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.