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Hallmarks of female reproductive aging in physiologic aging mice

Nature Aging volume 4, pages 1711–1730 (2024)Cite this article

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Abstract

The female reproductive axis is one of the first organ systems to age, which has consequences for fertility and overall health. Here, we provide a comprehensive overview of the biological process of female reproductive aging across reproductive organs, tissues and cells based on research with widely used physiologic aging mouse models, and describe the mechanisms that underpin these phenotypes. Overall, aging is associated with dysregulation of the hypothalamic–pituitary–ovarian axis, perturbations of the ovarian stroma, reduced egg quantity and quality, and altered uterine morphology and function that contributes to reduced capacity for fertilization and impaired embryo development. Ultimately, these age-related phenotypes contribute to altered pregnancy outcomes and adverse consequences in offspring. Conserved mechanisms of aging, as well as those unique to the reproductive system, underlie these phenotypes. The knowledge of such mechanisms will lead to development of therapeutics to extend female reproductive longevity and support endocrine function and overall health.

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Fig. 1: The phenotypes and hallmarks of female reproductive aging.
Fig. 2: The mechanisms of female reproductive aging in mice.

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Acknowledgements

We thank M. Beestrum at Northwestern University for assistance with the literature search and scoping review preparation. We acknowledge S. Tobin for critical input. This work was supported in part by National Institutes of Health grants (R01HD105752 to F.E.D., R01HD103384, AG029531 and AG056046 to T.R.K.), The Makowski Family Endowment (to T.R.K.), The Thomas J. Watkins Memorial Endowment (to F.E.D.) and the Global Consortium on Reproductive Longevity and Equity (T.R.K. and F.E.D.).

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Author notes

  1. These authors contributed equally: Julia L. Balough, Shweta S. Dipali, Karen Velez.

Authors and Affiliations

  1. Center for Reproductive Longevity and Equality, Buck Institute for Research on Aging, Novato, CA, USA

    Julia L. Balough & Francesca E. Duncan

  2. Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Shweta S. Dipali, Karen Velez & Francesca E. Duncan

  3. Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    T. Rajendra Kumar

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  1. Julia L. Balough
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J.L.B., S.S.D. and K.V. reviewed the literature, wrote the manuscript and prepared the figures. T.R.K. contributed to the conception of the review and revising and approving the manuscript for final submission. F.E.D. was responsible for conceiving, drafting and revising the manuscript and handling correspondence.

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Correspondence to Francesca E. Duncan.

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Nature Aging thanks Qingling Yang, Lindsay Wu, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Balough, J.L., Dipali, S.S., Velez, K. et al. Hallmarks of female reproductive aging in physiologic aging mice. Nat Aging 4, 1711–1730 (2024). https://doi.org/10.1038/s43587-024-00769-y

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