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

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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.