The attached application describes a two year exploratory research project designed to begin to identify genetic modifiers of sarcopenia in the non-parasitic nematode Caenorhabditis elegans. Sarcopenia is the loss of muscle mass and muscle strength that occurs to varying degrees during aging in people. The resulting loss of muscle strength contributes to impairments in physical functioning in older people and serves as a risk factor for loss of independence, need for nursing home placement, and ultimately mortality. Studies in vertebrate animals and humans have provided evidence for multiple mechanisms, but clinical studies using treatments aimed at addressing some of these mechanisms have produced at best modest results. For example, clinical studies that use exogenous testosterone or growth hormone to supplement low levels found in some older people have yielded only minor increases in muscle strength. Hence there is a pressing need to identify new ways to study sarcopenia and to identify mechanisms that may be more amenable to intervention. We propose to use the nematode C. elegans to identify genetic modifiers of sarcopenia. During aging, C. elegans has been shown to develop sarcopenia and these losses appear to lead to declines in mobility and serve as a risk factor for mortality. Mutations in the insulin/IGF-1 receptor daf-2 have been shown to both increase worm longevity and to delay the development of sarcopenia. These effects of daf-2 mutations on sarcopenia are likely due to changes in gene expression in the muscles that then increase the resistance of muscle to the effects of aging and delay the development of sarcopenia.
We aim to identify genes that are targets of daf-2 signaling in muscle and test the effects of these genes on the development of sarcopenia using functional assays. We hope to identify genes that act to protect against sarcopenia which could then be tested for similar effects in mammals and ultimately people. Some of these genes may lead to targets for pharmacologic intervention to prevent or reverse sarcopenia in people. ? ? ? ?
