Functionally significant insulin-like growth factor I receptor mutations in centenarians
Functionally significant insulin-like growth factor I receptor mutations in centenarians
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DOI：
10.1073/pnas.0705467105
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发表时间：
2008-03-04
影响因子：
11.1
通讯作者：
Cohen, Pinchas
中科院分区：
文献类型：
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作者：
Suh, Yousin;Atzmon, Gil;Cohen, Pinchas
实验动物的寿命不是被动、随意的磨损过程，而是可以通过胰岛素/胰岛素样生长因子 I (IGFI) 途径的成分主动调节。编码胰岛素/IGFI途径成分的基因的完全或部分功能丧失突变会导致酵母、蠕虫、果蝇和小鼠的寿命延长。这种在整个进化过程中显着的保守性表明，该途径中信号传导的改变也可能影响人类的寿命。另一方面，进化权衡预测实验室的发现可能与人类无关，因为生命早期的适应成本很高。在这里，我们研究了一组德系犹太百岁老人、他们的后代和后代匹配对照的生化、表型和遗传变异，并证明了血清 IGFI 的性别特异性增加与百岁老人女性后代身材较小相关。对女性百岁老人的 IGF1 和 IGF1 受体 (IGF1R) 基因的序列分析显示，相对于对照，百岁老人中 IGF1R 基因的杂合突变过多，这些突变与高血清 IGFI 水平和转化淋巴细胞中测量的 IGFIR 活性降低相关。因此，人类 IGF1R 的基因改变导致 IGF 信号通路改变，从而增加了人类长寿的易感性，表明该通路在调节人类寿命中发挥着作用。
Rather than being a passive, haphazard process of wear and tear, lifespan can be modulated actively by components of the insulin/insulin-like growth factor I (IGFI) pathway in laboratory animals. Complete or partial loss-of-function mutations in genes encoding components of the insulin/IGFI pathway result in extension of life span in yeasts, worms, flies, and mice. This remarkable conservation throughout evolution suggests that altered signaling in this pathway may also influence human lifespan. On the other hand, evolutionary tradeoffs predict that the laboratory findings may not be relevant to human populations, because of the high fitness cost during early life. Here, we studied the biochemical, phenotypic, and genetic variations in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls and demonstrated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous mutations in the IGF1R gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan.