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Objective: Our objective was to investigate the overall and sex‐specific relationships between the presence and severity of knee osteoarthritis (KOA) and muscle composition, power, and energetics in older adults. Methods: Male and female patients (n = 655, mean ± SD age 76.1 ± 4.9 years; 57% female) enrolled in the Study of Muscle, Mobility, and Aging completed standing knee radiographs and knee pain assessments. Participants were divided into three groups using Kellgren‐Lawrence grade (KLG) of KOA severity (0–1, 2, or 3–4). Outcome measures included whole‐body muscle mass, thigh fat‐free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics. Results: Overall, the presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (P trend < 0.036). Sex‐specific analysis revealed reduced energetics only in female patients with KOA (P trend < 0.007) compared to female patients without KOA. In models adjusted for age, sex, race, nonsteroidal anti‐inflammatory drug administration, site or technician, physical activity, height, and participants with abdominal adiposity with KLG 3 to 4 had greater MFI (mean 0.008%, 95% confidence interval [CI] 0.004%–0.011%) and lower leg power (mean −51.56 W, 95% CI −74.03 to −29.10 W) and specific power (mean −5.38 W/L, 95% CI −7.31 to −3.45 W/L) than those with KLG 0 to 1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power, and specific power. Conclusion: Muscle health is associated with the presence and severity of KOA and differs by sex. Although muscle composition and power are lower in both male and female patients with KOA, regardless of pain status, mitochondrial energetics is reduced only in female patients. [ABSTRACT FROM AUTHOR]

Objective Sociodemographic, lifestyle, and medical variables influence total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations. The relationship between these factors and "free" T remains unclear. We examined 21 sociodemographic, lifestyle, and medical predictors influencing calculated free T (cFT) in community-dwelling men across ages. Design This is a cross-sectional analysis in 20 631 participants in the Androgens in Men Study. Methods Individual participant data (IPD) were provided by 9 cohorts. Total T was determined using mass spectrometry, SHBG using immunoassays, and cFT using the Vermeulen formula. Associations were analyzed using 2-stage random effects IPD meta-analyses. Results Cohort median ages ranged from 40 to 76 years and median cFT concentrations from 174.3 to 422.8 pmol/L. In men aged 17-99 years, there was a linear inverse association of cFT with age (−57.2 pmol/L [95% confidence interval, −69.4, −44.9] per 1 SD increase in age). Calculated free T increased with increasing baseline body mass index (BMI) among men with BMI < 23.6 kg/m2, but decreased among men with BMI > 23.6 kg/m2 (−24.7 pmol/L [−29.1, −20.3] per 1 SD increase in the 25.4-29.6 kg/m2 BMI range). Calculated free T was lower in younger men, who were married or in a de facto relationship (−18.4 pmol/L [−27.6, −9.3]) and in men who formerly smoked (−5.7 pmol/L [−8.9, −2.6]), were in poor general health (−14.0 pmol/L [−20.1, −7.8]), and had diabetes (−19.6 pmol/L [−23.0, −16.3]), cardiovascular disease (−5.8 pmol/L [−8.3, −3.2]), or cancer (−19.2 pmol/L [−24.4, −14.1]). Conclusions Calculated free T was most prominently associated with age and BMI. The linear, inverse association with age, nonlinear association with BMI, and presence of diabetes, cancer, and sociodemographic factors should be considered when interpreting cFT values. [ABSTRACT FROM AUTHOR]

