Tests of an anti-aging therapy in mice are boosting hopes at Mayo Clinic and the University of Minnesota about a potential COVID-19 treatment that could reduce deaths and hospitalizations and improve vaccine effectiveness.
Survival increased in mice with COVID-like illnesses when they received drugs that removed senescent cells — sometimes called "retirement" or "zombie" cells that no longer divide or grow, but persist in the body, according to research published Tuesday by Mayo and U researchers in the journal Science.
While success in mice doesn't guarantee success in people, the results give the researchers confidence as they proceed with two human clinical trials in which they remove senescent cells from COVID-19 patients using high doses of the supplement fisetin. 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.
"If you've got a lot of senescent cells, what's going to happen is you're going to have an exaggerated response ... and you're going to get all of these things that happen in older people that kill them with COVID," said Dr. James Kirkland, director of Mayo's Kogod Center on Aging and a lead author of the Science study.
Kirkland and colleagues were among the first to hypothesize how infectious agents prompt senescent cells to increase harmful inflammation in the body. They also discovered how substances such as fisetin — a coloring agent in fruits and vegetables — clear out senescent cells.
The latest finding comes amid substantial declines in COVID-19 activity in Minnesota, which on Wednesday reported that its rate of new infections fell below the state's pandemic caution threshold for the first time since April 2020. Hospitalizations for COVID-19 in Minnesota fell to 192 on Tuesday, the lowest number since spring last year. The state has reported 603,144 infections in the pandemic, adding 150 more infections on Wednesday along with eight more COVID-19 deaths.
While vaccination progress has slowed, nearly 3 million people 12 and older in Minnesota have received a shot and 2.7 million have completed the one- or two-dose series. Mayo and U researchers said a new therapy would be critical even if the pandemic dissipates in Minnesota. Other parts of the world haven't received broad access to vaccine and are in need of treatments to combat the pandemic, which also could rise again in the U.S. if variants of the coronavirus become more severe or vaccine-resistant.
Senescent research at Mayo and the U started years before COVID-19 but was adapted to see if it could make a difference in the pandemic. Discoveries from this work could lead to senescent cell therapies for people with various aging conditions such as arthritis or dementia or to treatments for the next pandemic.
"This approach is improving the resilience to pathogen exposure — one being coronaviruses like SARS-CoV-2 — in the elderly," said Paul Robbins, a co-director of the Institute on the Biology of Aging and Metabolism at the U Medical School. "This will just increase the chances of survival whether it's pneumonia or COVID-19 or COVID-24 or whatever is going to be next."
A key U contribution was its "dirty mouse facility," mixing pristine lab mice with ordinary mice carrying a coronavirus similar to the one that causes COVID-19 in people. All the older lab mice died after exposure, while the younger ones survived. However, when the older mice received treatment to reduce senescent cells, more than half survived.
It made intuitive sense that removing senescent cells could address related conditions of aging, said Dr. Laura Niedernhofer, the other co-director of the U aging center and a lead author of the Science report, but it was surprising to see its impact on a new and unrelated infection.
"That is just pretty amazing that this approach to treating biology of aging protects you from [bad outcomes from] infection," she said.
One of Mayo's trials has recruited 51 out of a goal of 70 patients hospitalized with COVID-19 to compare outcomes and antibody levels between those who receive fisetin and those who don't.
Mayo and the U are starting a second trial using fisetin to try to prevent severe COVID-19 illness and complications in nursing home residents, whose ages and illnesses can make vaccines less effective.
"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.
Drugs such as metformin are already being tested at the U and other institutions to interfere with those processes in people with COVID-19. While fisetin is available over the counter as an anti-aging supplement, Kirkland discouraged people from taking it on their own to protect against COVID-19.
The dosage level is probably too low in supplements to have an impact, he said, compared with the clinical-grade doses being used in the trials. However, there are unknown risks to taking high doses of fisetin — which Mayo received permission to administer after filing the kind of investigational new drug application with the U.S. Food and Drug Administration that is usually reserved for experimental new drugs.
"We're playing with a fundamental aging mechanism," Kirkland said. "We don't know what all the potential downsides could be."