mTOR

The mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. ^[1] Over more than two decades of research, mTOR has been established as a central regulator of many fundamental cell processes, from protein synthesis to autophagy, and its deregulated signaling is implicated in the progression of cancer, diabetes, and the aging process. ^[1] mTOR forms two structurally and functionally distinct multi-subunit complexes, mTOR complex 1 (mTORC1), which is sensitive to rapamycin, and mTOR complex 2 (mTORC2), which is not directly inhibited by the drug. ^[2]

As part of mTORC1, mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. ^[3] mTOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. ^[4] The lysosome senses nutrient availability through its physical and functional association with mTORC1, and in response the MiT/TFE transcription factors exert feedback regulation on lysosome biogenesis. ^[5] mTOR also plays a crucial role in regulating autophagy, and its inhibition relieves the suppression of this catabolic recycling program. ^[6] The two complexes have a common catalytic subunit yet phosphorylate distinct substrates, with the most well-characterized mTORC2 substrates including Akt, PKC, and SGK, which are members of the AGC protein kinase family. ^{[7] [4]}

Given the pathway's central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signaling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. ^[8] Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, and different forms of fasting and amino acid restriction selectively impact the activity of mTOR among the key nutrient-sensing geroprotective signalling pathways that promote healthy longevity. ^[9] Inhibition of the protein kinase mTOR with the FDA-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. ^[10]

Specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies, and recent clinical trials have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. ^[10] Among calorie-restriction mimetics, rapamycin acts as an inhibitor of mTOR while metformin activates AMP-activated protein kinase, both operating as pharmaceutical anti-aging strategies alongside lifestyle options such as fasting and fasting-mimicking diets. ^[11] mTORC1 inhibitors are being evaluated in various aging-associated metabolic diseases, and current work aims at safer and more selective inhibition of the complex in clinical settings. ^[12]