Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila

Autoři: Kelly Jin aff001;  Kenneth A. Wilson aff002;  Jennifer N. Beck aff002;  Christopher S. Nelson aff002;  George W. Brownridge, III aff002;  Benjamin R. Harrison aff001;  Danijel Djukovic aff005;  Daniel Raftery aff005;  Rachel B. Brem aff002;  Shiqing Yu aff007;  Mathias Drton aff008;  Ali Shojaie aff009;  Pankaj Kapahi aff002;  Daniel Promislow aff001
Působiště autorů: Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America aff001;  Buck Institute for Research on Aging, Novato, California, United States of America aff002;  Davis School of Gerontology, University of Southern California, University Park, Los Angeles, California, United States of America aff003;  Dominican University of California, San Rafael, California, United States of America aff004;  Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America aff005;  Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, United States of America aff006;  Department of Statistics, University of Washington, Seattle, Washington, United States of America aff007;  Department of Mathematics, Technical University of Munich, Munich, Germany aff008;  Department of Biostatistics, University of Washington, Seattle, Washington, United States of America aff009;  Department of Biology, University of Washington, Seattle, Washington, United States of America aff010
Vyšlo v časopise: Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila. PLoS Genet 16(7): e1008835. doi:10.1371/journal.pgen.1008835
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008835


In most organisms, dietary restriction (DR) increases lifespan. However, several studies have found that genotypes within the same species vary widely in how they respond to DR. To explore the mechanisms underlying this variation, we exposed 178 inbred Drosophila melanogaster lines to a DR or ad libitum (AL) diet, and measured a panel of 105 metabolites under both diets. Twenty four out of 105 metabolites were associated with the magnitude of the lifespan response. These included proteinogenic amino acids and metabolites involved in α-ketoglutarate (α-KG)/glutamine metabolism. We confirm the role of α-KG/glutamine synthesis pathways in the DR response through genetic manipulations. We used covariance network analysis to investigate diet-dependent interactions between metabolites, identifying the essential amino acids threonine and arginine as “hub” metabolites in the DR response. Finally, we employ a novel metabolic and genetic bipartite network analysis to reveal multiple genes that influence DR lifespan response, some of which have not previously been implicated in DR regulation. One of these is CCHa2R, a gene that encodes a neuropeptide receptor that influences satiety response and insulin signaling. Across the lines, variation in an intronic single nucleotide variant of CCHa2R correlated with variation in levels of five metabolites, all of which in turn were correlated with DR lifespan response. Inhibition of adult CCHa2R expression extended DR lifespan of flies, confirming the role of CCHa2R in lifespan response. These results provide support for the power of combined genomic and metabolomic analysis to identify key pathways underlying variation in this complex quantitative trait.

Klíčová slova:

Diet – Drosophila melanogaster – Genome-wide association studies – Metabolic networks – Metabolic pathways – Metabolites – Metabolomics – RNA interference


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