Scientists Reverse the Aging Clock: Restore Age-Related Vision Loss Through Epigenetic Reprogramming

Advanced Vision Technology Concept

Scientists at Harvard Medical School have achieved the restoration of vision in mice by rejuvenating aged eye cells in the retina, effectively reverting them to a more youthful gene function.

  • Proof-of-concept study represents first successful attempt to reverse the aging clock in animals through epigenetic reprogramming.
  • Scientists turned on embryonic genes to reprogram cells of mouse retinas.
  • Approach reversed glaucoma-induced eye damage in animals.
  • Approach also restored age-related vision loss in elderly mice.
  • Work spells promise for using same approach in other tissues, organs beyond the eyes.
  • Success sets stage for treatment of various age-related diseases in humans.

Harvard Medical School scientists have successfully restored vision in mice by turning back the clock on aged eye cells in the retina to recapture youthful gene function.

The team’s work, described today (December 2, 2020) in Nature, represents the first demonstration that it may be possible to safely reprogram complex tissues, such as the nerve cells of the eye, to an earlier age.

In addition to resetting the cells’ aging clock, the researchers successfully reversed vision loss in animals with a condition mimicking human glaucoma, a leading cause of blindness around the world.

The achievement represents the first successful attempt to reverse glaucoma-induced vision loss, rather than merely stem its progression, the team said. If replicated through further studies, the approach could pave the way for therapies to promote tissue repair across various organs and reverse aging and age-related diseases in humans.

“Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” said senior author David Sinclair, professor of genetics in the Blavatnik Institute at Harvard Medical School, co-director of the Paul F. Glenn Center for Biology of Aging Research at HMS and an expert on aging.

Sinclair and colleagues caution that the findings remain to be replicated in further studies, including in different animal models, before any human experiments. Nonetheless, they add, the results offer a proof of concept and a pathway to designing treatments for a range of age-related human diseases.

“If affirmed through further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and to the fields of biology and medical therapeutics for disease at large,” Sinclair said.

For their work, the team used an adeno-associated virus (AAV) as a vehicle to deliver into the retinas of mice three youth-restoring genes–Oct4, Sox2, and Klf4–that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors.

The treatment had multiple beneficial effects on the eye. First, it promoted nerve regeneration following optic-nerve injury in mice with damaged optic nerves. Second, it reversed vision loss in animals with a condition mimicking human glaucoma. And third, it reversed vision loss in aging animals without glaucoma.

The team’s approach is based on a new theory about why we age. Most cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must read only genes specific to their type. This regulatory function is the purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.

This theory postulates that changes to the epigenome over time cause cells to read the wrong genes and malfunction–giving rise to diseases of aging. One of the most important changes to the epigenome is DNA methylation, a process by which methyl groups are tacked onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful patterns of DNA methylation are lost, and genes inside cells that should be switched on get turned off and vice versa, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biologic age of a cell or tissue.

Yet, whether DNA methylation drives age-related changes inside cells has remained unclear. In the current study, the researchers hypothesized that if DNA methylation does, indeed, control aging, then erasing some of its footprints might reverse the age of cells inside living organisms and restore them to their earlier, more youthful state.

Past work had achieved this feat in cells grown in laboratory dishes but fell short of demonstrating the effect in living organisms.

The new findings demonstrate that the approach could be used in animals as well.

Overcoming an important hurdle

Lead study author, Yuancheng Lu, research fellow in genetics at HMS and a former doctoral student in Sinclair’s lab, developed a gene therapy that could safely reverse the age of cells in a living animal.

Lu’s work builds on the Nobel Prize winning discovery of Shinya Yamanaka, who identified the four transcription factors, Oct4, Sox2, Klf4, and c-Myc, that could erase epigenetics markers on cells and return these cells to their primitive embryonic state from which they can develop into any other type of cell.

Subsequent studies, however, showed two important setbacks. First, when used in adult mice, the four Yamanaka factors could also induce tumor growth, rendering the approach unsafe. Second, the factors could reset the cellular state to the most primitive cell state, thus completely erasing a cell’s identity.

