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BackgroundPrevalence of heart failure (HF) increases significantly with age, coinciding with age-related changes in body composition that are common and consequential. Still, body composition is rarely factored in routine HF care.Methods and resultsThe Health, Aging, and Body Composition study is a prospective cohort study of nondisabled adults. Using yearly dual-energy x-ray absorptiometry, body composition was assessed in the Health, Aging, and Body Composition study over 6 years, comparing those who developed incident HF versus those who did not. Among 2815 Health, Aging, and Body Composition participants (48.5% men; 59.6% whites; mean age, 73.6±2.9 years), 111 developed incident HF over the 6-year study period. At entry into the Health, Aging, and Body Composition study, men and women who later developed HF had higher total body mass when compared with those versus those who did not develop HF (men, 80.9±10 versus 78.6±12.9 kg, P=0.05; women, 72.7±15.0 versus 68.2±14.2 kg, P=0.01, respectively). However, after developing HF, loss of total lean body mass was disproportionate; men with HF lost 654.6 versus 391.4 g/y in non-HF participants, P=0.02. Loss of appendicular lean mass was also greater with HF (-419.9 versus -318.2 g/y; P=0.02), even after accounting for total weight change. Among women with HF, loss of total and appendicular lean mass were also greater than in non-HF participants but not to the extent seen among men.ConclusionsIncident HF in older adults was associated with disproportionate loss of lean mass, particularly among men. Prognostic implications are significant, with key sex-specific inferences on physical function, frailty, disability, and pharmacodynamics that all merit further investigation.

Background Grip strength is a robust indicator of overall health, is moderately heritable, and predicts longevity in older adults. Methods Using genome-wide linkage analysis, we identified a novel locus on chromosome 18p (mega-basepair region: 3.4–4.0) linked to grip strength in 3 755 individuals from 582 families aged 64 ± 12 years (range 30–110 years; 55% women). There were 26 families that contributed to the linkage peak (cumulative logarithm of the odds [LOD] score = 10.94), with 6 families (119 individuals) accounting for most of the linkage signal (LOD = 6.4). In these 6 families, using whole genome sequencing data, we performed association analyses between the 7 312 single nucleotide (SNVs) and insertion deletion (INDELs) variants in the linkage region and grip strength. Models were adjusted for age, age2, sex, height, field center, and population substructure. Results We found significant associations between genetic variants (8 SNVs and 4 INDELs, p  < 5 × 10−5) in the Disks Large-associated Protein 1 (DLGAP1) gene and grip strength. Haplotypes constructed using these variants explained up to 98.1% of the LOD score. Finally, RNAseq data showed that these variants were significantly associated with the expression of nearby Myosin Light Chain 12A (MYL12A), Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1), Erythrocyte Membrane Protein Band 4.1 Like 3 (EPB41L3) genes (p  < .0004). Conclusions The DLGAP1 gene plays an important role in the postsynaptic density of neurons; thus, it is both a novel positional and biological candidate gene for follow-up studies aimed at uncovering genetic determinants of muscle strength. [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]

