; 344 men) from the Study of Muscle, Mobility and Ageing completed assessments of D3Cr muscle mass, magnetic resonance imaging (MRI) thigh muscle volume, 1-RM leg strength and leg extension power, 4 m walking speed and cardiorespiratory fitness (VO2 peak). Regression models estimated annualised percent differences with age for each outcome. RESULTS:In men, progressively lower D₃Cr muscle mass with advancing age (-0.5%/year in young adults to -1.4%/year in oldest-old) paralleled the pattern observed for leg strength and walking speed (P > .05). Larger age-associated differences were observed for leg power and VO₂ peak, and smaller for MRI thigh muscle volume. In women, D₃Cr muscle mass was already lower in young adulthood (-0.6%/year) and remained relatively stable thereafter, a pattern similar to MRI thigh muscle volume. However, age-related differences in strength, power and VO₂ peak in women generally exceeded those in D₃Cr muscle mass, while walking speed aligned more closely. CONCLUSION:Age-associated differences in muscle mass tracked closely with strength (men) and functional capacity. These results indicate that the role of low muscle mass in functional decline has been underestimated, emphasising the importance of strategies to preserve/enhance muscle mass throughout adulthood.

Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.

Microgravity accelerates skeletal muscle degeneration, mimicking aspects of aging, yet its effects on muscle cell function remain underexplored. Using a muscle lab-on-chip model onboard the International Space Station (ISS), we examined 3D-bioengineered myobundles derived from young and older adult donors under microgravity. Electrical stimulation applied intermittently to the myobundles revealed reduced contraction magnitude in microgravity and decreased protein levels of myosin heavy chain 7, a main isoform in slow-twitch muscle fibers. Transcriptomic profiling revealed active myogenesis across ground and spaceflight samples, but younger electrically stimulated myobundles displayed enhanced mitochondrial-related gene expression in microgravity, while older and non-electrically stimulated myobundles were less responsive. Comparative analysis between young and older derived myobundles identified 86 muscle-specific age-associated genes altered in microgravity, linked to inflammation, mitochondrial dysfunction, and cellular stress. These findings highlight a unique age-related molecular response in microgravity and underscores electrical stimulation as a potential countermeasure. These insights advance our understanding of muscle aging and degeneration in microgravity, guiding future therapeutic strategies.

Background Ageing is accompanied by progressive declines in skeletal muscle mass and strength, culminating in sarcopenia, a condition that contributes to frailty, multimorbidity, and mortality. Age-related changes to mitochondria lead to oxidative damage and dysfunction and are proposed to occur early in the trajectory of sarcopenia, supporting the candidacy of mitochondrial-protective therapies. Here, we test the efficacy of mitochondrial uncoupler BAM15 in age-dependent sarcopenic mouse models. Methods Male and female MitoQC mice aged 24 months received either standard chow or chow supplemented with BAM15 (0.033% mg/g) ad libitum for eight weeks (n=13–14/group). Young (3-month-old) mice served as reference controls (n=8/group). Muscle mitochondrial respiration was assessed in permeabilized fibres, and contractile function was measured in isolated extensor digitorum longus and soleus muscles. Mitophagy was quantified by immunofluorescence confocal microscopy. Data were analyzed using one-or two-way ANOVA followed by Dunnett’s or Bonferroni’s multiple comparison tests. Results Aged male and female mice exhibited reduced gastrocnemius muscle mass relative to body mass compared with young controls (p<0.05; ~18% and ~32% loss, respectively). BAM15 did not alter muscle size but reversed the age-related loss of contractile function in EDL muscles, to that of the young reference controls in both sexes (p<0.05; ~33% in males, ~16% in females). In male mice, BAM15 improved mitochondrial efficiency, evidenced by restoration of Complex I–linked respiration and decreased proton leak (~52% improvement; p<0.05), and normalized protein levels of oxidative stress marker 4-HNE, without changes in mitophagy or mitochondrial content. In females, BAM15 did not improve mitochondrial parameters, which may be, in part, due to aged female muscle exhibiting unchanged Complex I leak and 4-HNE protein abundance, alongside lower complex I subunit (NDUFB8) protein abundance. Conclusions BAM15 improved skeletal muscle mitochondrial efficiency and contractile function in aged male mice, supporting the potential of mitochondrial uncoupling as a therapeutic strategy for sarcopenia. ### Competing Interest Statement K.L.H. and W.L.S. declare commercial interest in Life Biosciences Inc and Uncoupler Biosciences. Australian National Health and Medical Research Council, APP2013278

