Researchers at Brown and the University of Rochester are testing whether an HIV drug can reduce DNA-triggered inflammation and slow the aging process.

The federal Advanced Research Projects Agency for Health (ARPA-H) is supporting the multicenter study with up to $22 million over five years. It’s led by John Sedivy, PhD, director of the Center on the Biology of Aging at Brown, and Vera Gorbunova, PhD, co-director of the Rochester Aging Research Center.

“What’s new and really exciting about this project is that the goal is not to treat diseases, but to treat aging itself—the normal, healthy process of human aging,” says Sedivy, the Hermon C. Bumpus Professor of Biology. “While aging has been successfully slowed down in model organisms and even in primates, this project will launch a large, credible clinical trial with healthy older people to see if a drug can slow the human aging process.”

Gorbunova, a longtime collaborator of Sedivy’s, adds, “Aging underlies many chronic diseases, but it’s rarely targeted directly.”

While the mechanisms driving age-related decline have been studied extensively in model organisms such as mice, the extent to which those findings can be extrapolated to humans and translated into effective therapies is unknown.

One of the drivers, which the Sedivy-Gorbunova team discovered and have studied for more than a decade, is what they call the “dark genome.” As people grow older, their cells can begin to mistake parts of their own genetic material for viral threats, triggering chronic inflammation that contributes to physical and cognitive decline. The new project will test whether this internal “false alarm” can be safely reduced, helping older adults stay healthier for longer.

The study will focus on retrotransposons, virus-like sequences that make up a large portion of the human genome. Unlike actual viruses, retrotransposons cannot exit cells and infect other cells, but they seek to propagate themselves within the host’s DNA. Sedivy and Gorbunova have shown that retrotransposons become increasingly active with age, leading to inflammation that contributes to tissue decline.

“When we are young, our cells are good at keeping retrotransposons suppressed,” Gorbunova says. “As we age, that control weakens, and the immune system begins to respond as if the body is under viral attack.”

This persistent, age-related immune response has been linked to a range of diseases, like neurodegeneration, cancer, diabetes, and autoimmune diseases. Sedivy and Gorbunova were the first to show that a type of retrotransposon called LINE-1 can directly activate interferon signaling—the same defense system cells use to detect viral infections—and create a false alarm in the form of inflammation.

The ARPA-H-funded project will test whether Censavudine, a drug originally developed to treat HIV, can suppress retrotransposon activity and reduce biological aging. Censavudine works by inhibiting reverse transcriptase, an enzyme that retrotransposons rely on to replicate.

In earlier studies with mice, similar HIV drugs reduced interferon signaling and chronic inflammation associated with aging. The new project will test long-term Censavudine treatment in mice, followed by a randomized clinical trial in humans.

“The ultimate success would provide a way to restore order in the cells and forestall at least some of the molecular ravages of age,” Sedivy says.

The study could help pave the way for therapies designed to preserve overall health and function as people grow older, the researchers say.

“Our hope is that by dialing down retrotransposons, we can help people remain healthier, stronger, and mentally sharper as they age,” Gorbunova says. “That would be a profound shift in how we think about aging and intervention.”