Is Rapamycin a Dietary Restriction Mimetic?

Abstract Since the initial suggestion that rapamycin, an inhibitor of target of rapamycin (TOR) nutrient signaling, increased lifespan comparable to dietary restriction, investigators have viewed rapamycin as a potential dietary restriction mimetic. Both dietary restriction and rapamycin increase lifespan across a wide range of evolutionarily diverse species (including yeast, Caenorhabditis elegans, Drosophila, and mice) as well as reducing pathology and improving physiological functions that decline with age in mice. The purpose of this article is to review the research comparing the effect of dietary restriction and rapamycin in mice. The current data show that dietary restriction and rapamycin have different effects on many pathways and molecular processes. In addition, these interventions affect the lifespan of many genetically manipulated mouse models differently. In other words, while dietary restriction and rapamycin may have similar effects on some pathways and processes; overall, they affect many pathways/processes quite differently. Therefore, rapamycin is likely not a true dietary restriction mimetic. Rather dietary restriction and rapamycin appear to be increasing lifespan and retarding aging largely through different mechanisms/pathways, suggesting that a combination of dietary restriction and rapamycin will have a greater effect on lifespan than either manipulation alone.