Lu and colleagues circumvented these hurdles by slightly modifying the approach. They dropped the gene c-Myc and delivered only the remaining three Yamanaka genes, Oct4, Sox2, and Klf4. The modified approach successfully reversed cellular aging without fueling tumor growth or losing their identity.

Gene therapy applied to optic nerve regeneration

In the current study, the researchers targeted cells in the central nervous system because it is the first part of the body affected by aging. After birth, the ability of the central nervous system to regenerate declines rapidly.

To test whether the regenerative capacity of young animals could be imparted to adult mice, the researchers delivered the modified three-gene combination via an AAV into retinal ganglion cells of adult mice with optic nerve injury.

For the work, Lu and Sinclair partnered with Zhigang He, HMS professor of neurology and of ophthalmology at Boston Children’s Hospital, who studies optic nerve and spinal cord neuro-regeneration.

The treatment resulted in a two-fold increase in the number of surviving retinal ganglion cells after the injury and a five-fold increase in nerve regrowth.

“At the beginning of this project, many of our colleagues said our approach would fail or would be too dangerous to ever be used,” said Lu. “Our results suggest this method is safe and could potentially revolutionize the treatment of the eye and many other organs affected by aging.”

Reversal of glaucoma and age-related vision loss

Following the encouraging findings in mice with optic nerve injuries, the team partnered with colleagues at Schepens Eye Research Institute of Massachusetts Eye and Ear Bruce Ksander, HMS associate professor of ophthalmology, and Meredith Gregory-Ksander, HMS assistant professor of ophthalmology. They planned two sets of experiments: one to test whether the three-gene cocktail could restore vision loss due to glaucoma and another to see whether the approach could reverse vision loss stemming from normal aging.

In a mouse model of glaucoma, the treatment led to increased nerve cell electrical activity and a notable increase in visual acuity, as measured by the animals’ ability to see moving vertical lines on a screen. Remarkably, it did so after the glaucoma-induced vision loss had already occurred.

“Regaining visual function after the injury occurred has rarely been demonstrated by scientists,” Ksander said. “This new approach, which successfully reverses multiple causes of vision loss in mice without the need for a retinal transplant, represents a new treatment modality in regenerative medicine.”

The treatment worked similarly well in elderly, 12-month-old mice with diminishing vision due to normal aging. Following treatment of the elderly mice, the gene expression patterns and electrical signals of the optic nerve cells were similar to young mice, and vision was restored. When the researchers analyzed molecular changes in treated cells, they found reversed patterns of DNA methylation–an observation suggesting that DNA methylation is not a mere marker or a bystander in the aging process, but rather an active agent driving it.

“What this tells us is the clock doesn’t just represent time–it is time,” said Sinclair. “If you wind the hands of the clock back, time also goes backward.”

The researchers said that if their findings are confirmed in further animal work, they could initiate clinical trials within two years to test the efficacy of the approach in people with glaucoma. Thus far, the findings are encouraging, researchers said. In the current study, a one-year, whole-body treatment of mice with the three-gene approach showed no negative side effects.

Reference: “Reprogramming to recover youthful epigenetic information and restore vision” by Yuancheng Lu, Benedikt Brommer, Xiao Tian, Anitha Krishnan, Margarita Meer, Chen Wang, Daniel L. Vera, Qiurui Zeng, Doudou Yu, Michael S. Bonkowski, Jae-Hyun Yang, Songlin Zhou, Emma M. Hoffmann, Margarete M. Karg, Michael B. Schultz, Alice E. Kane, Noah Davidsohn, Ekaterina Korobkina, Karolina Chwalek, Luis A. Rajman, George M. Church, Konrad Hochedlinger, Vadim N. Gladyshev, Steve Horvath, Morgan E. Levine, Meredith S. Gregory-Ksander, Bruce R. Ksander, Zhigang He and David A. Sinclair, 2 December 2020, Nature.
DOI: 10.1038/s41586-020-2975-4

Other authors on the paper include Benedikt Brommer, Xiao Tian, Anitha Krishnan, Margarita Meer, Chen Wang, Daniel Vera, Qiurui Zeng, Doudou Yu, Michael Bonkowski, Jae-Hyun Yang, Songlin Zhou, Emma Hoffmann, Margarete Karg, Michael Schultz, Alice Kane, Noah Davidsohn, Ekaterina Korobkina, Karolina Chwalek, Luis Rajman, George Church, Konrad Hochedlinger, Vadim Gladyshev, Steve Horvath and Morgan Levine.

