Exploring the cellular mechanisms of enhanced lifespan in bats

项目摘要/摘要 人类衰老的特征是生物和生理过程中的动态变化 影响健康和生活质量。鉴于快速老龄化的人口，具有特征和缓解 这些负面影响是生物学日益迫切的目标。实现这一目标的进展受到阻碍。 由于通常使用的、寿命较短的实验室动物(如小鼠)制造的工具不太理想 以确定包括人类在内的长寿哺乳动物的长寿过程。相比之下，蝙蝠， 为哺乳动物长寿提供了良好的研究体系。蝙蝠是最长寿的哺乳动物 他们的身体大小和极长的寿命在支系中至少进化了四次。许多蝙蝠也会保持它们的 在漫长的寿命中保持健康；例如，蝙蝠表现出较长的生育力，而且很少患癌症。 尽管这个群体有许多优势，但大多数蝙蝠实现它们的细胞过程 惊人的寿命在很大程度上仍是个未知数。这种疏忽在一定程度上是由于无法 研究人员需要准确估计野生蝙蝠的年龄，因为许多蝙蝠缺乏明显的 生物老化。因此，对蝙蝠衰老的研究大多局限于圈养的少数几种蝙蝠 或“标记和重新捕获”的克隆已经维持了几十年，其中组织收集是 必须是最小的。这个项目利用了一种新开发的基于甲基化的方法， 可靠地估计哺乳动物的时间年龄，包括野生蝙蝠，以克服这一障碍。这是一项新的 该方法将与野外和实验室工作相结合，对几类野生蝙蝠进行研究，以建立野生蝙蝠作为 长寿哺乳动物(如人类)细胞水平衰老的强大模型，并使用该模型开始 以确定延长寿命和减轻衰老相关发病率的细胞过程。初步数据 建议蝙蝠通过几个细胞过程将DNA损伤和细胞水平的衰老降至最低 涉及的具体过程可能因蝙蝠不同而不同。因此，每个额外采样的蝙蝠都有 有可能产生新的和信息丰富的结果。这个项目将通过完成两个项目来实现其目标 明确的目标。目标1是描述和比较与衰老相关的细胞过程之间的关系 以及来自叶甲科12个不同物种的野生蝙蝠组织的时间年龄， 包括寿命更长和寿命更短的代表。目标2是从功能上操纵和刻画 与衰老相关的细胞过程，如氧化应激、DNA损伤和衰老(以及其他)，使用 不同蝙蝠物种的原代细胞和IPSC细胞上的标准哺乳动物细胞培养方法，包括 目标1的特点。通过完成这些目标，该项目预计将确定细胞 与野生蝙蝠长寿有关的过程，可以减轻与衰老相关的发病率(例如，DNA 当在培养的细胞中操作时，会造成损伤和衰老)。有了这个关键的基础，这个项目是 预计将建立野生蝙蝠作为未来研究长寿哺乳动物细胞衰老的模型系统。

PROJECT SUMMARY/ABSTRACT Human aging is characterized by dynamic changes in biological and physiological processes that negatively impact health and quality of life. Given the rapidly aging human population, characterizing and mitigating these negative impacts is an increasingly urgent goal of biology. Progress toward this goal has been hampered by the fact that commonly used, shorter-lived lab animals (e.g., mouse) make less than ideal tools with which to identify the processes that drive longevity in longer-lived mammals, including humans. Bats, in contrast, provide an excellent study system for mammalian longevity. Bats are the longest-lived mammals relative to their body size and extreme longevity evolved at least four times in the clade. Many bats also maintain their health during their long lifespan; for example, bats display extended fertility and rarely if ever get cancer. Despite the numerous advantages of the group, the cellular processes by which most bats achieve their striking longevity remain largely unknown. This oversight has been driven, in part, by the inability of researchers to accurately estimate the chronological age of wild bats, given many bats’ lack of obvious signs of biological aging. As a result, studies of bat aging have been mostly limited to the few species for which captive or “mark and recapture” colonies have been maintained for decades, and in which tissue collection is necessarily minimal. This project takes advantage of a newly developed, methylation-based method that reliably estimates chronological age across mammals, including wild bats, to overcome this obstacle. This new method will be coupled with field- and lab- work on several clades of wild bats to establish wild bats as a powerful model for cellular-level aging in long-lived mammals, such as humans, and use this model to begin to identify cellular processes that drive longevity and mitigate aging-related morbidity. Preliminary data suggest that bats minimize DNA damage and cellular-level aging through several cellular processes, and that the specific processes involved likely vary from bat to bat. Each additional bat sampled therefore has the potential to yield novel and informative results. This project will achieve its goals through completion of two specific aims. Aim 1 is to characterize and compare the relationship between aging-related, cellular processes and chronological age in the tissues of wild bats from twelve diverse species from the Family Phyllostomidae, including longer and shorter -lived representatives. Aim 2 is to functionally manipulate and characterize aging-relevant cellular processes such as oxidative stress, DNA damage, and senescence (among others) using standard mammalian cell culture methods on primary and iPSC cells from diverse bat species, including those characterized for Aim 1. Through completion of these aims, the project is expected to identify cellular processes that are associated with longevity in wild bats and can mitigate aging-related morbidity (e.g., DNA damage, senescence) when manipulated in cells grown in culture. With this critical foundation, this project is expected to establish wild bats as a model system for future studies of cellular aging in long-lived mammals.