On the Search for Reliable Human Aging Models: Understanding Aging by Nuclear Reprogramming

摘要

Reprogramming technologies, and particularly the generation of induced pluripotent stem cells (iPSCs), have demonstrated the possibility of personalized disease modeling in a dish. Importantly, the fact that pluripotent stem cells can give rise to all cell types of an organism, along with the technical progress allowing for their isolation, brings to mind fantasies like the fountain of youth and eternal regeneration and represents one of the most promising scientific fields with clinical implications. Furthermore, increasing evidence indicates that aging "defects" observed in patient somatic cells could be erased or alleviated by direct reprogramming towards pluripotency and rapidly recapitulated upon directed differentiation to specific cell lineages (Liu et al., Nature 472:221-225, 2011a). Thus, iPSC models of aging facilitate human aging studies by shortening the time required for physiological manifestation of aging-related defects from years, in the case of a human being, to days when stem cell models are applied. Moreover, the combination of gene-editing and iPSC models of aging will also allow for the generation of precisely targeted reporter cell lines of high value for studying normal differentiation processes and high throughput screens. However, a major concern regarding the use of iPSCs for disease modeling has to be taken into account prior to their broad application in drug discovery studies, which is that the use of patient-derived iPSCs bears another important experimental limitation, the lack of appropriate genetically matched control lines (Soldner et al., Cell 146:318-331, 2011; Liu et al., Cell Stem Cell 8:688-694, 2011b).