Rapamycin / mTOR inhibition

Based on the provided literature, the mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase and a major effector of cell growth, proliferation, and protein synthesis regulation [2, 4]. The consensus across multiple model organisms shows that targeting this pathway with rapamycin extends lifespan, including in genetically heterogeneous mice when administered late in life [3, 8], and attenuates age-related pathologies such as atrial remodeling and fibrillation [9]. At the cellular level, rapamycin-mediated inhibition modulates autophagy and metabolic regulation [1, 9].

Despite its efficacy in lifespan extension, a notable physiological paradox exists: while interventions like calorie restriction improve insulin sensitivity via mTOR inhibition, chronic rapamycin administration paradoxically impairs glucose tolerance and insulin action [8]. Evidence demonstrates that this rapamycin-induced insulin resistance is specifically mediated by the disruption and loss of mTORC2, and importantly, it is uncoupled from the drug's longevity-promoting effects [8].