Background: A higher difference in estimated glomerular filtration rate by cystatin C versus creatinine (eGFRDiff = eGFRCys – eGFRCreat) is associated with decreased frailty risk. Since eGFRCreat is influenced by muscle more than eGFRCys, muscle mass may explain this association. Previous work could not account for this when considering regional muscle measures by imaging. Deuterated creatine (D3Cr) dilution measures whole body muscle mass (kilograms). We aimed to determine whether eGFRDiff is associated with D3Cr muscle mass and whether muscle mass explains the association between eGFRDiff and frailty. Methods: Cross‐sectional analysis within the multicenter MrOS Study at Year 14 (visit 4). 490 men of the original cohort of 5994 MrOS participants (aged ≥65 at enrollment) were included. Exposure was eGFRDiff (= eGFRCys – eGFRCreat), calculated using CKD‐EPI equations 2012/2021. Primary outcome was D3Cr muscle mass. Secondary outcome was phenotypic pre‐frailty (one or two criteria) and frailty (≥three criteria) including the following: weight loss, weakness, slow gait, physical activity, poor energy. The association of eGFRDiff with D3Cr muscle mass was examined by linear regression, that with prefrailty / frailty by multinomial logistic regression. Results: Mean ± SD age was 84 ± 4 years, eGFRCreat 68 ± 16, eGFRCys 52 ± 16, eGFRDiff −15 ± 12 mL/min/1.73 m2 and D3Cr muscle mass 24 ± 4 kg. For each SD increment in eGFRDiff, D3Cr muscle mass was 1.4 kg higher on average, p < 0.0001 (fully adjusted). Higher eGFRDiff was associated with lower odds of frailty (OR = 0.63 95% CI [0.45;0.89]), but this was partially attenuated and insignificant after additionally adjusting for D3Cr muscle mass (OR = 0.85 95% CI [0.58; 1.24]). Conclusions: Higher eGFRDiff is associated with lower odds of frailty among late‐life men. D3Cr muscle mass accounts for some of this association. This suggests that non‐GFR determinants of creatinine and cystatin C, such as muscle mass, play a role in explaining the association of eGFRDiff with frailty. Future studies are needed to confirm. [ABSTRACT FROM AUTHOR]

Background Slower gait speed may be driven by greater energy deficits and fatigability among older adults. We examined associations of walking energetics and perceived physical fatigability with gait speed among slower and faster walkers. Additionally, we used statistical mediation to examine the role of fatigability in the associations of walking energetics and gait speed using the Study of Muscle, Mobility and Aging (SOMMA). Methods Perceived physical fatigability was assessed using the Pittsburgh Fatigability Scale (PFS) Physical score (range 0–50, higher = greater). A 3-phase cardiopulmonary exercise treadmill test collected peak oxygen consumption (VO2peak, mL/kg/min), energetic cost of walking (ECW, mL/kg/m), and cost–capacity ratio (VO2/VO2peak*100, %). Slower (<1.01 m/s) versus faster (≥1.01 m/s) walkers were classified using median 4-m gait speed. Linear regressions and statistical mediation analyses were conducted. Results Slower walkers had lower VO2peak, higher ECW at preferred walking speed (PWS), and greater PFS Physical score compared to faster walkers (all p  < .05; N  = 849). One standard deviation (1- SD) higher VO2peak was associated with 0.1 m/s faster gait speed, while 1- SD higher ECW PWS, cost–capacity ratio at PWS and slow walking speed (SWS), and PFS Physical score were associated with 0.02–0.23 m/s slower gait speed. PFS Physical score was a significant statistical mediator in the associations between VO2peak (15.2%), SWS cost–capacity ratio (15.9%), and ECW PWS (10.7%) with gait speed and was stronger among slower walkers. Conclusions Slower walkers may be more influenced by perceptions of fatigue in addition to walking energetics. Our work highlights the importance of targeting both energetics and perceived fatigability to prevent mobility decline. [ABSTRACT FROM AUTHOR]

