On a microscopic scale, the most extreme case of heterochronic transplantation is somatic cell nuclear transfer, which has emerged as the basis for modern-day cloning approaches (Gurdon et al., 1958). By transferring an adult cell nucleus to a de-nucleated oocyte, a new individual can be generated. This technique encapsulates the full potential of reversing the biological age of a somatic cell to that of the new embryo. Interestingly, this implies that methylation patterns in the transferred nucleus are likely to reset by cytosolic components in the oocyte, suggesting another potential mechanism for rejuvenation.
To recapitulate this effect without the introduction of complex microscopic procedures, scientists discovered four critical “reprogramming factors” (Yamanaka factors), which, when expressed in somatic cells, could effectively reverse the developmental status to that of early embryos, generating induced pluripotent stem cells (iPSCs). Interestingly, low epigenetic ages around zero were predicted when epigenetic clocks were applied to iPSC samples. Almost all clocks showed considerable epigenetic age decreases compared with dermal fibroblasts used as the source of fully reprogrammed iPSCs.
Similar characteristics were observed in mice. In the case of mice, clocks reported a range of epigenetic ages of the identical iPSCs. Taken together, most human and mouse clocks reach a consensus in establishing age reversal that occurs as a result of reprogramming, although consistent predictions of age in these cells across different models remain a challenge.