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Sex differences in pharmacological interventions and their effects on lifespan and healthspan outcomes: a systematic
Marie Knufinke1, Michael R MacArthur1, Collin Y Ewald1
1Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
Abstract:
With an increasing aging population, the burden of age-related diseases magnifies. To alleviate this burden, geroprotection has been an area of intense research focus with the development of pharmacological interventions that target lifespan and/or healthspan. However, there are often sex differences, with compounds mostly tested in male animals. Given the importance of considering both sexes in preclinical research, this neglects potential benefits for the female population, as interventions tested in both sexes often show clear sexual dimorphisms in their biological responses. To further understand the prevalence of sex differences in pharmacological geroprotective intervention studies, we performed a systematic review of the literature according to the PRISMA guidelines. Seventy-two studies met our inclusion criteria and were classified into one of five subclasses: FDA-repurposed drugs, novel small molecules, probiotics, traditional Chinese medicine, and antioxidants, vitamins, or other dietary supplements. Interventions were analyzed for their effects on median and maximal lifespan and healthspan markers, including frailty, muscle function and coordination, cognitive function and learning, metabolism, and cancer. With our systematic review, we found that twenty-two out of sixty-four compounds tested were able to prolong both lifespan and healthspan measures. Focusing on the use of female and male mice, and on comparing their outcomes, we found that 40% of studies only used male mice or did not clarify the sex. Notably, of the 36% of pharmacologic interventions that did use both male and female mice, 73% of these studies showed sex-specific outcomes on healthspan and/or lifespan. These data highlight the importance of studying both sexes in the search for geroprotectors, as the biology of aging is not the same in male and female mice. Systematic Review Registration: [website], identifier [registration number].
Insights
Research on aging interventions often overlooks sex differences. Many studies use only male mice, missing potential benefits for females, as aging biology differs between sexes.
Area of Science:
- Gerontology and Pharmacology
- Preclinical Research Methodologies
- Sex Differences in Aging
Background:
- The aging population is growing, increasing the burden of age-related diseases.
- Geroprotective interventions aim to extend lifespan and healthspan but often neglect sex differences.
- Compounds are frequently tested primarily in male animals, potentially overlooking benefits for females.
Approach:
- A systematic literature review following PRISMA guidelines was conducted.
- Seventy-two studies on geroprotective interventions were analyzed.
- Studies were categorized into five subclasses: FDA-repurposed drugs, novel small molecules, probiotics, traditional Chinese medicine, and dietary supplements.
Key Points:
- Twenty-two out of sixty-four compounds showed positive effects on both lifespan and healthspan.
- 40% of studies used only male or unspecified sex mice.
- Of studies using both sexes, 73% reported sex-specific outcomes on lifespan and/or healthspan.
Conclusions:
- Aging biology exhibits significant sex differences, impacting geroprotective intervention efficacy.
- Preclinical research must include both male and female subjects to ensure comprehensive understanding and development of geroprotectors.
- Future geroprotective drug discovery should prioritize sex-inclusive study designs.
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