Erythropoietin as a multifaceted antiaging agent: Mechanisms and clinical potential

Human aging is driven by several interconnected hallmarks, including genomic instability, mitochondrial dysfunction, and cellular senescence, which collectively underlie pathologies such as neurodegeneration and metabolic decline. Despite advances in identifying senescence-associated biomarkers and pathways, conventional antiaging compounds such as resveratrol and fisetin, lack regulatory approval owing to insufficient evidence from large-scale trials. Drug repurposing provides a cost-efficient strategy to target aging pathways by leveraging existing pharmacologic safety profiles. Erythropoietin (EPO) exemplifies this approach, demonstrating pleiotropic antiaging effects through modulation of cell survival pathways and tissue-protective mechanisms. Recent advancements in nonhematopoietic EPO derivatives, such as carbamylated EPO, further unlock its development potential by decoupling therapeutic benefits from erythropoietic activity. This review analyzes EPO molecular antiaging mechanisms and clinical applications in age-related diseases (2015-2025), focusing on multiorgan systemic effects and derivative development beyond anemia. SIGNIFICANCE STATEMENT: This review highlights erythropoietin (EPO) as a promising repurposed drug for combating aging, targeting hallmarks such as oxidative stress and cellular senescence. Crucially, nonhematopoietic EPO derivatives circumvent traditional safety risks while retaining multipathway protective effects in brain, cardiovascular, and metabolic tissues. By leveraging established pharmacology, EPO offers a cost-efficient strategy to advance aging interventions, addressing age-related pathologies beyond anemia.