TGF-beta Sma/Mab signaling mutations uncouple reproductive aging from somatic aging.
TGF-beta Sma/Mab signaling mutations uncouple reproductive aging from somatic aging.
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DOI：
10.1371/journal.pgen.1000789
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
Murphy CT
中科院分区：
文献类型：
--
作者：
Luo S;Shaw WM;Ashraf J;Murphy CT
女性生殖停止是人类经历的最早的年龄相关衰退之一，发生在成年中期。同样，秀丽隐杆线虫的生殖期相对于其总寿命来说很短，在成年期15-20天后，生殖就会停止约三分之一。所有已知的延长C.秀丽隐杆线虫的生殖期也调节寿命，这表明生殖期通常与寿命有关。C. elegans有两条典型的TGF-β信号通路。我们最近发现，TGF-β Dauer通路通过胰岛素/IGF-1信号通路（IIS）调节寿命;在这里，我们表明该通路对生殖寿命有中度影响。相比之下，TGF-β Sma/Mab信号转导突变体表现出显著延长的生殖期，在某些情况下超过两倍的生殖跨度。Sma/Mab突变延长生殖寿命不成比例的寿命，并独立于已知的躯体衰老调节因子，如胰岛素/IGF-1信号传导和饮食限制。这是第一次发现一种独立于寿命调节生殖寿命的途径，也是第一次将TGF-β Sma/Mab途径鉴定为生殖衰老的调节剂。我们的研究结果表明，寿命和生殖跨度的调节可以解耦，虽然他们似乎通常是通过调节途径。女性生殖停止是人类经历的最早的衰老表型，随着越来越多的女性选择晚育，其作为临床问题的重要性正在增加。虽然已经做了很多工作来了解一般的衰老过程，但目前对生殖衰老的调节知之甚少。与长寿一样，高龄生育后代的能力可能也受到遗传调节。因此，了解调节生殖衰老的过程可能使我们能够解决与年龄相关的母亲不孕症和出生缺陷的问题。C.秀丽线虫和人类都有很长的生殖后寿命，这使得它们的生殖期可能是可延长的。C.线虫以前被用来发现衰老的保守调节因子，而在这里，我们用蠕虫来鉴定一种新的生殖衰老调节因子，一种高度保守的TGF-β信号通路。我们发现，TGF-β信号调节生殖老化独立的躯体老化。这是第一次发现一个途径，打破了通常连接这两个过程的耦合。我们的工作将为提高人类生育力和预防年龄相关的出生缺陷提供新的见解，并对生殖和长寿调节之间的进化关系具有影响。
Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15–20 day adulthood. All of the known mutations and treatments that extend C. elegans' reproductive period also regulate longevity, suggesting that reproductive span is normally linked to life span. C. elegans has two canonical TGF-ß signaling pathways. We recently found that the TGF-ß Dauer pathway regulates longevity through the Insulin/IGF-1 Signaling (IIS) pathway; here we show that this pathway has a moderate effect on reproductive span. By contrast, TGF-ß Sma/Mab signaling mutants exhibit a substantially extended reproductive period, more than doubling reproductive span in some cases. Sma/Mab mutations extend reproductive span disproportionately to life span and act independently of known regulators of somatic aging, such as Insulin/IGF-1 Signaling and Dietary Restriction. This is the first discovery of a pathway that regulates reproductive span independently of longevity and the first identification of the TGF-ß Sma/Mab pathway as a regulator of reproductive aging. Our results suggest that longevity and reproductive span regulation can be uncoupled, although they appear to normally be linked through regulatory pathways. Female reproductive cessation is the earliest aging phenotype humans experience, and its importance as a clinical issue is growing as more women opt to have children later in life. While much work has been done to understand the general aging process, little is currently known about the regulation of reproductive aging. Like longevity, the ability to produce progeny with advanced age is likely to be genetically regulated. Thus, understanding the processes that regulate reproductive aging may allow us to address the problems of maternal age-related infertility and birth defects. C. elegans and humans both have long post-reproductive life spans, leaving open the possibility that their reproductive spans might be extendable. C. elegans has been used previously to discover conserved regulators of aging, and here we use worms to identify a new regulator of reproductive aging, a highly conserved TGF-ß signaling pathway. We find that TGF-ß signaling regulates reproductive aging independently of somatic aging. This is the first identification of a pathway that breaks the coupling that normally links the two processes. Our work will provide new insights into the improvement of human fertility and prevention of age-related birth defects, and it has implications for the evolutionary relationship between reproduction and longevity regulation.
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影响因子：
56.9
作者：
Garsin, DA;Villanueva, JM;Ausubel, FM
通讯作者：
Ausubel, FM
DOI：
10.1073/pnas.0400848101
发表时间：
2004-05-25
影响因子：
11.1
作者：
Huang, C;Xiong, CJ;Kornfeld, K
通讯作者：
Kornfeld, K
影响因子：
3.3
作者：
Knight, CG;Azevedo, RBR;Leroi, AM
通讯作者：
Leroi, AM
影响因子：
4.5
作者：
Hughes SE;Evason K;Xiong C;Kornfeld K
通讯作者：
Kornfeld K
影响因子：
4.5
作者：
Andux, Sara;Ellis, Ronald E.
通讯作者：
Ellis, Ronald E.