Background Pulmonary function (PF) progressively declines with aging. Forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) are predictors of morbidity of pulmonary and cardiovascular diseases and all-cause mortality. In addition, reduced PF is associated with elevated chronic low-grade systemic inflammation, glucose metabolism, body fatness, and low muscle strength. It may suggest pleiotropic genetic effects between PF with these age-related factors. Methods We evaluated whether FEV1 and FVC share common pleiotropic genetic effects with interleukin-6, high-sensitivity C-reactive protein, body mass index, muscle (grip) strength, plasma glucose, and glycosylated hemoglobin in 3 888 individuals (age range: 26–106). We employed sex-combined and sex-specific correlated meta-analyses to test whether combining genome-wide association p values from 2 or more traits enhances the ability to detect variants sharing effects on these correlated traits. Results We identified 32 loci for PF, including 29 novel pleiotropic loci associated with PF and (i) body fatness (CYP2U1/SGMS2), (ii) glucose metabolism (CBWD1/DOCK8 and MMUT/CENPQ), (iii) inflammatory markers (GLRA3/HPGD , TRIM9 , CALN1 , CTNNB1/ZNF621 , GATA5/SLCO4A1/NTSR1 , and NPVF/C7orf31/CYCS), and (iv) muscle strength (MAL2 , AC008825.1/LINC02103 , AL136418.1). Conclusions The identified genes/loci for PF and age-related traits suggest their underlying shared genetic effects, which can explain part of their phenotypic correlations. Integration of gene expression and genomic annotation data shows enrichment of our genetic variants in lung, blood, adipose, pancreas, and muscles, among others. Our findings highlight the critical roles of identified gene/locus in systemic inflammation, glucose metabolism, strength performance, PF, and pulmonary disease, which are involved in accelerated biological aging. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness is largely understudied.Methods: In the Study of Muscle, Mobility, and Aging (SOMMA), we collected vastus lateralis biopsies from older adults (n=879,70-94 years,59.2% women). Maximal state 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta-coefficients expressed per 1 SD increment in the independent variable.Results: Max OXPHOS was associated with leg power for both women (β=0.12Watts/kg,p<0.001) and men (β=0.11Watts/kg,p<0.050). ATPmax was associated with leg power for men (β=0.09Watts/kg p<0.05) but was not significant for women (β=0.03Watts/kg,p=0.11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, βwomen=1.03mL/kg/min, βmen=1.32 mL/kg/min; ATPmax βwomen=0.87mL/kg/min, βmen=1.50mL/kg/min;all p<0.001).Conclusions: Higher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power. [ABSTRACT FROM AUTHOR]

Background African Caribbeans have higher levels of myosteatosis than other populations; however, little is known about the impact of myosteatosis on physical function in African Caribbeans. Herein, we examined the association between regional myosteatosis of the calf, thigh, and abdomen versus physical function in 850 African-Ancestry men aged 64.2 ± 8.9 (range 50–95) living on the Caribbean Island of Tobago. Methods Myosteatosis was measured using computed tomography and included intermuscular adipose tissue (IMAT) and muscle density levels of the thigh, calf, psoas, and paraspinous muscles. Outcomes included grip strength, time to complete 5 chair-rises, and 4-meter gait speed. Associations were quantified using separate linear models for each myosteatosis depot and were adjusted for age, height, demographics, physical activity, and chronic diseases. Beta coefficients were presented per standard deviation of each myosteatosis depot. Results Higher thigh IMAT was the only IMAT depot significantly associated with weaker grip strength (β = −1.3 ± 0.43 kg, p =.003). However, lower muscle density of all 4 muscle groups was associated with weaker grip strength (all p <.05). Calf and thigh myosteatosis (IMAT and muscle density) were significantly associated with both worse chair rise time and gait speed (all p <.05), whereas psoas IMAT and paraspinous muscle density were associated with gait speed. Conclusion Myosteatosis of the calf and thigh―but not the abdomen―were strongly associated with grip strength and performance measures of physical function in African Caribbean men. However, posterior abdominal myosteatosis may have some utility when abdominal images are all that are available. [ABSTRACT FROM AUTHOR]

