Evidence that the gene encoding insulin degrading enzyme influences human lifespan
Evidence that the gene encoding insulin degrading enzyme influences human lifespan
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DOI：
10.1093/hmg/ddn137
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发表时间：
2008-08-01
影响因子：
3.5
通讯作者：
Prince, Jonathan A.
中科院分区：
文献类型：
--
作者：
Hong, Mun-Gwan;Reynolds, Chandra;Prince, Jonathan A.
对模式生物的研究表明，胰岛素和胰岛素样信号通路的组成部分参与了寿命的调节，但这些发现与人类的相关性仍然不清楚。在这里，我们提供的证据表明，基因编码胰岛素降解酶（IDE）的变体可能会影响人类的寿命。我们采用了各种模型和不同的样本，可重复地表明IDE基因型频率在整个年龄谱中的相对变化，并允许检测与死亡年龄的关联。通过观察空腹血浆胰岛素水平和IDE mRNA表达的遗传相关性，提出了一个可行的分子基础。在整个人群中，出现的遗传模型是超显性的指示，其中关键标志物的杂合子具有增加的IDE mRNA表达和胰岛素水平，这反映在高龄时杂合性降低。本研究的一个关键和重复特征是IDE基因型频率随年龄增长的变化似乎仅发生在男性中，这一点得到了胰岛素水平仅与男性IDE相关的支持。结果表明，密切参与胰岛素代谢的基因与人类寿命的决定之间存在关系，但过度显性和性别特异性将是考虑澄清这些发现的生物学重要性的重要参数。
Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with age-at-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to be occurring only in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider clarifying the biological importance of these findings.