Where and How in the mTOR Pathway Inhibitors Fight Aging: Rapamycin, Resveratrol, and Metformin

Abstract

The molecular mechanisms underlying the quality and quantity of life extension appear to sometimes be orthogonal. For example, while resveratrol has continued to prove beneficial in reducing obesity, it has had less efficacy in extending lifespan. On the other hand, rapamycin and the chemically similar rapalogs extend lifespan across genera of life from yeast, to nematodes, to mice. Caloric restriction (CR) and bioavailable small molecules, which mimic a fasted state, upregulate autophagy, catabolism of fats over anabolism of carbohydrates, and decrease oxidative stress and inflammation. CR mimics are currently being investigated to elucidate the best dosage, route of administration, timing in life, where best to inhibit in the mTOR pathway, and effects of long-term use on mTORC1 verse mTORC2 complexes. Comparisons between rapamycin, resveratrol, and metformin targets, downstream pathway effects, dosage, and clinical trials will be discussed.