Exploring the cellular mechanisms of enhanced lifespan in bats

项目总结/摘要 人类衰老的特征是生物和生理过程的动态变化， 影响健康和生活质量。鉴于人口迅速老龄化， 这些负面影响是生物学日益紧迫的目标。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（例如，鼠标）使不太理想的工具， 以确定驱动长寿哺乳动物（包括人类）长寿的过程。相反，蝙蝠， 为哺乳动物寿命提供了一个极好的研究系统。蝙蝠是最长寿的哺乳动物， 它们的体型和极端长寿在进化枝中至少进化了四次。许多蝙蝠也保持着 蝙蝠在其漫长的生命周期中保持健康;例如，蝙蝠表现出延长的生育能力，很少患癌症。 尽管这一群体有许多优势，但大多数蝙蝠实现其功能的细胞过程 惊人的长寿在很大程度上仍是未知的。这一疏忽的部分原因是， 由于许多蝙蝠缺乏明显的衰老迹象， 生物老化因此，对蝙蝠衰老的研究大多局限于少数几个物种， 或“标记和重新捕获”的殖民地已经维持了几十年，其中组织收集是 必须是最小的。该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实际年龄，包括野生蝙蝠，以克服这一障碍。这个新 这种方法将与野外和实验室对几个野生蝙蝠分支的研究相结合，以建立野生蝙蝠作为一种 在长寿的哺乳动物，如人类，细胞水平老化的强大模型，并使用此模型开始 以确定促进长寿和减轻衰老相关发病率的细胞过程。初步数据 表明蝙蝠通过几个细胞过程最大限度地减少DNA损伤和细胞水平的衰老， 所涉及的具体过程可能因蝙蝠而异。因此，每增加一只蝙蝠， 产生新颖和信息丰富的结果的潜力。该项目将通过完成两个 具体目标。目的1是表征和比较与衰老相关的细胞过程之间的关系， 和年代年龄的野生蝙蝠的组织从12个不同的物种从家庭Phyllostomidae， 包括长寿和短命的议员。目标2是功能性地操作和表征 衰老相关的细胞过程，如氧化应激，DNA损伤和衰老（除其他外），使用 在来自不同蝙蝠物种的原代和iPSC细胞上的标准哺乳动物细胞培养方法，包括那些 目标1的特征。通过完成这些目标，该项目预计将确定蜂窝 与野生蝙蝠的寿命相关并可减轻衰老相关的发病率的过程（例如，DNA 损伤、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.