Abstract
A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed life span extension. Remarkably, this simple change in diet also blocked the prolongevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult life span; provide a mechanistic link between cellular anabolism and energy sensing pathways; and indicate that dietary adenine manipulations might alter metabolism to influence animal life span.
| Original language | English |
|---|---|
| Pages (from-to) | 101-112 |
| Number of pages | 12 |
| Journal | Cell Metabolism |
| Volume | 17 |
| Issue number | 1 |
| DOIs | |
| State | Published - 8 Jan 2013 |
Bibliographical note
Funding Information:We are grateful to Drs. Margaret Phillips and Elliott Ross and their respective labs, specifically Chelsea Pratt, Suong Nguyen, and Jimmy Woodson, for use of equipment and helpful discussions. We thank the numerous stock centers and colleagues for fly stocks. We also thank members of the Graff lab for support, reagents, and insights. This study was supported by the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Disease grants (R01 DK066556, R01 DK064261, and R01 DK088220 to J.M.G.), Inha University and The National Research Foundation of Korea (NRF, 2011-0030133 to K.-J.M.), and the KRIBB Research Initiative Program. J.M.G., D.S., J.M.S., K.-S.L., K.Y., J.S.K., and K.-J.M. conceived, designed, and interpreted the experiments. D.S., J.M.S., J.S., K.-S.L., K.Y., J.S.K., and K.-J.M. performed the experiments. J.M.G., D.S., and J.M.S. wrote the paper. J.M.G. is a cofounder and shareholder of Reata Pharmaceuticals.