Although low back pain (LBP) may persist or recur over time, few studies have evaluated the individual course of LBP over a long-term period, particularly among older adults. Based on data from the longitudinal Osteoporotic Fractures in Men (MrOS) Study, we aimed to identify and describe different LBP trajectories in older men and characterize members in each trajectory group. A total of 5 976 community-dwelling men (mean age = 74.2) enrolled at 6 U.S. sites were analyzed. Participants self-reported LBP (yes/no) every 4 months for a maximum of 10 years. Latent class growth modeling was performed to identify unique LBP trajectory groups that explained variation in the LBP data. The association of baseline characteristics with trajectory group membership was assessed using univariable and multivariable multinominal logistic regression. A 5-class solution was chosen; no/rare LBP (n  = 2 442/40.9%), low frequency-stable LBP (n  = 1 040/17.4%), low frequency-increasing LBP (n  = 719/12%), moderate frequency-decreasing LBP (n  = 745/12.5%), and high frequency-stable LBP (n  = 1 030/17.2%). History of falls (OR = 1.52), history of LBP (OR = 6.37), higher physical impairment (OR = 1.51–2.85), and worse psychological function (OR = 1.41–1.62) at baseline were all associated with worse LBP trajectory groups in this sample of older men. These findings present an opportunity for targeted interventions and/or management to older men with worse or increasing LBP trajectories and associated modifiable risk factors to reduce the impact of LBP and improve quality of life. [ABSTRACT FROM AUTHOR]

Objective We evaluated whether more severe back pain phenotypes—persistent, frequent, or disabling back pain—are associated with higher mortality rate among older men. Methods In this secondary analysis of a prospective cohort, the Osteoporotic Fractures in Men (MrOS) study, we evaluated mortality rates by back pain phenotype among 5215 older community-dwelling men (mean age, 73 years, SD = 5.6) from 6 sites in the United States. The primary back pain measure used baseline and Year 5 back pain questionnaire data to characterize participants as having no back pain, nonpersistent back pain, infrequent persistent back pain, or frequent persistent back pain. Secondary measures of back pain from the Year 5 questionnaire included disabling back pain phenotypes. The main outcomes measured were all-cause and cause-specific death. Results After the Year 5 exam, during up to 18 years of follow-up (mean follow-up = 10.3 years), there were 3513 deaths (1218 cardiovascular, 764 cancer, 1531 other). A higher proportion of men with frequent persistent back pain versus no back pain died (78% versus 69%; sociodemographic-adjusted HR = 1.27, 95% CI = 1.11–1.45). No association was evident after further adjustment for health-related factors, such as self-reported general health and comorbid chronic health conditions (fully adjusted HR = 1.00; 95% CI = 0.86–1.15). Results were similar for cardiovascular deaths and other deaths, but we observed no association of back pain with cancer deaths. Secondary back pain measures, including back-related disability, were associated with increased mortality risk that remained statistically significant in fully adjusted models. Conclusion Although frequent persistent back pain was not independently associated with risk of death in older men, additional secondary disabling back pain phenotypes were independently associated with increased mortality rate. Future investigations should evaluate whether improvements in disabling back pain affect general health and well-being or risk of death. [ABSTRACT FROM AUTHOR]

Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ± 4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [ n  = 305] with interleukin [IL-6, IL-1β, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%–92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p  < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p  > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se. [ABSTRACT FROM AUTHOR]

Background The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity. Methods The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age = 76.4, 56.5% women, and 85.9% non-Hispanic White) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95% CI]) for the likelihood of greater multimorbidity (4 levels: 0 conditions, N  = 332; 1 condition, N  = 299; 2 conditions, N  = 98; or 3+ conditions, N  = 35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions. Results Lower oxidative phosphorylation supported by fatty acids and/or complex I- and II-linked carbohydrates (eg, Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR = 1.32 [1.13, 1.54]) and separately with diabetes mellitus (OR = 1.62 [1.26, 2.09]), depressive symptoms (OR = 1.45 [1.04, 2.00]) and possibly chronic kidney disease (OR = 1.57 [0.98, 2.52]) but not significantly with other conditions (eg, cardiac arrhythmia, chronic obstructive pulmonary disease). Conclusions Lower muscle mitochondrial bioenergetic capacities were associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and are more strongly related to some conditions than others. [ABSTRACT FROM AUTHOR]