This work was supported in part by a Harvard Medical School Epigenetics Seed Grant and Development Grant, The Glenn Foundation for Medical Research, Edward Schulak, the National Institutes of Health (grants R01AG019719, R37AG028730, R01EY026939, R01EY021526, R01AG067782, R01GM065204, R01AG065403, R01EY025794, R24EY028767 and R21EY030276), and the St. Vincent de Paul Foundation.

Relevant disclosures: David Sinclair is a consultant to, inventor of patents licensed to, board member and equity owner of Iduna Therapeutics, a Life Biosciences company developing epigenetic reprogramming therapies, and an unpaid consultant to Zymo Research, an epigenetic tools company. Yuancheng Lu, Luis Rajman and Steve Horvath are equity owners of Iduna Therapeutics. George Church and Noah Davidsohn are co-founders of Rejuvenate Bio.

59 Comments on "Scientists Reverse the Aging Clock: Restore Age-Related Vision Loss Through Epigenetic Reprogramming"

  1. Playing God. This youth virus could merge with the coronavirus to cause a global pandemic of Millenialitis.

  2. Where’s the link to the original article in Nature Magazine? It’s always the mark of a poorly written news report when there’s no link to the original article!

  3. Incredible if this really works. It sounds better than stem cells.

  4. “Reverse the Aging Clock”? Have you SEEN Resident Evil? 🙂

  5. Sekar Vedaraman | December 2, 2020 at 2:52 pm | Reply

    Very Very Interesting.

    This is actually quiite personal for me.

    My dad had Glaucoma and passed away at the Age of 89. He didnt let the fact that he had Glaucoma stop him from leading a very veryb active life long — till his Knees became affected due to old age due to wear and tear and he steadfastly refused a Knee Transplant. He said I can see things physically but only as if it is a point of Light.

    He was a Scientist with Ph.D in Inorganic Chemistry from the University of Bombay and did PostDoctoral work at the All India Institute of Science at Bangalore.

    He always advised me that ne never missed his annual Eye Check up except one year, when he was extremely busy and could not go for his annual Check up. That is when he got Glaucoma. Said Early treatment could have saved a great deal more of his vision but it was not curablee.

    He also advised that ALL Scientists should develop the Third Eye of Insight. He said the Blind can actually SEE far Better than most Sighted People. This too, I have Expercience through Personal Experience as my Better Half — Did Social Service for The Blind and those whose vision is affected for many years.

    When the Almighty takes away one sense he improves the Other Five ( actually nine! ) Senses. Their sense of hearing is sharpened tremendously as well as other senses, and they can make out from the sound of the footfal and their other senses — on who has ccome into the room and Greet me Cheerily. They have been regular Visitors to my home and are dear friends of my better half .

    Anyway, Coming Back to the Medical Breaktthrough in this Area of Medical Science. HEARTFELT THANKS.

    Thought for Consuideration. MAYBE THE Fourth GENE , may play a role in repairing the Cornea of the affected eyesight. A wild guess. Scientists may need to prove, disprovee this hypothesis.

    Maybe finally we will see a Better World where the Blind can See and the Deaf Hear. Woldn’t that be wonderful , where not only do they have heightened senses which they have developed as a result of loss of EywSight. Hope they dont get too snooty.

    Eardrums also get damaged. Fix this problem next ! so the Deaf Can actaully Hear ad not just enjoy music vide vibrations!

    Taste and Smell are also impacted by C-19. These also need to be addressed ….

  6. My mother is blind now due to a surgery to remove the Glaucoma from her eyes. A local doctor in Jacksonville, Fla did surgery on my mother’s eyes and left her blind. I want my mother to see again before she transition to heaven. Please help me to help my mother, and may God bless your wisdom and understanding to achieve this great work that would benefit the world, starting with my mother Mrs. Ford.

