Linking Histone Modifications, HSF-1 activity and Lifespan

连接组蛋白修饰、HSF-1 活性和寿命

基本信息

批准号：
10508860
负责人：
Ursula H. Jakob
金额：
$ 22.62万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10508860
关键词：
Adult Affect Age Aging Animal Model Biological Biological Assay Biological Process Biology Biology of Aging Biosensor Caenorhabditis elegans Cells Climacteric Communities Complex Data Deposition Development Embryo Environment Epigenetic Process Eukaryota Event Future Gene Expression Genetic Goals HSF1 Heat shock factor Heat-Shock Response Histones Imaging Device Imaging Techniques Individual Individual Differences Individuality Larva Lead Life Link Longevity Maternal Age Molecular Monitor Mothers Motion Oocytes Organism Outcome Study Oxidation-Reduction Oxides Physiological Play Population Reactive Oxygen Species Research Resistance Role Sorting - Cell Movement Source Stress Testing Time Tissues Variant Work base experimental study fascinate follow-up genetic makeup healthspan heat shock transcription factor histone methylation histone modification imprint insight member neuronal cell body offspring oxidation sensor tool

项目摘要

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.

衰老领域最令人着迷的问题之一是：为什么有些生物体比其他生物体寿命更长？寿命差异不仅仅取决于基因构成或环境，这一点在以下情况下就变得很清楚：一项研究研究同基因生物，例如秀丽隐杆线虫。即使仔细地进行年龄同步和在统一的环境条件下培养，秀丽隐杆线虫种群中个体的寿命变化数倍。是什么导致了这种寿命差异？时钟何时设置？我们之前的工作证明同步的秀丽隐杆线虫种群中的个体在他们在早期发育过程中内源性活性氧（ROS）的水平。幼虫的分类根据其内源性氧化还原状态（即氧化与还原），然后是纵向生理学细胞生物学分析表明，氧化程度更高的幼虫所承受的压力显着增加抵抗力、成年期氧化还原状态更加降低以及寿命更长。我们发现这种增加抗应激性和寿命是由于 ROS 依赖性的 Set2 瞬时失活所致，Set2 是一种保守的 COMPASS 复合体的成员，该复合体负责 H3K4 的三甲基化（即 H3K4me3) 在真核生物中。据我们所知，这些研究不仅首次证明了氧化还原- 在生物学中调控组蛋白甲基化事件，但他们是第一个对早期生命如何发生机制提供见解的人事件可以延长寿命。我们现在将研究 H3K4me3 减少的机制发育过程中的水平会导致抗压能力增强并延长寿命。我们提出的研究以初步结果为指导，初步结果表明，全球死亡率下降之间存在迄今未知的联系。 H3K4me3 标记，以及热休克因子 HSF1 水平和活性的增加，HSF1 是最重要的因子之一。已知保守的长寿因素。我们将利用秀丽隐杆线虫的遗传工具来直接监测 H3K4me3 消耗对 HSF1 合成、稳定性和周转有影响，并在规定时间消耗 H3K4me3 水平点和特定组织中，以揭示生命周期中的个性何时、如何以及在哪些组织中出现。到确定发育性 ROS 变异的来源，我们将跟进令人兴奋的初步数据表明发育中的线虫幼虫（及其寿命）的氧化还原状态成反比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制见解兰辛效应是一种长期被认可但迄今为止主要是描述性的现象，它描述了母亲年龄与后代寿命呈负相关。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，以及随后发生的延缓衰老的事件。