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter 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 walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes. Article Highlights: The contributors to slower walking speed in older adults with diabetes remain unclear. This study was conducted to answer the question of how mitochondrial oxidative capacity and cardiorespiratory fitness impact walking speed in older adults with diabetes. We found that mitochondrial oxidative capacity, cardiorespiratory fitness, and walking speed were lower in older adults with diabetes compared with those without diabetes. In addition, mitochondrial oxidative capacity and cardiorespiratory fitness contributed to slower walking speed in those with diabetes. [ABSTRACT FROM AUTHOR]

Emerging studies highlight chrononutrition's impact on body composition through circadian clock entrainment, but its effect on older adults' muscle health remains largely overlooked. To determine the associations between chrononutrition behaviors and muscle health in older adults. Dietary data from 828 older adults (76 ± 5 years) recorded food/beverage amounts and their clock time over the past 24 h. Studied chrononutrition behaviors included: (1) The clock time of the first and last food/beverage intake; (2) Eating window (the time elapsed between the first and last intake); and (3) Eating frequency (Number of self‐identified eating events logged with changed meal occasion and clock time). Muscle mass (D3‐creatine), leg muscle volume (MRI), grip strength (hand‐held dynamometer), and leg power (Keiser) were used as outcomes. We used linear regression to assess the relationships between chrononutrition and muscle health, adjusting for age, sex, race, marital status, education, study site, self‐reported health, energy, protein, fiber intake, weight, height, and moderate‐to‐vigorous physical activity. Average eating window was 11 ± 2 h/day; first and last intake times were at 8:22 and 19:22, respectively. After multivariable adjustment, a longer eating window and a later last intake time were associated with greater muscle mass (β ± SE: 0.18 ± 0.09; 0.27 ± 0.11, respectively, p < 0.05). The longer eating window was also marginally associated with higher leg power (p = 0.058). An earlier intake time was associated with higher grip strength (−0.38 ± 0.15; p = 0.012). Chrononutrition behaviors, including longer eating window, later last intake time, and earlier first intake time were associated with better muscle mass and function in older adults. [ABSTRACT FROM AUTHOR]

Background Lower urinary tract symptoms (LUTS) in older men are associated with an increased risk of mobility limitations. Lower extremity muscle quality may represent a novel shared mechanism of both LUTS and mobility limitations. Methods We evaluated associations of thigh skeletal muscle measures (strength, area, and specific force) with total LUTS severity (American Urologic Association Symptom Index; AUASI) and voiding and storage subscores among 352 men aged ≥60 years enrolled in the Baltimore Longitudinal Study of Aging. Thigh muscle strength (Nm) was defined as maximum concentric 30°/s knee extensor torque, area (cm2), and specific force (Nm/cm2) defined as strength/area. Associations with AUASI score were estimated using multivariable linear regression and linear mixed models. Results Mean thigh muscle strength at baseline was 139.7Nm. In cross-sectional multivariable models, each 39Nm increment in thigh muscle strength and 0.28Nm/cm2 increment in specific force was associated with −1.17 point (95% CI: −1.93 to −.41) and −0.95 point (95% CI: −1.63 to −0.27) lower AUASI score, respectively. Similar associations were observed for voiding and storage subscores, although somewhat attenuated. In longitudinal analyses, baseline muscle measures were not associated with annual change in AUASI, and current changes in muscle measures and AUASI were unrelated. Conclusions Cross-sectionally, higher thigh muscle strength and specific force were associated with decreased LUTS severity in older men. However, we did not observe concurrent worsening LUTS severity with declining thigh muscle strength, area, or specific force in longitudinal analyses. [ABSTRACT FROM AUTHOR]

Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB‐related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission‐related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence. [ABSTRACT FROM AUTHOR]

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation‐responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation‐responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation‐responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age. [ABSTRACT FROM AUTHOR]

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein‐coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400‐m walking speed, and leg strength), and muscle size (thigh muscle volume and whole‐body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence. [ABSTRACT FROM AUTHOR]

