Wang Meng C, Oakley Holly D, Carr Christopher E, Sowa Jessica N, Ruvkun Gary
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS Genet. 2014 Dec 4;10(12):e1004752. doi: 10.1371/journal.pgen.1004752. eCollection 2014 Dec.
Reproductive senescence is a hallmark of aging. The molecular mechanisms regulating reproductive senescence and its association with the aging of somatic cells remain poorly understood. From a full genome RNA interference (RNAi) screen, we identified 32 Caenorhabditis elegans gene inactivations that delay reproductive senescence and extend reproductive lifespan. We found that many of these gene inactivations interact with insulin/IGF-1 and/or TGF-β endocrine signaling pathways to regulate reproductive senescence, except nhx-2 and sgk-1 that modulate sodium reabsorption. Of these 32 gene inactivations, we also found that 19 increase reproductive lifespan through their effects on oocyte activities, 8 of them coordinate oocyte and sperm functions to extend reproductive lifespan, and 5 of them can induce sperm humoral response to promote reproductive longevity. Furthermore, we examined the effects of these reproductive aging regulators on somatic aging. We found that 5 of these gene inactivations prolong organismal lifespan, and 20 of them increase healthy life expectancy of an organism without altering total life span. These studies provide a systemic view on the genetic regulation of reproductive senescence and its intersection with organism longevity. The majority of these newly identified genes are conserved, and may provide new insights into age-associated reproductive senescence during human aging.
生殖衰老乃衰老的一个标志。调控生殖衰老的分子机制及其与体细胞衰老的关联仍知之甚少。通过全基因组RNA干扰（RNAi）筛选，我们鉴定出32种秀丽隐杆线虫基因失活可延缓生殖衰老并延长生殖寿命。我们发现，除了调节钠重吸收的nhx - 2和sgk - 1外，这些基因失活中的许多都与胰岛素/IGF - 1和/或TGF -β内分泌信号通路相互作用来调节生殖衰老。在这32种基因失活中，我们还发现19种通过影响卵母细胞活性来延长生殖寿命，其中8种协调卵母细胞和精子功能以延长生殖寿命，5种可诱导精子体液反应以促进生殖长寿。此外，我们研究了这些生殖衰老调节因子对体细胞衰老的影响。我们发现其中5种基因失活可延长生物体寿命，20种可增加生物体的健康预期寿命而不改变总寿命。这些研究为生殖衰老的遗传调控及其与生物体长寿的交叉提供了一个系统的观点。这些新鉴定出的基因大多数是保守的，可能为人类衰老过程中与年龄相关的生殖衰老提供新的见解。
