Bench to bedside: is rapamycin headed for the docTOR?

Almost a century ago, calorie restriction (CR) was identified as a robust intervention for extending lifespan and healthspan, a discovery that captured the imagination of both scientists and the public. If the powerful mechanisms engaged by CR can be uncovered and harnessed through a pill, humans might be able to live longer and healthier lives. Here, we will discuss the evolution of rapamycin, an inhibitor of the mTOR (mechanistic Target Of Rapamycin) protein kinase, from an immunosuppressant to the most reproducible pharmacological geroprotector in geroscience. This is a rapidly evolving field, with the number of basic science studies, clinical trials, and off-label use of mTOR inhibitors by the general public expanding quickly. We review findings in model organisms that have revealed potent benefits of rapamycin not only for longevity but for the function of multiple organ systems and on the hallmarks of aging. We review completed and ongoing clinical trials of rapamycin and analogs for diseases of aging in humans, and discuss the challenges and side-effects of rapamycin that may limit its translation from the laboratory to the clinic. While the jury is still out, we conclude that rapamycin-or molecules that similarly act to inhibit mTOR-may yet realize the century-old dream of extending healthspan and lifespan with a small molecule.