Longevity Manual 61 [Cutting-Edge Longevity Research 1] Research on "Partial Reprogramming" to Rewind Cellular Age

Dusting off the pages or returning to factory settings?

So far, we have looked at ways to manage the speed of aging by maintaining the environment within our cells through daily habits such as diet, exercise, and sleep. To use an analogy, this is a solid maintenance strategy of "diligently dusting off each page of the blueprint to keep it readable."

However, the global research community is now taking on an even greater challenge. It is an attempt to "take cells that have been used for decades and have outdated systems, and bring only their age indicators closer to 'factory settings' while leaving their individual data (the cell's role and personality) intact." In this installment, we will introduce a technology that has been attracting attention in this field in recent years: "Partial Reprogramming."

Attempts at "rejuvenation" applying iPS cell technology

The foundation of this technology is the "iPS cell (induced pluripotent stem cell)" technology for which Dr. Shinya Yamanaka won the Nobel Prize. When four specific genes (Yamanaka factors: Oct4, Sox2, Klf4, c-Myc) are introduced into somatic cells such as skin cells, the cells are initialized to a state similar to stem cells, which can change into various tissues.

However, if this is done directly in a living body for a long period, there is a risk that the cells will forget their original roles (identity), causing the tissue structure to collapse or tumors (teratomas) to form. To use an office work analogy, it is like "intending to correct one page of a manual, but accidentally initializing the entire shared server, causing all the data necessary for work to be deleted."

Therefore, researchers tried a method of "what happens if we make the Yamanaka factors work 'partially' for a very short period and then turn them off immediately?" Research by Dr. Olova and colleagues at the University of Edinburgh (Olova N, Simpson DJ, Marioni RE, Chandra T. Partial Reprogramming De-ages Cells and Improves Tissue Function.) is one of the foundational findings in this field. This study showed that by expressing Yamanaka factors for a short period, it is possible for cells to change their "epigenetic clock" values—calculated from DNA methylation—in a younger direction while maintaining their original properties. This means there is a possibility that we can partially correct only the errors caused by aging while keeping the blueprint's role data intact.

Mouse experiment where lost vision was restored

The effects of this partial reprogramming have already been reported with concrete results in animal experiments. A report by a research team led by Professor David Sinclair of Harvard University (Lu Y, Brommer B, Tian X, et al. Reprogramming to Recover Youthful Epigenetic Information and Restore Vision.) was published in the scientific journal Nature in 2020 and attracted significant attention.

In this study, when partial reprogramming using three Yamanaka factors (Oct4, Sox2, Klf4) was performed on mice whose vision had declined due to aging or optic nerve damage, the axons of retinal ganglion cells regenerated, and the recovery of vision was confirmed. This result challenges the previous understanding that "once lost, nerve function cannot be restored," and is attracting attention as a finding that suggests "it is possible that some of the epigenetic information from youth remains in the cells in some form."

Currently, research is underway around the world to apply this not only to the eyes but also to various tissues such as the heart, liver, and nervous system. However, most of these studies are based on animal models such as mice, and safety and efficacy in humans have not yet been established. While excessive expectations should be avoided, this is a field where future research developments are worth watching.

The "foundation" for utilizing future technology

The day when this partial reprogramming technology can actually be used for human treatment may not be far off. However, there is a perspective that must not be overlooked here.

No matter how much technology to rewind cellular age (rejuvenation medicine) is put into practical use in the future, if our bodies themselves—the foundation—are being damaged daily by chronic inflammation or poor lifestyle habits, we will not be able to fully receive the benefits of such cutting-edge technology. To maximize the benefits of future technology, it remains meaningful to keep the basic state of our cells in good condition through "time-restricted eating (Part 7, Part 49)" and "moderate exercise (Part 46)" that we can practice now.

References

Rejuvenation of cells and improvement of tissue function by partial reprogramming
Paper Title: Partial Reprogramming De-ages Cells and Improves Tissue Function.
Authors: Olova N, Simpson DJ, Marioni RE, Chandra T
Journal: Nature Communications (2019)
Content: A study showing that short-term expression of Yamanaka factors may work to rejuvenate epigenetic clock values while maintaining cell identity.
Recovery of rejuvenated epigenetic information and restoration of vision by partial reprogramming
Paper Title: Reprogramming to Recover Youthful Epigenetic Information and Restore Vision.
Authors: Lu Y, Brommer B, Tian X, et al. (Harvard University)
Journal: Nature (2020)
Content: A study that performed partial reprogramming on mice with vision loss due to optic nerve damage or aging, demonstrating axon regeneration of retinal ganglion cells and recovery of vision.