Systems biology approaches identify metabolic signatures of dietary lifespan and healthspan across species

Tyler A. U. Hilsabeck, Vikram P. Narayan, Kenneth A. Wilson, Enrique M. Carrera, Daniel Raftery, Daniel Promislow, Rachel B. Brem, Judith Campisi and Pankaj Kapahi ()
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Tyler A. U. Hilsabeck: Buck Institute for Research on Aging
Vikram P. Narayan: Buck Institute for Research on Aging
Kenneth A. Wilson: Buck Institute for Research on Aging
Enrique M. Carrera: Buck Institute for Research on Aging
Daniel Raftery: Department of Anesthesiology and Pain Medicine, University of Washington
Daniel Promislow: University of Washington
Rachel B. Brem: Buck Institute for Research on Aging
Judith Campisi: Buck Institute for Research on Aging
Pankaj Kapahi: Buck Institute for Research on Aging

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species—random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

Date: 2024
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DOI: 10.1038/s41467-024-52909-y

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