Epigenetic reset reverses age- and glaucoma-related vision loss in mice

Source: Photo by Clément Falize on Unsplash

Scientists at Harvard Medical School (HMS) have restored vision in mice by rewinding aged cells in the retina to regain the function of youthful genes. In addition to resetting cells’ aging clock, researchers have demonstrated reversal of vision loss in animals with a disease mimicking human glaucoma. They say this achievement represents the first successful effort to reverse glaucoma-induced vision loss, rather than just halting its progression.

The proof-of-concept study represents the first successful attempt to reverse the aging clock in animals through epigenetic reprogramming. If replicated by further preclinical and clinical studies, the same strategy could enable the development of therapies that promote tissue repair in various organs, not just the retina, and reverse aging and age-related diseases in the man.

“Our study demonstrates that it is possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” said David Sinclair, PhD, professor of genetics at the Blavatnik Institute. from Harvard Medical School, co-director of the Paul F. Glenn Center for Biology of Aging Research at HMS, who is the senior author of the paper published by the team in Nature. “If confirmed by further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and for the fields of biology and medical therapeutics for disease in general.” , Sinclair said.

The team reports their studies in a paper titled “Reprogramming to Retrieve Epigenetic Information from Youth and Restore Vision.”

Aging is a degenerative process that leads to tissue dysfunction and ultimately death, the researchers wrote. One of the proposed causes of aging is the accumulation of what they call “epigenetic noise”, which disrupts gene expression patterns, leading to decreased tissue function and regenerative capacity. The researchers’ approach is designed to address this epigenetic theory of aging. The epigenome is actually a system for turning genes on and off in specific patterns, without altering the underlying DNA sequence of the genes. Most cells in the body contain the same genes, but have very diverse functions, and to achieve this degree of specialization, cells need only read genes specific to their type, which is the job of the epigenome.

The epigenetics theory of aging posits that changes in the epigenome over time cause cells to read the wrong genes and malfunction, which then gives rise to diseases of aging. One of the most important changes in the epigenome is DNA methylation, a process by which methyl groups are attached to DNA. DNA methylation patterns are established during embryonic development to produce the different cell types. Over time, youthful DNA methylation patterns are lost and genes inside cells that should be turned on are 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 biological age of a cell or tissue. “During aging, for reasons that are not yet clear, these patterns change in such a way that they can be used to calculate DNA methylation age, a representation of biological age that can predict health and future lifespans,” the team noted.

However, it is unclear whether DNA methylation leads to age-related changes inside cells. “Changes in DNA methylation patterns over time form the basis of aging clocks, but it is unclear whether older people retain the information needed to restore these patterns – and, if so, whether this could improve tissue function – is not known,” the scientists pointed out.

For their recently published study, the researchers hypothesized that if DNA methylation does indeed control aging, erasing some of its imprints could reverse the age of cells inside living organisms and restore to their earlier and younger state. “Having already found evidence for epigenetic noise as the underlying cause of aging, we wondered if mammalian cells might retain a faithful copy of epigenetic information earlier in life that could serve as instructions to reverse aging.” , they commented. Previous work had achieved this feat in cells grown in lab dishes, but failed to demonstrate the effect in living organisms.

The study’s lead author, Yuancheng Lu, a genetics researcher at HMS and a former doctoral student in Sinclair’s lab, has 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, c-Myc, that could erase epigenetic markers on cells and bring those cells back to their primitive embryonic state from which they can develop into any other type of cell.

Later studies, however, pointed to two major setbacks. First, when used in adult mice, Yamanaka’s four factors could also induce tumor growth, making the approach dangerous. Second, the factors could reset the cellular state to the most primitive cellular state, thereby completely erasing a cell’s identity. Lu and his colleagues circumvented these obstacles by slightly modifying the approach. They dropped the c-Myc gene and only delivered the three remaining Yamanaka genes, Oct4, Sox2, and Klf4 (collectively known as OSK). The modified approach succeeded in reversing cellular aging without fueling tumor growth or losing their identity.

To test whether the regenerative capacity of young animals could be achieved in adult mice, the researchers introduced the altered combination of three genes via an adeno-associated virus (AAV) into the retinal ganglion cells of adult mice with nerve damage. optical. They targeted the cells of 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 rapidly declines. Lu and Sinclair teamed up with Zhigang He, PhD, HMS Professor of Neurology and Ophthalmology at Boston Children’s Hospital, who studies neuroregeneration of the optic nerve and spinal cord.

They found that the treatment had multiple beneficial effects on the eye. It promoted nerve regeneration after optic nerve injury in mice with damaged optic nerves, leading to a two-fold increase in the number of surviving retinal ganglion cells after injury and a five-fold increase in nerve regrowth.

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

Following the encouraging findings in mice with optic nerve damage, the team teamed up with colleagues from the Schepens Eye Research Institute at Massachusetts Eye and Ear Bruce Ksander, associate professor of ophthalmology at HMS, and Meredith Gregory-Ksander , Assistant Professor of Ophthalmology at HMS. 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 resulting from normal aging.

In a mouse model of glaucoma, treatment resulted in increased electrical activity of nerve cells and a noticeable increase in visual acuity, measured by the animals’ ability to see moving vertical lines on a screen. Remarkably, he did this after glaucoma-induced vision loss had already occurred. “To our knowledge, this is the first example of reversal of vision loss after glaucomatous injury; previous attempts have focused on neuroprotection delivered at an early stage to prevent disease progression,” wrote authors.

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

The treatment also worked well in 12-month-old mice whose vision was declining due to normal aging. After treatment of aged mice, gene expression patterns and electrical signals from optic nerve cells were similar to those of young mice, and vision was restored. When the researchers analyzed the molecular changes in the treated cells, they discovered inverted patterns of DNA methylation, an observation suggesting that DNA methylation is not a mere marker or bystander of the aging process. , but rather an active agent that pilots it. “What this tells us is that the clock doesn’t just represent time, it is time,” Sinclair said. “If you wind up the hands of the clock, time also goes backwards.”

“Using the eye as a model system, we present evidence that ectopic expression of OSK transcription factors safely induces in vivo epigenetic restoration of aged CNS neurons, without causing loss of cellular identity or pluripotency. “, wrote the researchers. “Instead, OSK promotes a youthful epigenetic signature and gene expression pattern that causes neurons to function as if they were young again.”

Encouragingly, for their reported study, a year-long whole-body treatment of mice with the three-gene approach showed no negative side effects. The researchers said that if their findings are confirmed by further animal work, they could launch clinical trials within two years to test the approach’s effectiveness in people with glaucoma. The results so far are encouraging, they noted. “These data indicate that mammalian tissues retain a record of youthful epigenetic information – encoded in part by DNA methylation – that can be accessed to improve tissue function and promote regeneration in vivo.”


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