Predicting Longevity Responses to Dietary Restriction: A Stepping Stone Toward Precision Geroscience
| Autor: | Benjamin R Harrison, Ali Shojaie, Shiqing Yu, Christopher S. Nelson, Rachel B. Brem, Kenneth A. Wilson, Pankaj Kapahi, Mathias Drton, Jennifer N. Beck, Danijel Djukovic, George W. Brownridge, Daniel E. L. Promislow, Daniel Raftery, Kelly Jin |
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| Přispěvatelé: | Murphy, Coleen T |
| Rok vydání: | 2020 |
| Předmět: |
Aging
Cancer Research QH426-470 medicine.disease_cause Biochemistry Receptors G-Protein-Coupled RNA interference 0302 clinical medicine Receptors Metabolites Medicine and Health Sciences 2.1 Biological and endogenous factors Drosophila Proteins Insulin Developmental Aetiology Genetics (clinical) Genetics Regulation of gene expression 0303 health sciences Mutation biology Eukaryota Gene Expression Regulation Developmental Animal Models Genomics Nucleic acids Insects Drosophila melanogaster Genetic interference Experimental Organism Systems Metabolome Epigenetics Drosophila Metabolic Pathways Network Analysis Research Article Signal Transduction Computer and Information Sciences Arthropoda Longevity Quantitative trait locus Research and Analysis Methods G-Protein-Coupled Metabolic Networks 03 medical and health sciences Model Organisms Metabolomics Genome-Wide Association Studies medicine Animals Molecular Biology Gene Metabolic and endocrine Ecology Evolution Behavior and Systematics Nutrition Caloric Restriction 030304 developmental biology Biology and life sciences Organisms Computational Biology Human Genetics Genome Analysis biology.organism_classification Invertebrates Diet Metabolic pathway Metabolism Gene Expression Regulation Animal Studies RNA Generic health relevance Gene expression 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 16, Iss 7, p e1008835 (2020) PLoS genetics, vol 16, iss 7 |
| ISSN: | 1553-7404 |
| Popis: | 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. Author summary Dietary restriction extends lifespan across most organisms in which it has been tested. However, several studies have now demonstrated that this effect can vary dramatically across different genotypes within a population. Within a population, dietary restriction might be beneficial for some, yet detrimental for others. Here, we measure the metabolome of 178 genetically characterized fly strains on fully fed and restricted diets. The fly strains vary widely in their lifespan response to dietary restriction. We then use information about each strain’s genome and metabolome (a measure of small molecules circulating in flies) to pinpoint cellular pathways that govern this variation in response. We identify a novel pathway involving the gene CCHa2R, which encodes a neuropeptide receptor that has not previously been implicated in dietary restriction or age-related signaling pathways. This study demonstrates the power of leveraging systems biology and network biology methods to understand how and why different individuals vary in their response to health and lifespan-extending interventions. |
| Databáze: | OpenAIRE |
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