R01AG065265

Determinants and Outcomes of Age-Related Muscle Loss - Abstract / Project Summary

The understanding of processes that lead to age-related decline in muscle mass and its consequences has been fundamentally limited by imperfect methods of assessing total muscle mass. This has slowed the development of interventions to prevent skeletal muscle loss.

The long-term goal of this research is to gain a better understanding of the causes and consequences of low total muscle mass in older adults. The objectives of this project are to measure total muscle mass via the D3-creatine dilution method and determine its association with genetic and non-genetic risk factors, and their relation with falls, injurious falls, and fractures in two large, community-based cohorts of older adults.

This technique provides a direct and accurate estimate of total muscle mass from a single, fasting urine specimen. The central hypotheses are that lower total muscle mass is associated with novel genetic variants, which when used as instrumental variables in a Mendelian randomization analysis will demonstrate that lower total muscle mass directly increases the risk of incident falls, injurious falls, and fractures. Furthermore, the association of lifestyle predictors (diet and physical activity) with total muscle mass and with accelerated loss of total muscle mass will be partly mediated by inflammation marker interleukin-6 (IL-6).

Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims using up to 3,200 participants from two well-characterized cohorts, the Framingham Heart Study (FHS) and the Osteoporotic Fractures in Men (MROS) Study.

Aim 1 will identify genetic variants associated with total muscle mass estimated by D3-creatine dilution in the FHS and MROS cohorts by performing a genome-wide association study (GWAS). The availability of additional cohorts with D3-creatine and genotyping will bring the sample size to 8,400.

Aim 2 will determine the causal relation between total muscle mass estimated by D3-creatine dilution and incident falls, injurious falls, and fractures by using SNPs identified in Aim 1 as instrumental variables for total muscle mass in a Mendelian randomization analysis in the FHS and MROS cohorts.

Aim 3 will determine the cross-sectional associations of physical activity, dietary protein, essential amino acids (EAA), branched-chain amino acids (BCAA), and n-3 polyunsaturated fatty acids (N3-PUFA) with baseline total muscle mass in the FHS and MROS cohorts, as well as associations with the change in total muscle mass over an 18-month period in the FHS cohort. To minimize the chance of confounding, Aim 3 will also use a previously published GWAS on accelerometry-derived physical activity to perform a Mendelian randomization analysis of accelerometry-derived physical activity and total muscle mass. Lastly, Aim 3B will determine the implied indirect effect of activity and diet on muscle mass along a pathway delineated by IL-6.

This study has the potential to transform the field in terms of defining the impact of reduced muscle mass measured using a valid technology, D3-creatine dilution, which could also ultimately serve as an endpoint in drug trials.

Hebrew Rehabilitation Center

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Roslindale, Massachusetts 021311000 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 411% from $679,361 to $3,472,889.