Linking Histone Modifications, HSF-1 activity and Lifespan

老龄化领域最令人着迷的问题之一是：为什么一些生物体比其他生物体活得更长？ 寿命的变化并不仅仅是基于基因组成或环境变得清晰 一个研究同基因生物，如秀丽隐杆线虫。即使当仔细地同步年龄和 在统一的环境条件下培养，线虫种群中个体的寿命 有好几倍的差异。是什么导致了寿命的变化？时钟是什么时候设置的？我们之前的工作 证明线虫种群的个体在个体间表现出高度的差异 它们在早期发育过程中的内源活性氧(ROS)水平。幼虫的分选 根据它们的内源性氧化还原状态(即，氧化与还原)，然后是纵向生理 细胞生物学分析表明，氧化程度较高的幼虫显著增加了压力。 抵抗力，成年期氧化还原状态更低，寿命更长。我们发现，这一增长 抗逆性和寿命是由于一种保守的、依赖ROS的瞬时失活的Set2 COMPASS复合体的成员，该复合体负责H3K4的三甲基化(即， H3K4me3)。据我们所知，这些研究不仅提供了氧化还原的第一个证明- 生物学中受调控的组蛋白甲基化事件，但他们是第一个提供关于早期生命的机械性见解的人 运动可以延长寿命。我们现在将研究H3K4me3减少的机制 在发育过程中的水平会导致更强的抗压能力和延长寿命。我们建议的研究 是由初步结果指导的，这些结果表明，到目前为止尚不清楚的是， H3K4me3标志，以及热休克因子HSF1水平和活性的增加，是最 已知的保守长寿因素。我们将利用线虫中的遗传工具来直接监测 H3K4me3消耗对HSF1合成、稳定性和周转的影响，并在规定的时间消耗H3K4me3水平 点和特定的组织，以揭示生命周期中的个性何时、如何以及在什么组织中出现。至 确定发育中的ROS变异来自哪里，我们将跟踪令人兴奋的初步数据 这表明线虫幼虫发育过程中的氧化还原状态(以及它们的寿命)是相反的 与母亲的年龄和氧化还原状态有关。这些研究可能会带来新的机械论见解。 进入兰辛效应，这是一种很早就被认识到但到目前为止主要是描述性的现象，描述了 母亲年龄与子代寿命呈负相关。这些研究的结果 将为导致早期生命氧化还原变化的潜在机制提供全新的见解， 以及随后的延缓衰老的事件。

One of the most fascinating questions in the aging field is: Why do some organisms live longer than others? That lifespan variations are not solely based on the genetic makeup or the environment becomes clear when one studies isogenic organisms, such as Caenorhabditis elegans. Even when carefully age-synchronized and cultivated under uniform environmental conditions, the lifespan of individuals within a population of C. elegans varies several-fold. What causes this lifespan variation and when is the clock set? Our previous work demonstrated that individuals of a synchronized C. elegans population show high inter-individual differences in their levels of endogenous reactive oxygen species (ROS) during early development. Sorting of larval worms according to their endogenous redox states (i.e., oxidized vs. reduced) followed by longitudinal physiological and cell-biological assays revealed that larval worms that are more oxidized have significantly increased stress resistance, a more reduced redox state during adulthood and a longer lifespan. We found that this increase in stress resistance and lifespan is due to the ROS-dependent transient inactivation of Set2, a conserved member of the COMPASS complex, the complex which is responsible for the trimethylation of H3K4 (i.e., H3K4me3) in eukaryotes. To our knowledge, these studies not only provide the first demonstration of a redox- regulated histone methylation event in biology, but are the first to give mechanistic insights into how early life events can increase longevity. We will now investigate the mechanisms by which a decrease in H3K4me3 levels during development leads to increased stress resistance and extended lifespan. Our proposed studies are guided by preliminary results, which demonstrate a hitherto unknown link between the global reduction in H3K4me3 marks, and the increase in the levels and activity of the heat shock factor HSF1, one of the most conserved longevity factors known. We will exploit genetic tools in C. elegans to directly monitor the effects of H3K4me3 depletion on HSF1 synthesis, stability and turnover, and deplete H3K4me3 levels at defined time points and in specific tissues to reveal when, how and in what tissues the individuality in lifespan arises. To determine where developmental ROS variations come from, we will follow up on exciting preliminary data suggesting that the redox states in developing C. elegans larvae (and hence their lifespan) are inversely related to the age and redox state of the mother. These studies are likely to shed new mechanistic insights into the Lansing Effect, a long recognized but so far mostly descriptive phenomenon that describes the negative relationship between the maternal age and the lifespan of the offspring. The results of these studies will provide fundamentally new insights into the underlying mechanisms that lead to early life redox variations, and the subsequent events that delay aging.