Researchers from the University of Minnesota Medical School are collaborating with the Mayo Clinic to test the use of a senolytic therapy against COVID-19. The therapy targets the fundamental biology of aging.
Initial findings, published June 8 in Science, suggest that using drugs to clear out older, damaged cells could reduce the inflammation and immune system overreaction that leads to severe or fatal COVID cases.
The team has now moved onto human trials for the treatment.
Planting the seeds
The work was funded in the earliest phases by a seed grant from the Clinical and Translational Science Institute (CTSI) at the University of Minnesota in April 2020. This grant was awarded to co-lead author Paul Robbins, PhD, a UMN biochemistry professor to study how the cellular mechanisms of aging can be targeted to fight COVID-19.
“CTSI recognized very early in the pandemic that the research we were doing could be incredibly impactful in terms of preventing death and other adverse outcomes in people who became infected with SARS-CoV-2,” said co-lead author Laura Niedernhofer, MD, PhD, also a UMN biochemistry professor. “And the seed funding from CTSI was critical to getting this potential COVID-19 therapy off the ground.”
Finding the culprit behind adverse COVID-19 outcomes
Just one month after this critical seed grant, Niedernhofer herself was awarded an R01 supplement from the NIH National Institute on Aging with the goal of determining whether the adverse outcomes of COVID-19 are caused by senescent cells.
These are cells that have grown too old to grow or divide but linger in the body anyway. As a Star Tribune story on the team’s research explains:
"Senescent cells increase with age and chronic disease and could explain why older and unhealthier people make up more than 90% of Minnesota's 7,477 COVID-19 deaths."
The hypothesis was that if these cells could be removed, the adverse outcomes of SARS-CoV-2 could be mitigated.
James Kirkland, MD, PhD, director of Mayo's Kogod Center on Aging and a co-author of the Science study, explained the effect of accumulated senescent cells on viral infection to the Star Tribune:
"Senescent cells reduce the ability of normal cells to fight off viruses," Kirkland said, and they 'upregulate' the processes in which viruses bind to and enter healthy cells.
He also explained how this upregulation manifests in older COVID-19 patients:
"If you've got a lot of senescent cells, what's going to happen is you're going to have an exaggerated response to infection… and you're going to get all of these bad outcomes that happen in older people with COVID.”
Proving the treatment works
To determine whether targeting senescent cells could work against COVID-19, the research team worked with researchers from Mayo Clinic, including Kirkland, to study the effect of senolytic therapies on coronavirus mortality in mice. They tested fisetin, a natural product that gives color to fruits and vegetables, but which the team showed in 2018 also kills senescent cells.
First, they mixed healthy lab mice with ordinary mice carrying a virus similar to SARS-CoV-2, observing how the mice responded to the virus. Without treatment, all the older mice died after exposure. But when they administered high doses of fisetin to the mice, more than half of the older mice survived, showing that the team had discovered a critical mechanism in COVID-19 pathogenesis.
Bringing the treatment to humans
As a result of the work completed under both the CTSI seed grant and the R01 supplement, Drs. Niedernhofer, Kirkland, and Robbins were awarded a new R01 grant from the NIH National Institute on Aging in September 2020 to bring the treatment to humans in two clinical trials.
One trial is focused on patients who are already hospitalized with severe COVID, and another is on elderly people living in nursing homes. These trials are still ongoing, beginning in early 2021.
“We couldn’t have completed this work without the support of CTSI at the start,” Niedernhofer said. “They funded critical pre-clinical studies, which ultimately led to additional funding from the NIH, our Science manuscript, and two clinical trials.”
While the results of the clinical trials have not been published yet, the earlier findings in mice suggest that targeting these senescent cells is a promising new approach for treating COVID-19 and other viral illnesses. Niedernhofer is amazed the therapy has shown such promise, considering how seemingly unrelated aging and COVID-19 are:
"It’s incredible that an approach for treating the biology of aging could also protect people from severe outcomes of COVID-19.”