In their experiments using mice and human liver tissue, the researchers uncovered how the aging process triggers the death of certain liver cells. By identifying this process, they were able to reverse it in the animals using an investigational drug.

The findings, published in the journal Nature Aging, offer hope for the millions of individuals with liver damage caused by factors such as high cholesterol, obesity, and diabetes. The lead author of the study, Dr. Anna Mae Diehl, emphasized the potential impact of their discovery, stating, “Our study demonstrates that aging is at least partially reversible. You are never too old to get better.”

The researchers set out to explore how non-alcoholic liver disease progresses to cirrhosis, a severe condition characterized by scarring and organ failure. Aging is a significant risk factor for cirrhosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), affecting one in three adults globally.

Through their studies on mice, the researchers identified a distinct genetic signature associated with aging livers. They found that aged livers exhibited increased activation of genes that promote the death of hepatocytes, the primary functioning cells of the liver.

Dr. Diehl explained, “We discovered that aging triggers a form of programmed cell death in hepatocytes known as ferroptosis, which is iron-dependent. Metabolic stressors exacerbate this death pathway, leading to liver damage.”

Analyzing human liver tissue, the team found that individuals with obesity and MASLD displayed the same genetic signature seen in aged livers. The activation of key genes promoting cell death through ferroptosis provided a clear target for intervention.

“There are mechanisms we can utilize to inhibit this process,” Dr. Diehl noted.

In their animal studies, the researchers induced MASLD in young and old mice through diet and treated them with either a placebo or Ferrostatin-1, a drug that inhibits the cell death pathway. After treatment, the livers of the mice given Ferrostatin-1 resembled those of young, healthy livers, even in older animals on the disease-inducing diet.

“This is a promising development,” Dr. Diehl remarked. “It’s as if we transformed the livers of old mice consuming unhealthy diets into those of teenagers with the same diet.”

Furthermore, the team investigated the impact of liver ferroptosis on other organs as MASLD progresses, noting that damaged livers contribute to ferroptotic stress in the heart, kidneys, and pancreas. The genetic signature was able to distinguish between healthy and diseased organs, highlighting the interconnected nature of organ function.

“Our study demonstrates that by addressing ferroptotic stress, we can reverse the damage caused by aging and non-alcoholic liver disease,” Dr. Diehl concluded.

Alongside Dr. Diehl, the study authors include Kuo Du, Liuyang Wang, Ji Hye Jun, Rajesh K. Dutta, Raquel Maeso-Díaz, Seh Hoon Oh, and Dennis C. Ko. The research received support from the 2021 AASLD Pinnacle Award, the National Institutes of Health, and Boehringer Ingelheim Pharmaceuticals, Inc.