Vitamin C, ACSL4, and Ferro-Aging: Mechanistic Insights and Translational Perspectives from Primate Studies.

The concept of ferro-aging has been proposed as an evolutionarily conserved, iron-driven aging trajectory orchestrated by acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4), which links lipid peroxidation, cellular senescence, and systemic organ decline in primates. Emerging evidence from non-human primate studies suggests that vitamin C (VC), traditionally viewed as a broad-spectrum antioxidant, has been proposed to interact with and inhibit ACSL4 activity at supraphysiological concentrations, potentially reversing multi-omic markers of biological age and preserving neural architecture, functional connectivity, and metabolic homeostasis in aged individuals. However, the precise molecular mechanism of VC-mediated ACSL4 inhibition remains unconfirmed, and the geroprotective efficacy of VC in humans is yet to be validated. This Perspectives critically critically discusses the mechanistic underpinnings of the VC-ACSL4-ferro-aging axis, examines key limitations of current evidence, and highlights the translational potential and unresolved challenges of targeting ferro-aging for promoting healthy aging.