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community‐based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin‐1, myomesin‐2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin‐2, alpha‐actinin‐2, and skeletal muscle alpha‐actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha‐actinin‐3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging. [ABSTRACT FROM AUTHOR]

Performance fatigability is typically experienced as insufficient energy to complete daily physical tasks, particularly with advancing age, often progressing toward dependency. Thus, understanding the etiology of performance fatigability, especially cellular‐level biological mechanisms, may help to delay the onset of mobility disability. We hypothesized that skeletal muscle energetics may be important contributors to performance fatigability. Participants in the Study of Muscle, Mobility and Aging completed a usual‐paced 400‐m walk wearing a wrist‐worn ActiGraph GT9X to derive the Pittsburgh Performance Fatigability Index (PPFI, higher scores = more severe fatigability) that quantifies percent decline in individual cadence‐versus‐time trajectory from their maximal cadence. Complex I&II‐supported maximal oxidative phosphorylation (max OXPHOS) and complex I&II‐supported electron transfer system (max ETS) were quantified ex vivo using high‐resolution respirometry in permeabilized fiber bundles from vastus lateralis muscle biopsies. Maximal adenosine triphosphate production (ATPmax) was assessed in vivo by 31P magnetic resonance spectroscopy. We conducted tobit regressions to examine associations of max OXPHOS, max ETS, and ATPmax with PPFI, adjusting for technician/site, demographic characteristics, and total activity count over 7‐day free‐living among older adults (N = 795, 70–94 years, 58% women) with complete PPFI scores and ≥1 energetics measure. Median PPFI score was 1.4% [25th–75th percentile: 0%–2.9%]. After full adjustment, each 1 standard deviation lower max OXPHOS, max ETS, and ATPmax were associated with 0.55 (95% CI: 0.26–0.84), 0.39 (95% CI: 0.09–0.70), and 0.54 (95% CI: 0.27–0.81) higher PPFI score, respectively. Our findings suggested that therapeutics targeting muscle energetics may potentially mitigate fatigability and lessen susceptibility to disability among older adults. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine associations of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults. Methods: Cross‐sectional data from 829 adults ≥70 years of age were used. Abdominal, subcutaneous, and visceral AT and thigh muscle fat infiltration (MFI) were quantified by magnetic resonance imaging. SM mitochondrial energetics were characterized in vivo (31P‐magnetic resonance spectroscopy; ATPmax) and ex vivo (high‐resolution respirometry maximal oxidative phosphorylation [OXPHOS]). ActivPal was used to measure physical activity ([PA]; step count). Linear regression adjusted for covariates was applied, with sequential adjustment for BMI and PA. Results: Independent of BMI, total abdominal AT (standardized [Std.] β = −0.21; R2 = 0.09) and visceral AT (Std. β = −0.16; R2 = 0.09) were associated with ATPmax (p < 0.01; n = 770) but not following adjustment for PA (p ≥ 0.05; n = 658). Visceral AT (Std. β = −0.16; R2 = 0.25) and thigh MFI (Std. β = −0.11; R2 = 0.24) were associated with carbohydrate‐supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 609). Total abdominal AT (Std. β = −0.19; R2 = 0.24) and visceral AT (Std. β = −0.17; R2 = 0.24) were associated with fatty acid‐supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 447). Conclusions: Skeletal 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. [ABSTRACT FROM AUTHOR]

The relationship between testosterone and related hormones and cardiovascular and mortality outcomes is debated. The authors of this study obtained individual patient–level data from 9 cohort studies and aggregate data from 11 studies in total. These data enabled them to describe the associations of testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol with all-cause mortality, cardiovascular death, and incident cardiovascular events while accounting for other cardiac risk factors. Background: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. Purpose: To clarify associations of sex hormones with these outcomes. Data Sources: Systematic literature review to July 2019, with bridge searches to March 2024. Study Selection: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. Data Extraction: Independent variables were testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. Data Synthesis: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. Limitations: Observational study design, heterogeneity among studies, and imputation of missing data. Conclusion: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668) [ABSTRACT FROM AUTHOR]

