TELOMERE LENGTH PREDICTS REPLICATIVE CAPACITY OF HUMAN FIBROBLASTS
TELOMERE LENGTH PREDICTS REPLICATIVE CAPACITY OF HUMAN FIBROBLASTS
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DOI：
10.1073/pnas.89.21.10114
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发表时间：
1992-11-01
影响因子：
11.1
通讯作者：
HARLEY, CB
中科院分区：
文献类型：
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作者：
ALLSOPP, RC;VAZIRI, H;HARLEY, CB
当来自不同供体的人类成纤维细胞在体外生长时，其有限复制能力的变化中只有一小部分可以用供体的实际年龄来解释。因为我们之前已经证明端粒（染色体末端富含鸟嘌呤的序列）会在培养细胞的整个生命周期中缩短，所以我们希望确定初始端粒长度的变化是否会解释复制能力中无法解释的变化。对 31 名供体（年龄 0-93 岁）细胞的分析表明，增殖能力与供体年龄之间（m = -0.2 每年倍增；r = -0.42；P = 0.02）以及端粒 DNA 和供体年龄之间（m = -15 个碱基对每年；r = -0.43；P = 0.02）之间的相关性相对较弱。然而，复制能力和初始端粒长度之间存在显着的相关性，在供体的整个年龄范围内都有效（m = 每千碱基对 10 次倍增；r = 0.76；P = 0.004），表明端粒较短的细胞株比端粒较长的细胞株经历的倍增明显更少。这些观察结果表明，端粒长度是人类体细胞衰老的生物标志物，并且与端粒损失在此过程中的因果作用一致。我们还发现来自哈钦森-吉尔福德早衰症供体的成纤维细胞具有较短的端粒，这与它们在体外分裂潜力的降低一致。相比之下，精子 DNA 的端粒并没有随着供体年龄的增长而减少，这表明维持端粒长度的机制（例如端粒酶表达）可能在种系组织中活跃。
When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.