TOR‐mediated regulation of metabolism in aging

Abstract

SummaryCellular metabolism is regulated by the mTOR kinase, a key component of the molecular nutrient sensor pathway that plays a central role in cellular survival and aging. The mTOR pathway promotes protein and lipid synthesis and inhibits autophagy, a process known for its contribution to longevity in several model organisms. The nutrient‐sensing pathway is regulated at the lysosomal membrane by a number of proteins for which deficiency triggers widespread aging phenotypes in tested animal models. In response to environmental cues, this recently discovered lysosomal nutrient‐sensing complex regulates autophagy transcriptionally through conserved factors, such as the transcription factors TFEB and FOXO, associated with lifespan extension. This key metabolic pathway strongly depends on nucleocytoplasmic compartmentalization, a cellular phenomenon gradually lost during aging. In this review, we discuss the current progress in understanding the contribution of mTOR‐regulating factors to autophagy and longevity. Furthermore, we review research on the regulation of metabolism conducted in multiple aging models, including Caenorhabditis elegans, Drosophila and mouse, and human iPSCs. We suggest that conserved molecular pathways have the strongest potential for the development of new avenues for treatment of age‐related diseases.

The Aging Metabolome—Biomarkers to Hub Metabolites

“…Changes in nutritional and epigenetic state are integral to aging. This can be judged by the central role of the mTOR pathway [ 9,10 ] and histone/DNA methylation [ 58,59 ] in organismal aging. αKG has emerged as master regulatory metabolite in aging biology as it is a key TCA intermediate, a cofactor for numerous transamination reactions, [ 60,61 ] a cofactor for the prolyl hydroxylase dependent hydroxylation of the transcription factor hypoxia inducible factor‐1 (HIF‐1) [ 62–64 ] and a cofactor for epigenetic enzymes, histone, and DNA demethylases.…”

Maf1 phenotypes and cell physiology

“…This line of inquiry was prompted by the knowledge that treatments known to extend lifespan in various organisms (e.g. TOR inhibition and calorie restriction) lead to Maf1-dependent repression [11,14,43] while deletion of Maf1 in yeast reduces chronological lifespan [42,44]. The tm6082 allele removes the phylogenetically conserved box C region, including three of the four β-sheets that make up the central core of Maf1 along with additional sequences (a total of 79 amino acids) and introduces 37 different amino acids in their place [42,45,46].…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…On the contrary, mTORC2 mainly serves to control cell survival and proliferation, via activating the Akt pathway (Zoncu, Efeyan & Sabatini, 2011). On the basis of its pro‐anabolic capability and central role in governing metabolic homeostasis, numerous evidence has demonstrated that inhibition of mTOR activity could lead to extended lifespan among mammalian species, implying a direct link between mTOR pathway and aging (Antikainen, Driscoll, Haspel, & Dobrowolski, 2017). Regarding the pathophysiological association between aging and Alzheimer's disease, the impact of mTOR in Alzheimer's disease has therefore been extensively investigated.…”