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The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans

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  • Nan Wu

    (Yunnan University)

  • Yi-Cheng Ma

    (Yunnan University)

  • Xin-Qian Gong

    (Yunnan University)

  • Pei-Ji Zhao

    (Yunnan University)

  • Yong-Jian Jia

    (Yunnan University)

  • Qiu Zhao

    (Yunnan University)

  • Jia-Hong Duan

    (Yunnan University)

  • Cheng-Gang Zou

    (Yunnan University)

Abstract

Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional program involved in peroxisome function and biogenesis in long-lived glp-1(e2141ts) mutant Caenorhabditis elegans worms. Subsequently, we show that supplementation with α-ketobutyrate, an intermediate of the transsulfuration pathway, extends lifespan in wild-type worms. Alpha-ketobutyrate augments the production of NAD+ via the lactate dehydrogenase LDH-1, leading to SIR-2.1/SIRT1-mediated enhanced peroxisome function and biogenesis, along with a concomitant increase in the expression of acox-1.2/ACOX1 in the peroxisomal fatty acid β-oxidation pathway. ACOX-1.2/ACOX1 promotes H2O2 formation, thereby resulting in activation of SKN-1/NRF2. This transcription factor in turn extends the lifespan of worms by driving expression of autophagic and lysosomal genes. Finally, we show that α-ketobutyrate also delays the cellular senescence in fibroblast cells through the SIRT1-ACOX1-H2O2-NRF2 pathway. This finding uncovers a previously unknown role for α-ketobutyrate in organismal lifespan and healthspan by coordinating the NAD+-SIRT1 signaling and peroxisomal function.

Suggested Citation

  • Nan Wu & Yi-Cheng Ma & Xin-Qian Gong & Pei-Ji Zhao & Yong-Jian Jia & Qiu Zhao & Jia-Hong Duan & Cheng-Gang Zou, 2023. "The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35899-1
    DOI: 10.1038/s41467-023-35899-1
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