  7. Richard Barzini | December 2, 2020 at 6:28 pm | Reply

    I have a 12 year old beagle with cateracts in both eyes….can you help him?

  8. How about we move out of the dark ages and stop testing on animals?

    • You want to be the first to have a method like this tested on you?

    • Stand up and scream,”do the test on me!”. You’ll get more respect and it might even be deserved……

    • You do realize that all life on earth is designed to hold up other life right? In other words, all animals are expendable as long as it promotes life overall. In fact that is the only reason we exist. We evolved specifically to push life forward at any cost. At least that is natures rules. We, obviously, have limits and made rules to govern ourselves.

      In other words, animals who we deem not sentient, are expendable if there is a good reason for it such as feeding other species of helping us evolve. That is exactly why they exist if you believe the laws of nature are something we should respect.

      We shouldn’t go around hurting things for no reason (aka slaughtering them for fun), but using them to experiment is no different than frying them up and eating them with a potato.

  9. Will this possible miracle help my father’s blindness from Macular Degenerative?At 85

    • WARREN WITTENBORN | December 6, 2020 at 9:33 pm | Reply

      Dennis, Lineage Cell Therapeutics announced positive interim results from the ongoing 24-patient Phase 1/2a clinical study of Lineage’s lead product candidate OptRegen. OpRegen product candidate is a cell replacement therapy. OpRegen is comprised of retinal pigment epithelium cells and is being tested for the treatment of advanced dry age-related macular degeneration (dry AMD) with geographic atrophy

  10. Closely analogous to retinal cells being brain cells outside the brain, so are the hair cells in cochleas. Ear drums don’t resemble brain cells. So, try to grow some fresh unwilted hair cells in mice cochleas, please. Cochleas as an experimental site have the advantage of being less interdependent upon nearby cells than are retinas. They’re isolated inside a bony spiral — hence much easier to inject accurately.

  11. I would volunteer to be your first human subject.

  12. Hi, Ms. Hemalatha from India. Lost partial vision in right eye due to central retinal artery occlusion with cilioretinal artery sparing. Can this therapy help in restoring my vision. Would be very grateful for any assistance and advice.

  13. When is thus available to the public and where?

  14. Age related Macular Degeneration while not mention in the article is possible to change with the same primary research. I sure hope so since clinical solutions (like the other commenter’s mothers surgery) are fairly primitive and need a better solution. Great background supporting info in the article also,thanks!

    • Lineage Cell Therapeutics announced positive interim results from the ongoing 24-patient Phase 1/2a clinical study of Lineage’s lead product candidate for age related macular degeneration. All 8 of these patients were treated with a new “thaw-and-inject” formulation of OpRegen and 4 were treated using the Gyroscope Orbit Subretinal Delivery System (Gyroscope SDS). Data presented at AAO showed improvements in visual acuity in Cohort 4 patients, with treated versus fellow eye comparisons reaching statistical significance at 9 and 12 months following OpRegen administration. These improvements were maintained for up to 24 months in some patients. A trend towards slower GA growth was observed in the first 6 Cohort 4 patients, a trend maintained for as long as 24 months in patients with 24-month data available. Previously reported structural improvements in the retina and decreases in drusen density have continued with evidence of durable engraftment of OpRegen cells in treated patients, some more than 4 years following administration, with no immunosuppression utilized beyond the perioperative period. Overall, OpRegen appears to be well-tolerated in all patients treated to date. The final four patients in the study were treated during November and will provide additional visual acuity data in the coming months.

  15. Please help. My husband is only 50 and has glaucoma!

  16. Where are they getting to embryonic cells
    Aborted babies?

    • @Greg B. You evidently did not understand the method. No embryonic cells are used at all. Rather, the three genes are prepared in an AAV vector into the eye of the mice, penetrate the retinal cells (the way the AAV vector sequences know how; AAV is based on a virus), and the newly introduced genes cause the host retinal cells to express their own genes in a manner that younger cells normally would, restoring younger function. Pretty darn nifty, actually.

