Grant: Project Grant

Stem cells are the progenitor cell populations that give rise to all tissues in our body, and are responsible for the stable propagation of our genomes into the next generation. In response to external and internal cues, stem cells commit to specific cell lineages in a process termed cell differentiation. In this proposal, we show that critically eroded and damaged chromosome ends (telomeres) allow differentiated, non-dividing stem cells to revert back to a proliferative state and permit the formation of stem cell tumors called teratomas. We will test the implications of this inappropriate rewiring of cell fate in age-associated disease. In this proposal we will: 1) Develop tools that enable us to characterize the unstably differentiated cells and the tumors that they form in mice. 2) We will assess the incidence of these inappropriately dividing cells in mouse tissues during aging. We will test whether their presence correlates with tissue dysfunction, and whether this dysfunction is reversible upon repair of damaged telomeres. 3) We will employ genetic techniques to selectively cull these inappropriately dividing cells in older animals, to determine if their removal ameliorates age-associated disease and tissue decline. In summary, we believe we have uncovered a mechanism that may be an extremely important means by which cellular aging leads to tissue aging and cancer development. We have developed genetic tools in our laboratory that will enable us to test whether critically eroded telomeres, and their ability to promote the inappropriate proliferation of differentiated cells, results in the persistence of abnormal cell types in old animals and tissues, and whether the removal of these cells improves animal health. These studies may have wide-ranging implications for our understanding of the aging process, and how to influence it to our advantage.