Ferro-aging: A novel paradigm linking iron overload, lipid peroxidation and cellular senescence

Iron is a double-edged sword in aging, and age-related iron accumulation acts as a critical amplifier, rather than a sole driver, of ageing; disrupted iron homeostasis with progressive iron accumulation drives oxidative stress, mitochondrial damage and inflammaging. Ferroptosis and cellular senescence, two critical aging-related processes, share upstream drivers like oxidative stress and lipid peroxidation. This study proposed the novel ferro-aging paradigm, a cascade pathway where age-related iron overload initiates iron-catalyzed reactive oxygen species production and lipid peroxidation, ultimately inducing cellular senescence and ferroptosis to exacerbate, rather than independently cause, tissue dysfunction and age-related diseases. Iron accumulation in senescent cells stems from dysregulated iron uptake, storage, efflux, impaired ferritinophagy, and critical mitochondrial dysfunction. Senescent cells acquire ferroptosis resistance, leading to persistent tissue accumulation and chronic inflammation. Ferroptosis and senescence interact dynamically and form a positive feedback loop, with lipid peroxidation as the core executor. Ferro-aging participates in multiple age-related diseases of the nervous, cardiovascular, metabolic and skeletal systems. Targeting iron homeostasis, lipid peroxidation, senescent cells, and mitochondrial function provides promising anti-aging interventions. This review clarifies the connotation and mechanism of ferro-aging, and reveals its potential as a unified target for delaying aging and treating age-related diseases.