“We think the various causes of aging may be addressable with a single treatment to reset the cell,” said Harvard scientist David Sinclair, the paper’s senior author. “So in the future, we could get one treatment — it could be a pill, it could be an injection — to go back 10 years [in cellular life], and then we’ll repeat that process every 10 years.”
That kind of miracle drug won’t be developed overnight. The paper’s authors detail experiments with mice that would have to be replicated in humans before Sinclair’s vision could be realized. Scientists would also have to overcome potential safety and regulatory hurdles.
But the paper supports what Sinclair, a genetics professor at Harvard’s Blavatnik Institute and codirector of the Paul F. Glenn Center for Biology of Aging Research, calls the “information theory of aging” that identifies the epigenome as the primary culprit in the aging process. The epigenome, a kind of cellular operating system, regulates which genes are turned on, or expressed, and which turned off, or not expressed.
Scientists have long suspected that aging is caused by genetic malfunctions such as mutations or misfolded proteins. The study, however, concludes those malfunctions themselves may be triggered by the loss of epigenetic information over time. Essentially, the study found, the cell’s machinery for fixing normal wear and tear in the DNA breaks down over time, allowing harmful genetic mutations to be expressed.
This is important for drug discovery because restoring the process by which stretches of DNA are turned on and off to control the pace of cellular aging looks to be easier than trying to reprogram genetic mutations, the study’s authors contend.
The study is already drawing interest in the biomedical world and from many in the emerging field of geroscience who believe the best way to treat a variety of maladies is to attack the aging process itself.
“We always talk about slowing [aging] down,” said Jay Olshansky, public health professor at the University of Illinois at Chicago, who said he was eager to review Sinclair’s methodology. “Going back in time has generally not been thought to be in the cards. But if, in fact, you can reverse attributes of aging, that is a game changer.”
In experiments described in the study, the scientists first made temporary and fast-healing cuts in the DNA of lab mice, mimicking the double-stranded DNA breaks that are seen in human cells as they undergo a succession of breaks and repairs over the years.
By speeding the breakage, scientists were able to induce epigenetic changes that caused the mice to quickly lose their youthful vigor, and look and act older. Then the scientists administered a three-gene therapy called OSK that reversed the epigenetic changes set in motion by the DNA breaks and restored the lab mice to their youthful state.
Sinclair, an Australian-born biologist who’s a leader in the field, said the study validated an “epiphany” he had in 1996 when it first dawned on him that the epigenome played a key role in aging and it might be possible to manipulate it, like rebooting a computer.
“It is the cell’s reaction to damage and the resulting loss of epigenetic information that drives mammalian aging forward,” the study’s authors write in the Cell article.
Much remains unclear about the techniques deployed by Sinclair’s team to drive aging forward and backward, and whether they could be replicated in humans. Sinclair and his coauthors acknowledge they don’t understand precisely how the gene therapy was able to reset the biological clock in mice, though they believe they activated a kind of “back-up copy of epigenetic software” that reprogrammed cells.
“It is now apparent that mammals retain a back-up copy of youthful epigenetic information that can safely restore the function of old tissues, akin to reinstalling software,” the authors wrote in the Cell article.
Thomas Rando, director of the Broad Stem Cell Research Center at the University of California Los Angeles, has long studied the role of epigenetics in aging but wasn’t involved in the Sinclair study. For researchers, he said, the study’s most critical takeaway is the model scientists created to modulate the aging process. That will be valuable to drug developers in testing experimental disease treatments, he said.
“The idea is that this might be a better model of the natural aging process,” Rando said. “I think it could be.”
James Kirkland, director of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic in Rochester, Minn., said epigenetics may just be one of several major drivers of aging, along with inflammation, damaged or “senescent” cells, and problems with the function of progenitor cells, which create specialized cell types. These drivers may be linked, he said.
But regardless of whether epigenetics is a primary diver, he said, the findings in the Cell study look likely to propel aging research forward.
Sinclair has been on a decades-long scientific quest to reverse aging. In an earlier breakthrough, outlined in a Cell article in March 2018, he and his colleagues rejuvenated 20-month-old mice by treating them with a molecule called nicotinamide mononucleotide, or NMN. Soon these geriatric rodents were outracing two-month-old mice in a lab.
Back in 2020, his scientific team also used the same three-gene cocktail employed in the epigenetic study to restore lost sight in blind mice.
But significant hurdles remain before these feats can be attempted in human studies, including how to allay fears that efforts to change the age of cells carry the risk of causing uncontrolled growth and cancer.
“That’s the biggest risk in this whole field of aging reprogramming,” Rando said. “There will always be a safety issue in attempts to reverse aging. There will always be the risk of unwanted outcomes in mucking with the genome.”
At least half a dozen biotech companies globally are working on therapies that can stretch life spans, including a pair in Massachusetts cofounded by Sinclair, Life Biosciences in Boston and MetroBiotech in Worcester. One of the best funded is San Francisco-based Altos Labs, which has financial backing from Amazon founder Jeff Bezos.
All of those companies face a formidable obstacle: the Food and Drug Administration, which approves new medicines in the United States, currently doesn’t categorize aging as a disease. So to win FDA approval, all drug candidates must target some other illness, such as diabetes or Alzheimer’s, potentially narrowing the scope of research.
While the biotech startups are taking a variety of approaches to human age reversal, Sinclair believes the findings published Thursday could point the way to rethinking basic assumptions about aging.
“We’ve unlocked a major cause of aging,” he said. “A lot of the information to be young again still exists in the cell, and much of the DNA in our bodies is intact.”
Robert Weisman can be reached at robert.weisman@globe.com.