Aging is associated with a decline of function at the organismal level that has origins in cellular deterioration and the loss of tissue homeostasis. Age-related changes in both mitochondrial energy metabolism and stem cell function are widely reported; however, the interplay between mitochondrial dynamics, aging, and stem cell behavior has been virtually neglected. The PIs' laboratories use the powerful genetics of the fruit fly Drosophila melanogaster to elucidate the mechanisms underlying metabolic regulation of stem cell behavior and lifespan. In mammals, the peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1) family of transcription co-activators regulates several key metabolic processes, including mitochondrial biogenesis and energy metabolism. Moreover, increases in PGC-1 expression and mitochondrial biogenesis have been implicated in the life-extending mechanism of dietary restriction in a number of species, including humans. These laboratories have discovered that the Drosophila PGC-1 family homolog (dPGC-1) is a potent inducer of mitochondrial biogenesis, and targeted expression of dPGC-1 in the intestine is sufficient to extend lifespan. Furthermore, long-lived flies overexpressing dPGC-1 display robust maintenance of intestinal and germline stem cells. These findings have profound implications for the understanding of the relationship between metabolism, stem cell biology and lifespan determination. This proposal will build upon these studies by addressing three Specific Aims: 1) To examine the impact of overexpression of the Drosophila PGC-1 (dPGC-1) homolog on metabolism and lifespan 2) To characterize the relationship between stem cell behavior and mitochondrial metabolism 3) To characterize the mechanisms of dPGC-1-mediated longevity. Drosophila PGC-1 expression will be induced in multiple tissues and at different time-points, followed by analysis of changes in metabolism, behavior and longevity. Simultaneously, stem cell number, activity, and differentiation potential will be characterized in the intestine and ger line using well-characterized markers in combination with immunofluorescence microscopy. Lastly, the mechanism by which dPGC-1 overexpression leads to lifespan extension will be examined by studying intestinal function in aging flies and conducting genetic epistasis experiments with previously characterized longevity pathways.
This collaborative proposal addresses the relationship between two distinct and critical areas of aging research: mitochondrial modulation of lifespan and aging-related changes in stem cell behavior. Our work to explore the interplay between mitochondrial number and activity, tissue homeostasis, and longevity has major implications for the development of new therapies to treat age-onset diseases in humans, including the use of stem cells in regenerative medicine.
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