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, discovered and researched by the Sedivy-Gorbunova team 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.

“We have known for years that non-infection related inflammation increases with age and is linked to poor aging outcomes,” said Andrew Brack, ARPA-H program manager and creator of the PROSPR program. “Because LINE-1 retrotransposons have recently been reported to increase inflammation as we age, we are excited about the possibility that anti-retroviral therapies, which have the added benefit of a long history of safety in non-diseased populations, will extend healthspan.”

From discovery to intervention

The study will focus on retrotransposons, virus-like sequences sometimes referred to as “selfish DNA” 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. Transposons normally stay dormant, but research over the past 15 years by Sedivy and Gorbunova has 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 said. “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 age-related diseases, such as neurodegeneration, cancer, diabetes and autoimmune diseases. Research by Sedivy and Gorbunova was the first to show that LINE-1 retrotransposons can directly activate interferon signaling — the same antiviral defense system cells use to detect viral infections — creating a false alarm in the form of age-related inflammation.

Building on those discoveries, the ARPA-H–funded project will test whether a drug originally developed to treat HIV can suppress retrotransposon activity and reduce biological aging. The drug, Censavudine, also known as TPN-101, inhibits 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 extend that work by testing long-term Censavudine treatment in mice, followed by a randomized clinical trial in humans. There will be sites for laboratory research with animals at Brown and the University of Rochester.

The clinical phase of the study, which will take place at the University of Rochester, UConn Health in Connecticut and the University of Texas Medical Branch, will aim to enroll at least 200 healthy adults ages 60 to 65, who will receive either Censavudine or a placebo for 48 weeks. The researchers will assess changes in intrinsic capacity, a World Health Organization framework that includes mobility, cognition, vitality, sensory function and psychological health, along with molecular markers of biological aging, physical performance and overall health.

Most of the ARPA-H funding will support the clinical trials, with approximately $2 million allocated to Brown. Sedivy and Gorbunova will oversee the entire project over its five years.

“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 said.

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

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