细胞衰老与细胞自噬的生物学关联及其意义

Biological relevancy and its significance of cellular senescence and autophagy

细胞衰老是指细胞生理功能的衰减,包括增殖能力下降、细胞周期停滞、对促凋亡应激不敏感、衰老相关基因和蛋白表达增加,伴有形态学衰老改变,渐趋死亡的现象,其至少可分为复制性衰老和应激诱导的衰老。细胞自噬属于细胞"自食"现象,是细胞依赖溶酶体的分解代谢过程,能降解受损蛋白、衰老或损伤的细胞器等细胞结构,可被多种应激所触发。细胞自噬的典型特征是形成自噬体并呈递给溶酶体,该过程在蛋白质和细胞器质量控制中起基础作用并维持了细胞能量的稳态。最新研究表明,自噬与细胞衰老密切相关,参与蛋白酶和自噬相关调节的BAG蛋白家族中BAG3/BAG1比值在复制性衰老时增高,且BAG3在细胞衰老时能介导自噬的激活。在Ras诱导的细胞衰老进程中亦可观察到较高的自噬活性。再者,自噬作为生物机体抗衰老的效应因子的遗传学证据已在低等真核生物中发现。还有研究证实,作为人类精液主要组分的亚精胺能够触发组蛋白H3脱乙酰基作用,此改变上调了自噬相关转录物的表达,继而引发自噬活性增强,从而延缓了多种细胞的衰老进程。另有研究显示,在P53/Arf的正常调节下,小鼠的衰老进程得以延缓,而Arf在细胞自噬过程的调节中亦是不可或缺的。总之,自噬活性的改变影响细胞衰老进程并可作为细胞衰老新的效应机理。

Cellular senescence is defined as cell cycle arrest,death approaching,limited capacity to proliferate,altered responsiveness to apoptosis stimuli,altered senescence associated gene expression,remarkable morphologic transformation in vitro.There are at least two types of cellular senescence： replicative senescence and stress-induced senescence.Autophagy is ＂self eating＂ phenomenon,and also the catabolism,which is depended on lysosomes and has the role of cleaning up damaged proteins and senescent or damaged organelle,can be triggered by diverse stimulus,and autophagy is characterized by the formation of autophagosomes,which plays a basally active role in the quality control of proteins or organelles and the maintenance of cell energy homeostasis.More recently,it has been demonstrated that autophagy plays a very indispensable role in cellular senescence.The members of the BAG protein family regulate the proteasomal and autophagic signaling pathway,and that the ratio of BAG3/BAG1 is elevated during cell replicative senescence.Obviously,BAG3 mediates the activation of autophagy in the processes of cellular senescence.It also can be observed that autophagy is highly activated in Ras-induced senescent cells.Furthermore,genetic evidence of autophagy as an anti-age effector has been provided in lower eukaryotes.Spermidine is the major component of human sperm and can trigger deacetylation of histone H3.The altered acetylation status of the chromatin leads to significant upregulation of various autophagy-related transcripts,results in triggering autophagy and enhancing longevity.Other studies suggest that p53 and its positive regulator,Arf（the so-called super-p53/Arf） exhibit resisted aging under their normal gene regulation.It is exciting that Arf can also positively modulate autophagy.Conceivably,autophagy contributes to cellular senescence establishment and is an effector mechanism of cellular senescence.