Background Lower urinary tract symptoms (LUTS) and mobility limitations are bidirectionally associated among older adults, but the role of skeletal muscle remains unknown. We evaluated cross-sectional associations of muscle health and physical performance with LUTS. Methods We used data from 377 women and 264 men aged >70 years in the Study of Muscle, Mobility and Aging (SOMMA). LUTS and urinary bother were assessed using the LURN Symptom Index-10 (SI-10; higher = worse symptoms). Muscle mass and volume were assessed using D3-creatine dilution (D3Cr) and magnetic resonance imaging. Grip strength and peak leg power assessed upper/lower extremity physical performance. 400-m walk, Short Physical Performance Battery (SPPB), and Four Square Step Test (FSST) assessed global physical performance. Mobility Assessment Tool-short form (MAT-sf) assessed self-reported mobility. We calculated Spearman correlation coefficients adjusted for age, body mass index, multimorbidity, and polypharmacy, chi-square tests, and Fisher's Z -test to compare correlations. Results Among women, LURN SI-10 total scores were inversely correlated with FSST (r s = 0.11, p  = .045), grip strength (r s = −0.15, p  = .006), and MAT-sf (r s = −0.18, p  = .001), but not other muscle and physical performance measures in multivariable models. LURN SI-10 was not associated with any of these measures among men. Forty-four percent of women in the lowest tertile of 400-m walk speed versus 24% in the highest tertile reported they were at least "somewhat bothered" by urinary symptoms (p  < .001), whereas differences among men were not significant. Conclusions Balance and grip strength were associated with LUTS severity in older women but not men. Associations with other muscle and physical performance measures varied by LUTS subtype but remained strongest among women. [ABSTRACT FROM AUTHOR]

Background How magnetic resonance (MR) derived thigh muscle volume and deuterated creatine dilution derived muscle mass (D3Cr muscle mass) differentially relate to strength, fitness, and other functions in older adults—and whether associations vary by sex—is not known. Methods Men (N  = 345) and women (N  = 482) aged ≥70 years from the Study of Muscle, Mobility, and Aging completed leg extension strength (1-repetition max) and cardiopulmonary exercise testing to assess fitness (VO2peak). Correlations and adjusted regression models stratified by sex were used to assess the association between muscle size measures, study outcomes, and sex interactions. Results D3Cr muscle mass and MR thigh muscle volume were correlated (men: r  = 0.62, women: r  = 0.51, p  < .001). Each standard deviation (SD) decrement in D3Cr muscle mass was associated with lower 1-repetition max strength (−14 kg men, −4 kg women, p  < .001 for both; p -interaction = .003) and lower VO2peak (−79 mL/min men, −30 mL/min women, p  < .001 for both, p -interaction:.016). Each SD decrement in MR thigh muscle volume was also associated with lower strength (−32 kg men, −20 kg women, p  < .001 for both; p -interaction = .139) and lower VO2peak (−217 mL/min men, −111 mL/min women, p  < .001 for both, p -interaction = .010). There were associations, though less consistent, between muscle size or mass with physical performance and function; associations varied by sex. Conclusions Less muscle—measured by either D3Cr muscle mass or MR thigh muscle volume—was associated with lower strength and fitness. Varied associations by sex and assessment method suggest consideration be given to which measurement to use in future studies. [ABSTRACT FROM AUTHOR]

