Mammalian Target of Rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental stimuli, including nutrients and growth factors. Extensive research during the last few decades has attributed a crucial role to the mTOR pathway in the regulation of fundamental cellular processes, such as anabolism, autophagy, immune response, and oxidative stress, and have demonstrated that dysregulated mTOR signalling is implicated in cancer progression and ageing. mTOR is a serine/threonine protein kinase belonging to the phosphatidylinositol kinase-related kinase (PIKK) family, which participates in two distinct protein complexes, known as mTORC1 and mTORC2. Increasing evidence suggests that mTORC1 plays a fundamental role in mitochondrial regulation and turnover through the positive modulation ERR-α and PGC1-α transcriptional target programmes and 4E-BP-dependent translational regulation, resulting in increased oxidative phosphorylation and mitochondrial ROS production. Blunted mRNA translation during mTORC1 inhibition delays ageing by reducing oxidative and proteostatic stress sources, consistent with the observation that loss of the mTORC1 substrate S6K1 also extends life span in mammals. A plausible scenario is that inhibition of mTORC1 slows ageing by increasing autophagy, which helps clear damaged proteins and mitochondria, the accumulation of which is also associated with increased oxidative stress and ageing-related diseases, including cancer. mTORC2 also integrates inputs from growth/proliferation control networks, cytoskeletal dynamics, lipid metabolism, and proteostasis (chaperone-mediated autophagy, UPR); however, the specific contribution of this signalling node to ageing and disease remains comparatively less explored.

Therapeutic intervention of the mTOR pathway can prolong lifespan in several organisms and confers protection against most major age-related diseases. Several drugs, including sirolimus and everolimus, are already clinically approved and currently used in different settings, and others are under development. Although the presence of side effects currently precludes their use in otherwise healthy individuals, mTOR inhibitors might become widely used to slow aging and reduce age-related diseases.

In this Special Issue, we invite researchers to contribute original research articles discussing novel cellular and molecular mechanisms mediated by the mTOR pathway in ROS regulation, immune response and autophagy control, and their role in cancer biology and ageing. Studies characterizing the specific crosstalk between mTOR and other signalling pathways (e.g., AMPK, PI3K/AKT) and emerging stress adaptation mechanisms (stress granule assembly, Unfolded Protein Responses) are particularly encouraged. Review articles describing the current state of the art are also welcome.

Potential topics include but are not limited to the following:

• Role of mTORC1 and mTORC2 regulation in cancer biology, chemoresistance, and ageing and molecular underpinnings thereof
• Molecular basis of the interplay between ROS control, autophagy, mitophagy, and metabolic dysfunction in cancer cells: from mTOR and AKT signalling pathways to functional impact
• Role of mTOR-driven ageing
• Role of mTOR in mitochondria biology, interorganelle communication, and organelle homeostasis
• Innovative therapeutic approaches aimed at counteracting and normalizing the mTOR pathway in cancer cells: from nanotechnology to tailored medicine