Clearing “zombie cells” improved scarred livers in a small trial

As we age, some of our cells stop dividing but don’t die. These senescent cells, sometimes called “zombie cells”, sit in the tissue and release a steady stream of signals that cause inflammation and help scar tissue form. Drugs that kill them selectively are called senolytics. The best-studied pair is dasatinib (a cancer drug) plus quercetin (a plant compound found in onions and apples, here in a much higher dose). They have worked in many mouse studies. The open question is whether they do anything useful in people.

A team at Amsterdam University Medical Center tested them on a common disease where senescent cells are thought to play a role: MASH, the inflammatory form of fatty liver disease (it used to be called NASH). In MASH, fat in the liver triggers inflammation, and over the years the liver can scar (fibrosis), which can end in cirrhosis or liver cancer. Fatty liver disease affects almost 40% of people worldwide, according to the paper.

What they did

The researchers enrolled 31 people with MASH and moderate to advanced scarring, confirmed by a liver biopsy. Seventeen got the drugs and fourteen got identical-looking placebo pills; neither the patients nor the doctors knew who got what. The drugs were taken in bursts, because senescent cells don’t divide and build up slowly: three days a week for three weeks, then four weeks off, and this seven-week cycle was repeated three times (21 weeks in total). At the end, everyone had a second biopsy, and three pathologists who didn’t know who had been treated scored the samples.

What they found

• Less scarring. The main goal was an improvement of the scarring by at least one stage without the inflammation getting worse. That happened in 8 of 17 people on the drugs (47%) and 1 of 14 on placebo (7%).
• Less inflammation. The inflammatory form of the disease cleared up in 9 of 17 treated people (53%) against 1 of 14 on placebo.
• Molecular signs that the drugs hit their target. The team read out which genes were active in individual cells of the biopsies. After treatment, gene patterns typical of senescent cells and of scarring were weaker, and there were fewer of the cells that produce scar tissue (stellate cells) and fewer immune cells. In the placebo group these patterns did not improve.
• Side effects were common but passed. 82% of people on the drugs reported side effects, against 43% on placebo, most often headache. None were judged serious and drug-related. One person stopped because of stomach complaints and tiredness. Platelet counts (blood cells that help clotting) were lower in the treated group.

Blood tests that are often used to follow the disease, such as liver enzymes and scans of liver stiffness, did not differ clearly between the groups.

How sure can we be?

The authors themselves call the result “hypothesis-generating rather than confirmatory”. With only 31 people, a difference of a few patients changes the numbers a lot. Four people did not complete the trial; the main analysis counted them as non-responders. When the researchers tried other reasonable ways of handling these missing biopsies, the result stayed in the same direction, but under the most pessimistic assumption it was no longer statistically significant. There was also an imbalance by chance: far more people in the drug group had type 2 diabetes (76% against 36%). And 21 weeks is short for a disease that develops over many years.

Why it matters

Senolytics have been tested in people before, mostly in small open studies where everyone knew they were treated. This is a randomized, placebo-controlled trial with a hard outcome, a biopsy read by blinded experts, and it found a large effect on scarring. That makes it one of the clearer signals so far that clearing senescent cells can change a human disease. It is also a reminder that these drugs have side effects: dasatinib is a prescription cancer drug and was given here under close medical supervision. The authors call for a larger trial to confirm the effect and to find the best dose and schedule.