Background: Walking slows with aging often leading to mobility disability. Mitochondrial energetics has been found to be associated with gait speed over short distances. Additionally, walking is a complex activity but few clinical factors that may be associated with walk time have been studied. Methods: We examined 879 participants ≥70 years and measured the time to walk 400 m. We tested the hypothesis that decreased mitochondrial energetics by respirometry in muscle biopsies and magnetic resonance spectroscopy in the thigh and is associated with longer time to walk 400 m. We also used cardiopulmonary exercise testing to assess the energetic costs of walking: maximum oxygen consumption (VO2peak) and energy cost–capacity (the ratio of VO2, at a slow speed to VO2peak). In addition, we tested the hypothesis that selected clinical factors would also be associated with 400‐m walk time. Results: Lower Max OXPHOS was associated with longer walk time, and the association was explained by the energetic costs of walking, leg power, and weight. Additionally, a multivariate model revealed that longer walk time was also significantly associated with lower VO2peak, greater cost–capacity ratio, weaker leg power, heavier weight, hip and knee stiffness, peripheral neuropathy, greater perceived exertion while walking slowly, greater physical fatigability, less moderate‐to‐vigorous exercise, less sedentary time, and anemia. Significant associations between age, sex, muscle mass, and peripheral artery disease with 400‐m walk time were explained by other clinical and physiologic factors. Conclusions: Lower mitochondrial energetics is associated with needing more time to walk 400 m. This supports the value of developing interventions to improve mitochondrial energetics. Additionally, doing more moderate‐to‐vigorous exercise, increasing leg power, reducing weight, treating hip and knee stiffness, and screening for and treating anemia may reduce the time required to walk 400 m and reduce the risk of mobility disability. [ABSTRACT FROM AUTHOR]

Background Muscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults. Methods We associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D3-creatine dilution), muscle fat infiltration (magnetic resonance imaging), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO2 peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate-to-vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: women—≥88 cm, men—≥102 cm) and gender. Results Among older adults aged 75 (interquartile range: 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall (N  = 362) but were positively associated among participants with a high waist circumference (β: 25.2; 95% confidence intervals [95% CI]: 11.7, 40.4; p  = .0002; N  = 160). Muscle fat infiltration and liver fat were positively associated (β: 15.2; 95% CI: 6.8, 24.3; p  = .0003; N  = 378). Carbohydrate-supported maximum oxidative phosphorylation (before adjustment) and VO2 peak (after adjustment; β: −12.9; 95% CI: −20.3, −4.8; p  = .003; N  = 361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (β: −4.0; 95% CI: −11.6, 4.2; p  = .32; N  = 321). Conclusions Skeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted. [ABSTRACT FROM AUTHOR]

Background The effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community-dwelling older adults both overall, and in relation, to sociodemographic characteristics. Methods We examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N  = 820, age = 76.4 years, 58.2% women) participating in the Study of Muscle, Mobility, and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance. Results Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR versus men (all p  < .05). Total activity (56%) and time of activity (20%) accounted for most of the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (p  < .001). Compared to the latest decile of acrophase, those in the earliest and midrange categories had more total activity (p  = .02). Being in a married-like relationship and a more stable financial situation were associated with stronger rhythms; higher education was associated with less rhythm strength (all p  < .05). Conclusions Older age was associated with dampened circadian behavior; behaviors were sexually dimorphic. Some sociodemographic characteristics were associated with circadian behavior. We identified a behavioral phenotype characterized by early time of day of peak activity, high rhythmic amplitude, and more total activity. [ABSTRACT FROM AUTHOR]

