Unlocking the aging brain: mTORC1 as a convergent integrator for neurodegeneration and therapeutic intervention

Aging is the primary risk factor for neurodegenerative diseases, characterized by a progressive decline in cellular homeostasis. Central to this process is the mammalian target of rapamycin complex 1 (mTORC1), a convergent integrator regulator of metabolism that integrates nutrient sensing with cellular growth. While essential for development, chronic mTORC1 hyperactivity, termed mTORopathy, emerges during aging, driving a deleterious cycle of mitochondrial dysfunction, neuroinflammation, and impaired protein clearance. This pathological state promotes the accumulation of toxic proteins, such as amyloid-beta, tau, and alpha-synuclein, while simultaneously suppressing autophagy and glymphatic function. Furthermore, mTORC1 overactivation in glial cells fuels inflammaging by inducing cellular senescence and the senescence-associated secretory phenotype (SASP), which compromises blood-brain barrier integrity and synaptic plasticity. Conversely, pharmacological inhibition of mTORC1 using rapamycin or its analogs (rapalogs) has demonstrated significant neuroprotective potential. By restoring autophagic flux, rebalancing metabolic axes (AMPK/SIRT1), and suppressing chronic inflammation, these compounds can rescue synaptic function and reactivate neurogenesis. This review synthesizes current evidence regarding mTORC1 as a convergent integrator for brain aging and evaluates the clinical prospects of mTOR-targeted therapies in mitigating neurodegenerative decline.