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D-beta-hydroxybutyrate extends lifespan in C. elegans.

Clare Edwards1, John Canfield2, Neil Copes2

  • 1Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, USA .

Aging
|August 17, 2014
PubMed
Summary

Beta-hydroxybutyrate (βHB) supplementation extended the lifespan of C. elegans nematodes by 20%. This ketone body acts as a histone deacetylase (HDAC) inhibitor, activating conserved stress response pathways for longevity.

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Area of Science:

  • Gerontology
  • Molecular Biology
  • Biochemistry

Background:

  • Ketone body beta-hydroxybutyrate (βHB) is a known histone deacetylase (HDAC) inhibitor.
  • While protective in disease models, βHB's impact on aging remains understudied.
  • Understanding βHB's role in aging can reveal novel longevity pathways.

Purpose of the Study:

  • To investigate the effect of βHB supplementation on the lifespan of C. elegans.
  • To elucidate the molecular mechanisms underlying βHB-mediated lifespan extension.
  • To assess βHB's influence on age-related stress resistance and neurodegenerative models.

Main Methods:

  • Lifespan assays in C. elegans with βHB supplementation.
  • RNA interference (RNAi) to knock down specific genes (HDACs, F55E10.6).

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  • Genetic analysis involving longevity pathways (DAF-16/FOXO, SKN-1/Nrf) and key regulators (SIR-2.1, AAK-2).
  • Assessment of thermotolerance, glucose toxicity, and aggregation of amyloid-beta and alpha-synuclein.

    • Main Results:

    • βHB supplementation extended mean lifespan in C. elegans by approximately 20%.
    • Lifespan extension was dependent on HDACs, DAF-16/FOXO, SKN-1/Nrf, SIR-2.1, and AAK-2.
    • βHB upregulated βHB dehydrogenase activity, suggesting a metabolic adaptation.
    • βHB improved thermotolerance, partially mitigated glucose toxicity, and delayed neurodegenerative pathologies.

    Conclusions:

    • D-βHB extends lifespan in C. elegans by inhibiting HDACs and activating conserved stress response pathways.
    • βHB's mechanism appears similar to dietary restriction, involving metabolic and stress resilience pathways.
    • βHB shows potential therapeutic benefits for age-related decline and neurodegenerative diseases.