A two-drug combination frequently used in anti-aging research causes brain damage in mice, University of Connecticut researchers report in the March 16 issue of PNAS. The findings should make doctors cautious about prescribing the drug combo prophylactically, but also suggest new ways to understand multiple sclerosis.
"When you administer this cocktail to an animal, young or old, the myelin is damaged, which makes it disappear. Even worse in the young animals" than in the aged ones, says UConn School of Medicine immunologist Stephen Crocker.
Myelin is the insulation around the nerves. When it disappears, nerves don't work as well, and people can develop numbness, pain, and lose the ability to walk. They can also have problems thinking and remembering. Missing myelin is the primary cause of multiple sclerosis. And Crocker and his colleagues saw it happen to mice when treated with dasatinib+quercetin (D+Q) at doses often used to treat aging-related inflammation and metabolic disorders.
D+Q is a popular combination of medicines in anti-aging research. Many studies have shown it works to eliminate aged cells that contribute to inflammation and other age-related symptoms. It is being tested for a range of diseases, from type II diabetes to Alzheimer's. People in the anti-aging scene sometimes even use it off-label, though the medical community discourages this. Very few studies have looked at its effect on the brain.
Evan Lombardo '23 (CLAS), currently a Dartmouth neuroscience graduate student, and Robert Pijewski '21 Ph.D., now at Anna Maria College, were working in Crocker's lab when they wondered if it was possible to rejuvenate the brains of people with multiple sclerosis, and potentially heal their symptoms, using D+Q. They tried it on mice, both young (6 to 9 months) and old (22 months), as well as on brain cells cultured in a dish in the lab. The brain cells were oligodendrocytes, the cells that are supposed to grow and maintain myelin.
The results were dramatic. Healthy mice have myelin surrounding the axons (nerve cells) in the brain. It looks like dark rings around the lighter axon. But the mice treated with D+Q had much less myelin around their axons after the treatment, and the damage was worse in the younger mice. The corpus callosum, a region that connects the cerebral cortex to other parts of the brain and is associated with a range of important functions, also disappeared in mice treated with D+Q. This is known to happen sometimes to people who received chemotherapy, and causes the symptoms popularly referred to as "chemo brain".
When the researchers looked closely at the damaged brain tissue, they found clues as to why the myelin had disappeared. The myelinating cells—oligodendrocytes—hadn't died. They'd regressed into a juvenile form of themselves. And the metabolism of the cells was abnormal, too.
"We suspect the drugs are choking off energy the cells need, and the cells respond by reducing complexity, reverting to a younger state, but less functional," Crocker says.
Interestingly, these cells that have reverted look very much like a distinct population of cells found in people with multiple sclerosis. It suggests that in multiple sclerosis, myelinating cells might come under stress and revert to a younger stage. It also means those cells might be able to recover. And that is what the researchers are working on now.
"If we can mimic this, we have an amazing opportunity to see if the cells can recover and repair the brain," Crocker says.
