Should rapamycin be prescribed ubiquitously as an anti-aging supplement? That is the question the authors of this commentary ask after a short overview of what is known of the beneficial effects of rapamycin on mechanisms relevant to aging. Research into inhibition of the two mTOR complexes, mTORC1 and mTORC2, via compounds such as rapamycin, is well funded at the present time. Numerous companies are attempting to push mTOR inhibitors through clinical trials. It is perhaps the largest outgrowth of research into the slowing of aging produced by the practice of calorie restriction, in which benefits are largely mediated by an increased efficiency of the cellular housekeeping processes of autophagy. The question at the end of the day is whether the effect sizes here are large enough to chase hard, in comparison to those that can be obtained via exercise or calorie restriction, given that we know that exercise and calorie restriction have only a limited effect on the shape of human aging. We should aim higher.
mTOR (mammalian target of rapamycin) plays a significant role in age-related stem cell dysfunction through various mechanisms highlighting its potential as an anti-aging target to rejuvenate stem cell function. In fact, mTOR regulates many of the hallmarks of aging. A breakthrough study in 2009 showing the lifespan extending properties of rapamycin in genetically heterogenous mice led to significant research into rapamycin as an anti-aging intervention. Since that time, rapamycin has been well studied in aging and age-related functional decline mainly through the modulation of autophagy, mitochondrial function, insulin signaling, and senescence.
TOR is a heavily conserved serine/threonine kinase with homologues in several eukaryotes from yeast to humans, highlighting its importance in cellular processes. The mammalian version, mTOR exists as two distinct complexes, mTOR1 and mTOR2 that are structurally and functionally different. The mTOR1 complex acts as a central nutrient sensor and regulator of cell proliferation, growth, and survival. mTOR2 activity is usually preserved during acute rapamycin treatment but prolonged exposure can reduce mTOR2 activity as well. Hyperactive mTOR activity with aging seems to have deleterious consequences in somatic stem cells, especially muscle-derived stem cells.
Rapamycin and other compounds have been demonstrated to have significant senotherapeutic effects (i.e. selective ability to restore or eliminate senescent cells). Not only has rapamycin has been demonstrated to reduce senescence in muscle-derived stem cells by our group, but others have demonstrated that blocking mTOR reduces stem cell senescence and associated secretory phenotypes.
Should rapamycin be prescribed ubiquitously as an anti-aging supplement? There is certainly a preponderance of evidence demonstrating the safety of rapamycin in healthy and aged humans that has been well reviewed. Since its approval in 1999 by the FDA, rapamycin has been used by millions of patients with very few mild but reversible side effects. However, one possible strategy is likely intermittent treatment at higher doses for prolonged periods of time. We additionally propose that a combinatorial approach may be in order to target senescence at multiple nodes (inhibition of anti-apoptotic pathways and mTOR) directly through the use of multiple senotherapeutic agents such as fisetin and rapamycin. Overall, the plethora of preclinical and clinical data using rapamycin strongly suggests that targeting mTOR and/or senescence is a promising therapeutic strategy to mitigate aging-related phenotypes and restore stem cell health and function.