mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership
Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactiv...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/15/8149 |
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| author | Angel Cayo Raúl Segovia Whitney Venturini Rodrigo Moore-Carrasco Claudio Valenzuela Nelson Brown |
| author_facet | Angel Cayo Raúl Segovia Whitney Venturini Rodrigo Moore-Carrasco Claudio Valenzuela Nelson Brown |
| author_sort | Angel Cayo |
| collection | DOAJ |
| description | Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this “senescence-associated secretory phenotype (SASP)” accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy—a highly regulated catabolic process—is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors. |
| first_indexed | 2024-03-10T09:13:50Z |
| format | Article |
| id | doaj.art-42dfc6d0c5b3417ab5771e2a7ab7b279 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:13:50Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-42dfc6d0c5b3417ab5771e2a7ab7b2792023-11-22T05:43:55ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215814910.3390/ijms22158149mTOR Activity and Autophagy in Senescent Cells, a Complex PartnershipAngel Cayo0Raúl Segovia1Whitney Venturini2Rodrigo Moore-Carrasco3Claudio Valenzuela4Nelson Brown5Center for Medical Research, University of Talca School of Medicine, Talca 346000, ChileCenter for Medical Research, University of Talca School of Medicine, Talca 346000, ChileCenter for Medical Research, University of Talca School of Medicine, Talca 346000, ChileDepartment of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, University of Talca, Talca 346000, ChileCenter for Medical Research, University of Talca School of Medicine, Talca 346000, ChileCenter for Medical Research, University of Talca School of Medicine, Talca 346000, ChileCellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this “senescence-associated secretory phenotype (SASP)” accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy—a highly regulated catabolic process—is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.https://www.mdpi.com/1422-0067/22/15/8149mTORautophagysenescence |
| spellingShingle | Angel Cayo Raúl Segovia Whitney Venturini Rodrigo Moore-Carrasco Claudio Valenzuela Nelson Brown mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership International Journal of Molecular Sciences mTOR autophagy senescence |
| title | mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership |
| title_full | mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership |
| title_fullStr | mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership |
| title_full_unstemmed | mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership |
| title_short | mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership |
| title_sort | mtor activity and autophagy in senescent cells a complex partnership |
| topic | mTOR autophagy senescence |
| url | https://www.mdpi.com/1422-0067/22/15/8149 |
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