The Journal Club returned for a Halloween special, and Dr. Oliver Medvedik looked at a recent paper showing that a combination of three drugs had a synergistic effect and increased lifespan greatly in fruit flies. The drugs all target parts of the nutrient sensing system, which controls metabolism, and its deregulation is proposed to be one of the reasons we age and can develop diseases like diabetes as we get older.
Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging. We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in Drosophila. Remarkably, the triple drug combination increased lifespan by 48%. Furthermore, the combination of lithium with rapamycin cancelled the latter’s effects on lipid metabolism. In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health.
Castillo-Quan, J. I., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., … & Partridge, L. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. Proceedings of the National Academy of Sciences, 116(42), 20817-20819.