Complex Interplay Between Estrogen and Aging via Lipid Metabolism and Inflammation Forms the Novel Treatment...

Atherosclerosis (AS) poses a substantial risk to human health, leading to serious cardiovascular and cerebrovascular incidents, such as myocardial infarction, coronary heart disease, and ischemic shock. The treatment and control of AS are challenging because of its complex pathogenesis and multiple risk factors. Notably, changes in the estrogen levels and aging are associated with the formation and progression of AS because of their involvement in lipid metabolism, inflammatory responses, coagulation and fibrinolytic systems. Emerging evidence suggests that estrogen modulates vascular senescence pathways, whereas aging exacerbates endothelial dysfunction induced by estrogen deficiency, thereby establishing a bidirectional pathogenic loop. However, the precise interplay between estrogen and aging in AS pathogenesis remains uncertain, particularly regarding whether their effects are synergistic or sequential, and how sex-specific aging trajectories influence this relationship. In this review, In this review, we provide a comprehensive analysis of the interplay among estrogen, aging, and AS, thereby laying the foundation for developing novel therapeutic approaches to AS management. We propose the integration of targeted aging interventions, such as the elimination of senescent cells or the inhibition of senescence-associated secretory phenotype (SASP), with refined estrogen replacement strategies that account for therapeutic timing, receptor subtype specificity, and aging-related vascular microenvironment changes. Future research should prioritize longitudinal studies to delineate estrogen-aging interactions during the menopausal transition, develop tissue-selective estrogen analogs, and design combinatorial therapies targeting hormonal deficits and cellular senescence. This dual-pathway strategy may overcome limitations of conventional estrogen replacement therapies while addressing the root causes of age-exacerbated AS pathogenesis.