In Pursuit of a Molecular Fountain of Youth: The Identification and Characterization of Lifespan Regulators in Drosophila

Abstract

Over the past century, average human lifespan has experienced steady increase despite lack of substantial intervention or understanding of the aging process. In fact, many organisms have the latent potential to live much longer than they normally do. This indicates lifespan determination is an active process subject to regulation. Components of this impending longevity are beginning to unravel through dietary and genetic studies in model systems. To date, several pathways indicate human lifespan extension through direct molecular intervention may be feasible, however, important limitations persist. A common thread among these conserved lifespan regulators is metabolism. Therefore, further insight into lifespan extending mechanisms may lie within tissues governing important metabolic processes. Here we describe a multi-tiered, strategy to identify Drosophila melanogaster mutants with extended lifespan based upon enrichment for insertions in genes that are expressed in metabolic tissues. Our results indicate metabolically relevant tissues are a rich source of genetic longevity regulation. We identified a regulator of G protein signaling (RGS) domain containing sorting nexin, termed snazarus (sorting nexin lazarus, snz). Flies with insertions into the 5' untranslated region of snz live up to twice as long as controls. Transgenic expression of UAS-Snz from the snz Gal4 enhancer trap insertion, active in metabolic tissues, rescued lifespan extension. Notably, old snz mutant flies remain active and fertile indicating that snz mutants have prolonged youthfulness, a goal of aging research. Since mammals have snz-related genes, it is possible that the functions of the snz family may be conserved to humans. Next, we identified the two key adenosine monophosphate (AMP) biosynthetic pathways as regulators of Drosophila longevity. We found that heterozygous mutation of anabolic components of the de novo as well as the salvage AMP biosynthesis pathways extend lifespan. These pathway mutations, and caloric restriction, increased adenosine mono- and diphosphate to adenosine triphosphate (ATP) ratios. Consistent with the altered ratios, lifespan extension was dependent on functional adenosine monophosphate-activated protein kinase (AMPK). Supplementing the diets of adult mutants with adenine restored adenosine nucleotide ratios and rescued lifespan extension. These data establish de novo and salvage AMP biosynthesis as determinants of adult lifespan. The dosage sensitivity and enzymatic nature of de novo and salvage AMP biosynthesis, and the conserved aspects of adenosine nucleotide derivatives and lifespan extension, indicate that these pathways are potentially amendable drug targets worth continued exploration.