Exploring the cellular mechanisms of enhanced lifespan in bats

探索蝙蝠寿命延长的细胞机制

• 批准号: 10509822
• 负责人: Vincent J. Lynch
• 金额: $ 24.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10509822
• 关键词: Advanced Development; Age; Aging; Animals; Antioxidants; Biological Aging; Biological Models; Biological Process; Biology; Body Size; Cell Aging; Cell Culture Techniques; Cell Line; Cell model; Cell physiology; Cells; Chiroptera; Chronology; Coupled; DNA Damage; Data; Disease; Family; Female; Fertility; Foundations; Future; Goals; Health; Human; Individual; Investigation; Longevity; Malignant Neoplasms; Mammalian Cell; Mammals; Metabolic; Methods; Methylation; Mitochondria; Modeling; Morbidity - disease rate; Mus; Organism; Oxidative Stress; Phenotype; Physiological Processes; Population; Process; Quality of life; Research; Research Personnel; Resources; Sampling; Scientist; Stress; Study models; System; Taxon; Time; Tissue Banks; Tissues; Virus; Work; Zoonoses; age related; base; cell type; healthspan; healthy aging; human old age (65+); induced pluripotent stem cell; insight; male; metabolic rate; novel; response; senescence; theories; tool; trait

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.

项目摘要/摘要 人衰老的特征是生物学和物理过程的动态变化，这些变化是负面的 影响健康和生活质量。鉴于人口迅速衰老，表征和缓解 这些负面影响是生物学越来越紧迫的目标。朝着这个目标的进步受到了阻碍 通过常用的，较短的实验室动物（例如，鼠标）的事实少于理想的工具 确定在包括人类在内的长寿哺乳动物中驱动寿命的过程。相反，蝙蝠 为哺乳动物寿命提供出色的研究系统。蝙蝠是最长的哺乳动物 他们的身体大小和极端寿命在进化枝中至少进化了四次。许多蝙蝠也保持了他们的 长期寿命的健康；例如，蝙蝠表现出延长的生育能力，如果曾经患有癌症，很少会出现。 尽管该组具有许多优势，但大多数蝙蝠实现的细胞过程 惊人的寿命仍然很大。这种疏忽的部分原因是 鉴于许多蝙蝠缺乏明显的迹象 生物衰老。结果，对蝙蝠衰老的研究主要仅限于占圈的少数物种 或“标记和重新捕获”菌落已维持数十年，在其中收集组织 一定很少。该项目利用了一种新开发的基于甲基化的方法 可靠地估计包括野生蝙蝠在内的跨哺乳动物的年代年龄，以克服这一障碍。这个新 方法将与几个野生蝙蝠的野外和实验室结合起来，以建立野蝙蝠作为一个 长寿哺乳动物（例如人类）的细胞水平衰老的强大模型，并使用此模型开始 确定驱动寿命并减轻与衰老相关的发病率的细胞过程。初步数据 建议通过几个细胞过程将蝙蝠最大程度地减少DNA损伤和细胞水平衰老，并且 涉及的特定过程可能因蝙蝠而异。因此，每增加一次蝙蝠采样 潜在产生新颖和信息丰富的结果。该项目将通过完成两个实现目标 具体目标。目标1是表征和比较与衰老相关的蜂窝过程之间的关系 来自来自phyllostomidae家族的十二种潜水员物种的野生蝙蝠组织的年龄和年龄 包括更长和较短的寿命代表。目标2是在功能上操纵和表征 使用衰老相关的细胞过程，例如使用氧化应激，DNA损伤和感应（等） 来自潜水蝙蝠物种的初级和IPSC细胞的标准哺乳动物细胞培养方法，包括 特征是目标1。通过完成这些目标，该项目有望识别蜂窝 与野生蝙蝠中寿命相关的过程并可以减轻与衰老相关的发病率（例如，DNA 损害，感应）当在培养物中生长的细胞中操纵时。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一种模型系统，用于对长寿命哺乳动物的细胞衰老的未来研究。