Sarcopenia is the decline in muscle mass and muscle strength that inevitably accompanies human aging. Loss initiates at middle age (even in healthy individuals) and progresses such that virtually everyone can expect to experience significant decline in muscle strength over time (approximately 50% strength loss by age 90). Unfortunately, this universal phenomenon is often sufficiently incapacitating such that assistance in basic life activities, such as walking and lifting, becomes necessary. Despite the substantial toll taken by sarcopenia, relatively little is understood about how and why sarcopenia occurs, especially at the molecular level. To date, genetic models have not been exploited to investigate molecular mechanisms of sarcopenia. We have found that C. elegans aging features age-related muscle decline that shares striking similarities to human sarcopenia. Moreover, we have identified one gene that plays a critical role in the process--AGE-1 PI3 kinase (known to act in the DAF-2 insulin-like signalling pathway that influences longevity). That downregulation of a single gene activity can markedly delay the onset of sarcopenia is highly encouraging. The overall goal of our research is to identify the genetic influences on C. elegans sarcopenia and to define molecular strategies that """"""""youthenize"""""""" muscle. We will pursue 3 aims: I) The molecular characterization of the effects of insulin-like signalling on C. elegans sarcopenia; II) The evaluation of the impacts of oxidative damage and caloric restriction on muscle healthspan; III) The execution of a genome-wide, non-biased RNAi screen to identify novel genes that influence sarcopenia. At the completion of the study we propose, we expect to provide a detailed molecular description of how nematode insulins and components of the canonical DAF-2 insulin signalling pathway influence nematode sarcopenia. We will also define how oxidative stress and caloric restriction protocols influence cellular aspects of muscle decline. Furthermore, we expect to identify novel genetic factors with major impacts on muscle aging. The end result should be a significant advance in the level of molecular and mechanistic detail with which we understand sarcopenia in the C. elegans model. Our hope is that the novel insight we anticipate will stimulate the search for conserved processes in mammals, and that data we generate may influence design of new therapeutic intervention strategies for combating human sarcopenia.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-B (02))
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Williams, John
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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