The Role of mTOR Signaling in Controlling Mammalian Life Span: What a Fungicide Teaches Us About Longevity

Extract

OPENING STATEMENT

Encouraging results with rapamycin suggest that the mammalian target of rapamycin (mTOR) is a promising pharmacological target for prolongevity intervention in mammals. In theory, such an approach mimics food, energy, and/or growth factor restriction, both of which have proven to be effective in animal models but are not practical for people interested in maximizing the healthy years of their life. In a recent mouse survival study conducted by the National Institute of Aging Intervention Testing Program (ITP) (1), mice were treated with rapamycin starting at late middle-aged (∼60 human years). In contrast to food restriction, which has variable, sometimes detrimental, effects in mice when initiated at an advanced age, rapamycin was effective in extending life span of genetically heterogeneous mice when treatment was begun in late life.

HOW A FUNGICIDE BECAME A POTENTIAL EXTENDER OF MAMMALIAN LIFE SPAN

Camardo has provided an excellent review of the early history of rapamycin (2). The story starts at Ayerst in Montreal, where scientists in the 1970s identified a macrocyclic lactone in a soil sample collected from Rapa Nui (Easter Island). Its original name was rapamycin after the source of the soil and was later designated as sirolimus, which is used in the medical literature. Rapamycin is a metabolite produced by Streptomyces hygroscopicus, a bacterium in the soil, and was first developed as an antifungal agent. Later, it was found to have immunosuppressive effects, which halted its potential use as an antifungal. Antitumor activity was first noted in 1975, but was not actively pursued by Wyeth Ayerst until 1997. Although it failed as a fungicide, rapamycin analogs (rapalogs) are used as an adjunctive therapy in clinics today to prevent host rejection in transplants, as a monotherapy for cancer treatments, and in drug-eluting stents to prevent restenosis of cardiac vessels. Because of the interesting and important effects it has on cells and organisms, much study has been devoted toward understanding its mode of action.