Background: Lower physical activity levels and greater fatigability contribute independently to slower gait speed in older adults. To fully understand the bidirectional relations between physical activity and fatigability, and to inform potential intervention strategies, we examined whether physical activity or fatigability explains more of the other factor's association on slower gait speed.Methods: Two generations (probands and offspring) of older adults (N = 2079, mean age 73.0 ± 10.0 years, 54.2% women, 99.7% White) enrolled in the Long Life Family Study were assessed at Visit 2 (2014-2017). Self-reported physical activity was measured with the Framingham Physical Activity Index and perceived physical fatigability using the Pittsburgh Fatigability Scale. Statistical mediation analyses were conducted separately by generation with linear mixed-effect models accounting for family relatedness and adjusted for demographics, health conditions, and field center.Results: Greater perceived physical fatigability explained the association of lower physical activity on slower gait speed via a 22.5% attenuation of the direct association (95% confidence interval [CI]: 15.0%-35.2%) for the probands and 39.5% (95% CI: 22.8%-62.6%) for the offspring. Whereas lower physical activity explained the association of greater perceived fatigability on slower gait speed via a 22.5% attenuation of the direct association (95% CI: 13.4%-32.8%) for the probands and 6.7% (95% CI: 3.8%-15.4%) for the offspring.Conclusions: Our findings suggest that the impact of greater perceived physical fatigability on the association between lower physical activity and slower gait speed differs between younger-old and middle-to-oldest-old adults, indicating perceived physical fatigability as a potential mediator in the disablement pathway. [ABSTRACT FROM AUTHOR]

Background: Circulating levels of procollagen type III N-terminal peptide (P3NP) may reflect increased fibrosis of skeletal muscle and other tissues with aging. Herein, we tested if P3NP was associated with baseline and 7-year change in physical function.Method: Participants (n = 400) were from the Long Life Family Study, a study of exceptional familial longevity. Plasma P3NP concentration was measured using a sandwich enzyme-linked immunosorbent assay (inter-assay coefficient of variation <5.5%). At baseline and 7-year follow-up visits, physical function was measured using the Short Physical Performance Battery (SPPB score 0-12), which consists of gait speed, balance, and chair-rise tests. Grip strength was measured using a handheld dynamometer. The association between log-transformed P3NP and physical function was examined using generalized estimating equations adjusted for familial relatedness, age, sex, height, weight, lifestyle characteristics, liver function, kidney function, lung function, and chronic disease prevalence.Results: Participants were aged 73.1 ± 15.2 years (range: 39-104), 54% female, had body mass index of 26.6 ± 4.3 kg/m2, and gait speeds of 1.0 ± 0.3 m/s. One standard deviation higher log-transformed P3NP was related to worse baseline SPPB score (β = -0.9points), gait speed (β = -0.05m/s), chair-rises per-second (β = -0.46chair-rises/10 seconds), and grip strength (β = -2.0kg; all p < .001). Higher P3NP was also associated with greater declines in gait speed (β = -1.41, p < .001) and transitioning to being unable to perform chair-rises (β = 0.41, p < .001) after 7 years.Conclusion: Plasma P3NP may be a strong, novel biomarker of current and future physical function. Future research is needed to extend our findings to other cohorts and determine mechanisms underlying these associations. [ABSTRACT FROM AUTHOR]

Background: Age-related deposition of fat in skeletal muscle is associated with functional limitations. Skeletal muscle fat may be present in people with preserved muscle mass or accompanied by muscle wasting. However, it is not clear if the association between muscle fat deposition and physical performance is moderated by muscle mass.Objective: To determine whether the association between midthigh intermuscular fat and physical performance is moderated by muscle area.Methods: We performed a cross-sectional analysis of the Health, Aging, and, Body Composition (ABC) study data collected in 2002-2003 (n = 1897, women: 52.2%). Midthigh muscle cross-sectional area (by computed tomography) and physical performance measures were compared across quartiles of intermuscular fat absolute area. Moderation analysis was performed to determine the conditional effect of intermuscular fat on physical performance as a function of muscle area. Conditional effects were evaluated at three levels of muscle area (mean and ± 1 standard deviation [SD]; 213.2 ± 53.2 cm2).Results: Simple slope analysis showed that the negative association between intermuscular fat area (cm2) and leg strength (N·m) was of greater magnitude (beta coefficient [b], 95% confidence interval [CI] = -0.288 [-0.427, -0.148]) in participants with greater muscle area (ie, 1 SD above the mean) compared to those with lower muscle area (ie, at mean [b = -0.12 {-0.248, 0.008}] or 1 SD below the mean [b = 0.048 {-0.122, 0.217}]). Similarly, the negative association of intermuscular fat with 400-m walk speed (m/s) and chair stand (seconds) was greater in those with higher muscle areas (p < .001) compared to those with lower muscle areas.Conclusions: The association between higher intermuscular fat area and impaired physical function in aging is moderated by muscle area. [ABSTRACT FROM AUTHOR]

