Genomic Instability as A Driver of Stem Cell Exhaustion
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SUMMARY Stem cell exhaustion is one of the key hallmarks of aging. In tissues throughout the body, there is a decline in stem cell number and function with age, leading to a loss of tissue homeostasis and regenerative capacity. Restoring youthful functionality to aged stem cells has been shown to improve the structure and function of aged tissues. As such, understanding the drivers of stem cell aging has the potential to reveal targets for rejuvenating tissue and even organismal aging. Despite the wealth of information on the phenotypic changes of stem cells with age, little is known about the underlying molecular mechanisms that drive those changes. Among those potential molecular mechanisms, we have explored genomic instability (another hallmark of aging) as a feature of aged stem cells. In the proposal, we propose that genomic instability and the accumulation of DNA damage underlie the age-related decline in stem cell number. Using muscle stem cells (MuSCs) as a model system, we have reported evidence of increases in DNA damage in aged MuSCs. This accumulation of DNA damage leads to an increased propensity of MuSCs to undergo a form of cell death called mitotic catastrophe when they attempt to enter the cell cycle when they are called upon to repair muscle. We found that this increased risk of cell death is associated with an age-related decrease in p53 activity, and that stabilizing or enhancing p53 reduces mitotic catastrophe and promotes muscle repair in aged mice. At the same time, we have found that that ATR, a key mediator of the DNA damage response (DDR), is highly active in quiescent MuSCs. The primary goal of the studies of this proposal are to explore the mechanistic relationship between two hallmarks of aging - genomic instability and stem cell exhaustion. Toward this goal, we will pursue three independent Specific Aims. In Aim 1, we will explore the role of p53 in the regulation of MuSC number during aging. We will use gain-of-function and loss-of-function genetic models to test this hypothesis. In Aim 2, we will examine the role of ATR in MuSC maintenance with age. These studies will include an unbiased phosphoproteomic screen to determine downstream mediators of ATR in MuSC maintenance. Aim 3 will focus on a p53 target gene, NDRG1, which has been shown to regulate genomic integrity in cancer cells under conditions of low proliferative states. In Preliminary Studies, we have found that NDRG1 slows MuSC activation, which is essential for the repair of DNA damage prior to cell division. We will examine the role of NDRG1 in MuSC activation during aging, again using gain-of-function and loss-of-function approaches. Together, these studies will advance our understanding of stem cell aging and highlight approaches to restore youthful function to aged stem cells as a way to enhance tissue homeostasis and repair in older individuals.
