Scientists at Harvard’s Wyss Institute for Biologically Inspired Engineering have used a combination of three longevity-associated genes, delivered through a one-time injection, to dramatically improve or reverse multiple age-related diseases in mice.
The findings, published Monday in Proceedings of the National Academy of Science, a prestigious scientific journal known as PNAS, suggest that targeting aging “holistically” through gene therapy holds the promise of eventually staving off a long list of age-related diseases in humans that today are treated separately.
Researchers at George Church’s Wyss Institute Lab in Boston’s Longwood Medical Area reported the combination gene therapy, which used a type of virus as a delivery vehicle, reversed diabetes and obesity in mice. The therapy also reversed heart and kidney failure in some mice and substantially improved heart and kidney function in others. While it didn’t target other major age-related diseases, such as cancers and dementia, those will be examined in later studies.
“If you hit enough specific diseases, you’re getting at the core aging components that are common to all of them,” Church, a Wyss core faculty member, said in an interview Monday. “Gene therapy gives you a testable therapy at scale in mice. And we can move from mice to dogs and then to humans. We’re focusing on the reversal of age-related diseases so we’ll be more healthy and youthful later in life.”
The research is part of a broader emerging field, sometimes called geroscience. Its advocates believe that the best way to treat a variety of illnesses — from cancers and heart disease to Alzheimer’s and macular degeneration — is to attack the aging process itself.
“We’re taking a holistic approach,” said Noah Davidsohn, a former research scientist in Church’s lab who is first author of the study. “Rather than attack specific diseases, we’re trying to make patients generally healthier and, in the process, getting rid of as many age-related diseases as possible. Nobody wants to be old and in a wheelchair and not doing anything.”
Boston’s biomedical hub has become a hotbed of geroscience research.
Last winter, 16 of the world’s top longevity scientists, including Harvard scientist David Sinclair, professor of genetics and director of the Paul F. Glenn Center for the Biology of Aging, formed a Boston-based academy that will seek to spotlight medical research on extending human life and developing drugs to slow the aging process. The nonprofit Academy for Health and Lifespan Research will share research and lobby governments in the United States, Europe, and elsewhere to increase funding and create new paths to approve age-slowing therapies.
Previous studies in the field have also sought to slow aging and extend healthy life spans through small molecules that increase blood flow and endurance, or weed out “zombie cells” that send out toxins causing age-related maladies. But the Wyss Institute is the first to use therapy that combines genes to boost protein levels that diminish with aging. The genes were selected from a database developed over the past decade at Church’s lab.
“We looked at the ones that had the biggest impact individually and then wanted to see if they would work more effectively in pairs and triples,” Church said. Such an approach, he said, had the greatest potential to target multiple diseases through a “one-and-done” injection into the blood or muscle, a simple procedure akin to getting an influenza vaccine shot.
When deployed against obesity, type II diabetes, heart failure, and renal failure, a “single formulation . . . was able to treat all four diseases,” according to the study published in PNAS. “These results emphasize the promise of gene therapy for treating diverse age-related ailments, and demonstrate a new approach of combination gene therapy that may improve healthspan and longevity by addressing multiple diseases at once.”
San Diego-based biotech startup Rejuvenate Bio, founded by Church and a pair of coauthors of the PNAS study, Davidsohn and Daniel Oliver, is pursuing a gene therapy to fight age-related diseases. The company has already begun working with the Cummings School of Veterinary Medicine at Tufts University in North Grafton to test the gene therapy combination in dogs.
Davidsohn, chief technology officer at Rejuvenate, said the company is focused for now on developing and marketing a treatment that can extend the “health span” of dogs, which can suffer from a range of age-related illnesses — including heart and kidney problems, obesity, dementia, and hearing and vision loss — similar to those afflicting humans.
His own 5-year-old dog, Bear, whom Davidsohn adopted while working in the Wyss Institute lab, was an inspiration and now holds the honorary title of chief inspiration officer at Rejuvenate. The company was launched in stealth mode about a year ago and now has eight employees.
While dogs will be an important market in their own right for the combination gene therapy, Davidsohn said, “We would be happy if this ended up in humans.”
Church said testing the experimental therapy in dogs is likely to take about two years. Then, if regulators approve it, clinical trials could begin in humans. But even if all goes well, he said, the gene therapy probably won’t be available as a marketed product for more than a decade.
By then, he said, the cost of a gene therapy — which now can top $1 million per patient for rare diseases — could drop to thousands of dollars per patient in what would be a much larger market to treat multiple age-related diseases.
Some supporters of age-slowing research, such as Jay Olshansky, public health professor at the University of Illinois at Chicago, have cautioned against expectations that scientists can radically lengthen life spans. Instead, they believe, the goal should be, as Olshansky puts it, “pushing out the red zone,” the time of frailty and disability at the end of life.
Church, however, has a more ambitious vision.
“The important thing is getting good at age reversal,” he said. “If age reversal truly works, there is no upper limit” on how long healthy lives can be extended.
Correction: An earlier version of this story incorrectly characterized the status of the collaboration between Rejuvenate Bio and George Church’s Wyss Institute Lab.