Mechanisms that promote the homeostasis of the proteome, or proteostasis, can slow aging and decrease the incidence of age-related diseases. The aim of our research proposal is to define the regulation of proteostasis in stem cells and how this network impinges upon stem cell function and aging. Because experiments with human embryonic stem cells (hESCs) have demonstrated their capacity to replicate continuously in the absence of senescence, we hypothesize that these cells could provide a novel paradigm to study the regulation of proteostasis and its demise in aging.