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

Nan Wu, Yi-Cheng Ma, Xin-Qian Gong, Pei-Ji Zhao, Yong-Jian Jia, Qiu Zhao, Jia-Hong Duan and Cheng-Gang Zou ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35899-1

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