Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction inC. elegans

Reproductive aging is one of the earliest human aging phenotypes, and mitochondrial dysfunction has been linked to oocyte quality decline. However, it is not known which mitochondrial metabolic processes are critical for oocyte quality maintenance with age. To understand how mitochondrial processes contribute toC. elegansoocyte quality, we characterized the mitochondrial proteomes of young and aged wild-type and long-reproductivedaf-2mutants. Here we show that the mitochondrial proteomic profiles of young wild-type anddaf-2worms are similar and share upregulation of branched-chain amino acid (BCAA) metabolism pathway enzymes. Reduction of the BCAA catabolism enzyme BCAT-1 shortens reproduction, elevates mitochondrial reactive oxygen species levels, and shifts mitochondrial localization. Moreover,bcat-1knockdown decreases oocyte quality indaf-2worms and reduces reproductive capability, indicating the role of this pathway in the maintenance of oocyte quality with age. Importantly, oocyte quality deterioration can be delayed, and reproduction can be extended in wild-type animals both bybcat-1overexpression and by supplementing with Vitamin B1, a cofactor needed for BCAA metabolism.