Sarcopenia, the loss of fat-free muscle mass during aging, leads to the loss of strength, mobility, and independence, and is a major contributor to the frailty syndrome. Studies indicate that the quantitative loss of myofibers during aging accounts for less than half of the loss of strength, indicating a qualitative defect in aging muscle. Recent pre-clinical studies in aging mice and mice fed high fat diets indicate that an important component of muscle dysfunction is due qualitative and quantitative defects in myofibril mitochondria. This includes decrease in the number of mitochondria and defects in oxidative metabolism involving the electron transport chain (ETC), tricarboxylic acid cycle (TCA cycle), and fatty acid (FA) beta-oxidation. These abnormalities appear to be linked to decreased activity of a set of transcriptional regulators including PGC-1 alpha, Nrf-1, PPAR isoforms, and TFAM that govern the expression of genes involved in mitochondrial biogenesis and intermediary metabolism. While aging and obesity diminish the activity of these factors, recent studies in murine models and man suggest that they can be upregulated by specific interventions, including calorie restriction (CR), exercise, and at least in mice, by the oral intake of resveratrol. The proposed randomized trial is designed to determine if oral resveratrol, when administered to elderly individuals at a dose of 2 grams per day for 12 weeks, can induce specific physiologic and/or molecular alterations that improve muscle function similar to those observed in the murine models. A series of studies is proposed that should allow us to identify pharmacodynamic activities of resveratrol in human subjects. The protocol is being submitted to the IRB for review. We have received permission from Meredith Hawkins, MD, at the Albert Einstein College of Medicine, to cross-file on her IND for resveratrol. The resveratrol will be supplied by RevGenetics, along with control capsules, at cost, and they have agreed to allow the FDA to examine the Master File. We shall submit the application to the FDA in the near future.
