Two research teams reverse the 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 adult cells into versatile stem cells, two teams say the proteins can roll back the clock for entire organisms – maybe one day humans. A group at a biotech company used gene therapy to administer some of the so-called Yamanaka factors to old mice and slightly extended their lifespans. And a separate team followed a similar strategy to reverse aging-like changes in genetically modified mice.

In both cases, the Yamanaka factors appear to have restored part of the animals’ epigenome, chemical modifications to DNA and proteins that help regulate gene activity, to a more youthful state. But scientists not involved in the work say the age reversal suggestions are premature. “These studies use reprogramming factors to reverse epigenetic changes that occur during aging,” says Matt Kaeberlein, a geroscientist at the University of Washington, Seattle, but that’s a far cry from rejuvenating an old animal.

Several groups had previously found genetically modified mice that begin expressing Yamanaka factors in adulthood and show a reversal of some symptoms of aging. To explore an approach that could lead to a more convenient treatment for people, San Diego-based company Rejuvenate Bio injected elderly mice (124 weeks old) with adeno-associated viruses (AAVs) that carry genes for three of the factors, collectively known. like OSK.

These animals lived another 18 weeks on average, compared to 9 weeks for a control group, the company reported in a preprint on bioRxiv this month. They also partially recovered DNA methylation patterns – a type of epigenetic mark – typical of younger animals. Although some studies have suggested that Yamanaka factors may promote cancer, Noah Davidsohn, Chief Scientific Officer and co-founder of Rejuvenate, says the company has so far found no obvious negative effects in mice given the genetical therapy.

“I would say it’s a provocation, maybe a breakthrough,” says Steven Austad of the University of Alabama at 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 part of a team led by Harvard Medical School geneticist David Sinclair that has backed several controversial “anti-aging” interventions over the past two decades. (Rejuvenate’s approach grew out of an earlier collaboration between Sinclair and Davidsohn, but Sinclair isn’t involved in the company’s research, Davidsohn says.) Sinclair’s team set out to test his “theory of information about aging”, which posits that our bodies age because of the cumulative loss of epigenetic marks. Cells’ DNA repair mechanisms, operating throughout life to repair DNA breaks 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 particular drug, makes 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 closer to that of older animals, and their health deteriorated. Within weeks, they lost their hair and pigment; within a few months, they showed multiple signs of tissue fragility and aging.

To see if the epigenetic degradation was reversible, the researchers injected some of these apparently aged mice with AAVs carrying OSK genes, which Sinclair’s group says could reverse vision loss in aging rodents. Analyzes of mouse muscles, kidneys and retinas suggest that the cocktail reversed some of the epigenetic changes induced by DNA breaks. The findings point to a way to move 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 the Altos Cambridge Institute of Science (opened last year by rejuvenation-focused company Altos Labs), praised the sophistication and thoroughness of the Harvard team’s study, but said the team’s indirect way of inducing epigenetic changes with dramatic DNA breaks that could have other effects makes it difficult to prove these changes cause aging. It’s also unclear to what extent 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 multiple contributing factors, and that in both papers the effects of OSK treatment were moderate: a small extension of lifespan in one and a partial reversal artificially induced symptoms in the other. “The leap that now aging is a program” that can be rolled back isn’t substantiated by research, says Vijg.

Yet both groups want to move their work to the clinic. Rejuvenate examines the mechanisms underlying the treatment’s action and fine-tunes its delivery and composition, says Davidsohn. “OSK might not be the last set” of factors, he adds. Sinclair says his team is already testing AAV-delivered OSK in the eyes of monkeys. “If these monkey studies go well and everything seems safe enough for humans, the plan is to go to the FDA immediately. [Food and Drug Administration] do a study in one or more [age-related] diseases of blindness”.

Leave a Comment