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.
We hypothesize that stem cells could have increased mechanisms to maintain the stability of their proteome. Proteostasis landscape schemes adapted from Douglas & Dillin (2010).
FOXO4, a forkhead transcription factor, regulates proteasome activity in human embryonic stem cells (hESCs) and is necessary for hESCs differentiation into neural cells. Therefore, our results establish a novel regulation of protein homeostasis in hESCs that links longevity and stress resistance in invertebrates with hESC function and identity (Vilchez et al, 2012b, Vilchez et al 2013). Representative images of immunocytochemistry after neural differentiation assay. Neuronal marker: β-III-tubulin, green. Nuclear staining: DAPI, blue Staining: David Vilchez, Leah Boyer.
Representative images of RFP expressed under control of the rpn-6 promoter. Rpn-6 expression is increased in the long-lived glp-1(e2141) animals relative to N2 worms. Scale bar, 100 µm (Vilchez et al, 2012a). Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders.