Using an in vivo multi-lifetime model to test mechanisms of aging

Project Summary Species exhibit stereotypic lifespans, suggesting an intrinsic hardwired limit. Our preliminary data shows that a population of mouse T cells can be iteratively boosted in vivo and passaged among young mice for >11 years (~4 mouse lifespans). This multi-lifespan T cell population remains functional, does not undergo unrestrained cell division, and like young memory T cells, undergoes rapid proliferative bursts upon further antigen/mitogen stimulation. We have now generated 10 indepdent ongoing cohorts of cells, ranging from 6-66 total boosts over 1-11 years, to study mechanisms by which functional cells can exceed their species’ lifespan while retaining cell identity, functional and proliferative competence, accumulating perhaps 100s or even 1000s of cell divisions, while not exhibiting signs of uncontrolled proliferation. Specific aims will reevaluate the Hayflick Limit, assess mutational burden and the accumulation of transcriptional noise, test whether a young host environment is responsible for maintaining everlasting functional persistence of transferred T cells, and evaluate metabolic adaptations that may support extreme longevity and maintenance of proliferative potential. Our long-term goal is to understand how a population of mammalian somatic cells has adapted the capacity to maintain vitality despite multi- lifetime chronological aging and an excessive history of proliferation, and to ultimately apply newly learned concepts and mechanisms to extend human health span. .