Doctoral Dissertation Research: Epigenetics of primate longevity

博士论文研究：灵长类长寿的表观遗传学

• 批准号: 1733896
• 负责人: David Watts
• 金额: $ 2.52万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1733896&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Epigenetics; primate; Doctoral; Dissertation; Research; Epigenetics; primate

Humans are long-lived compared with other mammals, including our closest living biological relatives, the chimpanzees. Yet the genetic and physiological bases of our remarkable longevity, as well as the processes underlying human aging, remain poorly understood. This project uses a comparative molecular approach to elucidate the unique human pattern of aging and long life by comparing the genetic regulatory changes that occur with age in chimpanzees with those observed in humans. Specifically, researchers will investigate the chemical alterations to DNA called methylation. Methylation is proving to be an important mechanism, via the adjustment of gene expression levels, in the control of temporal biological processes, including development and potentially aging. Results of this project will allow for the identification of genes that are differently regulated with age in the two species and thereby help identify which physiological mechanisms (for example, DNA damage repair or immune function) play critical roles specifically in human survival to advanced ages. This project has important current relevance because human populations are aging demographically at an unprecedented rate, and the need to manage and treat age-related medical issues is rapidly growing. This project will contribute to the training of graduate and undergraduate students in laboratory and analytical techniques and will relay results related to aging to members of the public through free educational programming.A growing body of recent research demonstrates a strong pattern of change in methylation levels at sites across the genome with age in humans that are so predictable that they can be used to estimate individual chronological age. Moreover, slight deviations among individuals in "methylation age" seem to reflect biological aging: elevated methylation age is associated with mortality risk, increased frailty, decreased grip strength and lung function, diminished cognitive performance, and increased cancer and cardiovascular disease risk. Thus, methylation age represents a valuable new approach for measuring biological aging, identifying factors that influence aging rate, and potentially uncovering the genetic regulatory changes that underlie physiological aging. The current study will generate genome-wide methylomes from 100 chimpanzee DNA samples collected from individuals aged 0 to 59 and identify which sites show changes in methylation levels with age. These data will be compared with existing human datasets to discover differences in the methylome landscape and methylation aging rate between the two species. Thus, this project extends the study of methylation age to a cross-species comparative context to illuminate the evolution of fundamental differences in life history between humans and other primates.

与其他哺乳动物相比，人类长期存在，包括我们最近的生物亲戚黑猩猩。然而，我们显着寿命的遗传和生理基础以及人类衰老的过程仍然知之甚少。该项目使用一种比较分子方法，通过比较与黑猩猩年龄的遗传调节变化与人类观察到的遗传调节变化，从而阐明了人类衰老和长寿的独特模式。具体而言，研究人员将研究称为甲基化的DNA的化学改变。通过调整基因表达水平，在时间生物学过程（包括发育和潜在衰老）中，甲基化是一种重要的机制。该项目的结果将允许鉴定两个物种中与年龄不同调节的基因，从而有助于确定哪些生理机制（例如，DNA损伤修复或免疫功能）在人类对高级年龄的生存中起着至关重要的作用。该项目具有当前重要的相关性，因为人口在人口统计学上以前所未有的速度衰老，并且需要管理和治疗与年龄相关的医疗问题的需求正在迅速增长。该项目将有助于对实验室和分析技术的研究生和本科生的培训，并将通过免费的教育计划将与衰老有关的结果传达给公众。越来越多的研究表明，越来越多的研究表明，在人类年龄的基因组中，甲基化水平的强烈变化模式随着人类的年龄而言，可以预测，以至于可以预测，以至于可以估计单独的成熟年龄。此外，“甲基化年龄”中个体的轻微偏差似乎反映了生物衰老：甲基化年龄升高与死亡率风险相关，脆弱性增加，抓地力降低和肺功能，认知能力降低，癌症和心血管疾病的风险增加。因此，甲基化年龄代表了一种测量生物老化，识别影响衰老率的因素以及潜在地揭示生理衰老构成的遗传调节变化的有价值的新方法。当前的研究将从0至59岁个个体收集的100个黑猩猩DNA样品中产生全基因组甲基组，并确定哪些位点随着年龄的增长而显示出甲基化水平的变化。这些数据将与现有的人类数据集进行比较，以发现两种物种之间甲基甲基景观和甲基化衰老率的差异。因此，该项目将甲基化年龄的研究扩展到了跨物种比较上下文，以阐明人类与其他灵长类动物之间人生历史的基本差异的演变。