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; Pankaj Kapahi

doi:10.1038/s41467-024-52909-y

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

Nat Commun. 2024 Oct 29;15(1):9330. doi: 10.1038/s41467-024-52909-y.

Authors

Tyler A U Hilsabeck^#^{1

2

3}, Vikram P Narayan^#^{1

4}, Kenneth A Wilson^{1

2}, Enrique M Carrera^{1

5}, Daniel Raftery⁶, Daniel Promislow^{7

8

9}, Rachel B Brem^{1

2

10}, Judith Campisi¹, Pankaj Kapahi^{11

12}

Affiliations

¹ Buck Institute for Research on Aging, Novato, CA, 94945, USA.
² Davis School of Gerontology, University of Southern California, University Park, University Park, Los Angeles, CA, 90089, USA.
³ Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
⁴ Department of Biology & Chemistry, Embry-Riddle Aeronautical University, Prescott, AZ, 86301, USA.
⁵ Dominican University of California, San Rafael, CA, 94901, USA.
⁶ Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.
⁷ Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
⁸ Department of Biology, University of Washington, Seattle, WA, 98195, USA.
⁹ Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA.
¹⁰ Department of Plant and Microbial Biology, University of California, Berkeley, CA, 94720, USA.
¹¹ Buck Institute for Research on Aging, Novato, CA, 94945, USA. [email protected].
¹² Davis School of Gerontology, University of Southern California, University Park, University Park, Los Angeles, CA, 90089, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Animals
Caloric Restriction
Diet
Drosophila / genetics
Drosophila / physiology
Drosophila melanogaster* / genetics
Drosophila melanogaster* / metabolism
Drosophila melanogaster* / physiology
Female
Genetic Variation
Humans
Longevity* / genetics
Longevity* / physiology
Male
Metabolomics / methods
Species Specificity
Systems Biology* / methods

Abstract

MeSH terms

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