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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.

BackgroundLow grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited.AimWe examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors.MethodsParticipants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index).ResultsMean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed.ConclusionsGrip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

BackgroundThe 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.MethodsWe 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 yrs, 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.ResultsAge was associated with several metrics of dampened RAR; women had stronger and more robust RAR vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P

BackgroundFalls 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.MethodsIn 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 one year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy (MRS) after an acute bout of exercise (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS).ResultsAt least one 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 400m walk gait speed (1.0 ± 0.2 vs. 1.1 ± 0.2, p

BACKGROUND: Aging is associated with declines in circadian functions. The effects of aging on circadian patterns of behavior are insufficiently described. 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 analyzed baseline assessments of older adults with wrist-worn free-living wrist-worn actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). We applied an extension to the traditional cosine curve to map RAR to activity data, calculating the parameters: rhythmic strength (amplitude); robustness (pseudo-F statistic); and timing of peak activity (acrophase). We also used function principal component analysis to determine 4 components describing underlying patterns of activity accounting for RAR variance. Linear models were used to examine associations between RAR and sociodemographic variables. RESULTS: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR metrics vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P

The 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and the Sarcopenia Definitions and Outcomes Consortium (SDOC) have recently proposed sarcopenia definitions. However, comparisons of the performance of these approaches in terms of thresholds employed, concordance in individuals and prediction of important health-related outcomes such as death are limited. We addressed this in a large multinational assembly of cohort studies that included information on lean mass, muscle strength, physical performance and health outcomes. White men from the Health Aging and Body Composition (Health ABC) Study, Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, USA), the Hertfordshire Cohort Study (HCS) and the Sarcopenia and Physical impairment with advancing Age (SarcoPhAge) Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over courses of 2.4-6 m. Deaths were recorded and verified. Definitions of sarcopenia were as follows: EWGSOP2 (grip strength

Background Aging is associated with central fat redistribution and skeletal muscle decline, yet the relationships of tissue compartments with heart failure (HF) remain incompletely characterized. We assessed the contribution of body composition to incident HF in elders. Methods and Results Participants from 2 older cohorts who completed dual-energy X-ray absorptiometry (DEXA) and, in one cohort, computed tomography were included. We evaluated associations with incident HF for DEXA principal components (PCs) and total lean, appendicular lean, total fat and trunk fat mass; and for computed tomography measures of abdominal visceral and subcutaneous fat, thigh muscle, intermuscular fat area and thigh muscle density. DEXA analysis included 3621, and computed tomography analysis 2332 participants. During median follow-up of 11.8 years, 927 participants developed HF. DEXA principal components showed no relationship with HF. After adjustment for height, weight, and cardiovascular risk factors, total lean mass was near significantly associated with higher HF (hazard ratio [HR], 1.25 per SD [1.00-1.56]), whereas total fat mass and thigh muscle density were significantly related to lower HF (HR, 0.82 [0.68-0.99] and HR, 0.87 [0.78-0.97], respectively). Patterns were similar for HF subtypes. The relationships with HF for total lean and fat mass were attenuated after adjusting for intercurrent atrial fibrillation or excluding high natriuretic peptide levels. Conclusions Total lean mass was positively associated, while total fat mass and thigh muscle density were inversely associated, with incident HF. These findings highlight the limitations of DEXA for assessment of HF risk in elders and support the preeminence of computed tomography-measured skeletal muscle quality over mass as a determinant of HF incidence.

Poor physical function is highly prevalent with aging, and strongly associated with D3-creatine muscle mass/weight. Using metabolomics, we previously identified several triglycerides consisting mostly of polyunsaturated fatty acids that were higher in older adults with good mobility. Here, we sought to further investigate polyunsaturated fatty-acid-related metabolites, i.e., oxylipins, and their associations with D3-creatine muscle mass/weight, gait speed, grip strength, and the Short Physical Performance Battery among 463 older men from the Osteoporotic Fractures in Men Study (MrOS). Oxylipins were measured in fasting serum using liquid chromatography-mass spectrometry. Muscle mass was estimated using D3-creatine dilution and adjusted for body size. We used linear regression to determine oxylipins associated with D3-creatine muscle mass/weight and physical performance, while adjusting for age, education, physical activity, Western dietary pattern, fish oil supplementation, and multiple comparisons. Among 42 oxylipins, none were associated with grip strength and 3 were associated with the Short Physical Performance Battery. In contrast, 18 and 17 oxylipins were associated with D3-creatine muscle mass/weight and gait speed, respectively. A subset of associations between oxylipins and gait speed were partially attenuated by D3-creatine muscle mass/weight. Higher levels of fatty acid alcohol and ketone oxylipins tended to be most strongly associated with gait speed and D3-creatine muscle mass/weight, potentially reflecting anti-inflammatory activity from these select oxylipins in MrOS older men.

BackgroundCut-points to define slow walking speed have largely been derived from expert opinion.MethodsStudy participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.ResultsAmong 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but

BackgroundIndependent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.MethodsWe pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.ResultsA total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.ConclusionsMidlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

Heterogeneous exposure associations (HEAs) can be defined as differences in the association of an exposure with an outcome among subgroups that differ by a set of characteristics. In this article, we intend to foster discussion of HEAs in the epidemiologic literature and present a variant of the random forest algorithm that can be used to identify HEAs. We demonstrate the use of this algorithm in the setting of the association between systolic blood pressure and death in older adults. The training set included pooled data from the baseline examination of the Cardiovascular Health Study (1989-1993), the Health, Aging, and Body Composition Study (1997-1998), and the Sacramento Area Latino Study on Aging (1998-1999). The test set included data from the National Health and Nutrition Examination Survey (1999-2002). The hazard ratios ranged from 1.25 (95% confidence interval: 1.13, 1.37) per 10-mm Hg increase in systolic blood pressure among men aged ≤67 years with diastolic blood pressure greater than 80 mm Hg to 1.00 (95% confidence interval: 0.96, 1.03) among women with creatinine concentration ≤0.7 mg/dL and a history of hypertension. HEAs have the potential to improve our understanding of disease mechanisms in diverse populations and guide the design of randomized controlled trials to control exposures in heterogeneous populations.

