Epigenetic Reprogramming to Reverse Aging in Old Mice


Researchers at Harvard Medical School have found a way to reverse the aging process and restore eyesight - at least in mice.


Aging is an inevitable part of life that most people live to experience. Although the longevity of humans has notably improved since we evolved 200,000 years ago, the multidimensional nature of aging has prevented us from fully understanding this sophisticated process.


On a molecular level, aging can be defined as the progressive deterioration of cells, tissue and organs, ultimately causing degeneration of bodily systems. DNA methylation is an identified marker for this aging and is the basis behind the body’s biological aging clock.


DNA methylation is the accumulation of epigenetic chemical marks caused by the addition of a methyl group to DNA molecules (What Is Epigenetics, 2019). By affecting gene function and expression, it interferes with the normal working of DNA by reducing abilities to regulate transcription - the process of making an RNA copy helping direct the synthesis of proteins.



https://www.labclinics.com/en/role-dna-methylation-disease/


“We set out with a question: if epigenetic changes are a driver of ageing, can you reset the epigenome?” - co-author Prof David Sinclair


David Sinclair and his team investigated epigenetic changes, using the eye as a model of the CNS tissue in humans. They proved that the ectopic expression of Oct4, Sox2 and Klf4 genes (OSK), delivered into mice using harmless adeno-associated viruses as a vector, could reprogramme retinal ganglion cells to restore vision loss. (Sinclair et al., 2020)


OSK genes are 3 out of the 4 famous transcription factors (Oct4, Sox2, Klf4, Myc) known as Yamanaka factors, discovered by Shinya Yamanaka in 2006 (Yamanaka, 2006) as a means of inducing adult skin cells back to pluripotent stem cells. However, a detrimental fault to his discovery was the possibility of cancerous cells. Hence, a decision was made in this particular study to exclude the Myc, an oncogene deemed unessential for the initiation of cellular programming. By avoiding exposure to all 4 factors, researchers were able to prevent unwanted tumor growth.


Key research findings include

  • promotion of axon regeneration

  • restoration of youthful DNA methylation patterns

  • reversal of vision loss caused by glaucoma and natural aging

These are discussed in further detail below.


Axon regeneration post-injury

Researchers crushed the optic nerves of mice using forceps and subsequently delivered OSK to the optic nerve.



https://www.nature.com/articles/d41586-020-03119-1


The result? Some retinal ganglion cells were not only prevented from dying, but also were able to grow axons. Longer durations of OSK induction were further shown to increase the distance extended by axons.


In other words, mice that lost their eyesight from nerve damage generated NEW nerves after the genetic treatment, ultimately restoring their vision! This discovery was particularly astonishing as mammals typically lose their regenerative potential of the optic nerve very early on in life in embryonic stages.


Restoration of youthful DNA methylation patterns

An additional area of inquiry was whether older individuals retain information from their past to restore younger DNA methylation patterns. Upon looking at DNA methylation patterns of the retinal ganglion cells, it was observed that changes caused by the inflicted “crush injury” were analogous to those in aging mice, which could be reversed along with the treatment of OSK genes.


However, it is still unclear from this study whether DNA methylation directly impacts rejuvenation or is simply an accompanied change to the restoration of vision.


Recovery of vision in mice with glaucoma

Glaucoma is a degenerative optic neuropathy, and although a leading cause of age-related blindness in adults over 60 (Harvard Health Publishing, 2020), there are no known treatments. It is caused by the progressive deterioration of the optic nerve, often due to the buildup of pressure within the eye.



https://www.health.harvard.edu/staying-healthy/the-facts-about-glaucoma


To mimic human glaucoma in mice, researchers injected microbeads into mice eyes, inducing increased intraocular pressure by preventing normal drainage of the aqueous humor. The damage caused to the retinal ganglion cells caused the number of retinal ganglion cells and axonal density to decline significantly. Although the mice were at a rather early stage of damage (compared to the near-total blindness people with glaucoma can experience), the treatment restored approximately half of the visual acuity lost from increased intraocular pressure.


Previous attempts focused on neuroprotection delivered from early stages to prevent the disease from progressing. This finding was the first published occurrence where a reversal of vision loss was observed after a glaucomatous injury.


Reversal of vision loss in old mice

Another experiment conducted explored the possibility of reversing vision loss caused by natural aging. By injecting OSK into the eyes of 11 month old mice (roughly middle age in mice terms), the expression of OSK was induced over the span of 4 weeks.


These middle-aged mice usually lose around 15% of visual acuity relative to younger mice. Contrarily, older mice treated with OSK genes had restored visual acuity, where they were found to have the same visual acuity score as younger, 5 month old mice. The same DNA methylation patterns were also noted in the younger and older mice. It was thus concluded that OSK induction had restored vision in mice to some degree.


All in all...

Although the effects of OSK in humans are yet to be tested, this research has opened the door to possibilities of resetting the aging clock by epigenetic programming, treating age related conditions in the eye and beyond.






Works cited

Harvard Health Publishing. (2020). The facts about glaucoma. Harvard Health. https://www.health.harvard.edu/staying-healthy/the-facts-about-glaucoma


Nature Editorial. (2020). Sight restored by turning back the epigenetic clock. Nature. https://www.nature.com/articles/d41586-020-03119-1?error=cookies_not_supported&code=b2504acc-34a8-4cdb-a6d5-8041b59b71c5


Role of DNA methylation in Disease. (2019, January 8). Labclinics. https://www.labclinics.com/en/role-dna-methylation-disease/


Sinclair, D., Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., ... Wang, C. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature. https://www.nature.com/articles/s41586-020-2975-4


What is Epigenetics. (2019, September 5). DNA Methylation. https://www.whatisepigenetics.com/dna-methylation/


Yamanaka, S. (2006, August 25). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. PubMed. https://pubmed.ncbi.nlm.nih.gov/16904174/




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