BACKGROUND:Peak oxygen consumption during exercise (VO2peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO2peak variation are not clear. Our objective is to understand the microRNA (miRNA) signatures that relate to VO2peak variation, which could provide insights to novel mechanisms that contribute to low VO2peak. METHODS:We used small RNA sequencing to analyze baseline, cross-sectional serum samples from 72 participants (70- to 91-year old). We analyzed samples from individuals with low or high VO2peak (N = 18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO2peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. RESULTS:We identified 1055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO2peak (P < .05). After P-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The Area Under the Curve for the five miRNAs ranged from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70% to 80% and 80% to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO2peak (P < .05) and miR-519a-3p remained significant based on adjusted P-values. CONCLUSIONS:We identified a miRNA signature of VO2peak in older individuals that might provide insights to novel mechanisms that drive low VO2peak. Future studies will validate the findings in a larger, longitudinal study cohort.

In the United States, older adults who self-identify as Black have a disproportionately higher incidence of mobility disability compared to those who are White. Whether older adults who are Black also have lower fitness and mitochondrial energetics has not been adequately investigated. The study of muscle, mobility and aging (SOMMA) examined 879 participants aged ≥ 70 years old, including 116 who self-identified as Black. Mitochondrial respiration (Max OXPHOS) was measured in permeabilized fibers from muscle biopsies. Cardiorespiratory fitness (VO2 peak) was determined by a cardiopulmonary exercise test. Education, income, financial resources, race, sex, and age were determined by self-report. We used propensity score matching to match Blacks with Whites with a 1:1 ratio. Black (n = 90) and White (n = 90) groups were matched for age, sex, SOMMA multimorbidity index, BMI, muscle mass, physical activity, marital status, educational achievement, and whether financial needs were met (all p > 0.05). Despite being well matched for these variables, those who identified as Black had a slower 400-m walking speed (0.97 vs. 1.03 m/s, p = 0.014), lower Max OXPHOS (50.8 vs. 60.9 (pmol/(s*mg)), p = 0.0002), and lower cardiorespiratory fitness (1391 vs. 1566 mL/min, p = 0.007) when compared to those who identified as White. Multivariate regression showed that VO2 peak and Max OXPHOS, but not socioeconomic factors, attenuated the race difference in 400-m walking speed. In conclusion, while the etiology of race differences in mobility is multifactorial, our data indicate that muscle mitochondrial respiration and cardiorespiratory fitness may contribute to the slower walking speed of individuals who identify as Black compared to White.

We analyzed the association between RDW and skeletal muscle mitochondrial energetics and how skeletal muscle mitochondrial energetics may mediate the associations of RDW with physical and cognitive performance. The study analyzed cross-sectional baseline data from the Study of Muscle, Mobility and Aging (SOMMA) that enrolled 864 participants aged 70 and older (mean=76.3 years). RDW, clinical and demographic parameters were assessed. Comprehensive evaluations were conducted for both physical and cognitive function using objective and subjective measures. Elevated RDW values were significantly correlated with decreased physical performance, evidenced by reduced cardiorespiratory fitness (VO2peak) and longer time to 400 m Walk, alongside impaired cognitive performance. Higher RDW values also demonstrated robust negative associations with various measurements of mitochondrial energetics, including maximal ATP production and oxidative phosphorylation. Mediation analysis revealed that impaired mitochondrial function partly mediated the associations between RDW values and VO2peak, and other physical and cognitive performance. These findings suggest that higher RDW is associated with declines in various physical and cognitive performance, with skeletal muscle mitochondrial energetics serving as a potential mediating factor. Causal inferences about potential mediation are limited by the cross-sectional design of the study. Nevertheless, the findings highlight the value of RDW as a potential biomarker for age-related declines in physical and cognitive function partly mediated by mitochondrial energetics.

Alterations in energy metabolism may drive fatigue in older age, but prior research primarily focused on skeletal muscle energetics without assessing other systems and utilized self-reported measures of fatigue. We tested the association between energy metabolism in the brain and an objective measure of fatigability in the Study of Muscle, Mobility and Aging (N = 119, age 76.8 ± 4.0 years, 59.7% women). Total brain cerebral metabolic rate of oxygen (CMRO2) was measured using arterial spin labeling and T2-relaxation under spin tagging MRI protocols. Accelerometry-based fatigability status during a fast-paced 400 m walk was determined using the Pittsburgh Performance Fatigability Index (PPFI, higher = worse). Confounders included skeletal muscle energetics, measured in vivo using spectroscopy and ex vivo using respirometry, cardiorespiratory fitness (VO2peak), weight, medication count, and multimorbidity. Multivariable logistic regression models were used to estimate the association (odds ratio (OR)) of CMRO2 with PPFI > 0 compared to the referent group PPFI = 0. Models were first adjusted for age and sex and further adjusted for confounders. In this sample, 41.2% had PPFI > 0 (median 3.3% [0.4%-8.0%]). Higher CMRO2 was associated with exhibiting performance fatigability (age- and sex-adjusted OR = 1.61, 95% CI: 1.06, 2.45, p = 0.03). This association remained significant after adjusting for in vivo skeletal muscle energetics and VO2peak, suggesting that performance fatigability is associated with multi-system impairments in older adults.

