Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress

Susceptibility to the biological consequences of aging varies among organs and individuals. We analyzed hepatocyte transcriptomes of healthy young and aged male mice to generate an aging hepatocyte gene signature, used it to deconvolute transcriptomic data from humans and mice with metabolic dysfunction-associated liver disease, validated findings with functional studies in mice and applied the signature to transcriptomic data from other organs to determine whether aging-sensitive degenerative mechanisms are conserved. We discovered that the signature enriches in diseased livers in parallel with degeneration. It is also enriched in failing human hearts, diseased kidneys and pancreatic islets from individuals with diabetes. The signature includes genes that control ferroptosis. Aged mice develop more hepatocyte ferroptosis and liver degeneration than young mice when fed diets that induce metabolic stress. Inhibiting ferroptosis shifts the liver transcriptome of old mice toward that of young mice and reverses aging-exacerbated liver damage, identifying ferroptosis as a tractable, conserved mechanism for aging-related tissue degeneration. The mechanisms underlying susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) in aging are incompletely understood. Here the authors show that an aging hepatocyte gene signature is enriched in MASLD liver tissue and contains ferroptosis genes. Experiments in mice show that metabolic stress increases ferroptosis in liver tissue in old compared to young animals and that blocking ferroptosis in old animals reduces the susceptibility to metabolic stress.