Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
Ann N Y Acad Sci. 2010 Aug;1204:156-62. doi: 10.1111/j.1749-6632.2010.05640.x.
In the nematode Caenorhabditis elegans and the fruit fly Drosophila, loss of the germline stem cells activates lifespan-extending FOXO-family transcription factors in somatic tissues and extends lifespan, suggesting the existence of an evolutionarily conserved pathway that links reproductive state and aging. Consistent with this idea, reproductive tissues have been shown to influence the lifespans of mice and humans as well. In C. elegans, loss of the germ cells activates a pathway that triggers nuclear localization of the FOXO transcription factor DAF-16 in endodermal tissue. DAF-16 then acts in the endoderm to activate downstream lifespan-extending genes. DAF-16 is also required for inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling to extend lifespan. However, the mechanisms by which inhibition of insulin/IGF-1 signaling and germline loss activate DAF-16/FOXO are distinct. As loss of the germ cells further doubles the already-long lifespan of insulin/IGF-1 pathway mutants, a better understanding of this reproductive longevity pathway could potentially suggest powerful ways to increase healthy lifespan in humans.
在秀丽隐杆线虫和果蝇中，生殖干细胞的缺失会激活体细胞组织中延长寿命的 FOXO 家族转录因子，从而延长寿命，这表明存在一种进化上保守的途径，将生殖状态和衰老联系起来。与这一观点一致，生殖组织也被证明会影响小鼠和人类的寿命。在秀丽隐杆线虫中，生殖细胞的缺失会激活一条途径，触发 FOXO 转录因子 DAF-16 在肠组织中的核定位。然后，DAF-16 在肠内发挥作用，激活下游延长寿命的基因。DAF-16 也需要抑制胰岛素/胰岛素样生长因子 1（IGF-1）信号来延长寿命。然而，抑制胰岛素/IGF-1 信号和生殖细胞缺失激活 DAF-16/FOXO 的机制是不同的。由于生殖细胞的缺失使胰岛素/IGF-1 途径突变体已经很长的寿命进一步延长一倍，因此更好地理解这种生殖长寿途径可能会为增加人类健康寿命提供有力的方法。
