Scientists in the Intervention Testing Program have found that the antioxidant astaxanthin and the seasickness medication meclizine, both sold over the counter, significantly extend median lifespan in mice [1].
Astaxanthin and meclizine are in, but fisetin is out
The Intervention Testing Program (ITP) has existed for about 20 years, and it is considered the gold standard for testing longevity interventions in mice for good reasons. First, ITP uses genetically heterogeneous HET3 mice rather than the inbred strains that are usually used in studies. Second, it uses a lot of those mice, which ensures considerable statistical power. Finally, the studies are run in three research centers simultaneously, with conditions meticulously replicated in order to increase overall reliability.
The ITP’s first major success came in the late 2000s, when rapamycin was found to substantially extend lifespan in mice even if given later in life [2]. Since then, while a hundred molecules have been tested, only three of them have produced significant increases in lifespan: acarbose, canagliflozine, and 17α-estradiol. There have also been some notable failures, such as with resveratrol and metformin. You can learn more about the program’s workings from our interview with one of its leaders, Prof. Richard Miller.
Any new data coming out of the ITP is met with excitement and anticipation. Earlier this month, in a new paper, the researchers announced that two more compounds were found to significantly increase mouse lifespan: astaxanthin and meclizine. The former increased the median lifespan by 12%, and the latter increased it by 8%. Unfortunately, both seemed to work only in males. Five more molecules, fisetin, SG1002 (a hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate, failed to produce statistically significant results.
Who are the winners?
Excitingly, both astaxanthin and meclizine are over-the-counter compounds and the first ones to be found effective by the ITP. Astaxanthin is a naturally occurring antioxidant and inflammation modulator. It belongs to the carotenoid family of molecules and gives salmon its pink color. Algae, yeast, trout, krill, shrimp, and crayfish also contain it. Algae are the original source, and the astaxanthin they contain is passed up the food chain. Astaxanthin has an excellent safety profile and is widely available as a supplement.
Meclizine has been in use for decades against seasickness and vertigo and as an antihistamine. Recently, it was found to inhibit the protein complex mTORC1 [3]. Rapamycin, the best-known geroprotective molecule, is a potent inhibitor of mTORC1 as well. However, it also inhibits a closely related protein complex, mTORC2, which can be harmful and accounts for rapamycin’s questionable safety profile. Meclizine, on the other hand, seems to act exclusively on mTORC1.
However, as Richard Miller explained in his recent appearance on Peter Attia’s podcast, the researchers were unable to prove that the lifespan extension produced by meclizine was due to mTORC1 inhibition. Meclizine’s benefits for the central nervous system could be an alternative explanation.
Sex specificity and fisetin’s failure
Both molecules were given to mice in relatively high doses, which might pose a problem for translation into humans, but this remains to be seen. As to the sex specificity, there is nothing new about it: all four molecules that were successful in the ITP work either only in one sex or better in one sex than in the other.
One of the possible reasons is the observed sex-related differences in the drug’s blood concentration. For instance, rapamycin works better in females, and in the ITP experiments, females had higher concentrations of rapamycin in the blood. For astaxanthin and meclizine, the concentration was higher in males. Hence, it might be possible to achieve an effect in females by adjusting dosage.
Among the failed compounds, fisetin deserves a special mention. This naturally occurring polyphenol has been touted as a reasonably potent senolytic, a drug that removes senescent cells. Fisetin has shown some effectiveness in animal models, even causing lifespan and healthspan extension in wild-type mice [4], which led to its acceptance into the ITP. Interestingly, the drug was unable not only to extend lifespan but even to remove senescent cells, according to the popular senescence marker p16. Here, too, the problem might be with the dosage, meaning that fisetin’s ITP “career” is not necessarily over.
Literature
[1] Harrison, D. E., Strong, R., Reifsnyder, P., Rosenthal, N., Korstanje, R., Fernandez, E., … & Miller, R. A. (2023). Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. GeroScience, 1-22.
[2] Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., … & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395.
[3] Allen, S. A., Tomilov, A., & Cortopassi, G. A. (2018). Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochemical pharmacology, 155, 298-304.
[4] Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., … & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28.
