Tissue-specific mitochondrial turnover with aging and energy restriction

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DESCRIPTION (provided by applicant): The candidate is a new investigator at Colorado State University (CSU). The candidate's long-term goal is to obtain independent funding to develop a research laboratory that uses an integrative and translational approach to investigate the interaction of energy and protein metabolism and their roles in the healthy aging of skeletal muscle. The immediate career goal is to obtain a protected period of research to develop skills for the assessment of potential tissue-specific mitochondrial turnover to changes in energy and with aging. Specifically, the proposed project addresses the protein turnover and mitochondrial theories of aging, and challenges the paradigm that protein turnover increases during periods of energy restriction (ER). The project will examine short and long- term changes in mitochondria turnover by redundant measurements to complete a comprehensive assessment of turnover. It is proposed that changes in mitochondria turnover will be mediated at the step of translation, since translation is an energetically expensive process. The mTOR and PGC-lot pathways, as well as AMPK activation will be explored as mediators of transcription and translation. The current proposal exploits the applicant's experience with stable isotopic tracers although new methods will be learned in the laboratory of Dr. Marc Hellerstein (UC-Berkeley, key consultant). Significant training aspects will be directed by Dr. Greg Cartee (University of Michigan, co-mentor) and Dr. Michael Pagliassotti (CSU, co- mentor) with instruction on the use of laboratory animals, ER methodology, tissue isolation techniques, and studies of cellular signaling. Study design, oversight and professional mentorship in aging research will be provided by Dr. Manfred Diehl (CSU, Director of the Center on Aging, co-mentor). RELEVANCE: Mitochondria deterioration has been proposed as causative to age-related decline in function. The current proposal seeks to understand how acute feeding, energy status (energy restricted (ER) or adequately fed), and tissue location effect age-induced changes in mitochondria turnover. It is hoped that the understanding of these processes will aid in safe and effective strategies for successful aging.