Aging in iPS cells

(iPSC) technology [1] holds the promise of recreating disease in vitro in a patient-specific manner. There has been considerable success in using iPSC models to study early-onset genetic diseases, such as our own work on familial dysautonomia [2] or primary herpes simplex encephalitis [3]. The modeling of late-onset diseases in iPSC-derived lineages has been more challenging and such studies often report phenotypes that inadequately recapitulate the disease (reviewed in [4]). Our recent study [5] demonstrates the failure of patient-specific donor cells to maintain age-associated markers during iPSC reprogramming and subsequent differentiation. Such rejuvenated iPSC-derived lineages therefore may not be suitable to model late-onset disease. Taking cues from a premature aging disorder known as Hutchinson-Gilford progeria syndrome (HGPS), we present a strategy for reintroducing age-like features in iPSC-derivatives towards the more faithful modeling of late-onset disease. Age is the most important risk factor in many late-onset disorders such as Parkinson's disease (PD) as illustrated by the fact that PD patients do not develop symptoms until later in life. Therefore, it is imperative to consider age as well as genetic mutations when attempting to model these diseases in vitro. Previously, it was unclear whether a donor cell from an old individual would maintain its age-associated properties following conversion into other cell fates ex vivo. However, recent studies have presented evidence that markers of cellular age, including mitochondrial fitness and telomere length, are reset to a young-like state when old donor fibroblasts are reprogrammed to iPSCs (reviewed in [6]). Indeed, our own study defines a broad set of age-associated markers, and we demonstrate the rejuvenation of old donor fibroblasts based on those markers. The corresponding iPSCs derived from old donors no longer exhibit features that distinguish old from young primary cells including abnormal nuclear morphologies, accumulated DNA damage, increased reactive oxygen specifies (ROS), reduced levels of a set of nuclear organization proteins, and loss of heterochromatin markers. We could not be sure, however, whether pluripotency simply suppresses " age " by downregulating age-related proteins such as progerin. Indeed HGPS iPSCs also show a loss of the Editorial age-associated markers at the pluripotency stage. Therefore, iPSCs were differentiated into a fibroblast-like cell in order to match the phenotype of the donor fibroblasts used for reprogramming. We were able to show that similar to the pluripotency stage, iPSC-derived fibroblasts from old donors appear " young " , suggesting that the cell's intrinsic molecular clock is …