MTOR

The MTOR kinase belongs to the target of rapamycin group of enzymes which regulate cellular growth and proliferation. TOR enzymes, homologues of MTOR, have been linked to ageing in lower organisms. In yeast, deletions in the nutrient-responsive TOR pathway increased lifespan, and caloric restriction failed to further increase lifespan. Similarly, in roundworms, TOR deficiency more than doubled the lifespan, and TOR disruption in fruit flies also extended lifespan. In invertebrates, a functional link between MTOR and insulin (INS)/IGF1 signalling has been proposed, which further hints of a role for MTOR in ageing. Mice hypomorphic for mTOR have reduced mTORC1 expression, are smaller and live 20% longer. Female mice heterozygous for both mTOR and mLST8 also exhibit decreased mTORC1 activity and extended life span but have normal glucose tolerance and insulin sensitivity. While rapamycin also disrupts the mTORC2 complex, the lifespan extension is mediated through the mTORC1 complex. MTORC1 activity is reduced in the tissues of three long lived mice mutants: Snell dwarf mice (POU1F1 mutants), GHR knockout mice and PAPPA knock-out mice. In GHR knockout mice mTORC2 signalling is upregulated. Treating GHR knockout mice with rapamycin causes no further downregulation of mTORC1 but does interfere with mTORC2 and disrupts whole body homoeostasis. There, mTORC1 and mTORC2 play different roles in the ageing process. In human cell cultures MTOR inhibition supresses the senescence associated secretory phenotype (SASP), which can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR normally acts to regulate the SASP by promoting IL1A translation, which in turn promotes NFKB1 transcriptional activity. More work is needed to determine whether MTOR is associated with human ageing but it is a promising target for further research.