Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.
Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.
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DOI：
10.1371/journal.pgen.1003941
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发表时间：
2013-11
期刊：
影响因子：
4.5
通讯作者：
Tatar M
中科院分区：
文献类型：
--
作者：
Bai H;Kang P;Hernandez AM;Tatar M
减少胰岛素/IGF信号增加许多动物的寿命。为了了解胰岛素/IGF如何介导果蝇的寿命，我们用胰岛素/IGF调节转录因子dFOXO在长寿胰岛素/IGF信号传导基因型中进行了染色质免疫沉淀测序分析。当胰岛素/IGF减少延长寿命时，激活素配体Dawdle被dFOXO结合和抑制。减少激活素信号传导改善老年果蝇肌肉中的性能和蛋白质稳态。通过Smad结合元件的激活素信号传导抑制肌肉内自噬特异性基因8a（Atg 8a）的转录，这是控制自噬速率的因素。Atg 8a在肌肉中的表达足以增加寿命。这些数据揭示了胰岛素信号传导如何通过控制激活素信号传导来调节衰老，激活素信号传导反过来控制自噬，这代表了长寿保证的潜在保守分子基础。虽然肌肉内激活素的减少自主地延缓了该组织的功能性衰老，但肌肉中的这些作用也减少了远离大脑的胰岛素样肽的分泌。大脑胰岛素分泌减少可能会通过减少全身胰岛素/IGF信号传导来增强长寿保障。众所周知，在许多情况下，胰岛素/IGF信号的减少减缓了衰老。这个过程需要叉头转录因子（FOXO）。FOXO调节许多基因的表达，与缓慢衰老相关的基因列表令人印象深刻。但是很少有数据表明FOXO实际上减缓衰老的机制或基因。在这里，我们确定了一个新的FOXO目标，磨蹭，果蝇中的激活素样配体。我们发现，肌肉中激活素信号的下调，而不是在脂肪组织中，导致寿命延长。部分是因为它抑制了Smox转录因子（一种Smad转录因子）对关键自噬基因Atg 8a的负转录抑制。这种双重信号级联自主地改善肌肉性能（在细胞和功能水平上测量），并非自主地延长寿命，因为它减少了大脑中胰岛素肽的分泌。这项工作开发了胰岛素/IGF信号传导的自主-非自主相互作用的新兴模型，作为衰老控制的系统综合机制。
Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling. It is widely known that reduced insulin/IGF signaling slows aging in many contexts. This process requires the forkhead transcription factor (FOXO). FOXO modulates the expression of many genes, and the list of those associated with slow aging is impressive. But there are few data indicating the mechanisms or genes through which FOXO actually slows aging. Here, we identify a novel FOXO target, dawdle, the Activin-like ligand in fruit flies. We show that down-regulation of Activin signaling in muscle, but not in adipose tissue, leads to extended lifespan. In part it does so when it alleviates the negative transcriptional repression of its Smox transcription factor (a Smad transcription factor) upon a keystone autophagy gene, Atg8a. This double signaling cascade autonomously improves muscle performance (measured at cellular and functional levels) and nonautonomously extends lifespan as it reduces the secretion of insulin peptides from the brain. The work develops the emerging model for interacting autonomous-nonautonomous roles of insulin/IGF signaling as a systems integrative mechanism of aging control.
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影响因子：
7.8
作者：
Bai H;Kang P;Tatar M
通讯作者：
Tatar M
影响因子：
7.7
作者：
Jennings, Barbara H.;Wainwright, S. Mark;Ish-Horowicz, David
通讯作者：
Ish-Horowicz, David
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
全基因组DFOXO靶标和对压力和胰岛素信号转导的转录组响应的拓扑。
影响因子：
9.9
作者：
Alic, Nazif;Andrews, T. Daniel;Giannakou, Maria E.;Papatheodorou, Irene;Slack, Cathy;Hoddinott, Matthew P.;Cocheme, Helena M.;Schuster, Eugene F.;Thornton, Janet M.;Partridge, Linda
通讯作者：
Partridge, Linda
影响因子：
4.8
作者：
Ding, Yan;Kim, Jin Kuk;Choi, Mary E.
通讯作者：
Choi, Mary E.