How do scientists decide which interventions are worth testing in humans for potential health- and/or lifespan benefits?

One way to start is to examine how interventions perform in model organisms such as mice. The Interventions Testing Program (ITP), a federally-funded initiative that began in 2002, tests drugs that may delay mouse aging, with the hope of eventually identifying new longevity interventions for humans. The program aims to take an unbiased approach to interventions testing as possible and to make all data publicly available.

In this episode, Matt goes over recent ITP tests of a broad range of interventions that includes a vasodilator, a beta-blocker, a drug to reverse cyanide poisoning, and more. The drugs are alpha-ketoglutarate, 2,4-dinitrophenol, hydralazine, nebivolol, 16α-hydroxyestriol, sodium thiosulfate, and canagliflozin. He discusses which of these interventions produces lifespan benefits in mice, gender differences in effects, results from previous studies of the interventions, and the importance of examining the life expectancy of controls when evaluating the results of lifespan experiments.

Matt has served on the ITP steering committee since 2012.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

This is the paper Matt discusses in this podcast episode. Researchers tested the effects of seven drugs—alpha-ketoglutarate, 2,4-dinitrophenol, hydralazine, nebivolol, 16α-hydroxyestriol, sodium thiosulfate, and canagliflozin—on mice. 16α-hydroxyestriol significantly increased male mouse lifespan, but decreased female mouse lifespan. Canagliflozin also increased male mouse lifespan and decreased female mouse lifespan when mice received it in later life. The other drugs produced no lifespan effects on mice.

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience

Matt often mentions the importance of accounting for the lifespan of controls—a standard or baseline group of animals that researchers use to compare with the group that receives the treatment or intervention being tested—when evaluating geroscience experiments. This paper elaborates on why short-lived controls in mouse experiments can cause researchers to report exaggerated longevity effects of a given intervention. It also suggests ensuring a control mouse lifespan of around 900 days to ensure legitimacy of results.

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

This study laid some of the groundwork for the investigation of alpha-ketoglutarate in the Interventions Testing Program. Researchers found that alpha-ketoglutarate reduced chronic inflammation and extended health- and lifespan in mice without inducing any significant adverse effects.

Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test

Rejuvant is a sustained release alpha-ketoglutarate supplement that describes itself as "the first patented, science-backed longevity supplement that reduces biological age and gives you the focused energy you need today". This study reports an eight-year decrease in biological aging as measured by DNA methylation clocks after an average of seven months of Rejuvant supplementation. One of the study's coauthors is a Rejuvant scientific consultant.

Canagliflozin extends life span in genetically heterogeneous male but not female mice

This study reports the first Interventions Testing Program experiment with canagliflozin, a drug use to treat type 2 diabetes and to reduce the risk of several other diseases in people with type 2 diabetes. Male mice that started taking canagliflozin from a young age until their deaths experienced a median lifespan extension of 14 percent. The age for 90th percentile survival also increased by nine percent in male mice. Female mice did not experience similar benefits from taking the drug.