mTOR as a central regulator of lifespan and aging

Papadopoli, David; Boulay, Karine; Kazak, Lawrence; Pollak, Michael; Mallette, Frédérick A.; Topisirović, Ivan; Hulea, Laura

doi:10.12688/f1000research.17196.1

Cited by 269 publications

(242 citation statements)

References 275 publications

(303 reference statements)

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“…Another interesting relation between mTOR pathway and autophagy is the association to lifespan and aging; mainly because it has been observed that inhibition of mTOR could bring as a consequence delay of aging due to autophagy stimulation resulting in a mitophagy increase (172). In fact, it is well-documented that inhibition of key components of mTOR and its counterpart in invertebrates TOR pathways, results in an extension of life span in part by the influence of mTOR on the called "hallmarks of aging, " an interesting an extensive review about this subject is broadly reviewed in Papadopoli publication (173).…”

Section: Glutaminolysis and Mtorc1 In Cancermentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Glutaminolysis and Mtorc1 In Cancermentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…Rapamycin, (International Nonproprietary Name: sirolimus), is an inhibitor of mTOR, which results in an extended life span and prevents age-related diseases [157][158][159][160] by mediating SIRT1 expression [161,162]. mTOR is a serine-threonine kinase that plays a role in modulating cell survival, growth, proliferation, motility, protein synthesis and transcription [163] and inducing autophagy [164][165][166].…”

Section: Rapamycinmentioning

confidence: 99%

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

et al. 2020

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Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.

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“…Autophagy has a central role in promoting health and longevity by removal of toxic material such as damaged organelles and large protein aggregates while this process is impaired in neurodegenerative diseases and αSyn pathology [80,81]. The p.A53Tproteome shows that neurons are under stress as proteins involved in the UPR or the heat-shock stress response, proteasome assembly and regulation, known to be orchestrated by mTORC1 in neurons, are significantly upregulated [77]. Accumulation of unfolded or misfolded proteins in p.A53T-neurons, including a large portion of RBPs that have an intrinsic propensity to aggregate, would result in misregulation of the autophagic system.…”

Section: Discussionmentioning

confidence: 99%

High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease

Antoniou

Prodromidou

Kouroupi

et al. 2020

Preprint

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Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)based disease models represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson's disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores diseaseassociated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the neuroprotective effects of BX795 that comprised a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuron-like cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have developed an adaptable platform based on p.A53T iPSC-derived neurons for drug screening and identified a promising small molecule with potent neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.3 Key words α-synuclein, p.A53T α-synuclein mutation, induced pluripotent stem cell derived neurons, drug screening, mTOR signaling, mRNA metabolism, proteostasis AcknowledgementsWe thank Drs. Tamotsu Yoshimori and Terje Johansen for providing GFP-LC3 and mChery-GFP-p62 plasmids, respectively.

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mTOR as a central regulator of lifespan and aging

Cited by 269 publications

References 275 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease

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