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

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，人类的寿命更长，包括我们最近的生物亲戚黑猩猩。然而，我们非凡长寿的遗传和生理基础，以及人类衰老的潜在过程，仍然知之甚少。该项目使用比较分子方法，通过比较黑猩猩与人类中观察到的随年龄增长而发生的遗传调控变化，阐明人类独特的衰老和长寿模式。具体来说，研究人员将研究DNA的化学改变，称为甲基化。甲基化被证明是一个重要的机制，通过调节基因表达水平，在控制时间的生物过程，包括发展和潜在的老化。该项目的结果将允许识别两个物种中随年龄变化而受到不同调节的基因，从而帮助识别哪些生理机制（例如，DNA损伤修复或免疫功能）在人类生存到老年的过程中发挥关键作用。该项目具有重要的现实意义，因为人口正在以前所未有的速度老龄化，管理和治疗与年龄相关的医疗问题的需求正在迅速增长。该项目将有助于对研究生和本科生进行实验室和分析技术方面的培训，并将通过免费教育项目向公众传达与衰老相关的结果。最近越来越多的研究表明，随着人类年龄的增长，基因组中各位点的甲基化水平发生了强烈的变化，这种变化是如此可预测，以至于它们可以用来估计个体的实际年龄。此外，“甲基化年龄”的个体之间的轻微偏差似乎反映了生物衰老：甲基化年龄升高与死亡风险，虚弱增加，握力和肺功能下降，认知能力下降以及癌症和心血管疾病风险增加有关。因此，甲基化年龄代表了一种有价值的新方法，用于测量生物衰老，识别影响衰老速率的因素，并可能揭示生理衰老背后的遗传调控变化。目前的研究将从从0至59岁的个体中收集的100个黑猩猩DNA样本中产生全基因组甲基化组，并确定哪些位点显示甲基化水平随年龄变化。这些数据将与现有的人类数据集进行比较，以发现两个物种之间甲基化景观和甲基化老化率的差异。因此，该项目将甲基化年龄的研究扩展到跨物种的比较背景下，以阐明人类和其他灵长类动物之间生活史的根本差异的演变。