Rubin Harry
Department of Molecular and Cell Biology and Virus Laboratory, Life Sciences Addition, University of California, Berkeley, CA 94720-3200, USA.
Arch Gerontol Geriatr. 2002 May-Jun;34(3):275-86. doi: 10.1016/s0167-4943(01)00221-7.
According to the 'Hayflick limit', human fetal fibroblasts have a uniform, limited replicative lifespan of about 50 population doublings in cell culture. This concept was extrapolated to diverse cells in the body. It seemed to decrease with the age of the cell donor and, as a form of cell senescence, was thought to underlie the aging process. More discriminating analysis, however, showed that the fibroblasts decayed in a stochastic manner from the time of their explantation, at a rate that increased with the number of population doublings in culture. There was no consistent relation to the age of the donor. Despite the contradictory evidence, the original version of the Hayflick limit retained its general acceptance. Cell senescence was attributed to the absence of telomerase in the fibroblasts, which resulted in shortening of telomeres at each division until they fell below a critical length needed for further division. However, it is well established that stem cells in renewing tissues undergo many more than 50 divisions in a lifetime, without apparent senescence. Contrary to early findings of no telomerase in most tissues, their stem cells retain telomerase and presumably telomere length despite many divisions in vivo. Massive accumulation of lipofuscin granules occurs under stress in long term crowded cultures, but the granules dissipate on subculture or neoplastic transformation. The overall results indicate a critical disjunction between cell senescence in vitro and aging in vivo. By contrast, cell culture has been useful in showing a need for telomere capping in maintaining cell stability and viability. It may also provide information about the biochemical mechanism of lipofuscin production.
根据“海弗利克极限”，人类胎儿成纤维细胞在细胞培养中具有约50次群体倍增的统一、有限的复制寿命。这一概念被外推到体内的各种细胞。它似乎随着细胞供体年龄的增长而降低，并且作为细胞衰老的一种形式，被认为是衰老过程的基础。然而，更具区分性的分析表明，成纤维细胞从其接种之时起就以随机方式衰退，衰退速率随着培养中群体倍增次数的增加而加快。与供体年龄没有一致的关系。尽管有相互矛盾的证据，但海弗利克极限的原始版本仍然被广泛接受。细胞衰老被归因于成纤维细胞中缺乏端粒酶，这导致每次分裂时端粒缩短，直到它们缩短到低于进一步分裂所需的临界长度。然而，众所周知，更新组织中的干细胞一生中经历的分裂次数远超过50次，却没有明显的衰老迹象。与大多数组织中没有端粒酶的早期发现相反，它们的干细胞尽管在体内经历了多次分裂，但仍保留端粒酶并可能保持端粒长度。在长期拥挤培养的应激条件下会出现脂褐素颗粒的大量积累，但这些颗粒在传代培养或肿瘤转化时会消散。总体结果表明体外细胞衰老与体内衰老之间存在关键脱节。相比之下，细胞培养有助于表明维持细胞稳定性和活力需要端粒帽。它还可能提供有关脂褐素产生的生化机制的信息。
