The role of mTOR in age-related diseases

Chrienová, Žofia; Nepovimová, Eugenie; Kuča, Kamil

doi:10.1080/14756366.2021.1955873

Cited by 45 publications

(28 citation statements)

References 245 publications

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“…Stresses linked to hallmarks of aging (see mTORC1 and Age-Related Stressors ) impinge on mTORC1 activity and SG formation (see SGs and mTORC1 Signaling ). Conversely, enhanced mTORC1 signaling ( Papadopoli et al, 2019 ) and SG formation ( Cao et al, 2020 ) have been linked to age-related processes, and MTOR and SG levels often correlate with the severity of age-related diseases ( Papadopoli et al, 2019 ; Liu and Sabatini, 2020 ; Chrienova et al, 2021 ). However, the crosstalk between mTORC1 and SG formation in the context of aging progression is poorly explored.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases

et al. 2021

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The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks such as mitochondrial malfunction, loss of proteostasis, genomic instability and telomere shortening impinge on mTORC1 thereby contributing to age-related processes. Stress granules (SGs) constitute a cytoplasmic non-membranous compartment formed by RNA-protein aggregates, which control RNA metabolism, signaling, and survival under stress. Increasing evidence reveals complex crosstalk between the mTORC1 network and SGs. In this review, we cover stressors elicited by aging hallmarks that impinge on mTORC1 and SGs. We discuss their interplay, and we highlight possible links in the context of aging and age-related diseases.

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Section: Discussionmentioning

confidence: 99%

mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases

et al. 2021

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“…Inhibition of mTORC1 activity has long been known to increase both health‐ and lifespan and to slow biological ageing [ 96 ]. Experiments from the 1930s showed that rats exposed to calorie restriction lived for longer compared with rats that consumed an ad libitum diet [ 97 ].…”

Section: Living Longer and Healthier Through Inhibition Of Mtorc1mentioning

confidence: 99%

The mTOR–lysosome axis at the centre of ageing

et al. 2021

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Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy–lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two‐way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy–lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy–lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

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“…Previously, we demonstrated that SV40 polyoma virus T antigen might disrupt metabolism involving carbohydrates, amino acids, and nucleotides in the spontaneous lens tumor of transgenic mice ( 33 ) in line with the present findings. The two targets of mTOR (p70S6 kinase and 4EP1/2) modulate ribosome biogenesis and the metabolism of glucose and lipids ( 34 ). In this study, low expression of mTOR and its phosphorylated form in T-expressing spontaneous liver and pancreatic tumors might account for the dysfunctional effects of T antigen on biosynthesis, which was seen in our investigation.…”

Section: Discussionmentioning

confidence: 99%

The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells

et al. 2022

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JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G2 arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, β-catenin, β-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen transcriptionally targeted viral carcinogenesis, microRNAs in cancer, focal adhesion, p53, VEGF, phosphoinositide 3 kinase-Akt, and Forkhead box O signaling pathways, fructose and mannose metabolism, ribosome biosynthesis, and choline and pyrimidine metabolism. At a metabolomics level, it targeted protein digestion and absorption, aminoacryl-tRNA biosynthesis, biosynthesis of amino acids, and the AMPK signal pathway. At a proteomic level, it targeted ribosome biogenesis in eukaryotes, citrate cycle, carbon metabolism, protein digestion and absorption, aminoacryl-tRNA biosynthesis, extracellular-matrix-receptor interaction, and biosynthesis of amino acids. In lens tumor cells, T antigen might interact with various keratins, ribosomal proteins, apolipoproteins, G proteins, ubiquitin-related proteins, RPL19, β-catenin, β-TRCP, p53, and CCAAT-enhancer-binding proteins in lens tumor cells. T antigen induced a more aggressive phenotype in mouse and human cancer cells due to oncogene activation, inactivation of tumor suppressors, and disruption of metabolism, cell adhesion, and long noncoding RNA-microRNA-target axes.

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The role of mTOR in age-related diseases

Cited by 45 publications

References 245 publications

mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases

mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases

The mTOR–lysosome axis at the centre of ageing

The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells

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