Dysregulation of mTORC1/autophagy axis in senescence

Carroll, Bernadette; Korolchuk, Viktor I.

doi:10.18632/aging.101277

Cited by 7 publications

(5 citation statements)

References 8 publications

(11 reference statements)

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“…Finally, nutrient sensing pathways are of particular socio-economic significance as their perturbation is associated with the process of ageing and contributes to a number of age-related conditions including cancer, neurodegeneration and cardiovascular disease as highlighted in several reviews in this issue [ 182 , 183 , 184 ]. Thus, deregulation of mTORC1 has been described in cellular and organismal senescence where it can remain active even during nutrient deprivation [ 176 – 178 ]. This could drive uncontrolled growth, hypertrophy and chronic suppression of autophagy, all potential contributing factors in age-related pathology [ 179 – 181 ].…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

mTORC1 as the main gateway to autophagy

Rabanal-Ruiz

Otten

Korolchuk

2017

Essays in Biochemistry

318

230

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Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis. Under nutrient-rich conditions mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway. Its close signalling interplay with the energy sensor AMP-activated protein kinase (AMPK) dictates whether the cell actively favours anabolic or catabolic processes. Underlining the role of mTORC1 in the coordination of cellular metabolism, its deregulation is linked to numerous human diseases ranging from metabolic disorders to many cancers. Although mTORC1 can be modulated by a number of different inputs, amino acids represent primordial cues that cannot be compensated for by any other stimuli. The understanding of how amino acids signal to mTORC1 has increased considerably in the last years; however this area of research remains a hot topic in biomedical sciences. The current ideas and models proposed to explain the interrelationship between amino acid sensing, mTORC1 signalling and autophagy is the subject of the present review.

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Section: Challenges and Future Perspectivesmentioning

confidence: 99%

mTORC1 as the main gateway to autophagy

Rabanal-Ruiz

Otten

Korolchuk

2017

Essays in Biochemistry

318

230

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“…Upregulated pathways in Sin3a-LOF AT2 cells included oxidative phosphorylation, mitochondrial dysfunction, sirtuin signaling, EIF2 signaling, and mTOR signaling. Interestingly, these pathways are all linked to cellular senescence (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53).…”

Section: A Novel Mouse Model Of Conditional At2 Stem Cell Senescencementioning

confidence: 99%

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Yao

Guan

Carraro

et al. 2019

Preprint

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Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfb activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfb activation, block fibrogenesis.

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“…Previously, we reported clemastine enhances autophagy while suppressing the mTOR pathway in vitro and in vivo ( Li et al, 2021 ), both of which exhibit strong interplay with cellular senescence ( Kang et al, 2011 ; Kwon et al, 2017 ; Park et al, 2020 ). Especially, suppression of mTOR plays pivotal roles in preventing cellular senescence in a way either dependent or independent autophagy ( Carroll and Korolchuk, 2017 ; Carroll et al, 2017 ; Park et al, 2020 ). Thus, we further examined whether clemastine altered mTOR activity in myelin debris-treated OPCs.…”

Section: Resultsmentioning

confidence: 99%

Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

Xie

Pan

Xu³

et al. 2021

Front. Cell Dev. Biol.

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Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer’s disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.

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Dysregulation of mTORC1/autophagy axis in senescence

Cited by 7 publications

References 8 publications

mTORC1 as the main gateway to autophagy

mTORC1 as the main gateway to autophagy

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

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