mTOR 与细胞衰老

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mTOR and Cellular Senescence

Now that the research community has finally woken up to the significance of cellular senescence in aging, a point long advocated for by the SENS Research Foundation and Methuselah Foundation, scientists are busily patching it in to their existing understanding and models of aging. This is just as true for studies of mechanistic target of rapamycin (mTOR) as elsewhere. This is one of the more popular areas of research to emerge from the study of calorie restriction, an intervention that slows aging in near all species tested to date. There is a sizable contingent of researchers interested in finding ways to mimic some fraction of the benefits of calorie restriction through therapies that target mTOR.

现在,研究团体终于意识到细胞衰老在衰老中的重要性,这是 SENS 研究基金会和玛土撒拉基金会长期倡导的一个观点,科学家们正忙于修补他们现有的理解和衰老模型。这对雷帕霉素(mTOR)机制靶的研究和其他地方一样正确。这是一个更受欢迎的领域的研究出现的研究卡路里限制,一种干预,延缓衰老的几乎所有物种测试日期。有相当一部分研究人员感兴趣的是,通过靶向 mTOR 的治疗,找到方法来模拟卡路里限制的部分益处。

Since calorie restriction slows aging, albeit to a much larger degree in short-lived animals than in humans, it is generally agreed that it also slows the accumulation of senescent cells, one of the causes of aging. Thus to the degree that mTOR is involved in the calorie restriction response, we should also expect mTOR to be relevant in some ways to the harms done by cellular senescence: either reducing the number of cells that become senescent, or reducing the harm done by cells once they are senescent. Since we know that calorie restriction doesn’t greatly extend life in humans (though it is very good for long term health), we should not expect these effects to be large. Certainly, senolytic therapies that clear out senescent cells should have a much greater positive impact on health and longevity.

由于卡路里限制可以延缓衰老,尽管短寿命动物的衰老程度比人类要大得多,人们普遍认为它还可以延缓衰老细胞的积累,而衰老细胞是衰老的原因之一。因此,就 mTOR 参与卡路里限制反应的程度而言,我们也应该期望 mTOR 在某些方面与细胞衰老所造成的伤害有关: 要么减少衰老细胞的数量,要么减少衰老细胞所造成的伤害。既然我们知道卡路里限制不能大大延长人类的寿命(尽管它对长期健康非常有益) ,我们就不应该期望这些影响会很大。当然,清除衰老细胞的衰老疗法应该对健康和长寿有更大的积极影响。

The mechanistic target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinasethat senses and integrates a diverse set of environmental and intracellular signals, such as growth factors and nutrients to direct cellular and organismal responses. The name TOR (target of rapamycin) is derived from its inhibitor rapamycin. We now know that the role of mTOR goes far beyond proliferation and coordinates a cell-tailored metabolic program to control cell growth and many biological processes including aging, cellular senescence, and lifespan.

雷帕霉素(rapamycin,mTOR)是一种进化保守的丝氨酸-苏氨酸激酶,它能感受并整合一系列环境和细胞内的信号,如生长因子和营养物质,引导细胞和生物体的反应。名称 TOR (雷帕霉素的靶)源于其抑制剂雷帕霉素。我们现在知道,mTOR 的作用远远超出了细胞增殖和协调细胞定制的代谢程序,以控制细胞生长和许多生物过程,包括老化,细胞衰老和寿命。

Rapamycin is currently the only known pharmacological substance to prolong lifespan in all studied model organisms and the only one in mammals. Rapamycin was shown to extend the lifespan of genetically heterogeneous mice at three independent test locations by about 10-18% depending on sex. Interestingly, treatment was only started late when the mice were 600 days of age equivalent to roughly 60 years of age in a human person. This proposes that inhibition of mTOR in the elderly might be enough to prolong life. The findings were confirmed and extended in mice, in which rapamycin treatment started earlier. However, they failed to substantially observe larger effects on longevity.

