Doctoral Dissertation Research: Cellular Senescence in Human Age-Related Mortality and Lifespan

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。与非人类灵长类动物相比，现代人寿命更长，而且往往在高龄时仍保持活跃。然而，人类在生物学和衰老时间方面的差异的进化并没有得到很好的理解。这篇博士论文使用基于实验室的细胞实验来识别人类基因组中充当调节衰老“开关”的元素。通过定义这些开关的基因序列是如何在人类中进化的，研究人员增加了对人类衰老和生命史进化的当前理解。对细胞衰老过程的关注也可以为其他基础和临床研究界提供信息。在与博物馆和教学中心的合作下，研究人员开发了展览和在线学习材料，以更广泛地强调人类衰老进化和进化论的研究。该项目涉及对本科生的培训，包括那些来自STEM中代表性不足的背景的学生，他们将从事生物人类学和相关领域的职业。与黑猩猩相比，人类寿命更长，这一观察结果表明，衰老的生物学机制存在进化差异。一种假设是，在人属的进化过程中，细胞衰老可能已经减速。在这个项目中，研究人员使用人类膝关节作为模型系统来检查组织衰退和功能障碍。实验产生功能失调的膝关节软骨细胞，使用下一代测序测定来表征细胞调节网络的变化，包括蛋白质表达和编码这些蛋白质的基因如何被调节，这些变化定义了衰老过程。然后将该实验数据集与计算遗传分析相结合，以了解人类序列进化在修改这些网络中的作用以及可能导致的组织衰退的后果。这些公开的数据集可以作为生物人类学、衰老、基因调控和关节生物学等领域研究的重要资源。鉴于缺乏关节组织细胞的综合数据集，特别是在衰老和细胞衰老的背景下，这项研究对生物医学界和研究与年龄相关的关节疾病（如骨关节炎）的人具有潜在的兴趣。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Modern humans are longer-lived relative to non-human primates and often remain active at advanced ages. However, the evolution of differences in the biology and timing of aging in humans is not well understood. This doctoral dissertation uses laboratory-based cellular experiments to identify elements of the human genome that act as ‘switches’ to regulate aging. By defining how the genetic sequences of these switches have evolved in humans, the investigators add to the current understanding of human senescence and life history evolution. The focus on cellular aging processes also may inform other basic and clinical research communities. In conjunction with museums and pedagogical centers, the researchers develop exhibits and online learning materials to highlight this research on the evolution of human aging and evolutionary theory more broadly. The project involves the training of undergraduate students, including those from underrepresented backgrounds in STEM, for careers in biological anthropology and related fields.The observation of elongated lifespan in humans relative to chimpanzees suggests evolutionary differences in the biological mechanisms of aging. One hypothesis is that during the evolution of the genus Homo there may have been deceleration in cellular senescence. In this project, the researchers use the human knee joint as a model system for examining tissue decline and dysfunction. Experiments are performed to generate dysfunctional knee cartilage cells, using next-generation sequencing assays to characterize shifts in cell regulatory networks, both in the expression of proteins and how the genes encoding these proteins are regulated, that define the senescence process. This experimental dataset is then combined with computational genetic analyses to understand the role of human sequence evolution in modifying these networks and the consequences to tissue decline that may have resulted. These publicly-available datasets can serve as an important resource for research in the fields of biological anthropology, aging, gene regulation, and joint biology. Given the dearth of comprehensive datasets for joint tissue cells, particularly in the context of aging and cellular senescence, this research is of potential interest to the biomedical community and those studying age-related joint diseases such as osteoarthritis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.