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

Author

Listed:
  • Tyler A. U. Hilsabeck

    (Buck Institute for Research on Aging
    University Park
    Salk Institute for Biological Studies)

  • Vikram P. Narayan

    (Buck Institute for Research on Aging
    Embry-Riddle Aeronautical University)

  • Kenneth A. Wilson

    (Buck Institute for Research on Aging
    University Park)

  • Enrique M. Carrera

    (Buck Institute for Research on Aging
    Dominican University of California)

  • Daniel Raftery

    (Department of Anesthesiology and Pain Medicine, University of Washington)

  • Daniel Promislow

    (University of Washington
    University of Washington
    Tufts University)

  • Rachel B. Brem

    (Buck Institute for Research on Aging
    University Park
    University of California)

  • Judith Campisi

    (Buck Institute for Research on Aging)

  • Pankaj Kapahi

    (Buck Institute for Research on Aging
    University Park)

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.

Suggested Citation

  • Tyler A. U. Hilsabeck & Vikram P. Narayan & Kenneth A. Wilson & Enrique M. Carrera & Daniel Raftery & Daniel Promislow & Rachel B. Brem & Judith Campisi & Pankaj Kapahi, 2024. "Systems biology approaches identify metabolic signatures of dietary lifespan and healthspan across species," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52909-y
    DOI: 10.1038/s41467-024-52909-y
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    References listed on IDEAS

    as
    1. Yann W. Yap & Patricia M. Rusu & Andrea Y. Chan & Barbara C. Fam & Andreas Jungmann & Samantha M. Solon-Biet & Christopher K. Barlow & Darren J. Creek & Cheng Huang & Ralf B. Schittenhelm & Bruce Morg, 2020. "Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Angli Xue & Yang Wu & Zhihong Zhu & Futao Zhang & Kathryn E. Kemper & Zhili Zheng & Loic Yengo & Luke R. Lloyd-Jones & Julia Sidorenko & Yeda Wu & Allan F. McRae & Peter M. Visscher & Jian Zeng & Jian, 2018. "Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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