Question

How important (quantitatively) is variation in genes affecting the Tor pathway to human longevity?

Please support answer with citations of studies

Answer 1

mTOR research started in 1970s with yeast and Rapamycin (identified from Streptomyces bacteria). Till now very few population studies have been completed. SNPs may play vital role in mTOR pathway and its other regulating and interdependent genes. For latest literature update you may read review by Kennedy BK et.al., www.cell.com/cell-metabolism/pdf/S1550-4131%2816%2930227-3.pdf , One more latest review from M. Kaeberlein http://journals.sagepub.com/doi/10.1177/0300985815591082

Harries LW etal studied the expression of mTOR-related transcripts in two populations InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). Expression of 27/56 (InCHIANTI) and 19/44 (SAFHS) genes were associated with age after correction for multiple testing. 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets. They conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals.

Marc Francaux et al., (Nutrients 2016, 8(1), 47) studied understand the molecular mechanisms involved in the anabolic resistance observed in elderly people. Nine young (22 ± 0.1 years) and 10 older (69 ± 1.7 years) volunteers performed a one-leg extension exercise consisting of 10 × 10 repetitions at 70% of their 3-RM, immediately after which they ingested 30 g of whey protein. Muscle biopsies were taken from the vastus lateralis at rest in the fasted state and 30 min after protein ingestion in the non-exercised (Pro) and exercised (Pro+ex) legs. Plasma insulin levels were determined at the same time points. No age difference was measured in fasting insulin levels but the older subjects had a 50% higher concentration than the young subjects in the fed state (p < 0.05). While no difference was observed in the fasted state, in response to exercise and protein ingestion, the phosphorylation state of PKB (p < 0.05 in Pro and Pro+ex) and S6K1 (p = 0.059 in Pro; p = 0.066 in Pro+ex) was lower in the older subjects compared with the young subjects. After Pro+ex, REDD1 expression tended to be higher (p = 0.087) in the older group while AMPK phosphorylation was not modified by any condition. In conclusion, they showed that the activation of the mTORC1 pathway is reduced in skeletal muscle of older subjects after resistance exercise and protein ingestion compared with young subjects, which could be partially due to an increased expression of REDD1 and an impaired anabolic sensitivity.

In one of the quantitative statistical studies rapamycin (mTOR) pathway genes (genes MTOR, RPTOR, and RICTOR and the important downstream effector gene RPS6KA1 for association with human longevityas well as health span phenotypes) of humans by Brian J. Morris et.al., (J Gerontol A Biol Sci Med Sci. 2015 Feb; 70(2): 133–142). This group of researchers found no association of 6 tagging single-nucleotide polymorphisms for MTOR, 61 for RPTOR, 7 for RICTOR, or 5 for RPS6KA1 with longevity. Of 40 aging-related phenotypes, no significant association with genotype was seen. Thus common genetic variation (minor allele frequency ?10%) in MTOR, RPTOR, RICTOR, and RPS6KA1 is not associated with extreme old age or aging phenotypes in this population.

Mannick JB et.al studied the effect of Everolimus (RAD001) (40-O-(2-hydroxyethyl) derivative of sirolimus acts as an inhibitor of mammalian target of rapamycin (mTOR) Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species. In the selected 65 year old volunteers RAD001 significantly enhanced the response to the influenza vaccine by about 20%. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. mTOR inhibition may have beneficial effects on immunosenescence in the elderly, which should indirectly extend the life span of elders.