Enhanced Branched-Chain Amino Acid Metabolism Improves Age-related Reproductive Function

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Reproductive aging is one of the earliest aging phenotypes, and mitochondrial dysfunction has been linked to a decline in oocyte quality. However, the mitochondria-related processes that are critical for oocyte quality maintenance with age have not been fully identified. We isolated mitochondria from young and aged wild-type and long-reproductive daf-2 mutant C. elegans for proteomic analysis. We found that the mitochondrial proteomic profiles of young wild-type and daf-2 worms are similar and are distinct from mitochondrial proteins of aged wild-type animals. The first enzyme of the branched-chain amino acid (BCAA) metabolism pathway, BCAT-1, is more abundant in young and daf-2 mitochondria. Upon knockdown of bcat-1 in daf-2 , reproduction is shortened, mitochondrial ROS levels are elevated, and mitochondria shift to a perinuclear distribution within the mature oocytes. Moreover, bcat-1 knockdown decreases daf-2 oocyte quality and reduces reproductive capability in late age, indicating the importance of this pathway in the maintenance of oocyte quality with age. Importantly, we can extend reproduction in wild-type animals both by bcat-1 overexpression and by supplementing vitamin B1, a cofactor needed for the BCAA metabolism.


  • BCAT-1 is abundant in mitochondria isolated from young wild-type worms and the long-lived mutant daf-2 .

  • Downregulating bcat-1 in daf-2 mutants reduces daf-2 reproductive span, alters mitochondrial oocyte distribution, and elevates mtROS in mature oocytes.

  • Overexpression of bcat-1 extends reproductive capability.

  • Supplementation with thiamine (vitamin B1) extends reproductive capability.

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  1. Review coordinated by Life Science Editors.

    Reviewed by: Dr. Angela Andersen, Life Science Editors

    Potential Conflicts of Interest: None

    Background: The ability to reproduce decreases with age in many animals - including humans and worms. Oocytes age earlier than other tissues, and their decline in quality contributes to reduced reproduction. Diminished mitochondria number/activity in human oocytes correlates with age-related decline.

    Question: Does mitochondrial dysfunction cause (or just correlate with) reduced egg quality?

    Summary: The authors compared the proteomes of mitochondria isolated from young worms, old worms and daf-2 mutant worms (c. elegans) (insulin/igf-1 receptor mutant) that have longer lifespans & longer reproductive lifespan.

    • Mitochondria from young & mutant worms had high levels of BCAT-1 (branched chain aminotransferase).
    • RNAi of bcat-1 reduced the longevity, reproductive longevity & egg quality of daf2 mutants, and increased mitochondrial activity/mtROS.
    • Similar effects of bcat-1 kd in wt worms, but interestingly the effects on reproductive longevity were more severe in wt than daf2 mutants (from a quick look), but there was no effect on lifespan in wt animals.
    • Overexpressing bcat-1 in wt extended reproduction & egg quality but not lifespan.
    • Treating animals with vitamin B1 (a cofactor downstream of BCAT1 in BCAA metabolism) delayed reproductive aging, slightly extended lifespan, improved oocyte quality, reduced mtROS in aged worms..

    Advance: BCAT-1 levels/BCAA metabolism correlate with mitochondrial quality & reproductive longevity. Vit B1, which promotes BCAA metabolism, can extended reproductive longevity.

    Significance: More/strong evidence that dysfunctional mitochondria cause a decline oocyte quality, reduce reproductive longevity. If vitamin B1 supplements are a safe way to delay age-related decline of eggs in female mammals (humans) that would be amazing. .

    Ang asks:

    • is this effectively dietary restriction of BCAA? Would that be a better (albeit perhaps more difficult to sustain) approach?

    • How does this relate to some recent papers pointing out that mitochondria in eggs are special (e.g. Cheng et al. Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment, Science 2022; Rodriguez-Nuevo et al., Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I, Nature 2022) and a role for BCAA in longevity (e.g. Richardson et al., Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice, Nature Aging 2021).

    • How does low BCAA metabolism lead to mitochondrial dysfunction/oocyte aging? Is it related to accumulation of amino acids in the cytosol and toxicity to mitochondria? (e.g. Hughes et al., Cysteine toxicity drives age-related mitochondrial decline by altering iron homeostasis, Cell 2020).

    • Overall these data support the idea that oocytes are particularly vulnerable to conditions that drive aging, and conserved aging mechanisms in the soma and germline as well as across species.