  17. Kamlesh Mehrotra | December 3, 2020 at 6:20 am | Reply

    I have constant bilateral eye tearing. I have had bilateral DCR, laser assisted cataracts. surgery of both eyes, used Restasis and Xiadra but watery eyes continue. I have to wipe out tears by taking out sun glasses. Someone suggested try glass tube which requires maintenance and it’s edge is visible to others.
    Am I candidate for epigenetic reprogramming? If so, please advise list of doctors. I live in NJ, USA.

    • Are you a mouse? If so, you are a candidate for this technique. If not, you will need to wait until the FDA tests this and approves it for humans.

  18. I’m extremely happy to have run across this article, hope restored…. I was in my early twenties when I was informed that I had early signs of glaucoma , ultimately resulting in surgery, which was performed in 2016. I went back for a vision test and 2018 and things seem to be going okay, since then I have lost my medical insurance my vision has deteriorated quickly since, I would be willing to be a test participant .

  19. I am interested how do I start? Where do I go? I lost my righ eye sight do do a ball the hit me.

  20. Where are these embryonic cells coming from?
    Aborted baby brains?

    • @L.A.D: You did not understand the method. No embryonic cells are used at all. See my response to Greg B., above.

  21. Start testing on prisoners, maybe their worthless lives can be put to some kind of good use!

  22. Would this procedure correct bullseye macuropathy or could it reverse or replace the cellular death this condition I the cause of

  23. I think this is really great. Unfortunately I could only read a very little bit of it. Does this mean I can read hard cover science fiction again?

  24. There is no God but ALLAH and Muhammad is the messenger of ALLAH.

    THAT is the Shahada the testimony of truth it is what ALL creatures say when born. Even the ants say it so does the elephant so did YOU when birthed from your mother. By ALLAH is it so and by ALLAH will this be known world wide.

  25. This comment is for Blah: maybe they should start testing on your brain to replace what it seems you don’t have. Prisioners are people not animals, you sound more like the resemblance of an animal. So I think you should volunteer to be tested first.

  26. Where do I sign up? My vision is very bad…

  27. With new technology the trial period shouldn’t take years like in the 70s and before hopefully this gets approved for human trials quick

  28. where do I sign up for human trials?

  29. I am also interested as I have been diagnosed with glycoma and cataracts in both eyes.. mid fifties, female

  30. We are an evolutionarly hodgepodge made largely of bacteria, viruses, fungi and archaea. Our eyes see less than 1 percent of the light spectrum, retinas detach easily – even the humble shrimp has better vision! We are also fitted with sub-optimal plumbing (breathing, eating, excretory and reproductive) and programmed to die. But perhaps this should not come as a surprise: we are part of a world where at least 40 percent of animal species are parasites, and over 99 percent of all species that ever lived are extinct.

  31. Practiced optometry for 45 years, saw many slowly lose vision from glaucoma, it sounds promising. Will read the scientific papers, although I am no geneticist (sp?). I can in my mind extrapolate to many other anomalies of aging. Great work. to Blah, OK to start with prisoners, as soon as you sign up as trial human #1.

  32. Wonderful info! I didn’t read all the comments, but i’m concerned about my wife’s vision and I left her email on the subscribe window above. She is thinking about cataract surgery and I want her to read all info she can related to her vision. I as well want to subscribe, so I’ll fill my info below. Thanks

  33. The article indicated that the treatment promoted nerve regeneration. If that is so, could this be a potential treatment for optic nerve damage caused by NAION?

  34. I was diagnosed with glaucoma 2 years ago and now have lost vision in my right eye. I am 71 and in good health so I am very interested in this topic.

  35. I’d volunteer for this. First in line. Vision is so crucial to me as a single parent utilizing my eyesight to ensure income coming into my home

  36. Yea, yeah, let’s talk in around a couple of decades later, until it will be available for those who need it most – elderly people around the globe, not only in the leading countries and for elderly like Bill Gates

  37. I have glaucoma I’m 54 and that sounds amazing, I would love to be able to see like I did in my twenties

  38. Best century yet.

    • who knows! may god keep us and our families alive and motivated till the day this technology will be available to the public.

  39. Don’t bring God into this. We were allowed knowledge and its our decision on what we do with it. If those who think this is an opportunity, then the more courage to you.

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