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Today, we want to draw attention to a new study that shows how partial cellular reprogramming was able to reverse cellular aging and address age- and injury-induced blindness in mice.

Epigenetic alterations

One of the proposed reasons we age is the changes to gene expression that our cells experience as we get older; these are known as epigenetic alterations. These alterations cause harmful changes to cellular function and gradually shift our cells from a youthful to aged state.

Gene expression is modified by the addition of epigenetic markers to the DNA that change the pattern of gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands.

This is how our cells know what types of cells they are and what they should be doing, as the epigenetic instructions are there to guide them and ensure that we develop and grow properly. Essentially, epigenetic markers turn genes on and off, which, in turn, change what a cell does and how it functions.

However, as we age, our cells are exposed to environmental factors and are subject to negative changes in their genomes through epigenetic mechanisms. These alterations accumulate over time and are strongly correlated with the decline observed in aging cells.

Resetting the age of cells in mice

We have talked about the potential of partial cellular reprogramming in previous articles, and there have now been a number of demonstrations that reverse epigenetic alterations and so reset aged cells to youthful function.

In this new study, an impressive team of researchers, including George Church, David Sinclair, Vadim Gladyshev, Steve Horvath, and Michael Bonkowski, has used the technique of partial cellular reprogramming to reset epigenetic alterations that occur in cells during aging, thus restoring youthful function in mice.

To achieve this, they used just three reprogramming factors, Oct4, Sox2, and Klf4, to reverse age-related epigenetic markers and rejuvenate the old cells in the eyes of mice. The approach was able to regenerate the eyes of mice suffering from age- or injury-induced blindness by encouraging the cells to revert to a more youthful level of function and thus regenerative capacity.

The study also shows that old cells and tissues retain an accessible memory of youthful epigenetic information, which allows the functional age of the cell to be reset. It is also consistent with the findings of other mouse studies in which similar techniques have been used to reverse cellular aging via partial cellular reprogramming.

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1–3. Changes to DNA methylation patterns over time form the basis of an ‘ageing clock’4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns don’t just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

Conclusion

Some researchers suggest that changes to the epigenetic state of cells merely reflect the age of a cell and its underlying aging, somewhat like the hands on a watch showing the time while the cogs and workings behind the watch face are the underlying causes of those changes.

However, this study adds yet more support for the proposal that epigenetic alterations are not merely an indication of the age of a cell but are much more likely to directly drive aging. It is certainly very compelling when the cells of mice are partially reprogrammed and they regain youthful function; if this is not a demonstration of rejuvenation, then I don’t know what is!

The race to translate partial cellular reprogramming to humans is now the focus of several companies, and progress in this area seems to have been moving along at quite a rapid pace since Salk Institute researchers first demonstrated the technique in mice back in 2016.

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Literature

[1] Lu, Y., Krishnan, A., Brommer, B., Tian, X., Meer, M., Vera, D. L., … & Yang, J. H. (2019). Reversal of ageing-and injury-induced vision loss by Tet-dependent epigenetic reprogramming. bioRxiv, 710210.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
  1. August 6, 2019

    Dr Sinclair sent me a preprint of his new book
    “Lifespan – The Revolutionary Science of Why we Age – and Why We don’t Have To” (Simon& Schuster) – I Interviewed him extensively on video at Harvard medical school July 10th. I am integrating that footage into my new aging film (To Age Or Not to Age – Transforming the Human Condition) as I write this. David evaded no question, and explained his theory of the underlying cause of aging, stretching across the hallmarks of aging. I am making the 90 minutes of raw interview to his PR people, and may allow individuals to view it on Vimeo.

  2. August 7, 2019

    Robert: can you notify me when the video is able to be viewed?
    Thanks so much
    John Durso

  3. September 8, 2019

    What would be the most appropriate was to keep up to date with the work of the people mentioned above?

    I’m not in the medical profession, just extremely interest in these fields.

    Kind regards
    Paul

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