Background The D3-creatine (D3-Cr) dilution method is of emerging interest for estimating total-body skeletal muscle mass. This review explores the association of muscle mass estimated via D3-Cr with various clinical outcomes and provides a summary of the literature comparing D3-Cr with other body composition techniques. Methods A literature search was conducted on PubMed/MEDLINE and Web of Science for studies using D3-Cr to measure muscle in adult populations (ie, ≥18 years old) from inception until September 2023. Results Out of the 23 included studies, 15 investigated the correlation between D3-Cr and clinical outcomes. More consistent associations were reported for mortality (100%, n  = 2), mobility disability (100%; n  = 5), falls and fractures (100%; n  = 3), physical performance (63.3%; n  = 11), muscle strength (44.4%; n  = 9), and muscle composition (33.3%; n  = 3). However, conflicting findings were also reported for such correlations. Among the 23 studies, 14 compared D3-Cr-estimated muscle with other body composition techniques, including magnetic resonance imaging (MRI) as a reference method. Strong and positive correlations were found between D3-Cr and MRI. Nonetheless, variations in muscle measurements were noted, with differences in D3-Cr values ranging from 0.62 kg lower to 13.47 kg higher compared to MRI. Conclusions D3-Cr-estimated muscle mass may be a valuable predictor of clinical outcomes showing consistent associations with falls and fractures, mobility disability, and mortality. However, less consistent associations were found with muscle strength and composition, and physical performance. Although a strong correlation exists between D3-Cr-estimated muscle mass and MRI measurements, under- or overestimation may occur. [ABSTRACT FROM AUTHOR]

Background Gut dysbiosis has been linked to frailty, but its association with early mobility decline is unclear. Methods First, we determined the cross-sectional associations between walking speed and the gut microbiome in 740 older men (84 ± 4 years) from the MrOS cohort with available stool samples and 400 m walking speed measured in 2014–2016. Then, we analyzed the retrospective longitudinal associations between changes in 6 m walking speed (from 2005–2006 to 2014–2016, calculated by simple linear equation) and gut microbiome composition among participants with available data (702/740). We determined gut microbiome composition by 16S sequencing and examined diversity, taxa abundance, and performed network analysis to identify differences in the gut microbiome network of fast versus slow walkers. Results Faster 400 m walking speed (m/s) was associated with greater microbiome α-diversity (R  = 0.11; p  = .004). The association between a slower decline in 6 m walking speed and higher α-diversity (R  = 0.07; p  = .054) approached borderline significance. Faster walking speed and less decline in walking speed were associated with a higher abundance of genus-level bacteria that produce short-chain fatty acids, and possess anti-inflammatory properties, including Paraprevotella , Fusicatenibacter , and Alistipes , after adjusting for potential covariates (p  < .05). The gut microbiome networks of participants in the first versus last quartile of walking speed (≤0.9 vs ≥1.2 m/s) exhibited distinct characteristics, including different centrality measures (p  < .05). Conclusions Our findings suggest a possible relationship between gut microbiome diversity and mobility function, as indicated by the associations between faster walking speed and less decline in walking speed over 10 years with higher gut microbiome diversity in older men. [ABSTRACT FROM AUTHOR]

Background Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. Methods In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70–94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax) after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. Results At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0 ± 0.2 vs 1.1 ± 0.2, p <.001), reported fewer alcoholic drinks per week in the past year (2.4 ± 4.3 vs 2.8 ± 4.4, p =.054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6 ± 4.4 vs 4.2 ± 3.4, p <.05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p =.008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p =.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02–1.73, p =.033). However, covariates accounted for the increased risk. Conclusions Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway. [ABSTRACT FROM AUTHOR]

The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70–94 years). A Short Physical Performance Battery (SPPB) score ≤8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (eg, Maximal Complex I&II OXPHOS: Women = 55.06 ± 15.95; Men = 65.80 ± 19.74; p  < .001) and in individuals with mobility impairment compared to those without (eg, Maximal Complex I&II OXPHOS in women: SPPB ≥ 9 = 56.59 ± 16.22; SPPB ≤ 8 = 47.37 ± 11.85; p  < .001). Muscle energetics were negatively associated with age only in men (eg, Maximal ETS capacity: R  = −0.15, p  = .02; age/sex interaction, p  = .04), resulting in muscle energetics measures that were significantly lower in women than men in the 70–79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70–79 age group (70–79 age group, odds ratio [OR]age-adjusted = 1.78, 95% confidence interval [CI] = 1.03, 3.08, p  = .038; 80+ age group, ORage-adjusted = 1.05, 95% CI = 0.52, 2.15, p  = .89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment. [ABSTRACT FROM AUTHOR]