Laura Niedernofer didn’t set out to study the biology of aging. Early in her career, she focused on the health impact of DNA damage and how it plays out in rare childhood disorders, an area of inquiry still important to her. Maybe split - In her quest to understand DNA repair, she studied chemistry, then cell biology, then genetics, and joined a lab noted for work in this area. There she discovered that if mice are unable to repair their DNA, they age faster. “I just got fascinated,” says Niedernhofer, who heads up the University’s Institute on Biology of Aging and Metabolism. “I went from studying a rare pediatric disease to studying aging in all of us. The analogies of what goes wrong in our bodies are identical as far as I can tell.”
As we age and our immune system becomes less efficient, senescent cells — damaged cells that have stopped dividing — accumulate and contribute to inflammation. This sets the stage for illnesses associated with aging. By targeting senescent cells, Niedernhofer and her colleagues think there’s a very good chance that they can mitigate some of the worst effects of aging.
“We know if you are older or those with chronic diseases you have more senescent cells than a young person,” says Neidernhofer. “We think those cells cause a lot of inflammation. So if you go into a new infection with already elevated inflammation levels, the inflammation levels compound, your immune system can do more harm than good.”
Niedernhofer is leading efforts to develop a new drug class called senolytics. The Mayo Clinic is currently running nearly a dozen clinical trials of senolytics targeting such health issues as Alzheimer’s, kidney disease, osteoarthritis and other conditions — even COVID-19. The hope is that senolytics reduce the mortality rate from COVID-19 for this particularly vulnerable population.
“Viruses are bad for everybody so it wasn’t clear to me that senolytics would work,” says Niedernhofer. “We’re thinking now that these drugs should work for anything that causes sepsis or pneumonia in the elderly. We’re even thinking of using them to boost the response of vaccines in the elderly since often vaccines aren't as robust when administered to elderly populations.”
Of course senescence isn’t all bad. Niedernhofer describes it as a “healthy response” when cells are stressed. To prevent cancer, senescence is one way your body can stop dysfunctional cells from replicating. But as we get older, the cells tend to accumulate and eventually become a liability. Senolytics step in where the immune system leaves off by clearing out cellular detritus. The treatment won’t necessarily extend human lifespan, but it could improve quality of life for the elderly.
One roadblock is the lack of a baseline to work from in determining when to prescribe the drugs. “We don’t have good tests,” says Niedernhofer. “That’s an area where the field is lagging. It would be great if you could go to a doctor’s office and say ‘how many senescent cells do I have to determine when to start treatment, but right now we don’t have a lot of data about what’s normal for a particular age.”
That is likely to change in the coming years thanks to a big push by the National Institutes of Health, which is funneling resources toward the creation of a map of cellular senescence in healthy human aging. The project rivals the most ambitious scientific endeavors, like the Human Genome Project in ambition. Once complete, scientists will gain a more complete picture of senescence, including where and when it occurs, and what it looks like.
Ultimately, whether studying rare diseases in children or the role of senescence in the old, Niedernhofer is sensitive to the real-world impact of her work. “The average person coming into the healthcare system right now is in their 70s and has multiple diseases, which is costly from a healthcare standpoint,” she says. “But I’m also thinking about what that feels like. They’re probably not very mobile or independent and feel robbed of a high quality of life. The idea is to prevent that.” – Stephanie Xenos
Watch a conversation with Dr. Niedernhofer and social gerontologist Dr. Tetyana Shippee.