Mobility inevitably declines with age, more in some than other people, often leading to mobility disability with dependency, decreased quality of life, and enormous health care costs. The role of age-related biological changes in skeletal muscle on the decline in mobility is poorly understood. We hypothesize that muscle mass and the capacity to produce ATP are strong determinants of the mobility disability in older adults. Based on advances from laboratory studies of muscle aging, we also hypothesize that denervation, oxidative damage, and decreased autophagic flux interact and contribute to declines in fitness, endurance and an increased risk of mobility disability. We will also use transcriptomic profiling by RNAseq to discover patterns of gene expression that play important roles in the loss of mobility with aging. In the Study of Muscle Mobility and Aging (SOMMA), a prospective, longitudinal study of men and women age 70 to 90, our team of experts in clinical and laboratory sciences will use innovative and state-of- the-art technologies with rigorous quality control to test these hypotheses and discover new pathways for the loss of mobility with aging. We will measure quadriceps contractile volume by MRI and total muscle mass by d3 creatine dilution. We will use 31PMRS to assess the capacity of the quadriceps to generate ATP (ATPmax). In tissue form, muscle biopsies quantify denervation and oxidative damage to contractile proteins. SOMMA will be the first to quantify autophagic flux to assess the role of autophagy in the loss of mobility with aging. We use respirometry on fresh tissue to quantify the contribution of mitochondria to ATPmax and mobility disability. These properties interact: for example, decreased autophagic flux promotes the accumulation of oxidative damage and denervation, and understanding these relationships will guide the analysis and interpretation of our results. Furthermore, we will use unbiased RNA-sequencing (RNA-seq) to profile the entire transcriptome to discover new associations between clusters of genes and individual variation in rates of loss of fitness (peak VO2), muscle mass, and risk of mobility disability. Field centers at Wake Forest and Pittsburgh, with exceptional track records for recruiting and retaining older adults in complex studies, will enroll 875 women and men age 70?89 with a gait speed ? 1.0 m/s, providing sufficient power to identify important relationships between individual and combinations of properties and the risk of mobility disability. SOMMA may identify and prioritize targets for new therapeutics and tailored exercise regimens. We also will create a unique archive of tissue, blood, with longitudinal data about important clinical outcomes that the scientific community can use to efficiently test new hypotheses about muscle and loss of mobility with aging.

R01AG059416

2018-06-15

2023-05-31