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

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.

2 Hydroxybutyric Acid-Producing Bacteria in Gut Microbiome and Fusobacterium nucleatum Regulates 2 Hydroxybutyric Acid Level In Vivo

“…Interestingly, Fusobacterium nucleatum [ 30 , 39 , 40 , 41 , 42 ] and Peptostreptococcus anaerobius [ 43 , 44 ] have also been implicated in the development of colorectal cancer. Moreover, Studies have shown that supplementation with 2-KB extends the lifespan in wild-type worms [ 45 ]. Elderly mice fed with autophagy-induced metabolite 2-KB can prevent hair loss [ 46 ].…”

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes

“…Interestingly, this activation is independent of the P38-MAPK pathway but involves the nuclear factor ELT-3, nuclear hormone receptor NHR-49, and mediator complex subunit MDT15. Most recently, Wu et al (2023) proposed a cascade of events activating SKN-1 initiated by alpha-ketobutyrate (α-KB) supplementation ( Wu et al, 2023 ). Addition of α-KB leads to increased expression of the enzyme ACOX1, which is involved in the peroxisomal fatty acid β-oxidation pathway.…”

Electrocatalytic Systems for NOx Valorization in Organonitrogen Synthesis

“…The CuS electrocatalyst was universal for other substrates, such as furfural, cyclopentanone, and cycloheptanone, further broadening the system of electrocatalytic synthesis of oximes (Figure 6e). [56] NH 2 OH produced by electrochemical method, and in situ reacted with keto-based organic compounds to form oximes, not only avoids the huge energy consumption and security uncertainties associated with storage, but also combine with active hydrogen to produce more complex organic nitrogen-containing products. With the deepening and expansion of exploration, it is believed that electrocatalytic synthesis of oxime will shine in medicine, chemical industry and other fields.…”