Campisi J
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
In Vivo. 2000 Jan-Feb;14(1):183-8.
Normal cells do not divide indefinitely due to a process termed cellular or replicative senescence. Several lines of evidence suggest that replicative senescence evolved to protect higher eukaryotes, particularly mammals, from developing cancer. Senescent cells differ from their presenescent counterparts in three way: 1) they arrest growth and cannot be stimulated to reenter the cell cycle by physiological mitogens; 2) they become resistant to apoptotic cell death; 3) they acquire altered differentiated functions. Replicative senescence occurs because, owing to the biochemistry of DNA replication, cells acquire one or more critically short telomere. The mechanism by which a short telomere induces the senescent phenotype is unknown. Recent findings suggest that certain types of DNA damage and inappropriate mitogenic signals can also cause cells to adopt a senescent phenotype. Thus, cells respond to a number of potentially oncogenic stimuli by adopting a senescent phenotype. These findings suggest that the senescence response is a fail-safe mechanism that protects cells from tumorigenic transformation. Despite the protection from cancer conveyed by cellular senescence and other mechanisms that suppress tumorigenesis, the development of cancer is almost inevitable as mammalian organisms age. Why is this the case? Certainly, aging predisposes cells to accumulate mutations, several of which are necessary before malignant transformation occurs, particularly in humans. However, many benign or relatively well-controlled tumors may also harbor many potentially oncogenic mutations, suggesting that the tissue microenvironment can suppress the expression of many malignant phenotypes. Although the idea remains controversial, cellular senescence has also been proposed to contribute to organismal aging. Senescent cells have recently been shown to accumulate with age in human tissues. One possibility is that the tissue microenvironment is disrupted by the accumulation of dysfunctional senescent cells. Thus, mutation accumulation may synergize with the accumulation of senescent cells, leading to increasing risk for developing cancer that is a hallmark of mammalian aging.
由于细胞衰老或复制性衰老过程，正常细胞不会无限增殖。多项证据表明，复制性衰老的进化是为了保护高等真核生物，尤其是哺乳动物，使其免受癌症侵害。衰老细胞与其衰老前的对应细胞在三个方面存在差异：1）它们停止生长，生理促有丝分裂原无法刺激其重新进入细胞周期；2）它们对凋亡性细胞死亡产生抗性；3）它们获得了改变的分化功能。复制性衰老的发生是因为，由于DNA复制的生物化学特性，细胞获得了一个或多个严重缩短的端粒。短端粒诱导衰老表型的机制尚不清楚。最近的研究结果表明，某些类型的DNA损伤和不适当的促有丝分裂信号也可导致细胞呈现衰老表型。因此，细胞通过呈现衰老表型来应对多种潜在的致癌刺激。这些发现表明，衰老反应是一种故障安全机制，可保护细胞免于致瘤性转化。尽管细胞衰老和其他抑制肿瘤发生的机制可预防癌症，但随着哺乳动物机体衰老，癌症的发生几乎不可避免。为什么会这样呢？当然，衰老使细胞易于积累突变，其中一些突变在恶性转化发生之前是必需的，尤其是在人类中。然而，许多良性或相对可控的肿瘤也可能含有许多潜在的致癌突变，这表明组织微环境可抑制许多恶性表型的表达。尽管这一观点仍存在争议，但细胞衰老也被认为与机体衰老有关。最近的研究表明，衰老细胞会随着年龄的增长在人体组织中积累。一种可能性是，功能失调的衰老细胞的积累会破坏组织微环境。因此，突变积累可能与衰老细胞的积累协同作用，导致患癌风险增加，这是哺乳动物衰老的一个标志。
