Induced pluripotent stem (iPS) cells are a novel source for derivation of donor populations in cell replacement therapy. However, because the major applications of iPS cells relate to diseases predominately affecting elderly populations such as heart failure, stroke, and neurodegenerative disease, it is likely that the majority of iPS cells derived for future clinical use will be isolated from senescent and aged somatic cell populations of elderly patients. Currently it is not known how aging and senescence affect the capacity of somatic cells to be reprogrammed. It is also not known whether aging and senescence affect the subsequent differentiation of iPS cells and the efficiency of their iPS cell derivatives. This NIH Challenge Grant proposal will address these questions. We propose to derive iPS cell lines from fibroblasts of elderly (>70 years old), middle-age (40-50 years old), and newborn (1-2 week old) patients. We will assess whether aging and senescence may impair reprogramming efficiency as well as gene expression, capacity for pluripotency, and sensitivity to oxidative stress and DNA damage in iPS cells. We will differentiate iPS cells derived from patients of all age groups into functional endothelial cells and compare the in vitro and in vivo functions of these cells with endothelial cells derived from human embryonic stem cells and human microvascular endothelial cells (HMECs). Finally, we will compare iPS cells derived from elderly patients with a rapidly aged line of iPS cells in which the Sirtuin (silent mating type information regulation 2 homolog) 6 (also known as SIRT6) gene has been knocked down. Collectively, these results will provide valuable information for future clinical translation of patient-specific iPS cell therapies. PUBLIC HEALTH RELEVANCE: Aging has been shown to impair the integrity, function, and proliferative capacity of many adult stem cells such as hematopoietic stem cells, muscle satellite cells, and cardiac progentior cells. We propose to analyze the effects of aging and senescence upon somatic cells that undergo cellular reprogramming into iPS cells. This study will provide valuable insight into the process of aging and yield useful information on how patient-specific pluripotent cells may be used in elderly patients suffering from such diseases as heart failure, stroke, and neurodegenerative disease.