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Female aging: when translational models don’t translate

Abstract

For many pathologies associated with aging, female patients present with higher morbidity and more frequent adverse events from treatments compared to male patients. While preclinical models are the foundation of our mechanistic understanding of age-related diseases, the most common models fail to recapitulate archetypical female aging trajectories. For example, while over 70% of the top age-related diseases are influenced by the systemic effects of reproductive senescence, we found that preclinical studies that include menopausal phenotypes modeling those seen in humans make up <1% of published aging biology research. The long-term impacts of pregnancy, birthing and breastfeeding are also typically omitted from preclinical work. In this Perspective, we summarize limitations in the most commonly used aging models, and we provide recommendations for better incorporating menopause, pregnancy and other considerations of sex in vivo and in vitro. Lastly, we outline action items for aging biology researchers, journals, funding agencies and animal providers to address this gap.

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Fig. 1: Menopause is associated with the majority of age-related diseases, but few preclinical studies incorporated a menopausal phenotype.

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Acknowledgements

The authors thank J. Bergmann for assistance in the literature search as well as the members of the laboratory of F.A. for reviewing and editing this Perspective. The authors also gratefully acknowledge the funding sources that supported this work including the National Institute on Aging (NIA; R01 AG061005, to F.A.), NIA R01 AG052978 (to F.A.), NIA R01 AG066198 (to F.A.), NIH T32AG021885-19 (to G.G.), NIH T32GM008208 (to G.G.) and NIH T32AG021885-19 (to Z.R.H.).

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Author notes

  1. These authors contributed equally: Gabrielle Gilmer, Zachary R. Hettinger.

Authors and Affiliations

  1. Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding Rehabilitation, Boston, MA, USA

    Gabrielle Gilmer, Zachary R. Hettinger & Fabrisia Ambrosio

  2. Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Charlestown, MA, USA

    Gabrielle Gilmer, Zachary R. Hettinger, Julie K. Silver & Fabrisia Ambrosio

  3. Medical Scientist Training Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Gabrielle Gilmer

  4. Cellular and Molecular Pathology Graduate Program, University of Pittsburgh, Pittsburgh, PA, USA

    Gabrielle Gilmer

  5. Department of Physical Medicine & Rehabilitation, Harvard Medical School, Boston, MA, USA

    Zachary R. Hettinger, Julie K. Silver & Fabrisia Ambrosio

  6. Department of Geriatric Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Zachary R. Hettinger

  7. Department of Social and Behavioral Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA

    Yetsa Tuakli-Wosornu

  8. Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Yetsa Tuakli-Wosornu

  9. Department of Occupational Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Elizabeth Skidmore

  10. Department of Physical Medicine and Rehabilitation, Massachusetts General Hospital, Boston, MA, USA

    Julie K. Silver

  11. Department of Physical Medicine and Rehabilitation, Brigham and Women’s Hospital, Boston, MA, USA

    Julie K. Silver

  12. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Rebecca C. Thurston

  13. Divisions of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN, USA

    Dawn A. Lowe

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Contributions

All authors made substantial contributions in the following areas: (1) conception and design of the study, acquisition of data, analysis and interpretation of data, drafting of the article; (2) final approval of the article version to be submitted; and (3) agreement to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy are appropriately investigated, resolved and the resolution documented in the literature. The specific contributions of the authors are as follows: Conceptualization: G.G., Z.R.H. and F.A. Writing—original draft: G.G., Z.R.H. and F.A. Writing—review and editing: G.G., Z.R.H., Y.T.-W., E.S., J.K.S., R.C.T., D.A.L. and F.A.

Corresponding author

Correspondence to
Fabrisia Ambrosio.

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Competing interests

R.C.T. is a consultant and advisor for Astellas Pharma, a consultant for Bayer and on the medical advisory board at Hello Therapeutics. The remaining authors declare no competing interests.

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Nature Aging thanks Bérénice Benayoun and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Gilmer, G., Hettinger, Z.R., Tuakli-Wosornu, Y. et al. Female aging: when translational models don’t translate.
Nat Aging (2023). https://doi.org/10.1038/s43587-023-00509-8

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  • Received: 09 May 2023

  • Accepted: 25 September 2023

  • Published: 05 December 2023

  • DOI: https://doi.org/10.1038/s43587-023-00509-8

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