title: Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies.
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.
authors: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Drew
authors: D
authors: Stenesen
authors: Jae Myoung
authors: JM
authors: Suh
authors: Jin
authors: J
authors: Seo
authors: Kweon
authors: K
authors: Yu
authors: Kyu-Sun
authors: KS
authors: Lee
authors: Jong-Seok
authors: JS
authors: Kim
authors: Kyung-Jin
authors: KJ
authors: Min
authors: Jonathan M
authors: JM
authors: Graff
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000096:biosynthesis*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000265:Adenylosuccinate Synthase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D031204:Caloric Restriction; D004330:Drosophila / Q000201:enzymology / Q000378:metabolism; D005216:Fat Body / Q000378:metabolism; D006579:Heterozygote; D008136:Longevity; D009154:Mutation; D034622:RNA Interference
chemical_list: D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D000265:Adenylosuccinate Synthase