Estrogen-Mediated Suppression of IL-11 as a Hormonal Mechanism Underlying Female Longevity Advantage

Abstract

The female longevity advantage (averaging 4 to 6 years globally) stems from reduced susceptibility to inflammaging, the chronic, low-grade inflammation driving age-related diseases like fibrosis and cardiovascular decline [10]. Interleukin 11 (IL-11), a gp130-family cytokine, has emerged as a pivotal inflammaging mediator: Its genetic or pharmacological inhibition extends mouse median lifespan by 22.5% in males and 25% in females, with enhanced healthspan benefits in the latter [20-29]. Here, we propose that estrogen\'s direct suppression of IL-11 transcription via estrogen receptor-alpha (ERalpha)-mediated interference with NF-kappa B/AP-1 on the IL-11 promoter in osteoblasts, fibroblasts, and endothelial cells establishes a premenopausal \"hormonal firewall\" against IL-11-driven senescence and multi-organ fibrosis [0-9]. In contrast, testosterone exhibits neutral or permissive effects, correlating with elevated IL-11 in hyperandrogenic states like polycystic ovary syndrome (PCOS) [30-40]. To test this, we developed an ordinary differential equation (ODE) model integrating IL-11 dynamics with upstream triggers (e.g., Ang II, c-Myc/miR-23 derepression) and suppressors (SIRT1 deacetylates IL-11 promoter histones; p53 represses IL-11/c-Myc; NRF2 quenches NF-kappa B) [10, 12]. In persistent inflammaging simulations (impaired degradation, k_deg=0.1), high estrogen (1.0 arbitrary units) reduced steady-state IL-11 by 63% (179.96 to 65.77 at t=20 days), cascading to 40-50% lower STAT3/NF-kappa B activation and triad cytokines (TNF-alpha/IL-6/IL-1beta). [11,13]. Synergy with high SIRT1/p53/NRF2 amplified suppression to [~]74% for IL-11 [16,17]. Post-menopausal estrogen decline erodes this buffer, but cumulative pre-menopausal protection persists, explaining sustained sex gaps post-65. [32,34]. This framework predicts estrogen replacement therapy (HRT) could mitigate inflammaging equitably, narrowing longevity disparities. [35]. Validation via sex-stratified IL-11 cohorts and HRT-fibrosis trials is warranted, positioning IL-11 as a sex-specific therapeutic nexus.