雷帕霉素是目前唯一已知的在所有研究的模式生物中延长寿命的药理物质,也是哺乳动物中唯一的一种。在三个独立试验地点,雷帕霉素被证明可以根据性别延长基因异质小鼠的寿命约10-18% 。有趣的是,只有当老鼠600天的年龄相当于人类大约60岁的时候,治疗才开始得比较晚。这提示老年人抑制 mTOR 可能足以延长寿命。这些发现在雷帕霉素治疗开始较早的小鼠身上得到了证实和延伸。然而,他们没有实质性地观察到对长寿的更大影响。

It is now accepted that mTOR inhibition increases lifespan; yet, the mechanism through which this occurs is still uncertain. mTORC1 inhibition may not delay aging itself, but may delay age-related diseases. However, many researchers directly link the longevity effects of mTOR inhibitors to a decrease in aging. Conserved hallmarks of aging have recently been proposed and include telomere attritionepigenetic alterations, genomic instability, loss of proteostasis, deregulated nutrient sensingmitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mTOR network is known to regulate some of these aging hallmarks. Ultimately, the prominence of mTORC1 signaling in aging likely reflects its exceptional capacity to regulate such a wide variety of key cellular functions.

现在人们已经认识到 mTOR 抑制可以延长寿命; 然而,其发生的机制仍然不确定。mTORC1抑制可能不会延缓衰老本身,但可能延缓与年龄有关的疾病。然而,许多研究人员直接将 mTOR 抑制剂的长寿效应与衰老的减少联系起来。保守的衰老特征最近被提出,包括端粒磨损、表观遗传改变、基因组不稳定、蛋白质平衡丧失、营养感受失调、线粒体功能障碍、细胞衰老、干细胞衰竭和细胞间通讯改变。众所周知,mTOR 网络控制着这些老化的标志。最终,mTORC1信号在衰老中的突出表现可能反映了其调节如此广泛的关键细胞功能的异常能力。

Cellular senescence has been suggested to function as a tumor suppressor mechanism and promotor of tissue remodeling after wounding. However, senescent cells may also directly contribute to aging. Senescent cells show marked changes in morphology including an enlarged size, irregular cell shape, prominent and sometimes multiple nuclei, accumulation of mitochondrial and lysosomal mass, increased granularity and highly prominent stress fibers that are accompanied by shifts in metabolismand a failure of autophagy. Interestingly, many of these phenotypes are regulated by mTORC1 in various cell types. The secretion of proinflammatory mediators by senescent cells contributes to aging and has been termed senescence-associated secretory phenotype (SASP). Recent data identified a main role of mTORC1 to promote the SASP. Rapamycin blunts the proinflammatory phenotype of senescent cells by specifically suppressing translation of IL1A.

细胞衰老被认为是肿瘤抑制机制和促进伤后组织重塑的机制。然而,衰老细胞也可能直接导致衰老。衰老细胞具有明显的形态学变化,包括体积增大、细胞形态不规则、细胞核突出、有时有多个细胞核、线粒体和溶酶体聚集、细胞粒度增大、应力纤维高度突出,伴有代谢变化和自噬失败。有趣的是,许多这些表型是由 mTORC1在各种细胞类型的调节。衰老细胞分泌促炎性介质促进衰老,被称为衰老相关分泌表型(SASP)。最近的数据确定了 mTORC1的主要作用,促进 SASP。雷帕霉素通过特异性抑制 IL1A 的翻译降低衰老细胞的促炎症表型。

Despite maintaining a nondividing state, senescent cells display a high metabolic rate. Metabolic changes characteristic of replicative senescence often show a shift to glycolytic metabolism away from oxidative phosphorylation (which is also observed in proliferative cells), despite a marked increase in mitochondrial mass and markers of mitochondrial activity. This might stem from a rise in lysosomal pHas a consequence of proton pump failure, which leads to an inability to get rid of damaged organellessuch as mitochondria caused by a failure of autophagy. Dysfunctional mitochondria not cleared by autophagy in senescent cells produce reactive oxygen species, which cause cellular damage including DNA damage. mTORC1 has been postulated as main driver of these metabolic changes. Hence, rapamycin treatment prevents metabolic stress and delays cellular senescence.

尽管保持不分裂状态,衰老细胞显示出高代谢率。尽管线粒体质量和线粒体活性标志物明显增加,但复制性衰老特征的代谢变化常常表现为糖酵解代谢的转变,远离氧化磷酸化(在增殖细胞中也可观察到)。这可能源于质子泵失效导致溶酶体 pH 值升高,从而导致无法清除受损细胞器,如自噬失败引起的线粒体。衰老细胞中的自噬不能清除功能障碍的线粒体产生活性氧类,这会导致细胞损伤,包括 DNA 损伤。mTORC1被认为是这些代谢变化的主要驱动因素。因此,雷帕霉素治疗可以预防代谢应激和延缓细胞衰老。

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