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Harvard researchers restore vision in blind mice and unlock new clues for aging reversal

April 14, 2021

New work completed by Harvard Medical School scientists has revealed epigenetic clues for curing age-related diseases and reversing aging itself.
Researchers at the Sinclair Lab experimented with mice to determine whether aged and damaged cells could revert to a young and healthy state.
The scientists proved that epigenetic reprogramming could be used to reverse aging and restore healthy organ function.

A recent study has demonstrated that it is possible to safely reverse the age of complex tissues such as the retina and restore youthful biological function. During a Wednesday Afternoon Lecture Series held in February 2021, the NIH invited Dr. David A. Sinclair to explain one of the latest breakthroughs in aging research. Dr. Sinclair is a Professor of Genetics and Co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School. He has been listed among the Top 50 people in Health Care and the 100 Most Influential People in the World by Time Magazine. The new research (which was led by Dr. Sinclair) investigated epigenetic (factors influencing gene expression) means for resetting the cell’s aging clock and thus restoring vision. It was supported by the National Institute of Aging and the National Eye Institute – and published in Nature. Aging underlies most late-life diseases, including Alzheimer’s, heart disease, and diabetes. Multiple studies have already identified molecular and biological hallmarks of aging such as mitochondria dysfunction, stem cell loss, and telomere shortening. Gene expression (epigenetic basis of aging) is known to play a major role in aging. Dr. Sinclair’s work focused on epigenetic reprogramming – probing whether a cell that is old based on a variety of factors such as loss of function and gene expression could revert to a young and healthy state. This is an advanced and delicate approach to aging research because any destabilized (rogue) cells could cause cancer and dysfunctionality will result in disease. The Harvard research team based their working assumption on work completed in the 1940s by an MIT researcher. Claude Shannon, who was widely regarded as ‘the father of information theory’ discovered that noise could be removed from information transmission and storage systems by maintaining a backup copy to reconstitute the original message. Dr. Sinclair’s team investigated whether this same solution could be applied to the biology of aging. Genetic or epigenetic information is a relatively pristine state when we are young. However, cells will lose this information as we age. But is there a reset switch? Did the cells ever store a more youthful version of their gene expression pattern (younger identity)? DNA changes known as methylation are a good marker of aging cells and are known to play a role in information storage. It is often used as an accurate predictor of biological aging. But when it comes to this ability to store information, Dr. Sinclair argues that an animal cell behaves much like an optical CD. “A scratched CD will skip and the reader will not read the right songs. And that’s a problem. It’s similar to what happens in a mammalian cell and in basically any eukaryotic cell. They don’t read the right genes at the right time and it just gets worse over time until eventually that you just switch the machine off. You don’t want to hear it anymore. And if I’m talking about cells, the cells we can see have lost their youthful gene expression patterns and actually look like they are starting to express genes that should really have no place within that cell type,” Dr. Sinclair elaborates. “But imagine you could polish the CD and get it to play the beautiful music again. That’s what we are trying to do here,” he adds. Numerous past studies show that it might be possible to reprogram a cell. Scientists have been able to clone tadpoles for decades. In the late 2000s, Nobel prize-winning researcher Dr. Shinya Yamanaka demonstrated that by adding just four genes into an adult skin cell, he could induce the cell to assume the form of embryonic stem cells (which are essentially the body’s raw materials). While this prior research isn’t definitive on how you can improve the health of a living animal, it offers some clues. “We do know some species can regenerate themselves dramatically. You can even take off the limb of some species such as axolotl. Even lizards of course regrow parts (limbs) and young mice can regrow fingertips. So, this is not an impossibility. In fact, in humans, you can take out a chunk of liver and it regrows surprisingly quickly as long as you are still youthful,” says Dr. Sinclair. The research team experimented with model mice to test their theory on epigenetic reprogramming (as a potential solution to aging and the diseases of aging). A virus that caused damage and injury to the optic nerve was injected into mice. Treatment was then administered that over-expressed three previously identified genes. In the reprogrammed (treated) mice, the scientists noted that the neurons of the optic nerve regrew and the injury was reversed. Glaucoma – a disease that results in permanent vision loss — was also induced in the study mice. When the same epigenetic treatment was administered, the research team noted that vision was restored. This is a particularly interesting breakthrough given that glaucoma is a leading cause of blindness that affects more than 70 million people globally. Data also showed improved expression of genes that are known to reverse aging. Notably, there were no adverse effects such as toxicity, cancer, and the loss of identity in the study animals. Further investigation is ongoing to help determine how long the positive effects can last, and how many times the reprogramming treatment needs to be administered for optimal benefits. Researchers are also looking at how epigenetic reprogramming could be used to treat various other conditions. Already, early evidence suggests the same method could help improve hearing loss. “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,” said Dr. Sinclair.

References: https://videocast.nih.gov/watch=41438

Harvard researchers restore vision in blind mice and unlock new clues for aging reversal

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