Comparative Genomics of Longevity

概要：这项计划项目资助（PPG）的总体目标，题为“比较基因组学， 长寿，”是确定负责健康和长寿的分子机制，重点是 基因组/表观基因组的稳定性在长寿啮齿类动物物种，然后制定战略，以适应这些 有利于人类健康的机制。啮齿动物是比较衰老研究的理想群体，因为它们 尽管它们的寿命非常不同，在小鼠中为2-4年， 裸鼹鼠、海狸、豪猪和松鼠的寿命超过20年。表征 负责这种寿命差异的过程可能使干预衰老的发展成为可能。 预防、延缓或治疗与年龄有关的疾病的过程。因此，这个PPG的中心假设是， 长寿物种已经进化出更有效的机制来维持基因组/表观基因组的稳定性， 预防与年龄有关的疾病，这可以延长其他物种的健康寿命。上 在PPG阶段，我们生成了支持我们中心假设的令人兴奋的数据。具体来说，我们发现 DNA双链断裂修复作为一种与长寿密切相关的机制;我们能够提高 通过引入来自海狸的特定氨基酸变化，在小鼠细胞中进行DNA修复;我们表明， 裸鼹鼠透明质酸合成酶2基因改善小鼠健康;我们获得的证据表明，突变率 在短寿命物种中更高，我们开发了一个报告小鼠生物学年龄的模型， 长寿物种的多组学特征。该PPG由四个高度集成的 项目和三个核心。项目1（Vera Gorbunova）的重点是负责提高效率的机制， 长寿物种的基因组/表观基因组稳定性。项目2（Andrei Seluanov）研究了 最长寿的啮齿类动物裸鼹鼠的长寿和抗癌能力。项目3（扬·维耶格） 研究长寿物种是否具有较低的突变和表突变频率， 吞吐量单小区方法。项目4（Vadim Gladyshev）使用组学方法来识别基因， 参与基因组和表观基因组稳定性的途径，这些途径在长寿物种中受到差异调节。的 研究小组由五名致力于长寿研究的研究人员组成，他们是比较研究方面的专家。 生物学和DNA修复（Gorbunova），抗癌和长寿啮齿动物（Seluanov），诱变和 高通量、单细胞方法（Vijg）、比较基因组学（Gladyshev）和生物信息学（Zhang， 核心C）。此外，该团队还开发了一系列原始啮齿动物细胞和组织，以及裸鼹鼠。 菌落，特别是为了促进寿命的比较研究（Seluanov，核心B）。这个专家的集合 让我们对长寿的生物学有了前所未有的了解。这支调查小组的地位独特， 使用细胞、分子和基因组方法相结合的方法进行跨物种寿命的研究。

SUMMARY: The overarching goal of this Program Project Grant (PPG), entitled “Comparative Genomics of Longevity,” is to identify molecular mechanisms responsible for health and longevity, with the focus on genome/epigenome stability in long-lived rodent species, and then develop strategies to adapt these mechanisms to benefit human health. Rodents are an ideal group for comparative aging studies because they are phylogenetically related, even though their lifespans are extremely diverse, ranging from 2-4 years in mice and rats to over 20 years in naked mole rats, beavers, porcupines, and squirrels. Characterization of the processes responsible for this disparity in lifespan may enable the development of interventions in the aging process to prevent, delay or cure age-related diseases. The central hypothesis of this PPG, therefore, is that long-lived species have evolved more efficient mechanisms to maintain genome/epigenome stability and prevent age-related diseases, which can be adapted to extend the healthspan of other species. In the first phase of the PPG, we generated exciting data that support our central hypothesis. Specifically, we identified DNA double strand break repair as a mechanism that strongly correlates with longevity; we were able to improve DNA repair in mouse cells by introducing specific amino acid changes from the beaver; we showed that the naked mole rat hyaluronan synthase 2 gene improved mouse health; we obtained evidence that mutation rates are higher in short-lived species, we developed a model that reports the biological age of mice, and we identified multiple omics profiles characteristic of long-lived species. This PPG is comprised of four highly integrated projects and three cores. Project 1 (Vera Gorbunova) is focused on mechanisms responsible for more efficient genome/epigenome stability in long-lived species. Project 2 (Andrei Seluanov) studies mechanisms responsible for longevity and cancer-resistance of the longest-lived rodent, the naked mole rat. Project 3 (Jan Vijg) investigates whether long-lived species have lower frequencies of mutations and epimutations using novel, high throughput single-cell approaches. Project 4 (Vadim Gladyshev) uses omics approaches to identify genes and pathways involved in genome and epigenome stability that are differentially regulated in long-lived species. The research team consists of five investigators dedicated to longevity research who are experts in comparative biology and DNA repair (Gorbunova), cancer-resistance and long-lived rodents (Seluanov), mutagenesis and high throughput, single-cell approaches (Vijg), comparative genomics (Gladyshev), and bioinformatics (Zhang, Core C). Moreover, the team has developed a collection of primary rodent cells and tissues, and naked mole rat colonies, specifically to facilitate comparative studies of longevity (Seluanov, Core B). This assembly of expertise allows unprecedented insight into the biology of longevity. This team of investigators is uniquely positioned to pursue studies of longevity across species using a combination of cell, molecular, and genomic approaches.