Novel longevity mechanisms regulated by insulin-like signaling

描述（由申请人提供）：影响衰老的各种机制首先在C. elegans，其中发现寿命通过减少胰岛素/IGF-1信号传导（rIIS）而增加，并且这种寿命延长需要转录因子β-16/FoxO，其被IIS抑制。In C.在线虫中，R16指导发育成幼虫滞育（dauer），其能够承受恶劣的条件，并且在许多rIIS场景中，dauer-like性状出现在成虫中。因此，一个著名的模型表明，rIIS减缓了C。在成年期，Elegans通过允许β-16激活与dauer相关的机制来衰老。但是，rIIS也可以扩展C。秀丽线虫的寿命很长，而不会诱导出类似道尔的特征。我们的新结果解释了后一个发现，即rIIS不仅可以通过激活dauer来延长寿命， 相关的过程，但也通过成年保护计划，涉及一些不同的下游机制。根据这个模型，dauer相关过程克服了转录因子SKN-1/Nrf的其他基本要求，这也被IIS抑制。通过确定一个IIS调节的长寿程序，似乎是从dauer发展途径的区别，这个模型开辟了新的途径，了解IIS如何影响衰老。 令人惊讶的是，响应于rIIS，SKN-1最显著地上调细胞外基质（ECM）基因，特别是特定的胶原蛋白。衰老导致人类ECM恶化，并带来毁灭性后果，以及C.优雅我们发现，rIIS和其他各种延长寿命的干预措施可以促进C. elegans成年人这种成年胶原/ECM基因表达通常是这些干预措施所需的长寿，除非rIIS诱导dauer性状。这些数据表明，ECM维护可能是广泛的重要寿命保证，一种新的模式，具有广泛的影响，为老龄化领域，并建议ECM维护的范例。 该项目将进一步测试和开发这些模型中的每一个，这些模型都是在我们的实验室中独特衍生的。在目标1中，它将测试我们假设的预测 与dauer相关的SKN-16活动克服了SKN-1对rIIS寿命的要求。这将涉及遗传分析，在dauer相关机制活跃或不活跃的rIIS条件下的β-16的表达谱，以及对一种或另一种条件可能重要的下游基因的鉴定（类似于胶原蛋白）。在目标2中，它将研究成年期胶原蛋白表达是否是长寿所必需的，因为它增强了角质层或其他结构的完整性，或者更多效性地影响衰老。它还将利用C. elegans进行筛选，以确定rIIS和其他长寿途径促进胶原蛋白维持的机制，从而确定影响衰老的新过程。这项工作对人类健康具有重要意义，因为IIS对寿命的影响似乎是保守的，而且还不知道长寿干预措施如何影响ECM，ECM的恶化在衰老中具有广泛的重要性。

DESCRIPTION (provided by applicant): Various mechanisms that influence aging were first identified in C. elegans, in which it was discovered that lifespan is increased by reduced insulin/IGF-1 signaling (rIIS), and that this lifespan extension requires the transcription factor DAF-16/FoxO, which is inhibited by IIS. In C. elegans, DAF-16 directs development into a larval diapause (dauer) that withstands harsh conditions, and in many rIIS scenarios dauer-like traits appear in adults. Accordingly, a prominent model suggests that rIIS slows C. elegans aging by allowing DAF-16 to activate dauer-associated mechanisms during adulthood. However, rIIS can also extend C. elegans lifespan robustly without inducing dauer-like traits. Our new results explain the latter finding by suggesting that rIIS can extend lifespan not only by activating dauer associated processes, but also through an adulthood protective program that involves some different downstream mechanisms. According to this model, dauer-associated processes overcome an otherwise essential requirement for the transcription factor SKN-1/Nrf, which is also inhibited by IIS. By identifying an IIS-regulated longevity program that seems to be distinguishable from the dauer developmental pathway, this model opens up new avenues for understanding how IIS affects aging. Surprisingly, in response to rIIS SKN-1 most prominently upregulates extracellular matrix (ECM) genes, especially particular collagens. Aging leads to ECM deterioration in humans, with devastating consequences, and to a decline in adulthood collagen expression in C. elegans. We find that rIIS and various other interventions that prolong life boost collagen expression in C. elegans adults. This adulthood collagen/ECM gene expression is generally required for longevity from these interventions, except when rIIS induces dauer traits. The data suggest that ECM maintenance may be broadly important for longevity assurance, a novel model that has wide-ranging implications for the aging field, and suggests paradigms for ECM maintenance. This project will further test and develop each of these models, which were derived uniquely in our lab. In Aim 1 it will test predictions of our hypothesis that dauer-related DAF-16 activities overcome the requirement for SKN-1 for rIIS longevity. This will involve genetic analyses, expression profiling of DAF-16 under rIIS conditions in which dauer-associated mechanisms are or are not active, and identification of downstream genes that may be important for one condition or the other (analogously to the collagens). In Aim 2, it will investigate whether adulthood collagen expression is needed for long life because it enhances integrity of the cuticle or other structures, or affects aging more pleiotropically. It wil also employ the advantages of C. elegans for screening to identify mechanisms through which rIIS and other longevity pathways promote collagen maintenance, thereby identifying new processes that influence aging. This work is significant for human health because the effects of IIS on longevity seem to be conserved, and because it is unknown how longevity interventions might influence the ECM, deterioration of which is broadly important in aging.