Loss of Oocyte Ribosomal Function as a Contribution to Female Reproductive Aging
Why, mechanistically, is female reproductive aging so accelerated in relation to the rest of the aging process? Researchers here point to a role for a progressive loss of ribosomes in oocytes. Cells contain many ribosomes, vital components of the cell where messenger RNA is translated into protein, and usually synthesize more as needed. Oocytes do not tend to synthesize new ribosomes, however, one of many differences in behavior intended to retain a much higher standard of cell quality during the reproductive lifespan. Female germline cells are among the most protected of all cell types, and have to be in order to maintain a sufficiently low level of reproductive failure for evolutionary success. Here, it is suggested that this ribosomal approach to increased cell quality produces the trade-off of a shorter cell life span and an earlier end to reproductive life span, as ribosomes are not replaced as they fail, and new oocytes are not created in adult life. In support of this view, researchers find that artificially reducing ribosome count in oocytes recapitulates the features of reproductive aging.
Protein synthesis declines with age across many tissues, but whether this decline actively contributes to physiological aging remains unclear. Oocytes may be particularly vulnerable because they rely on ribosomes synthesized during growth and maintained for prolonged periods without continual replacement. Here we show that declining translational capacity is a causal component of oocyte aging. An unbiased genetic screen identified ribosome dosage as a major determinant of oocyte longevity, and experimentally reducing ribosome abundance was sufficient to accelerate the loss of developmental competence and prematurely recapitulate meiotic defects that arise during natural aging, while also producing defects in early embryonic development.
Ribosomes isolated from aged Drosophila oocytes exhibit ∼50% lower translational activity despite only a modest reduction in ribosome abundance and preserved gross structure and composition, with both ribosomal subunits contributing to this functional decline. Protein synthesis also declines markedly in aged metaphase-I mouse oocytes. Together, these findings identify long-lived translational machinery as an intrinsic vulnerability of the oocyte and establish declining ribosome function as a mechanistic contributor to reproductive aging.