Adenosine Nucleotide Biosynthesis and AMPK Regulate Adult Life Span and Mediate the Longevity Benefit of Caloric Restriction in Flies

• Published in: Cell metabolism Vol. 17; no. 1; pp. 101 - 112
• Main Authors: Stenesen, Drew, Suh, Jae Myoung, Seo, Jin, Yu, Kweon, Lee, Kyu-Sun, Kim, Jong-Seok, Min, Kyung-Jin, Graff, Jonathan M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.01.2013
• Subjects: Adenine; Adenosine; Adenosine kinase; Adenosine Monophosphate - biosynthesis; Adenosine Triphosphate - metabolism; Adenylosuccinate Synthase - genetics; Adenylosuccinate Synthase - metabolism; AMP; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Animals, Genetically Modified - metabolism; ATP; Caloric Restriction; Data processing; Dietary restrictions; Drosophila; Drosophila - enzymology; Drosophila - metabolism; Energy; Energy balance; Energy metabolism; Enzymes; Fat body; Fat Body - metabolism; Heterozygote; Life span; Longevity; Metabolism; Muscles; Mutation; Nucleotides; Protein kinase; RNA Interference; RNA-mediated interference
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.12.006

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. ► Heterozygous AMP biosynthesis mutations act via AMPK to extend life span ► Tissue- and adult-specific transgenic expression of AMPK extends life span ► Dietary adenine reverses the life span extension of adult AMP biosynthesis mutants ► Addition of dietary adenine blocks the longevity effects of dietary restriction