Carboxymethyl-lysine is an advanced glycation end product that is detectable in the serum. Higher carboxymethyl-lysine levels have been associated with increased risk of coronary heart disease, stroke and cardiovascular mortality. We determined whether high carboxymethyl-lysine levels are also associated with the risk of peripheral artery disease in Cardiovascular Health Study participants who were all aged 65 years and older at baseline. Multivariate Cox proportional hazards models were used to determine the association of baseline carboxymethyl-lysine levels with incident peripheral artery disease in 3267 individuals followed for a median length of 10.0 years. A total of 157 cases of incident peripheral artery disease occurred during follow-up. No significant relationship between carboxymethyl-lysine and risk of peripheral artery disease was found (hazard ratio per standard deviation increment = 1.03; 95% confidence interval = 0.87, 1.23).

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

BackgroundBlood pressure (BP) and cholesterol are major modifiable risk factors for cardiovascular disease (CVD), but effects of exposures during young adulthood on later life CVD risk have not been well quantified.ObjectiveThe authors sought to evaluate the independent associations between young adult exposures to risk factors and later life CVD risk, accounting for later life exposures.MethodsThe authors pooled data from 6 U.S. cohorts with observations spanning the life course from young adulthood to later life, and imputed risk factor trajectories for low-density lipoprotein (LDL) and high-density lipoprotein cholesterols, systolic and diastolic BP starting from age 18 years for every participant. Time-weighted average exposures to each risk factor during young (age 18 to 39 years) and later adulthood (age ≥40 years) were calculated and linked to subsequent risks of coronary heart disease (CHD), heart failure (HF), or stroke.ResultsA total of 36,030 participants were included. During a median follow-up of 17 years, there were 4,570 CHD, 5,119 HF, and 2,862 stroke events. When young and later adult risk factors were considered jointly in the model, young adult LDL ≥100 mg/dl (compared with

BackgroundLean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.ObjectivesTo determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.MethodsWe performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).ResultsSeven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.ConclusionsIn conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

BackgroundTo determine if adiponectin levels are associated with weight loss, low muscle mass, and physical functioning among the elderly and to determine independent associations with incident disability and death.MethodsIncluded were 3,044 participants from the Health, Aging and Body Composition Study, who had whole-body dual energy absorptiometry performed to evaluate appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2), computed tomography measures of thigh muscle density, weight histories, estimates of physical functioning, and adiponectin levels at enrollment. Associations between adiponectin levels and body composition, weight loss, and physical functioning were assessed in multivariable linear regression models. Associations between adiponectin and incident disability and mortality were assessed in mediation analyses, adjusting for other factors.ResultsGreater adiponectin at baseline was independently associated with low FMI Z-score, lower waist circumference, low ALMI Z-score, low muscle density, a history of weight loss, and poor physical functioning (all p < .05). Greater adiponectin levels (per SD) were associated with incident disability [HR: 1.14 (1.08, 1.20), p < .001] and greater mortality [HR: 1.17 (1.10, 1.25), p < .001] in models adjusting for demographic factors, adiposity, and comorbid conditions. The association was completely attenuated and no longer significant (all p > 0.05) when adjusting for body composition, muscle density, weight loss, and physical functioning at baseline.ConclusionsGreater serum adiponectin levels are associated with historical weight loss, low skeletal muscle mass, low muscle density, and poor physical functioning. High adiponectin is associated with a greater risk of incident disability and death, but not independently of these factors.

BackgroundA goal of gerontology is discovering aging phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that strongly and independently associated with mortality and that statistically attenuated chronologic age could be used to define such a phenotype. We determined the association of a Biomarker Index (BI) with mortality and compared it with a validated Physiologic Index (PI) in older adults.MethodsThe indices were constructed in the Cardiovascular Health Study, mean (SD) age 74.5 (5.1) years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, insulin-like growth factor-binding protein 3, amino-terminal pro-B-type natriuretic peptide, dehydroepiandrosterone sulfate, and interleukin-6, and was built in test (N = 2,197) and validation (N = 1,124) samples. The PI included carotid intima-media thickness, pulmonary capacity, brain white matter grade, cystatin-C, and fasting glucose. Multivariable Cox proportional hazards models predicting death were calculated with 10 years of follow-up.ResultsIn separate age-adjusted models, the hazard ratio for mortality per point of the BI was 1.30 (95% confidence interval 1.25, 1.34) and the BI attenuated age by 25%. The hazard ratio for the PI was 1.28 (1.24, 1.33; 29% age attenuation). In the same model, the hazard ratio for the BI was 1.23 (1.18, 1.28) and for the PI was 1.22 (1.17, 1.26), and age was attenuated 42.5%. Associations persisted after further adjustment.ConclusionsThe BI and PI were significantly and independently associated with mortality. Both attenuated the age effect on mortality substantially. The indices may be feasible phenotypes for developing interventions hoping to alter the trajectory of aging.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.