Chronic mechanistic target of rapamycin inhibition: Preventing cancer to delay aging or vice versa?

Abstract

Caloric restriction prolongs lifespan and healthspan in all model systems tested so far, including yeasts, worms, flies, mice, rats, and monkeys (Rhesus macaques). Caloric restriction also improves healthspan, including reducing cancer development in mice and Rhesus macaques. Nonetheless, chronic caloric restriction to prolong life or healthspan, including cancer prevention, is unlikely to be popular or widely adopted for human clinical use. As caloric restriction inhibits mTOR, the pharmacologic mTOR inhibitor, rapamycin, was tested in lifespan extension and clearly prolonged lifespan and healthspan in mice even when started late in life. Although the types and prevalence of cancer in control and rapamycin-fed mice were similar, cancer-related deaths were delayed in mice fed rapamycin, demonstrating potential cancer prevention. Rapamycin and related pharmacologic mTOR inhibitors, collective dubbed “rapalogues,” are considered too dangerous for chronic human use for longevity extension or cancer prevention. Nonetheless, these data raise the interesting possibility that a pharmacologic intervention to suppress mTOR, or more specifically mTORC1, could prolong lifespan or healthspan in humans, including through cancer prevention, provided that a safe and effective agent for these purposes were identified. Many questions remain, including the specific mTOR-related pathway most appropriate for targeting, doses and schedules of specific agents for such purposes, and understanding specific mechanisms of action. The question arises as to whether rapalogues prolong life or delay aspects of aging by preventing cancer. This chapter will examine evidence to date and provide suggestions for major areas of needed research and possibilities for clinical trials and applications.