Harley C B
Geron Corporation, Menlo Park, CA 94025, USA.
Ciba Found Symp. 1997;211:129-39; discussion 139-44. doi: 10.1002/9780470515433.ch9.
Telomerase expression is repressed early in development in all normal somatic human tissues investigated to date, whereas activity and the expression of the RNA component for this enzyme are upregulated in almost all cases of malignant transformation and late-stage cancer. The telomere hypothesis of ageing and immortalization postulates that sufficient telomere loss on one or more chromosomes in normal somatic cells triggers cell senescence, whereas reactivation of the enzyme is necessary for cell immortalization. Measurements of telomere length and telomerase activity in cancer and during normal and accelerated human ageing in skin, blood, haemopoietic, skeletal muscle, vascular and CNS tissues support this model. Tissue culture studies of cell ageing and transformation have added to our understanding of telomere dynamics in these processes. Evolution of telomerase repression and mortality in somatic cells of long-lived organisms is consistent with antagonistic pleiotropy models in which cell senescence is a tumour suppressor mechanism: stringent repression of telomerase has a beneficial early effect in reducing the probability of cancer, but a deleterious, unselected late effect in its contributions to age-related disease.
迄今为止，在所有已研究的正常人体体细胞组织中，端粒酶的表达在发育早期受到抑制，而在几乎所有恶性转化和晚期癌症病例中，该酶的活性及其RNA组分的表达均上调。衰老和永生化的端粒假说是，正常体细胞中一条或多条染色体上足够的端粒丢失会触发细胞衰老，而该酶的重新激活是细胞永生化所必需的。在癌症以及皮肤、血液、造血、骨骼肌、血管和中枢神经系统组织的正常和加速人类衰老过程中端粒长度和端粒酶活性的测量结果支持了这一模型。细胞衰老和转化的组织培养研究增进了我们对这些过程中端粒动态变化的理解。长寿生物体体细胞中端粒酶抑制和死亡率的演变与拮抗性多效性模型一致，在该模型中细胞衰老是一种肿瘤抑制机制：端粒酶的严格抑制在早期对降低癌症发生概率具有有益作用，但在其对年龄相关疾病的影响方面具有有害的、未被选择的后期作用。
