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 are arguing that the proteins could turn back the clock for entire organisms — perhaps one day. Humans. One group at a biotechnology company used gene therapy to deliver some of the so-called Yamanaka factors into old mice, modestly extending their lives. A separate team followed a similar strategy to reverse the aging-like changes in transgenic mice.
Either way, Yamanaka’s factors seem to have restored a portion of the animals’ epigenome, chemical alterations 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 about changing the age are premature. “These studies use reprogramming factors to reverse the epigenetic changes that occur during aging,” says Matt Kaeberlin, a gerontologist at the University of Washington, Seattle, “but that’s a far cry from making an old animal young again.”
Several groups have already found that transgenic mice that begin to express Yamanaka factors in adulthood show a reversal of some of the symptoms of aging. To explore an approach that might lead to a more practical treatment for people, San Diego-based Rejuvenate Bio injected aged mice (124 weeks old) with adeno-associated viruses (AAVs) that carried genes for three of the factors, collectively known as OSK.
These animals lived another 18 weeks on average, compared to 9 weeks for a control group, the company says It was reported in a preliminary version on bioRxiv this month. They also partially restored DNA methylation patterns — a type of epigenetic mark — typical of younger animals. Although some studies have indicated that Yamanaka’s agents can promote cancer, Noah Davidson, Rejuvenate’s chief scientific officer and co-founder, says the company has yet to find any clear negative effects in mice given gene therapy.
“I would say it’s provocative — and potentially a breakthrough,” says Stephen Ostad of the University of Alabama, Birmingham, who studies the biology of aging. “But it will have to be replicated and the mechanism explored before we can say for sure.”
Second study Posted yesterday in cell, from a team led by David Sinclair, a geneticist at Harvard Medical School, who has supported several controversial “anti-aging” interventions over the past two decades. (The Rejuvenate approach grew out of an earlier collaboration between Sinclair and Davidsohn, but Sinclair wasn’t involved in the company’s research, Davidsohn says.) Sinclair’s team set out to test an “information theory of aging,” which posits that our bodies age because of the cumulative loss of epigenetic markers. . He argues that cells’ DNA repair mechanisms, which operate throughout life to repair DNA wounds and other damage, degrade these markers.
To test the theory in mammals, the team genetically engineered a strain of mouse that, when given a specific drug, makes an enzyme that cuts its DNA at 20 locations in the genome, which are then faithfully repaired. This was followed by widespread changes in the cells’ DNA methylation patterns and gene expression, consistent with Sinclair’s theory. The mice ended up with an epigenetic signature more like that of older animals, and their health declined. Within weeks, they lost their hair and pigment. Within months, they showed multiple signs of weakness and aging of the tissues.
To see if the epigenetic degradation is reversible, the researchers injected some of these seemingly elderly mice with AAVs that carried OSK genes, which Sinclair’s group recently reported can reverse vision loss in aged rodents. Analyzes of the mice’s muscles, kidneys, and retinas indicate that the cocktail reversed some of the epigenetic changes caused by DNA breaks. The findings suggest a way to move animal lifespan “back and forth at will,” says Sinclair, and support the idea of epigenome-targeting therapies for aging in humans.
Molecular biologist Wolf Reck, director of the Altos Cambridge Institute for Science (opened last year by regeneration-focused Altos Labs), praises the sophistication and comprehensiveness of the Harvard team’s study, but says the indirect team is making epigenetic changes with dramatic DNA. Breaks that can have other effects make it difficult to prove that these changes cause aging. It’s also unclear how well mice with induced DNA break down naturally aging animals, says Jan Vig, a geneticist at Albert Einstein College of Medicine.
He and others stress that aging is a complex process with many 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 leap in age now is a program that ‘could be set back that is not justified by research,’ says Feige.
However, both groups want to move their work toward the clinic. Davidsohn says Rejuvenate is examining the mechanisms behind the treatment’s action and tweaking the way it’s delivered and configured. “OSK may not be the ultimate set” of factors, he adds. Sinclair says his team is already testing OSK provided by AAV in monkey eyes. “If those monkey studies go well and everything seems safe enough for humans, the plan is to apply immediately to the FDA.” [Food and Drug Administration] To do a study in one or more [age-related] Diseases of blindness.