Background: Fatigability is a construct that measures whole-body tiredness anchored to activities of a fixed intensity and duration; little is known about its epidemiology and heritability.Methods: Two generations of family members enriched for exceptional longevity and their spouses were enrolled (2006-2009) in the Long Life Family Study (LLFS). At Visit 2 (2014-2017, N = 2,355) perceived physical fatigability was measured using the 10-item self-administered Pittsburgh Fatigability Scale (PFS), along with demographic, medical, behavioral, physical, and cognitive risk factors.Results: Residual genetic heritability of fatigability was 0.263 (p = 6.6 × 10-9) after adjustment for age, sex, and field center. PFS physical scores (mean ± SD) and higher physical fatigability prevalence (% PFS ≥ 15) were greater with each age strata: 60-69 (n = 1,009, 11.0 ± 7.6, 28%), 70-79 (n = 847, 12.5 ± 8.1, 37%), 80-89 (n = 253, 19.3 ± 9.9, 65.2%), and 90-108 (n = 266, 28.6 ± 9.8, 89.5%), p < .0001, adjusted for sex, field center, and family relatedness. Women had a higher prevalence of perceived physical fatigability compared to men, with the largest difference in the 80-89 age strata, 74.8% versus 53.5%, p < .0001. Those with greater body mass index, worse physical and cognitive function, and lower physical activity had significantly higher perceived physical fatigability.Conclusions: Perceived physical fatigability is highly prevalent in older adults and strongly associated with age. The family design of LLFS allowed us to estimate the genetic heritability of perceived physical fatigability. Identifying risk factors associated with higher perceived physical fatigability can inform the development of targeted interventions for those most at risk, including older women, older adults with depression, and those who are less physically active. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia varies by ethnicity, and has a major impact on health in older adults. However, little is known about sarcopenia characteristics in African ancestry populations outside the United States. We examined sarcopenia characteristics in 2,142 African Caribbean men aged 59.0 ± 10.4 years (range: 40-92 years) in Tobago, and their association with incident mobility limitations in those aged 55+ (n = 738).Methods: Body mass index (BMI), grip strength, dual-x-ray absorptiometry (DXA) appendicular lean mass (ALM), and self-reported mobility limitations were measured at baseline, and 6 years later. Change in sarcopenia characteristics, including grip strength, grip strength/BMI, ALMBMI, and ALM/ht2, were determined. Foundations for the National Institutes of Health Sarcopenia Project (FNIH) and European Working Group for Sarcopenia in Older People 2 (EWGSOP2) cut-points were also examined. Odds ratios (OR) and 95% confidence intervals (CI) for mobility limitation were calculated using multivariable linear regression models adjusted for covariates.Results: Overall, sarcopenia prevalence was quite low using the FNIH (0.3%) and EWGSOP2 (0.6%) operational cut-points, but was higher in those aged 75+ (2.1% [FNIH] and 3.7% [EWGSOP2]). Prevalence was also higher when based on "weakness", versus "low ALM." When sarcopenia markers were examined separately, baseline levels, but not changes, were associated with incident mobility limitations. Baseline grip strength/BMI was a particularly strong risk factor for incident mobility limitations (OR per SD: 0.50; 95% CI: 0.37-0.68).Conclusions: Our findings suggest that grip strength normalized to body mass, measured at one time point, may be a particularly useful phenotype for identifying African Caribbean men at risk for future mobility limitations. [ABSTRACT FROM AUTHOR]