Sex as a major determinant of pro-longevity drug efficacy: a review of two decades of the NIA Interventions Testing Program

Aging is the primary risk factor for frailty, sarcopenia, and functional decline, as well as cancer, cardiovascular and neurodegenerative diseases. Gaining insight into the biological mechanisms of aging could lead to interventions that broadly reduce age-related morbidity and mortality. To identify interventions that extend lifespan and delay aging, the National Institute on Aging launched the Interventions Testing Program (ITP) in 2004. This multi-site effort uses genetically heterogeneous UM-HET3 mice to evaluate the effects of candidate compounds. Over the past two decades, the ITP has tested 54 agents in more than 30, 000 mice. This is the first comprehensive review of the program's results, with particular emphasis on a striking pattern of sex-specific responses. By presenting the full scope of the findings, readers can better understand the overall impact of the program and easily access detailed information on specific drugs of interest. Notably, most compounds that extended lifespan were effective primarily or exclusively in male mice. Dosage and age of treatment onset influenced efficacy and were also sexually dimorphic. These sex differences suggest that mechanisms of aging are sexually dimorphic and highlight the importance of recognizing biological sex as a modifier of treatment efficacy. Investigating the basis for these differences should enable more targeted and effective geroprotective strategies for both sexes.