Two research teams reverse signs of aging in mice | Science
A decade after Kyoto University biologist Shinya Yamanaka won a share of the Nobel Prize for discovering a cocktail of proteins that reprogram grown cells into versatile stem cells, two teams argue that proteins can turn back the clock on whole organisms—perhaps a day for people. A group at a biotech used gene therapy to deliver some of the so-called Yamanaka factors to old mice and modestly extended their lifespan. And a separate team pursued a similar strategy to reverse aging-like changes in genetically engineered mice.
In both cases, the Yamanaka factors appear to have restored part of the animals’ epigenome, the chemical modifications to DNA and proteins that help regulate gene activity, to a more youthful state. But scientists who were not involved in the work say suggestions of age change are premature. “These studies use reprogramming factors to reverse the epigenetic changes that occur during aging,” says Matt Kaeberlein, a geophysicist at the University of Washington, Seattle, but this is a far cry from rejuvenating an old animal.
Several groups had already found genetically modified mice that start expressing Yamanaka factors in adulthood show reversal of some aging symptoms. To explore an approach that could lead to a more practical treatment for humans, the San Diego-based company Rejuvenate Bio injected aged mice (124 weeks old) with adeno-associated viruses (AAVs) that carry genes for three of the factors, known collectively. as OSK.
These animals lived an average of 18 more weeks, compared with 9 weeks for a control group, the company reported in a preprint in bioRxiv this month. They also partially regained the DNA methylation patterns—a type of epigenetic mark—typical of younger animals. Although some studies have suggested that Yamanaka factors can promote cancer, Noah Davidsohn, Rejuvenate’s chief scientific officer and co-founder, says the company has so far found no apparent negative effects in mice given the gene therapy.
“I would say it’s provocative — perhaps a breakthrough,” says Steven Austad of the University of Alabama, Birmingham, who studies the biology of aging. “But it will need to be replicated and the mechanism explored before we can say for sure.”
The second study, published yesterday in Cell, is from a team led by Harvard Medical School geneticist David Sinclair, who has championed several controversial “anti-aging” interventions over the past 2 decades. (Rejuvenate’s approach grew out of an earlier collaboration between Sinclair and Davidsohn, but Sinclair is not involved in the company’s research, Davidsohn says.) Sinclair’s team set out to test his “information theory of aging,” the which assumes that our bodies age because of the cumulative loss of epigenetic marks. Cells’ DNA repair mechanisms, which work throughout life to repair DNA cuts and other damage, are what degrade these marks, he argues.
To test the theory in mammals, the team genetically engineered a strain of mouse that, when given a special drug, creates an enzyme that cuts their DNA at 20 sites in the genome, which are then faithfully repaired. Widespread changes in the cells’ DNA methylation patterns and gene expression followed, consistent with Sinclair’s theory. The mice ended up with an epigenetic signature more like that of the old animals, and their health deteriorated. Within weeks, they lost hair and pigment; within months, they showed multiple signs of tissue weakness and aging.
To see if the epigenetic degradation was reversible, the researchers injected some of these apparently aged mice with AAVs carrying the OSK genes, which Sinclair’s group recently reported could reverse vision loss in aged rodents. Analyzes of the mice’s muscles, kidneys and retinas suggest the cocktail reversed some of the epigenetic changes caused by DNA breaks. The findings point to a way to drive an animal’s age “forward and backward at will,” Sinclair says, and support the idea of epigenome-targeting treatments for aging in humans.
Molecular biologist Wolf Reik, director of Cambridge’s Altos Institute of Science (opened last year by the innovation-focused company Altos Labs), praised the sophistication and thoroughness of the Harvard team’s study, but says the team’s indirect way of driving change dramatic DNA epigenetic disruptions that may have other effects make it difficult to prove that those changes are what cause aging. It’s also unclear how well mice with induced DNA breaks mimic naturally aging animals, says Jan Vijg, a geneticist at Albert Einstein College of Medicine.
He and others point out that aging is a complex process with many contributing factors, and that in both papers, the effects of OSK treatment were modest: a small extension of lifespan in one, and a partial reversal of artificially induced symptoms. in the other. “The leap that aging is now a program” that can be reversed is not justified by the research, Vijg says.
However, both groups want to move their work to the clinic. Rejuvenate is looking at the mechanisms underlying the treatment’s action and changing its delivery and composition, says Davidsohn. “The OSK may not be the final set” of factors, he adds. Sinclair says his team is already testing AAV-delivered OSK in the eyes of monkeys. “If those monkey studies go well and everything seems safe enough for humans, the plan is to immediately apply to the FDA. [Food and Drug Administration] to make a study in one or more [age-related] diseases of blindness.”