Anti-aging Slowing Down the Human Aging Process

Researchers from the USA are spearheading a project to test whether reducing DNA-triggered inflammation can help older adults stay healthier for longer. The federal Advanced Research Projects Agency for Health has also awarded 22 million dollars to the project.

Rhode Island/USA – What if people could stay healthier, stronger and mentally sharper as they grow older — not by treating diseases one by one, but by slowing a biological process that drives aging itself? A study led by researchers at Brown University and the University of Rochester will test whether a drug developed to treat HIV can quiet a chronic immune response triggered by the body’s own DNA, to help preserve health and function later in life.

The project is supported by a contract up to 22 million dollars from the federal Advanced Research Projects Agency for Health (ARPA-H). The agency’s highly competitive awards are designed to accelerate bold ideas that, if successful, could reshape how medical providers approach major health challenges. The team is one of several selected by the agency’s Proactive Solutions for Prolonging Resilience (PROSPR) program.

Biology professors Vera Gorbunova, co-director of the Rochester Aging Research Center, and John Sedivy, director of the Center on the Biology of Aging at Brown, will lead the project. The study brings together other researchers from the University of Rochester and Brown as well as the University of Connecticut, University of Texas Medical Branch, University of Texas Health, University of Nebraska and Transposon Therapeutics, a biotech startup founded on intellectual property licensed from Brown.

“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,” Sedivy said. “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, said the study is one of the first to directly address aging.

“Aging underlies many chronic diseases, but it’s rarely targeted directly,” Gorbunova said. “This project builds on the University of Rochester’s longstanding leadership in aging research and gives us a unique opportunity to partner with other leading institutions to address one of the root causes of age-related decline.”

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 dollars 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.”

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