Project : USDA ARS

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Research Project: Sarcopenia, Nutrition, and Physical Activity

Location: Jean Mayer Human Nutrition Research Center On Aging

2019 Annual Report

Objectives
LAB NAME: Nutrition, Exercise Physiology, and Sarcopenia 1. Characterize the mechanisms associated with nutritional and contraction-related mediators of anabolic resistance associated with advancing age and/or obesity in animal models and humans. 2. Determine the effects of structured, long term interventions of aerobic walking and resistance physical activity on physical functioning in older adults with chronic kidney disease or limited mobility. 3. Determine the effects of structured, long term interventions of aerobic walking and resistance physical activity on cognitive functioning in older adults with chronic kidney disease or limited mobility.

Approach
LAB NAME: Nutrition, Exercise Physiology, and Sarcopenia Sarcopenia, the age-associated loss in skeletal muscle mass and function, is a contributing factor to the observed declines in physiological capacity and physical functioning with advancing age. The overall theme of this project will be to conduct basic and clinical studies focused on the identification, evaluation, and understanding of nutritional and physical activity interventions that possess anabolic properties in skeletal muscle and have the potential to prevent or reverse impaired motor and cognitive performance and/or physical dysfunction in older individuals. Our basic research program will focus on understanding the molecular mechanisms associated with age-related anabolic resistance in skeletal muscle. These basic studies will be uniquely synergized with our clinical/translational studies designed to evaluate the potential efficacy of nutritional and exercise interventions in older adults. Our proposed clinical studies will further seek to understand the role of structured physical activity and nutritional supplementation on changes in physical function and disability in older adults with mobility limitations as a consequence of anabolic resistance and/or sarcopenia. In addition, we will also examine the role of structured physical activity on changes in cognition and the role of physical activity on dementia risk. The pairing of clinical studies examining the influence of protein nutrition and physical activity on sarcopenia with basic approaches that identify the molecular landscape and potential targets in skeletal muscle for preventive interventions (nutritional, physical activity) may accelerate our ability to translate these findings to aging people.

Progress Report
This is the final report for project 8050-51000-091-00D. The project has made progress on all objectives outlined in the project plan. Culminating in year 5, researchers in the Nutrition, Exercise, and Sarcopenia Lab met the majority of the approved milestones. Objective 1. Characterize the mechanisms associated with nutritional and contraction-related mediators of anabolic resistance associated with advancing age and/or obesity in animal models and humans. Researchers in the lab have completed studies aimed at the identification of mechanisms underlying age-related changes in physical functioning. Researchers used metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6-month change in amino acids, fatty acids, and acylcarnitines with baseline and the 6-month changes in muscle strength, lower extremity function (short physical performance battery), and mobility (400M gait speed) in response to 6 months of a combined resistance exercise and nutritional supplementation intervention in functionally-limited older adults. Metabolites related to gut bacterial metabolism and insulin sensitivity were associated with function at baseline and with the 6-month change in function. These data suggest that gut microbial metabolism and insulin sensitivity may be involved in mechanisms that underlie physical functioning in older adults. To better understand the molecular changes associated with the loss of skeletal muscle mass with aging, researchers examined the role of microRNA in the aging process. Researchers in the lab demonstrated marked alterations in miRNA expression profile in adipose tissue from C57BL/6 mice with advancing age. At 24 months, there was a substantial decrease in the expression of miRNA in both miR-17/92 and other adipose-specific miRNA compared to 6 and 18-month-old animals. In these animals, researchers found similar changes in the expression of miRNA in skeletal muscle with age and in response to high-fat feeding. Researchers in the NEPS lab have previously reported that miR-17/92 expression in circulation is highly predictive of age and the anabolic response to exercise in humans. Using adenoviral gene vectors to overexpress miR-19-3p in human myocytes, researchers found that protein synthesis and anabolic signaling were increased at 3h compared to control, but miR-19b-3p could not reverse rapamycin-induced inhibition of protein synthesis. These changes were likely due to a blunted expression of the phosphatase and tensin homolog transcript and protein after overexpression. However, miR-19b had no effect on mitochondrial genes suggesting a role for miR-19b in regulating muscle protein turnover exclusively. Objective 2. Determine the effects of structured, long term interventions of aerobic walking and resistance physical activity on physical functioning in older adults with chronic kidney disease or limited mobility. The Lifestyle Interventions and Independence for Elders (LIFE) Study was a large multicenter randomized controlled trial, designed to compare the effects of a moderate intensity physical activity program with a successful aging health education program on the incidence of major mobility disability in older adults who were at high risk for mobility disability (scoring < 9 on the Short Physical Performance Battery) at baseline (N = 1,635). Researchers performed secondary analysis of the LIFE study data to examine the effect of physical activity dose on changes in physical functioning and the onset of major mobility disability. Physical activity dose was assessed at baseline and 24 months. Outcomes included the 400 m walk gait speed, the Short Physical Performance Battery, assessed at baseline, 6, 12, and 24 months, and onset of major mobility disability (objectively defined by loss of ability to walk 400 m in 15 min). When the physical activity arm or the entire sample were stratified by change in physical activity from baseline to 24 months, there was a dose-dependent increase in the change in gait speed and Short Physical Performance Battery from baseline at 6, 12, and 24 months. In addition, the magnitude of change in physical activity over 24 months was related to the reduction in the onset of major mobility disability. Researchers in the lab also analyzed the impact of the LIFE study intervention on the risk of developing physical frailty. Frailty was defined using the Study of Osteoporotic Fractures (unexpected weight loss (> 5% or 4.55 kg, inability to rise from a chair, self-reported reduced energy). Over 24 months of follow-up, the risk for frailty (n = 1623) was not different in the physical activity versus the health education group. Among the 3 criteria of the Study of Osteoporotic Fractures index, the physical activity intervention was associated with improvement in the inability to rise from a chair. Baseline frailty status did not modify the effect of physical activity on reducing the development of major mobility disability. These results indicate that a structured, moderate-intensity physical activity program was not associated with a reduced risk for frailty over 2 years among sedentary, community-dwelling older adults. However, importantly, the beneficial effect of physical activity on the incidence of major mobility disability did not differ between frail and non-frail participants. The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity, muscle cross sectional area, and fat accumulation in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150 kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). Mobility-limited (Short Physical Performance Battery =

Accomplishments
1. Progressive resistance training improves muscle fatigue and strength in older adults. Progressive resistance/strength training is consistently shown to improve muscle strength in older adults, but its effect on muscle fatigue in older adults with limited mobility remains unclear. ARS-funded researchers in Boston, Massachusetts recruited 70 mobility-limited older adults (age 70–92 years) and randomized them to either progressive resistance training or home-based flexibility three times per week for 12 weeks. Muscle fatigue and strength outcomes were assessed at baseline and 12 weeks. At follow-up, the progressive resistance training group showed a significant improvement in muscle fatigue and strength compared with home-based flexibility group. These results show that progressive resistance/strength training improves muscle fatigue and strength in mobility-limited older adults. As older adults are often affected by muscle and strength loss, the discovery of effective strength training interventions could prolong independence and quality of life in older adults.

U.S. DEPARTMENT OF AGRICULTURE

Jean Mayer Human Nutrition Research Center On Aging: Boston, MA