Higher cardiorespiratory fitness may be associated with better bone health in older age, though this has not been investigated using state-of-the-science VO2peak and HR-pQCT bone density, strength, and microarchitecture measures. We found that higher VO2peak associated with higher bone strength in men, but not women, which may inform fracture prevention interventions. Maintaining cardiorespiratory fitness among older adults holds potential benefits for bone health, though this association has not been investigated using gold-standard measures of VO2peak and state-of-the-science measures of bone density, strength, and microarchitecture. Participants included 123 men (age 76.2 ± 4.4 years, 93

Aging, a universal and inevitable process, is characterized by a progressive accumulation of physiological alterations and functional decline over time, leading to increased vulnerability to diseases and ultimately mortality as age advances. Lifestyle factors, notably physical activity (PA) and exercise, significantly modulate aging phenotypes. Physical activity and exercise can prevent or ameliorate lifestyle-related diseases, extend health span, enhance physical function, and reduce the burden of non-communicable chronic diseases including cardiometabolic disease, cancer, musculoskeletal and neurological conditions, and chronic respiratory diseases as well as premature mortality.Physical activity influences the cellular and molecular drivers of biological aging, slowing aging rates—a foundational aspect of geroscience. Thus, PA serves both as preventive medicine and therapeutic agent in pathological states. Sub-optimal PA levels correlate with increased disease prevalence in aging populations. Structured exercise prescriptions should therefore be customized and monitored like any other medical treatment, considering the dose-response relationships and specific adaptations necessary for intended outcomes. Current guidelines recommend a multifaceted exercise regimen that includes aerobic, resistance, balance, and flexibility training through structured and incidental (integrated lifestyle) activities.Tailored exercise programs have proven effective in helping older adults maintain their functional capacities, extending their health span, and enhancing their quality of life. Particularly important are anabolic exercises, such as Progressive resistance training (PRT), which are indispensable for maintaining or improving functional capacity in older adults, particularly those with frailty, sarcopenia or osteoporosis, or those hospitalized or in residential aged care. Multicomponent exercise interventions that include cognitive tasks significantly enhance the hallmarks of frailty (low body mass, strength, mobility, PA level, and energy) and cognitive function, thus preventing falls and optimizing functional capacity during aging. Importantly, PA/exercise displays dose-response characteristics and varies between individuals, necessitating personalized modalities tailored to specific medical conditions. Precision in exercise prescriptions remains a significant area of further research, given the global impact of aging and broad effects of PA.Economic analyses underscore the cost benefits of exercise programs, justifying broader integration into health care for older adults. However, despite these benefits, exercise is far from fully integrated into medical practice for older people. Many healthcare professionals, including geriatricians, need more training to incorporate exercise directly into patient care, whether in settings including hospitals, outpatient clinics, or residential care. Education about the use of exercise as isolated or adjunctive treatment for geriatric syndromes and chronic diseases would do much to ease the problems of polypharmacy and widespread prescription of potentially inappropriate medications. This intersection of prescriptive practices and PA/exercise offers a promising approach to enhance the well-being of older adults. An integrated strategy that combines exercise prescriptions with pharmacotherapy would optimize the vitality and functional independence of older people whilst minimizing adverse drug reactions.This consensus provides the rationale for the integration of PA into health promotion, disease prevention, and management strategies for older adults. Guidelines are included for specific modalities and dosages of exercise with proven efficacy in randomized controlled trials. Descriptions of the beneficial physiological changes, attenuation of aging phenotypes, and role of exercise in chronic disease and disability management in older adults are provided. The use of exercise in cardiometabolic disease, cancer, musculoskeletal conditions, frailty, sarcopenia, and neuropsychological health is emphasized. Recommendations to bridge existing knowledge and implementation gaps and fully integrate PA into the mainstream of geriatric care are provided. Particular attention is paid to the need for personalized medicine as it applies to exercise and geroscience, given the inter-individual variability in adaptation to exercise demonstrated in older adult cohorts. Overall, this consensus provides a foundation for applying and extending the current knowledge base of exercise as medicine for an aging population to optimize health span and quality of life.