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

• Published in: Nature communications Vol. 14; no. 1; pp. 240 - 14
• Main Authors: Wu, Nan, Ma, Yi-Cheng, Gong, Xin-Qian, Zhao, Pei-Ji, Jia, Yong-Jian, Zhao, Qiu, Duan, Jia-Hong, Zou, Cheng-Gang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 49/1; 631/80/39; 631/80/509; 631/80/642/2013; 64/11; Age related diseases; Aging; Animals; Biosynthesis; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Fatty acids; Humanities and Social Sciences; Hydrogen peroxide; Hydrogen Peroxide - metabolism; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Life span; Longevity - genetics; Metabolites; multidisciplinary; NAD; NAD - metabolism; NF-E2-Related Factor 2 - metabolism; Oxidation; Science; Science (multidisciplinary); Senescence; Signal transduction; Signaling; SIRT1 protein; Sirtuin 1 - metabolism; Supplements; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-35899-1

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 H 2 O 2 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-H 2 O 2 -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. Understanding how metabolites modulate longevity is crucial for reducing aging-related disease. Here, the authors demonstrate that α-ketobutyrate exhibits an anti-aging effect by coordinating NAD + -SIRT1 signaling and peroxisome function.