Reprogramming using overexpression of the Yamanaka factors captures a portion of the changes that take place in early embryonic development, in the creation of youthful embryonic stem cells from old germline cells. Reprogramming can erase cell state, slowly turning adult somatic cells into what are known as induced pluripotent stem cells, analogous to embryonic stem cells. But researchers have realized that the potentially far more interesting outcome is that prior to transformation, cells shift their epigenetic patterns towards a more youthful configuration. This reverses age-related mitochondrial dysfunction, and likely many other detrimental changes in cell behavior.
Thus the focus of reprogramming in academia and industry is shifting from the production of pluripotent cells for research and cell therapies to the rejuvenation of cells in aged living tissue. Researchers are earnestly seeking therapeutic modalities that can strike the balance between enough exposure to reprogramming factors to produce epigenetic rejuvenation, but not so much as to cause cells in tissue to become pluripotent and cancerous. This partial reprogramming is a challenge, but serious efforts to reach this goal are underway.
It has long seemed that the first rejuvenation therapies to reach the clinic and be demonstrated to slow aging in humans would be forms of senolytic drug capable of selectively clearing senescent cells. Groups working on partial reprogramming appear to be catching up rapidly, however. Efforts to build therapies atop the present understanding of partial reprogramming are now backed by massively greater funding than senolytic research and development. The field is moving rapidly as a consequence. With this as a background, the authors of today's open access review paper cast an eye over the present state of partial reprogramming as a basis for rejuvenation. It is an interesting read.
The long and winding road of reprogramming-induced rejuvenation
Epigenetic biomarkers of aging (aging clocks) can predict biological age through a variety of training approaches, even when based only on the variance of DNA methylation during aging. Interestingly, reacquisition of the lost epigenetic information may be observed during the natural rejuvenation process that occurs during early embryogenesis as well as during cell reprogramming. These strategies are in line with the notion of reprogramming-induced rejuvenation (RIR), a recent discovery wherein old cells can revert to a younger state upon transcription factor or chemical treatments. RIR is commonly accomplished through partial cell reprogramming, a method in which cells transiently undergo an induced pluripotent stem cell (iPSC) reprogramming. In this perspective, we discuss recent advances in this area, offer insights how they are related to the nature of aging and rejuvenation, and highlight potential advantages and drawbacks of this RIR and its translational potential.
It was shown that partial cell reprogramming can enhance the physiological function of human muscle stem cells, ameliorate the aging mouse transcriptome and metabolome in vivo, rejuvenate human dermal fibroblasts on a multi-omics level, and reverse the epigenetic clock in vitro. Furthermore, partial reprogramming can restore visual function in mice, prevent age-related physiological changes, and extend the remaining lifespan in wild-type mice. Present evidence suggests that pluripotency is not inherently linked to the rejuvenation process. However, it remains unclear whether pluripotency or certain transitionary cell states can be completely uncoupled from rejuvenation. A key question to be investigated is whether certain components contributing to biological age reversal can rejuvenate the entire epigenome or only certain loci.
There are legitimate concerns about the safety of Yamanaka factor-mediated partial reprogramming. To translate research in the field into clinical therapies, more research on the roadmap of partial reprogramming needs to be conducted. Furthermore, to better evaluate the results of in vivo cyclic reprogramming studies, in vitro cyclic reprogramming must be performed, and the difference between cyclic and continuous partial reprogramming must be identified. In conclusion, while partial reprogramming holds great therapeutic potential, the real focus should be on rejuvenation research, defining its nature and ways to quantify it. Another critical issue is the ability to quantify biological age as reprogrammed older cells acquire younger states. Understanding rejuvenation is also key to translational success, as benefits of age reversal must be considered against risks. More research into safety and tissue-specific responses of this technique are required.
View the full article at FightAging
