Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity

Abstract

Maximum longevity (ML) varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of ML could to converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study is a comparative approach using heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot and mass spectrometry, respectively. Our results demonstrate 1) the existence of differences species-specific in gene expression and protein content of mTORC1; 2) that the achievement of a longevity phenotype requires decreased and inhibited mTORC1; 3) decreased content of mTORC1 activators in long-lived animals, and 4) independence of phylogeny relationships on these changes. Altogether, our findings support mTORC1 down-regulation to achieve a longevous phenotype.

The Lipidome Fingerprint of Longevity

“…Despite the importance of understanding the mechanisms involved in longevity, the existence and nature of the molecular mechanisms determining and controlling this biological trait remains unclear. Some mechanisms discovered from studies within and among animal species, but not exclusively, include oxidative stress-related pathways [ 4 , 5 ], insulin signaling pathways [ 6 , 7 , 8 , 9 ] and mechanistic targets of rapamycin pathway [ 10 , 11 , 12 , 13 ]. Notably, genetic, dietary and pharmacological manipulations targeting some of these pathways resulted in more than 10-fold longevity extension in the worm Caenorhabditis elegans [ 14 ], but only about 1.4-fold longevity extension in rodents [ 15 , 16 ].…”

Pharmacological Approaches to Decelerate Aging: A Promising Path

“…In addition to biosynthesis pathways and autophagy, mTOR pathways have regulatory roles in mRNA translation, endoplasmic reticulum stress, mitochondrial function, cell stem regulation, and immune and stress responses. Therefore, mTOR pathways are influential in many aging-related processes [ 100 , 102 ].…”

mTORC1 is also involved in longevity between species

“…Heart tissue of eight mammalian species differing in longevity by more than one order of magnitude -from 3.5 years in mice to 46 years in horses-was studied. The results demonstrated: i) the existence of species-specific differences in gene expression and protein content of mTORC1; ii) that long-lived phenotypes correlate with low concentration of mTORC1; iii) the presence of low concentrations of mTORC1 activators and high concentration of mTORC1 inhibitors in long-lived animals, and: iv) that these differences are independent of phylogeny [8]. These observations suggest that down-mTORC1 is also involved in longevity between species To the best of our knowledge, that investigation is the first comparative study of gene expression and amount of mTOR proteins and their regulators as a function of species longevity [8].…”

“…The results demonstrated: i) the existence of species-specific differences in gene expression and protein content of mTORC1; ii) that long-lived phenotypes correlate with low concentration of mTORC1; iii) the presence of low concentrations of mTORC1 activators and high concentration of mTORC1 inhibitors in long-lived animals, and: iv) that these differences are independent of phylogeny [8]. These observations suggest that down-mTORC1 is also involved in longevity between species To the best of our knowledge, that investigation is the first comparative study of gene expression and amount of mTOR proteins and their regulators as a function of species longevity [8]. The positive activators of mTORC1 downstream activity, mTOR, Raptor, arginine, methionine and the methionine-related metabolites, SAM and homocysteine, negatively correlated with longevity.…”

“…However, the possible existence of relevant differences in mTORC1 and its regulatory components between mammalian species with different longevities has never been investigated. In a recent study [8], we used droplet digital PCR (ddPCR) and western blot methods to measure the steady-state levels of gene expression and protein content of the mTORC1 complex and its regulators in mammalian species with different longevities. Targeted metabolomics was also applied to measure the concentration of mTORC1 activators.…”