Reverse liver damage? Duke researchers gain ground on getting us there

To slow or maybe even reverse organ damage linked to aging, scientists must first figure out what goes wrong at the cellular level.

Duke University researchers are gaining ground on that quest with new insights on damage commonly done to people’s livers.

In a recent article published in Nature Aging, they describe success at reversing age-related damage to mice livers in the lab.

The discovery could help doctors better diagnose liver-related disease and determine appropriate treatment options, said Dr. Anna Mae Diehl , a hepatologist and a professor of medicine at Duke.

It might also help scientists find paths to better understanding age-related damage done to other organs, including the heart.

“People are putting themselves under metabolic stress at younger and younger ages,” said Diehl. “We’re trying to give people a healthy lifespan.”

Who is affected by accelerated liver damage?

Some people — particularly those with a condition called metabolic dysfunction-associated steatotic disease (MASLD) — have livers that age more quickly than others and are more prone to developing cirrhosis. People with cirrhosis have livers that are severely damaged, preventing them from functioning properly.

The accumulation of fat in their liver cells puts those cells under stress, prompting them to die at faster rates than their body can repair them.

In other words, they lose the battle between cell death and regeneration.

MASLD affects many people worldwide. People with obesity or diabetes are more prone to MASLD, with three-quarters of people with obesity or diabetes having the condition, according to the Cleveland Clinic.

Researchers found that the cells were aging due to a process called ferroptosis, programmed cell death that occurs when a cell is under specific types of stress.

“It starts to telegraph signals to its neighbors to say, ‘I’m in trouble here. Can you guys help me?’” Diehl said.

Ferroptosis is important because it clears away bad cells to make way for healthy ones, Diehl said.

“It’s sort of like pruning a bush, right? You cut away the dying parts.”

When this process begins to remove cells faster than new cells appear, the liver starts aging.

Found what’s broken? Let’s fix it.

After feeding mice a high fat diet, mimicking how MASLD would present in a human, the researchers treated each mouse with a chemical that reduces the cellular stress triggering ferroptosis.

“We were able to make it look young again,” said Diehl, “Just as if it hadn’t been under all that wear and tear for as long as it had been.”

These findings explain why current treatments for MASLD like Vitamin E, which alters how the body metabolizes iron, involved in ferroptosis, have benefited some patients.

This new study, demonstrating the relevancy of iron-induced cell death through ferroptosis, provides some basis for why Vitamin E can work as a treatment.

It’s important to note, however, that ferroptosis isn’t always harmful, said Dr. Paul Monga, professor of pathology and director of the Pittsburgh Liver Research Center at the University of Pittsburgh.

People with MASLD are at higher risk for developing liver cancer. Ferroptosis can actually play a helpful role in killing cancer cells, according to Monga.

“It’s cancer that brings patients to the hospital,” Monga said. “In that case, we want to kill the cancer cells, and we want to induce ferroptosis.”

Since ferroptosis can be harmful in earlier stages and helpful in later stages of MASLD, Monga and Diehl agree that researchers need to determine when a treatment that prevents ferroptosis would be helpful for patients with the disease.

From mice to humans

The next step for Diehl and her team is to better determine which patients are experiencing excessive cell death caused by ferroptosis at younger ages and could benefit from treatment preventing ferroptosis.

Diehl’s research team is currently working on building upon their RNA sequencing method to create a simpler, more practical blood test.

“In the best of all possible worlds,” Diehl says that if someone with MASLD enters her clinic, she could order a blood test to determine if their liver is aging and susceptible to ferroptosis.

“We would say, well, let’s try Vitamin E in you and see if that helps,” said Diehl. They could then repeat the blood test to determine if the aging decreased and the treatment is working.