Two Research Teams Reverse Signs of Aging in Mice
But doubts remain about whether cell reprogramming technique could one day help humans.
Jan. 23, 2023 (Science.org) – A decade after Kyoto University biologist Shinya Yamanaka won a share of a Nobel Prize for discovering a cocktail of proteins that reprogram adult cells into versatile stem cells, two teams argue the proteins can turn back the clock for entire organisms—perhaps one day humans. One group at a biotech used gene therapy to deliver some of the so-called Yamanaka factors into old mice, and modestly extended their life span. And a separate team followed 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, chemical modifications on DNA and proteins that help regulate gene activity, to a more youthful state. But scientists not involved in the work say suggestions of age reversal are premature. “These studies use reprogramming factors to reverse epigenetic changes that happen during aging,” says Matt Kaeberlein, a geroscientist at the University of Washington, Seattle, but that’s a far cry from making an old animal young again.
Several groups had already found genetically engineered mice that begin expressing Yamanaka factors in adulthood show reversal of certain aging symptoms. To explore an approach that might lead to a more practical treatment for people, San Diego–based company Rejuvenate Bio injected elderly (124-week-old) mice with adeno-associated viruses (AAVs) carrying genes for three of the factors, collectively known as OSK.
These animals lived another 18 weeks on average, compared with 9 weeks for a control group, the company reported in a preprint on bioRxiv this month. They also partially regained patterns of DNA methylation—a type of epigenetic mark—typical of younger animals. Although some studies have suggested Yamanaka factors can promote cancer, Noah Davidsohn, Rejuvenate’s chief scientific officer and co-founder, says the company has so far found no obvious negative effects in mice given the gene therapy.
“I would say it is provocative—possibly 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 backed several controversial “antiaging” interventions over the past 2 decades. (Rejuvenate’s approach grew from 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 “information theory of aging,” which posits that our bodies get old because of the cumulative loss of epigenetic marks. Cells’ DNA repair mechanisms, operating throughout a lifetime to fix DNA cuts and other damage, are what degrade these marks, he argues.
To test the theory in mammals, the team genetically engineered a mouse strain 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 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 older animals, and their health deteriorated. Within weeks, they lost hair and pigment; within months, they showed multiple signs of frailty and tissue aging.
To see whether the epigenetic degradation was reversible, the researchers injected some of these elderly seeming mice with AAVs carrying OSK genes, which Sinclair’s group recently reported could reverse loss of vision in aging rodents. Analyses of the mice’s muscles, kidneys, and retinas suggest the cocktail reversed some of the epigenetic changes induced by the DNA breaks. The findings point to a way to drive an animal’s age “forwards and backwards 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 says the team’s indirect way of inducing epigenetic changes with dramatic DNA breaks that could have other effects makes it hard to prove those changes are what’s causing aging. It’s also unclear how well mice with induced DNA breaks mimic naturally aging animals, says Jan Vijg, a geneticist at the Albert Einstein College of Medicine.
He and others stress 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 life span in one, and a partial reversal of artificially induced symptoms in the other. “The jump that now aging is a program” that can be wound backward isn’t justified by the research, Vijg says.
Still, both groups want to move their work toward the clinic. Rejuvenate is examining the mechanisms underlying the treatment’s action and tweaking its delivery and composition, Davidsohn says. “OSK might 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 studies in monkeys go well and everything looks safe enough for humans, the plan is to immediately apply to the FDA [Food and Drug Administration] to do a study in one or more [age-related] diseases of blindness.”