Aging Promotes Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-Organ Dysfunction by Inducing Ferroptotic Stress

Aging is an inevitable consequence of living that undermines cellular resiliency to cause tissue degeneration and eventual multi-organ dysfunction. Susceptibility to biological consequences of aging varies among organs and individuals. Stressors that challenge resiliency unmask these differences. Hence, aging increases the risk for failure of many metabolically-stressed organs and exacerbates liver degeneration related to obesity and diabetes. We discovered that aging promotes ferroptosis, a type of metabolism-regulated cell death, in hepatocytes. Hepatocytes that have launched the ferroptotic death program adapt their metabolism to survive but become damaged and dysfunctional. Metabolic stressors amplify this, increasing the burden of ferroptosis-adapted cells and liver damage. Blocking ferroptotic signaling in old livers reduces accumulation of adapted hepatocytes and reverts livers to a more youthful resilient state despite exogenous stressors. Ferroptosis is also induced in other organs that are damaged by chronic metabolic stress, identifying ferroptosis as a tractable conserved mechanism for aging-related multi-organ dysfunction.