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.

Figure 1:. Menopause affects the majority of age-related diseases, but few preclinical studies incorporated a menopausal phenotype.

A) The top 22 age-related diseases were grouped into 5 disease categories. On March 4, 2023, we performed a PubMed literature search for known menopause-related effects in humans when considering these top 22 age-related diseases (Figure 2B, Table S1). On July 4, 2023, another PubMed literature search was performed to determine the number of (a) clinical trials, (b) mammalian animal studies, and (c) menopause-inclusive mammalian, animal studies on each disease category (Figure 2C). Summary of disease categories and specific search terms are listed in Table S1. B) The percentage of the top age-related diseases that are known to be associated with onset of menopause. References used to determine the association between each disease and menopause are listed in Table S1. C) The number of articles on PubMed for clinical trials, mammalian studies, and menopause-inclusive mammalian studies for each disease category. Created in BioRender.

Figure 2:. Specific and actionable recommendations to researchers, peer-reviewed journals, providers of animals for aging research, and funding agencies to close the gap in our understanding of female aging.

Created in BioRender.