Great efforts have been placed on rejuvenation of aged cells in regenerative medicine research. Numerous studies demonstrate that the iPS reprogramming is not only able to alter cell fate, from terminally differentiated to pluripotent state, but also enable aged cells to adopt a more youthful state. The reprogramming process ameliorates many cellular hallmarks of aging, such as mitochondrial dysfunction, telomere length shortening, stem cell exhaustion, cellular senescence, and changes in histone marks.
During reprogramming of aged somatic cells, the expression of telomerase gene can be reactivated that attributes to the rejuvenation consequence (Marión and Blasco, 2010). In addition, the restoration of telomere length is observed during reprogramming aged fibroblasts to iPS cells (Lapasset et al., 2011a; Marion et al., 2009). Notably, certain types of genetic defects in telomerase components hindered the full restoration of telomerase activity and its ability to lengthen telomeres during reprogramming (Batista et al., 2011).
Furthermore, studies in reprogramming of aged fibroblasts show that the aging phenotypic mitochondrial dysfunction and the associated production of reactive oxygen species (ROS) are restored to a rejuvenated state in iPS cells and in their derivatives at early passages (Lapasset et al., 2011b; Prigione et al., 2011; Suhr et al., 2010)
Epigenetic dysregulation is a major driver of cellular damage observed during aging and in age-related disorders (Benayoun et al., 2015; Pollina and Brunet, 2011). The restoration of aging hallmarks to the youthful state during iPS reprogramming is mainly driven by epigenetic remodeling. For instance, iPS reprogramming of fibroblasts from Hutchinson–Gilford progeria syndrome (HGPS) patients results in restoration of age-associated epigenetic marks to wild-type levels (e.g., H3K9me3) (Liu et al., 2011a). Moreover, a recent study showed that iPS reprogramming erases age-associated epigenetic memory in aged cells showing the efficient restoration of epigenetic markers (e.g., 5hmC, H3K4me3, H3K9me3, and H3K27me3) and achieves enhanced rejuvenation in iPS-derived neurons compared with the neurons derived via direct conversion process (Yang et al., 2015).
Thus, based on the plastic and reversible nature of epigenetic mechanisms, epigenetic reprogramming/remodeling which referrers to changes in the stable transcriptional profile of a cell without alteration in DNA sequences could provide a promising avenue for therapeutics against age-related decline and diseases.