MTOR and Aging: An Old Fashioned Dress.

Giovanni Stallone,Giuseppe Grandaliano,Concetta Prisciandaro,Barbara Infante

doi:10.3390/ijms20112774

Giovanni Stallone, Giuseppe Grandaliano + Show 2 more

Open Access

https://doi.org/10.3390/ijms20112774

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Abstract

Aging is a physiologic/pathologic process characterized by a progressive impairment of cellular functions, supported by the alterations of several molecular pathways, leading to an increased cell susceptibility to injury. This deterioration is the primary risk factor for several major human pathologies. Numerous cellular processes, including genomic instability, telomere erosion, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular signal transduction represent common denominators of aging in different organisms. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the hypothesis that the mTOR signalling network plays a pivotal role in modulating aging. mTOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction, which has been shown to extend lifespan and slow the onset of age-related diseases across species. Herein we discuss the role of mTor signalling network in the development of classic age-related diseases, focused on cardiovascular system, immune response, and cancer.

Highlights

Aging is a time-dependent physiological functional decline that affects most living organisms, supported by alterations of several molecular pathways, and represents the most profound risk factor for many non-communicable diseases [1].Several studies suggest that aging should be defined as a disease [2,3,4,5]
In conditions characterized by increased reactive oxygen species (ROS) production, the Nuclear factor erythroid-related factor 2 (Nrf-2) activity might be inhibited with a subsequent ROS-induced rise in TNF-α levels, which in turn can up regulate NADPH oxidase (Nox) complex expression and activity, generating a vicious cycle [22]
This process is instrumental in the recycling of organelles, including mitochondria, endoplasmic reticulum, and peroxisomes. Mammalian target of rapamycin (mTOR) is well-known to inhibit autophagy, promoting the accumulation of protein aggregates and degenerated mitochondria leading to a deep dysregulation of mitochondrial functions

Summary

Introduction

Aging is a time-dependent physiological functional decline that affects most living organisms, supported by alterations of several molecular pathways, and represents the most profound risk factor for many non-communicable diseases [1]. Several cellular processes, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular-communication, represent common denominators of aging in different organisms In this scenario Mammalian target of rapamycin (mTOR) has been suggested to play a pivotal role [10]. Selman et al observed that mice lacking S6 kinase, one of the main targets of mTORC1 and one of the key enzyme regulating protein translation, present a prolonged lifespan along with an increased activity of AMPK [19]. This observation resembles what was observed in the caloric-restriction-induced extension of lifespan. In cells with hyperactive mTORC1 signalling, the consequent increase of elongation speed is accompanied by a significant alteration of protein folding [20]

Mitochondrial and Oxidative Stress

Inflammation

Autophagy

Cellular Senescence

11. Conclusions