The Association Between Body Composition, Mitochondrial Function and Fatigability and Physical Function in Older Adults

The 39 million Americans over the age of 65 accounted for 13% of the United States population in 2008. The absolute and relative number of older adults (age ≥65 years) is starting to rise rapidly as the baby boomers begin to turn 65. The prevalence of mobility disability in older (30%) adults is high and is a large public health concern as disability is associated with lower quality of life, higher health care costs, and mortality. There are many reasons for age-related disability, however; the role of changes to skeletal muscle remains unclear. Fatigue is also an independent risk factor for physical disability and is common among older adults. This dissertation aimed to provide novel insight into the association between skeletal muscle energetics, changes in regional body composition and physical function and fatigability in older adults. First, decreases in visceral and intermuscular adipose tissue as well as an increase in muscle density, a marker of intramyocellular fat, following a weight-loss and physical activity intervention, were shown to be related to improved physical performance. Next, mitochondrial function, measured by phosphocreatine recovery (mM ATP/s) in the quadriceps following an exercise-bout using 31P magnetic resonance spectroscopy, was examined in relation to walking performance (time to walk 400m) and perceived performance fatigability (perceived exertion following a 0.67ms treadmill-walk). Mitochondrial function was related to walking performance in higher functioning older adults and older adults who were functionally impaired but able to ambulate 400m without discomfort. Mitochondrial function was also significantly lower in those with high compared to low fatigability. This research provides novel evidence that function can be improved by targeting specific fat depots and mitochondrial function may impact overall function and fatigability. These findings could have large public health implications, as the etiology of age-related disability in regard to skeletal muscle is unclear. The prevalence of disability among older adults is quite high and is associated with increased health care costs and mortality. Clinicians, public health professionals and researchers can use this information to design interventions, treatments and future research studies focused on skeletal muscle to improve function in older adults

Hospitalization-Associated Change in Gait Speed and Risk of Functional Limitations for Older Adults

BACKGROUND: Hospitalization-associated functional decline is a common problem for older adults, but it is unclear how hospitalizations affect physical performance measures such as gait speed. We sought to determine hospitalization-associated change in gait speed and likelihood of new limitations in mobility and activities of daily living (ADLs). METHODS: We used longitudinal data over 5 years from the Health, Aging and Body Composition Study, a prospective cohort of black and white community-dwelling men and women, aged 70-79 years, who had no limitations in mobility (difficulty walking 1/4 mile or climbing 10 steps) or ADLs (transferring, bathing, dressing, and eating) at baseline. Gait speed, and new self-reported limitations in mobility and ADLs were assessed annually. Selected participants (n = 2,963) had no limitations at the beginning of each 1-year interval. Hospitalizations were self-reported every 6 months and verified with medical record data. Generalized estimating equations were used to examine hospitalization-associated change in gait speed and odds of new limitations over each 1-year interval. Fully adjusted models included demographics, hospitalization within the past year, health conditions, symptoms, body mass index, and health-related behaviors. RESULTS: In fully adjusted models, any hospitalization was associated with decrease in gait speed (-0.04 m/s; 95% confidence interval [CI]: -0.05 to -0.03) and higher odds of new limitations in mobility or ADLs (odds ratio = 1.97, 95% CI: 1.70-2.28), and separately with increased odds of new mobility limitation (odds ratio = 2.22, 95% CI: 1.90-2.60) and new ADL limitations (odds ratio = 1.84, 95% CI: 1.53-2.21). Multiple hospitalizations within a year were associated with gait speed decline (-0.06 m/s; 95% CI: -0.08 to -0.04) and greater odds of new limitations in mobility or ADLs (odds ratio = 2.96, 95% CI: 2.23-3.95). CONCLUSIONS: Functionally independent older adults experienced hospitalization-associated declines in gait speed and new limitations in mobility and ADLs

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

© 2021, The Author(s). Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256, 523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing

Impact of Weight Loss on Physical Function with Changes in Strength, Muscle Mass, and Muscle Fat Infiltration in Overweight to Moderately Obese Older Adults: A Randomized Clinical Trial

Purpose. Evaluate the effects of weight loss on muscle mass and area, muscle fat infiltration, strength, and their association with physical function. Methods. Thirty-six overweight to moderately obese, sedentary older adults were randomized into either a physical activity plus weight loss (PA+WL) or physical activity plus successful aging health education (PA+SA) program. Measurements included body composition by dual-energy X-ray absorptiometry, computerized tomography, knee extensor strength, and short physical performance battery (SPPB). Results. At 6 months, PA+WL lost greater thigh fat and muscle area compared to PA+SA. PA+WL lost 12.4% strength; PA+SA lost 1.0%. Muscle fat infiltration decreased significantly in PA+WL and PA+SA. Thigh fat area decreased 6-fold in comparison to lean area in PA+WL. Change in total SPPB score was strongly inversely correlated with change in fat but not with change in lean or strength. Conclusion. Weight loss resulted in additional improvements in function over exercise alone, primarily due to loss of body fat

Estimation of Skeletal Muscle Mass Relative to Adiposity Improves Prediction of Physical Performance and Incident Disability

Purpose We assessed the discrimination of lean mass estimates that have been adjusted for adiposity for physical functioning deficits and prediction of incident disability. Methods Included were 2,846 participants from the Health, Aging and Body Composition Study with available whole-body dual energy absorptiometry measures of appendicular lean mass index (ALMI, kg/m 2) and fat mass index (FMI, kg/m 2). Age-, sex-, and race-specific Z-Scores and T-Scores were determined by comparison to published reference ranges. ALMI values were adjusted for FMI (ALMI FMI) using a novel published method. Sex-stratified analyses assessed associations between lean mass estimates and the physical performance score, ability to complete a 400-meter walk, grip strength, and incident disability. Dichotomized definitions of low lean for age and sarcopenia were examined and their performance compared to the ALM-to-BMI ratio. Results Compared to ALMI T-Scores and Z-Scores, the ALMI FMI scores demonstrated stronger associations with physical functioning, and were similarly associated with grip strength. Greater FMI Z-Scores and T-Scores were associated with poor physical functioning and incident disability. Definitions of low lean for age and sarcopenia using ALMI FMI (compared to ALMI) better discriminated those with poor physical functioning and a greater risk of incident disability. The ALM-to-BMI ratio was modestly associated with grip strength and physical performance, but was not associated with completion of the 400-meter walk or incident disability, independent of adiposity and height. Conclusion Estimation of skeletal muscle mass relative to adiposity improves correlations with physical performance and prediction of incident disability suggesting it is an informative outcome for clinical studies

Body Composition and Incident Heart Failure in Older Adults: Results From 2 Prospective Cohorts

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

Impact of Incident Heart Failure on Body Composition Over Time in the Health, Aging, and Body Composition Study Population

Prevalence 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. The 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. Incident 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