Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling.
Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling.
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DOI：
10.18632/aging.100521
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Darzynkiewicz Z
中科院分区：
文献类型：
--
作者：
Halicka HD;Zhao H;Li J;Lee YS;Hsieh TC;Wu JM;Darzynkiewicz Z
两种不同的机制被认为是衰老的主要原因。由氧化磷酸化的副产物活性氧（ROS）引起的累积DNA损伤是这些机制之一（ROS概念）。有丝分裂原和营养敏感mTOR/S6信号传导的组成性刺激是第二种机制（TOR概念）。开发了流式细胞术和激光扫描细胞术方法来测量个体细胞中组成性DNA损伤/ROS-以及mTOR/S6-信号传导的水平。具体而言，未处理细胞中ATM的持续激活和γ H2 AX的表达似乎报告了内源性ROS诱导的组成性DNA损伤。Ser 235/236-核糖体蛋白（RP）、Ser 2448-mTOR和Ser 65 - 4 EBP 1的磷酸化水平告知沿着mTOR/S6途径的组成性信号传导。潜在的衰老抑制剂雷帕霉素、二甲双胍、2-脱氧葡萄糖、小檗碱、白藜芦醇、维生素D3和阿司匹林都降低了组成性DNA损伤信号传导的水平，如增殖中的A549、TK 6、WI-38细胞和促有丝分裂刺激的人淋巴细胞中γ H2 AX的表达降低所示。它们也都降低了细胞内ROS和线粒体跨膜电位Δ Em（线粒体供能的标志物）的水平，并降低了mTOR、RP-S6和4 EBP 1的磷酸化水平。最有效的是雷帕霉素。尽管这些药物各自的主要靶点可能不同，但数据与下游机制一致，其中mTOR/S6 K信号传导和翻译速率的下降与氧化磷酸化的降低相结合（通过Δ m显示），导致ROS和氧化DNA损伤的减少。由这些试剂诱导的翻译速率降低可以减缓细胞肥大并减轻细胞老化/衰老的其他特征。氧化性DNA损伤的减少可降低肿瘤转化的倾向，否则肿瘤转化可由编码癌基因或肿瘤抑制基因的DNA位点的修复错误引起。数据表明，组成型γ H2 AX表达、线粒体活性（ROS，Δ Δ H2 m）和mTOR信号传导的组合评估提供了足够的细胞应答范围，以评估衰老抑制剂的有效性。
Two different mechanisms are considered to be the primary cause of aging. Cumulative DNA damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Constitutive stimulation of mitogen- and nutrient-sensing mTOR/S6 signaling is the second mechanism (TOR concept). The flow- and laser scanning- cytometric methods were developed to measure the level of the constitutive DNA damage/ROS- as well as of mTOR/S6- signaling in individual cells. Specifically, persistent activation of ATM and expression of γH2AX in untreated cells appears to report constitutive DNA damage induced by endogenous ROS. The level of phosphorylation of Ser235/236-ribosomal protein (RP), of Ser2448-mTOR and of Ser65-4EBP1, informs on constitutive signaling along the mTOR/S6 pathway. Potential gero-suppressive agents rapamycin, metformin, 2-deoxyglucose, berberine, resveratrol, vitamin D3 and aspirin, all decreased the level of constitutive DNA damage signaling as seen by the reduced expression of γH2AX in proliferating A549, TK6, WI-38 cells and in mitogenically stimulated human lymphocytes. They all also decreased the level of intracellular ROS and mitochondrial trans-membrane potential ΔΨm, the marker of mitochondrial energizing as well as reduced phosphorylation of mTOR, RP-S6 and 4EBP1. The most effective was rapamycin. Although the primary target of each on these agents may be different the data are consistent with the downstream mechanism in which the decline in mTOR/S6K signaling and translation rate is coupled with a decrease in oxidative phosphorylation, (revealed by ΔΨm) that leads to reduction of ROS and oxidative DNA damage. The decreased rate of translation induced by these agents may slow down cells hypertrophy and alleviate other features of cell aging/senescence. Reduction of oxidative DNA damage may lower predisposition to neoplastic transformation which otherwise may result from errors in repair of DNA sites coding for oncogenes or tumor suppressor genes. The data suggest that combined assessment of constitutive γH2AX expression, mitochondrial activity (ROS, ΔΨm) and mTOR signaling provides an adequate gamut of cell responses to evaluate effectiveness of gero-suppressive agents.
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DOI：
10.18632/aging.100336
发表时间：
2011-06
期刊：
Aging
影响因子：
--
作者：
Bogomazova AN;Lagarkova MA;Tskhovrebova LV;Shutova MV;Kiselev SL
通讯作者：
Kiselev SL
DOI：
10.18632/aging.100273
发表时间：
2011-02
期刊：
Aging
影响因子：
--
作者：
Anisimov VN;Berstein LM;Popovich IG;Zabezhinski MA;Egormin PA;Piskunova TS;Semenchenko AV;Tyndyk ML;Yurova MN;Kovalenko IG;Poroshina TE
通讯作者：
Poroshina TE
DOI：
10.18632/aging.100040
发表时间：
2009-04-20
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV;Hall MN
通讯作者：
Hall MN
影响因子：
4.3
作者：
Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.
影响因子：
4.3
作者：
Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.