Shinya Yamamanaka, a biologist at Kyoto University, won the Nobel Prize for discovering a protein cocktail that reprograms adult cells into pluripotent stem cells, and a decade later, two research groups believe that this protein can turn the clock of an entire organism, and one day humans can too
.
A team at a biotech company used gene therapy to deliver some so-called mountain factors to older mice and moderately extended their lifespans
.
Another team used a similar strategy to reverse age-like changes
in genetically engineered mice.
In both cases, the mountain factor appears to have restored a part of the animal's epigenome (chemical modifications on DNA and proteins that help regulate gene activity) to a more youthful state
.
But scientists who were not involved in the study said the suggestion of an age reversal was premature
.
Matt Kaeberlein, a geriatrician at the University of Washington in Seattle, said: "These studies use reprogramming factors to reverse the epigenetic changes that occur during aging, but this is far from
making old animals young again.
”
Some research groups have found that genetically modified mice that begin expressing Yamanaka factor in adulthood are able to reverse certain symptoms of
aging.
To explore a potentially more practical treatment for humans, San Diego-based Rejuvenate Bio injected adeno-associated virus (AAV) carrying a three-factor gene into old (124-week-old) mice, collectively known as OSK
.
The animals lived an average of another 18 weeks, compared to 9 weeks
for the control group (firm).
It was reported this month in a preprint of bioRxiv that they also partially restored the pattern of DNA methylation, an epigenetic marker
of young animals.
Although some studies suggest that the mountain factor can promote cancer, Noah Davidson, chief scientific officer and co-founder of Rejuvenate, said the company has so far not found a significant negative effect
of gene therapy on mice.
Steven Austad, who studies the biology of aging at the University of Alabama, Birmingham, said: "I think this is a provocative breakthrough, probably a breakthrough
.
But before we can be sure, we need to replicate it and explore its mechanisms
.
”
The second study, published yesterday in Cell, comes from a team led by Harvard Medical School geneticist David Sinclair, who has supported several controversial "anti-aging" interventions
over the past 20 years.
(Davidson says Rejuvenate's approach stemmed from an early collaboration between Sinclair and Davidson, but Sinclair was not involved in the company's research
.
) Sinclair's team set out to test his "aging information theory," which holds that our bodies age due to the cumulative loss
of epigenetic markers.
He believes that the cell's DNA repair machinery, which repairs DNA cuts and other damage throughout life, is responsible for
the degradation of these markers.
To test this theory in mammals, the team genetically engineered a mouse strain that, when given a specific drug, produces an enzyme that can cut DNA at 20 sites in the genome and then faithfully repair
it.
Subsequently, the cells' DNA methylation patterns and gene expression changed extensively, which was consistent
with Sinclair's theory.
The epigenetic characteristics of these mice were more similar to those of older animals, and their health deteriorated
.
Within a few weeks, they lose hair and pigment; Within a few months, they show multiple signs of
weakness and tissue aging.
To see if epigenetic degradation is reversible, the researchers injected the old-looking mice with an AAV carrying the OSK gene, which Sinclair's team recently reported could reverse vision loss
in aging rodents.
Analysis of the muscles, kidneys and retinas of mice showed that cocktail reversed some of the epigenetic changes
caused by DNA breaks.
Sinclair said the findings point to a way to drive animal age "forward and backward at will" and support the idea
of treating human aging with epigenome targets.
Wolf Reik, a molecular biologist and director of the Altos Cambridge Institute of Science, praised the complexity and thoroughness of the Harvard team's research, but the team indirectly induced epigenetic changes through significant DNA breaks that could have other effects that make it difficult to prove that these changes are responsible
for aging.
Jan Vijg, a geneticist at the Albert Einstein School of Medicine, said it was unclear to what extent mice that induced DNA breaks mimicked naturally aging animals
.
He and others emphasize that aging is a complex process with multiple contributing factors, and in both papers, the effect of OSK treatment was moderate: one slightly extended lifespan, and the other partially reversed artificially induced symptoms
.
"Aging is now a jump plan that can be rolled back," Reik said, and this study doesn't prove that right
.
Still, both groups wanted to push their work to the clinic
.
Davidson said Rejuvenate is studying the therapy's mechanism of action and tweaking its delivery and ingredients
.
He added that "OSK may not be the ultimate factor.
"
Sinclair said his team is already testing AAV-delivered OSKs
in monkey eyes.
"If these studies in monkeys go well, and everything seems safe enough for humans, the program will immediately apply to the FDA (Food and Drug Administration) to conduct research
on one or more age-related blindness diseases.
"
Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice
