衰老过程中mTOR的异常激活与衰老：一种线粒体应激反应？
Aberrant mTOR activation in senescence and aging: A mitochondrial stress response?
作者信息
Nacarelli Timothy, Azar Ashley, Sell Christian
机构信息
Drexel University College of Medicine, 245N 15th Street, Philadelphia, PA 19102, United States.
Drexel University College of Medicine, 245N 15th Street, Philadelphia, PA 19102, United States.
出版信息
Exp Gerontol. 2015 Aug;68:66-70. doi: 10.1016/j.exger.2014.11.004. Epub 2014 Nov 6.
Abstract
Unexpected activation of mTOR signaling, measured by ribosomal S6 phosphorylation or ribosomal S6 kinase (p70S6K) activity, has been reported in aging-related settings. Evidence of elevated mTOR activity has been reported in the heart and muscle tissue in aged mice and humans, mouse models of progeria, and senescent human fibroblasts. We explore these reports and the possibility that activation of the mTOR/p70S6K kinase pathway may represent a ROS-mediated response to mitochondrial stress leading to the activation of senescence. This activation is a hallmark of both aged tissue and senescent human cells.
摘要
据报道，在与衰老相关的情况下，通过核糖体S6磷酸化或核糖体S6激酶（p70S6K）活性测量发现mTOR信号通路意外激活。在老年小鼠和人类的心脏和肌肉组织、早衰症小鼠模型以及衰老的人类成纤维细胞中，都有mTOR活性升高的证据。我们探讨了这些报道以及mTOR/p70S6K激酶途径的激活可能代表对线粒体应激的ROS介导反应从而导致衰老激活的可能性。这种激活是衰老组织和衰老人类细胞的一个标志。
相似文献
1
Aberrant mTOR activation in senescence and aging: A mitochondrial stress response?
Exp Gerontol. 2015 Aug;68:66-70. doi: 10.1016/j.exger.2014.11.004. Epub 2014 Nov 6.
2
ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis.
Autophagy. 2014;10(12):2223-38. doi: 10.4161/15548627.2014.981789.
3
Involvement of PI3K-AKT-mTOR pathway in protein kinase CKII inhibition-mediated senescence in human colon cancer cells.
Biochem Biophys Res Commun. 2013 Apr 19;433(4):420-5. doi: 10.1016/j.bbrc.2013.02.108. Epub 2013 Mar 21.
4
mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells.
Eur J Pharmacol. 2013 Sep 5;715(1-3):76-88. doi: 10.1016/j.ejphar.2013.05.051. Epub 2013 Jun 26.
5
In search of antiaging modalities: evaluation of mTOR- and ROS/DNA damage-signaling by cytometry.
Cytometry A. 2014 May;85(5):386-99. doi: 10.1002/cyto.a.22452. Epub 2014 Feb 22.
6
Indian Hedgehog regulates senescence in bone marrow-derived mesenchymal stem cell through modulation of ROS/mTOR/4EBP1, p70S6K1/2 pathway.
Aging (Albany NY). 2020 Apr 1;12(7):5693-5715. doi: 10.18632/aging.102958.
7
Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways.
Toxicol Lett. 2014 Aug 4;228(3):248-59. doi: 10.1016/j.toxlet.2014.05.015. Epub 2014 May 27.
8
Metabolic stress is a barrier to Epstein-Barr virus-mediated B-cell immortalization.
Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):E782-90. doi: 10.1073/pnas.1517141113. Epub 2016 Jan 22.
9
[Regulation of TOR complex 1 activity by stress].
Seikagaku. 2013 Mar;85(3):205-13.
10
mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging.
J Orthop Res. 2017 Jul;35(7):1375-1382. doi: 10.1002/jor.23409. Epub 2016 Sep 22.
引用本文的文献
1
Regulatory Interplay of p53, AMPK, and mTOR in Decidualization: Implications for Reproductive Competence and Cancer Biology.
