Spring 2022

Cleanup duty

New therapies designed to clear senescent cells from the body could keep our aging population healthier longer—and improve outcomes for COVID-19 patients, too


When COVID-19 began surging around the world in early 2020 and physicians were confronting a deadly disease they knew little about, scientists at the University of Minnesota’s Institute on the Biology of Aging and Metabolism (iBAM) swung into action to help.

“Early in the pandemic it became very clear that certain people were at greatest risk—the elderly, people with diabetes, and people with obesity,” says Laura Niedernhofer, M.D., Ph.D., professor of biochemistry in the Medical School and director of iBAM. “And one common thread between those groups? They all have increased levels of senescent cells.”

Senescent cells are aging cells that have stopped dividing but haven’t died. According to Niedernhofer, the burden of senescent cells in our body doubles with every decade of life.

“Senescent cells drive inflammation, and that inflammation then puts you at greater risk for disease and aging,” explains iBAM associate director Paul Robbins, Ph.D., also a professor of biochemistry in the Medical School. “If you have a perfectly healthy, robust immune system, your body clears these cells for you. But as we age, our immune response wanes and stops clearing these cells effectively.”

Niedernhofer, Robbins, and their iBAM colleagues didn’t wait to be asked if their research into senescent cells could be applied to fight COVID-19 infections, too. “This was really an instant reaction,” recalls Niedernhofer. “We’re here to think about the biology of aging, but more importantly, we’re here to help older Minnesotans. We felt it was our obligation to do everything we could to help rescue our most vulnerable populations from the lethality of COVID-19.”

But what if there were a drug that could help clear senescent cells and slow the onset of not just the aging process, but of the many diseases associated with aging, such as heart disease, cancer, type 2 diabetes, and Alzheimer’s disease?

That question led Niedernhofer and Robbins, working with colleagues at the Mayo Clinic, to become the first scientists to describe a new class of drugs called senolytics in 2015. More recently, they’ve shown that fisetin, a natural antioxidant found in various fruits and vegetables (apples, strawberries, onions, and cucumbers, for example), successfully clears senescent cells in mice.

“We do have preliminary data [indicating] that fisetin clears senescent cells in humans,” says Niedernhofer, “and there are now many clinical trials underway to study it further.”

Laura Niedernhofer, M.D., Ph.D., and Paul Robbins, Ph.D.

A new enemy

When COVID-19 struck, iBAM scientists quickly geared up to see whether the senolytics they were developing to promote healthier aging could also be used to treat the viral infection caused by SARS-CoV-2.

In a study led by iBAM investigator Christina Camell, Ph.D., researchers exposed aged mice to a coronavirus closely related to SARS-CoV-2. In the control group, all of the infected mice died; mice treated with a senolytic, however, had a 50–60% survival rate.

“The excitement around senolytics as a COVID-19 treatment has been growing,” says Camell, since the group’s results were published this past summer in the prestigious journal Science.

Now three clinical studies are underway in Minnesota to evaluate the success of treating COVID-19 patients with senolytics. The first trial focuses on hospitalized COVID patients at the Mayo Clinic; investigators already have treated most of the 70 patients they want to study, so Niedernhofer expects they’ll have answers about the senolytics’ effectiveness against COVID within months.

A second study, which just started this winter, will be conducted by physicians in the Medical School’s Department of Family Medicine and Community Health in nursing homes throughout Minnesota. Half of the people enrolled in the trial will receive a placebo, while the other half will get a senolytic. And once this nursing home clinical trial network is built, says Robbins, it should prove valuable for future iBAM studies.

Super senolytics

Researchers at the University of Minnesota Institute on the Biology of Aging and Metabolism are excited about the many possible uses for therapeutic senolytics beyond healthy aging and COVID-19:

Improving vaccine response: Early evidence indicates that senolytics can be used to improve response to a vaccine. Researchers foresee a scenario where people 65 and older might take senolytics for two weeks before getting their jabs.

Making kidneys viable for transplant: Senolytics could potentially help to rid older organs, which are not currently eligible for transplant, of senescent cells, thereby making them viable.

Tackling viral infections: Scientists also believe that senolytics may prove valuable in reducing mortality from a whole range of viral infections, including pneumonia and sepsis.

A third study in preparation will target people who have “long COVID,” who suffer long-term with such COVID symptoms as brain fog, shortness of breath, fatigue, and chronic pain. Says Robbins: “There’s preliminary evidence that senescent cells increase in long-haulers, so senolytics may be effective in reducing symptoms in these patients.”

Although fisetin is currently available as an over-the-counter supplement, Niedernhofer recommends against taking it to self-treat COVID-19.

“We don’t yet know the right dosing,” she says, “but I can promise you that what’s available in the marketplace right now is not what we’re developing. Those products are not regulated and can cause more harm than good.”

Investment to outcomes

This high-impact work stems from an intentional plan to improve the health of all Minnesotans.

In 2015, the Minnesota Legislature’s higher education funding bill included an unprecedented $30 million investment that allowed the U’s Medical School to establish four new Medical Discovery Teams (MDTs). The MDTs were designed to propel already strong programs into world-class research cohorts dedicated to addressing some of the state’s most pressing health care priorities: addiction, rural and Native American health, optical imaging and brain science, and the biology of aging.

That investment brought top researchers like Niedernhofer and Robbins to the U to continue building on their leading-edge research.

Additional philanthropic funding, including a recent $150,000 gift, directly supports iBAM’s work, which involves developing new senolytic therapies as well as better biomarkers—simple blood and urine tests—that could aid physicians in quickly diagnosing disease.

“The University of Minnesota has been an incredibly rich backdrop for our work studying the biology of aging,” says Niedernhofer, “providing so many opportunities for collaborations with colleagues across campus to find new applications for senolytics in treating diseases in the elderly.”

And with the state’s (and the world’s) aging population growing, there’s no better time for progress.

“We’re living in a time on this planet where the elderly population is doubling,” says Niedernhofer, “and each of those elderly people has an average of two chronic diseases. By targeting the biology of aging itself, instead of targeting specific diseases, with this new class of drugs called senolytics, we may be able to help people live healthier for a longer time.”