Study finds rapamycin shows greatest longevity effect in 20-year NIH Interventions Testing Program
The first comprehensive review of two decades of research from the National Institute on Aging’s Interventions Testing Program highlights 13 interventions that show promise in preclinical studies for significantly extending lifespan and improving healthspan.
Aging is the major risk factor for most chronic diseases including cancer, cardiovascular disease, neurodegenerative disease and metabolic disorders. Extending healthspan — how long we live without serious disabilities or disease — is a central goal of modern aging research.
Breakthrough of rapamycin
A landmark publication in the July 2025 issue of the Journal of Gerontology: Biological Science , is the first comprehensive review of the ITP’s discoveries using genetically heterogeneous mice. The paper’s first author, Nisi Jiang, PhD, who recently graduated from Nelson’s lab, conducted much of the analysis and proposed the idea to compile the landmark review.
The review found that the most effective compound tested through the ITP so far is rapamycin. Rapamycin was chosen because it inhibits the mammalian target of rapamycin (mTOR), a key protein that integrates signals from nutrients and hormones to regulate whether cells prioritize growth or shift toward repair and maintenance. Overactivation of mTOR has been linked to aging and age-related diseases.
“Scientists are beginning to understand that too much emphasis on growth comes at the expense of repair and maintenance,” Nelson said.
Rapamycin was first discovered in the 1960s, after it was isolated from bacteria found in the soil at Easter Island. It was discovered to suppress the mTOR pathway, thereby shunting energy from growth to maintenance. Rapamycin was first highlighted as a potential longevity drug by the Interventions Testing Program. The compound extended the lifespan of animal models by up to 28%, even when delivered in middle age or later in life. Ideally, drugs that extend lifespan would be effective late in life, not something you have to take your entire life,” Nelson said.
Looking ahead
All the ITP’s studies are published, and the data are freely available, hopefully encouraging further investigation and validation of compounds by the broader scientific community.
Nelson noted a surge in interest surrounding longevity and aging research in recent years. In the past three years, the ITP went from an average of four annual proposals to more than 28. Nelson said he’s also seen a significant uptick in PhD candidates entering the field of biology of aging research.
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.
Read the full open access paper:
Sex as a major determinant of pro-longevity drug efficacy: a review of two decades of the NIA Interventions Testing Program
https://academic.oup.com/biomedgerontology/article/80/8/glaf138/8213622
