Posted on Dec 03, 2020, 3 p.m.
According to a study co-authored by David Sinclair, a geneticist at Harvard Medical School Boston, published in Nature, vision has been restored in old mice with damaged retinal nerves by resetting some of the thousands of chemical markers that accumulate on DNA with age.
This study suggests a new approach to reversing age-related decline by reprogramming some cells to a more youthful state in which they are better able to repair or replace damaged tissues. However, the researchers note that thus far their work has only been carried out in mice and remains to be determined if this approach is translatable to humans, or to other tissues and organs that suffer the ravages of time.
“It is a major landmark,” says Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute for Biological Studies in La Jolla, California, who was not involved in the study. “These results clearly show that tissue regeneration in mammals can be enhanced.”
The body is affected by aging in numerous ways such as adding, removing or altering chemical groups like methyls on DNA. As a person ages, these epigenetic changes accumulate, some propose that tracking these changes may be a way of calibrating a molecular clock to measure biological age.
While chronological age is the number of years that a person has been alive, biological age is an assessment that takes into account biological wear and tear that can differ significantly from one’s chronological age. This has raised the possibility of epigenetic changes contributing to the effects of aging and questions such as if epigenetic changes are a driver of aging, can we reset the epigenome to reverse the clock?
Previous work conducted by Belmonte and colleagues suggested that this approach could work, reporting the effects of expressing 4 genes in mice genetically altered to age more rapidly than normal. Triggering these genes caused cells to lose their developmental identity and revert to a stem cell-like state. Rather than turning the genes on and leaving them as such the team turned them on for a few days then switched them off again with hopes of reverting the cells to a younger state without erasing their identity. This resulted in the mice aging more slowly, and they had a pattern of epigenetic markers indicative of younger animals. The disadvantage of this technique was that if the genes are present in extra copies or expressed for too long some of the mice developed tumors.
In this study, Sinclair and colleagues looked for safer ways to rejuvenate cells. The team removed one of the 4 genes used by Belmonte that is associated with cancer and added the other three genes into a virus that could deliver them into cells, including a switch that would allow the team to turn genes on by giving mice water that was injected with a drug; withholding this drug would switch the genes off.
Mammals lose the ability to regenerate components of the central nervous system early in development, as such the team decided to begin to test their approach there. First, the team injected a virus into the eye to see if expression of the 3 genes would allow the animals to regenerate injured retinal nerves, which had yet to be done with any treatment.
The team was able to show that their approach improved the visual acuity in mice with age-related vision loss or animals with increased pressure inside the eye which is a hallmark of glaucoma. According to the team, their approach also reset epigenetic patterns to a more youthful state in mice and human cells grown in the lab.
Lu remembers the first time that he saw a nerve regenerating from injured eye cells. “It was like a jellyfish growing out through the injury site,” he says. “It was breathtaking.”
While it is still unclear how cells preserve the memory of a more youthful epigenetic state, the team plans on continuing investigations to try and determine how. Meanwhile, Havard has licensed this technology to Life Biosciences to carry out preclinical safety assessments with the view to develop the approach for use in humans.
The results are “a major landmark” and “clearly show that tissue regeneration in mammals can be enhanced”, says developmental biologist Juan Carlos Izpisua Belmonte — but researchers caution that this result is still only in mice.
The approach will likely need considerable refinement before it can be safely deployed in humans. Research is ripe with a history of promising animal and cell findings that were not able to make the translation to humans. Ultimately the test will be when other labs try to reproduce this reprogramming work and try the approach in other organs that are affected by aging like the lungs, heart and kidneys.
According to Judith Campisi, who is a cell biologist at the Buck Institute for Research on Aging more data should be emerging rather quickly, as she explains,”There are many labs now who are working on this whole concept of reprogramming. We should be hopeful but, like everything else, it needs to be repeated and it needs to be extended.”
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Lu, Y. et al. Nature 588, 124–129 (2020).
Ocampo, A. et al. Cell 167, 1719–1733 (2016).