Estrogen-Mediated Suppression of IL-11 as a Hormonal Mechanism Underlying Female Longevity Advantage
Bibliographic record
Abstract
Abstract The female longevity advantage—averaging 4-6 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-α (ERα)-mediated interference with NF-κB/AP-1 on the IL-11 promoter in osteoblasts, fibroblasts, and endothelial cells— establishes a pre-menopausal “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-κB) [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-κB activation and triad cytokines (TNF-α/IL-6/IL-1β) [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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.002 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".