Reprod Sci. 2025 Sep 4. doi: 10.1007/s43032-025-01970-z.
2
β-hydroxybutyrate administered at reperfusion reduces infarct size and preserves cardiac function by improving mitochondrial function through autophagy in male mice.
J Mol Cell Cardiol. 2024 Jan;186:31-44. doi: 10.1016/j.yjmcc.2023.11.001. Epub 2023 Nov 16.
3
New Horizons in cellular senescence for clinicians.
Age Ageing. 2023 Jul 1;52(7). doi: 10.1093/ageing/afad127.
4
Lamin A to Z in normal aging.
Aging (Albany NY). 2022 Oct 17;14(20):8150-8166. doi: 10.18632/aging.204342.
5
Reduction of senescent fibro-adipogenic progenitors in progeria-aged muscle by senolytics rescues the function of muscle stem cells.
J Cachexia Sarcopenia Muscle. 2022 Dec;13(6):3137-3148. doi: 10.1002/jcsm.13101. Epub 2022 Oct 11.
6
Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer.
Oncogene. 2022 Oct;41(44):4893-4904. doi: 10.1038/s41388-022-02484-7. Epub 2022 Oct 4.
7
The Effect of Metabolites on Mitochondrial Functions in the Pathogenesis of Skeletal Muscle Aging.
Clin Interv Aging. 2022 Aug 22;17:1275-1295. doi: 10.2147/CIA.S376668. eCollection 2022.
8
Mitochondrial dysfunction in cell senescence and aging.
J Clin Invest. 2022 Jul 1;132(13). doi: 10.1172/JCI158447.
9
Age-Related Lysosomal Dysfunctions.
Cells. 2022 Jun 20;11(12):1977. doi: 10.3390/cells11121977.
10
The methyltransferase enzymes KMT2D, SETD1B, and ASH1L are key mediators of both metabolic and epigenetic changes during cellular senescence.
Mol Biol Cell. 2022 May 1;33(5):ar36. doi: 10.1091/mbc.E20-08-0523. Epub 2022 Feb 23.
本文引用的文献
1
mTOR Signaling from Cellular Senescence to Organismal Aging.
Aging Dis. 2013 Dec 5;5(4):263-73. doi: 10.14336/AD.2014.0500263. eCollection 2014 Aug.
2
Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function.
J Immunol. 2014 Sep 15;193(6):2821-30. doi: 10.4049/jimmunol.1302498. Epub 2014 Aug 8.
3
Inhibition of mTOR Prevents ROS Production Initiated by Ethidium Bromide-Induced Mitochondrial DNA Depletion.
Front Endocrinol (Lausanne). 2014 Jul 24;5:122. doi: 10.3389/fendo.2014.00122. eCollection 2014.
4
Short-term rapamycin treatment in mice has few effects on the transcriptome of white adipose tissue compared to dietary restriction.
Mech Ageing Dev. 2014 Sep;140:23-9. doi: 10.1016/j.mad.2014.07.004. Epub 2014 Jul 27.
5
Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program.
Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8832-7. doi: 10.1073/pnas.1405723111. Epub 2014 Jun 2.
6
Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin.
Cancer Biol Ther. 2014 May;15(5):586-92. doi: 10.4161/cbt.28164. Epub 2014 Feb 20.
7
Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome.
PLoS One. 2014 Jan 7;9(1):e83988. doi: 10.1371/journal.pone.0083988. eCollection 2014.
8
Where is mTOR and what is it doing there?
J Cell Biol. 2013 Nov 25;203(4):563-74. doi: 10.1083/jcb.201306041.
9
Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver.
Aging Cell. 2014 Apr;13(2):311-9. doi: 10.1111/acel.12175. Epub 2013 Dec 5.
10
mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome.
Science. 2013 Dec 20;342(6165):1524-8. doi: 10.1126/science.1244360. Epub 2013 Nov 14.
Zotero 插件