Aging Promotes Harmful Levels of Ferroptosis in the Liver and other Organs

Aging makes obesity-related liver conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD) both more likely to occur and worse when they do occur, more likely to progress towards fibrosis and liver failure. Researchers here point to an increased propensity to the cell death process of ferroptosis in liver cells as an important difference between old and young livers, and demonstrate that blocking ferroptosis can make old livers more youthful in the context of metabolic disease.

Researchers set out to understand how non-alcoholic liver disease develops into a severe condition called cirrhosis, in which scarring can lead to organ failure. Aging is a key risk factor for cirrhosis among those who have been diagnosed with non-alcoholic liver disease, known as metabolic dysfunction-associated steatotic liver disease, or MASLD. One in three adults worldwide have the disease. Studying the livers of mice, the researchers identified a genetic signature distinct to old livers. Compared to young livers, the old organs had an abundance of genes that were activated to cause degeneration of hepatocytes, the main functioning cells of the liver. "We found that aging promotes a type of programmed cell death in hepatocytes called ferroptosis, which is dependent on iron. Metabolic stressors amplify this death program, increasing liver damage."

Armed with their genetic signature of old livers, the researchers analyzed human liver tissue and found that the livers of people diagnosed with obesity and MASLD carried the signature, and the worse their disease, the stronger the signal. Importantly, key genes in the livers of people with MASLD were highly activated to promote cell death through ferroptosis. This gave the researchers a definitive target. Again turning to mice, the researchers fed young and old mice diets that caused them to develop MASLD. They then gave half the animals a placebo drug and the other half a drug called Ferrostatin-1, which inhibits the cell death pathway. Upon analysis after treatment, the livers of the animals given Ferrostatin-1 looked biologically like young, healthy livers - even in the old animals that were kept on the disease-inducing diet.

The team also looked at how the ferroptosis process in the liver impacts the function of other organs, which are often damaged as MASLD progresses. The genetic signature was able to differentiate between diseased and healthy hearts, kidneys and pancreases, indicating that damaged livers amplify ferroptotic stress in other tissues.


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