Scientists’ understanding of the biology of aging has progressed rapidly in the last three decades, starting with discoveries in the 1990s that certain genetic mutations dramatically extended the lifespan of laboratory animals.
Researchers have since been searching for drugs that can slow the progression of natural aging and the onset of age-related diseases in humans. Although several longevity drug candidates have been identified, none have yet been proven in large human trials designed specifically to slow biological aging.
Now, researchers at UT Health San Antonio are preparing one of the largest human trials aimed at testing whether three existing drugs — rapamycin, semaglutide and dapagliflozin — might slow some of the biological processes behind aging.
“This is the culmination of 50 years’ worth of aging research at UT Health San Antonio,” said Dr. Elena Volpi, director of UT Health San Antonio’s Sam and Ann Barshop Institute for Longevity and Aging Studies, and lead author of the study.
The study, which the researchers have coined the “VITAL-H” trial, has $38 million in federal contract support behind it. Expected to start later this year or earlier next year, the VITAL-H trial is the largest study the university’s aging institute has led, Volpi said.
Besides being a “first-of-its-kind study,” Volpi said, it’s also notable that such a significant trial is taking place locally in a Hispanic population that has historically been underrepresented in research.
“We will try to get deep into South Texas, because we want to give an opportunity to people who cannot normally participate in clinical trials to actually participate,” Volpi said. “Because we think it is important that everyone has a chance.”
The Barshop institute is home to 27 core faculty members and over 100 research personnel spanning a range of disciplines from molecular biology and neuroscience to pharmacology and drug discovery, and much more.
Founded in 1991 as the Aging Research and Education Center, the Barshop Institute’s roots date back to 1975, when Dr. Ed Masoro became one of the first scientists to study longevity interventions in lab mice. It became the Barshop Institute in 2001 following a large donation from Sam and Ann Barshop.
The search for drugs that might slow aging
The drugs being tested in the VITAL-H trial come out of decades of research into the biological drivers of aging.
Aging remains the most prominent risk factor for chronic diseases like cardiovascular disease, neurodegenerative diseases like Alzheimer’s, cancer and diabetes, even as life expectancy has increased to nearly 80 years old in the U.S.
Since around 2013, scientists have increasingly organized these biological processes into a framework known as the “hallmarks of aging,” helping researchers understand how our bodies gradually lose cognitive and physical function, and what interventions might slow that process.
“Over the past 50 years, there’s been an incredible increase in lifespan worldwide,” Volpi said. “But really the age of onset of the chronic diseases that will eventually debilitate us … hasn’t really changed.”
How three existing drugs became longevity candidates
In 2009, researchers, including several with the Barshop Institute, found that low doses of rapamycin — approved by the U.S. Food and Drug Administration in 1999 as an immune system suppressant — increased the lifespan of laboratory mice, with follow-up studies replicating those findings.
The landmark study was one of the first major studies showing that a drug could extend lifespan in mammals. Since then, rapamycin has been chief among the most promising and talked about anti-aging drug candidates.
But because lifespan extension has largely been observed only in animal models, scientists remain uncertain whether those benefits will translate to humans.
UT Health researchers also tested rapamycin on marmosets — small monkeys used in longevity research and kept by the university and Texas Biomedical Research Institute. The benefits, published in a 2019 paper, were not as robust as some researchers had expected, though the medication was generally safe.
More recently, a class of drugs known as GLP-1 agonists have earned a swarm of attention from scientists and the public. Semaglutide, known under brand names Ozempic, Wegovy and Rybelsus, has boomed in popularity in recent years for its weight loss effects.
Researchers have continued to uncover a diverse range of benefits besides glucose control and weight loss associated with semaglutide and other GLP-1 drugs, including reducing the risk of heart attacks and strokes, treating obstructive sleep apnea, fatty liver disease and chronic kidney disease.
This has led many in the research community to suggest a clinical trial designed specifically to test the drugs on healthy individuals as potential longevity candidates.
The last, and least well known drug in the VITAL-H trial is dapagliflozin, which belongs to a class of drugs known as sodium-glucose cotransporter 2 inhibitors used to treat diabetes.
These drugs help regulate blood sugar by fostering glucose elimination through urine, promoting metabolic health. They have also been found to impact certain pathways that influence aging, by lowering low-grade inflammation, a driver of aging commonly referred to as “inflammaging.”
Beyond lifespan
The VITAL-H study will be a large clinical trial with $38 million in federal support from the U.S. Department of Health and Human Services’ Advanced Research Projects Agency for Health (ARPA-H), which awarded UT Health one of the largest contracts in its latest funding round.
UT Health will work closely with Stanford University, the Buck Institute for Research on Aging and Columbia University on the study.
The trial will take place over three years, plus an additional six months of follow-up once participants stop taking the medications. It will include over 700 participants from South Texas, potentially closer to 1,000, aged 60 to 65 years old and in relatively good health.
“One of the big deals here will be not just to recruit all the patients, it will be to also retain them over the entirety of the study,” Volpi said. “We have been given a tall order by ARPA-H to retain at least 85% of the participants. We need to really work hard on ways [to keep them]. Otherwise we’re not going to have enough power to see differences.”
Because measuring lifespan in humans would take decades, researchers will instead track changes in biological markers of aging and overall health.
Participants will be bucketed into four groups: rapamycin, semaglutide, dapagliflozin and a placebo group. They will wear Oura rings, a wearable health tracker that gathers a range of health data, in addition to check-ins every few months to gather other health data and fill out surveys.
Researchers will also track a newer measure of aging known as “intrinsic capacity,” developed by the World Health Organization, which looks at physical and mental abilities such as strength, sleep, nutrition, cardiovascular health, sensory function and cognition.
The new measure places a greater emphasis on health span, the number of years lived in relatively good health, rather than simply living longer.
“What we’re looking for is for people to gain more years of health,” Volpi said. “Our hope is that at least one of these drugs will show an impact on slowing down the decline in intrinsic capacity that occurs with aging. We want to slow it down so that people can gain more years of healthy living, healthy life.”
“We want to start the declining process as late as possible to compress the decline towards the end of life so that we can live and work and be happy and do whatever we want to do for as long as we can.”
