Lakshmanane, B. | Search bioRxiv

bioRxiv2026

p53 restoration suppresses retrotransposon-driven chromosomal instability through nonlinear let-7 feedback and stochastic burst control

Long-read sequencing has revealed that concurrent LINE-1 (L1) retrotransposition events on non-homologous chromosomes frequently generate reciprocal chromosomal translocations early in tumorigenesis, establishing retrotransposons as active drivers of structural genome evolution (1). Endogenous mechanisms that constrain L1-mediated chromosomal instability remain incompletely defined. p53 transcriptionally induces tristetraprolin (TTP/ZFP36) and let-7 microRNAs, both directly and indirectly via repression of the MYC-LIN28 oncogenic axis (2). Mature let-7 suppresses human L1 retrotransposition by binding L1 mRNA and impairing ORF2p translation (3). Here we integrate these findings into a nonlinear dynamical systems model linking p53 activation, MYC-LIN28-let-7 feedback, and L1 RNA kinetics. Deterministic analysis uncovers bistability, with a sharp p53 activation threshold separating genome-unstable (high L1) and genome-stable (low L1) attractor states. Stochastic simulations reproduce the punctuated, clustered insertion patterns observed in tumors. Modest p53 restoration disproportionately collapses burst frequency, reducing cumulative structural rearrangement burden--including reciprocal translocations--by >70% under moderate assumptions. These results reposition p53 restoration as a threshold-dependent, retrotransposon-restrictive strategy to limit early genomic diversification and clonal evolution in cancer, with implications for pharmacologic reactivation therapies.

cancer biology↗

bioRxiv2025

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

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 estrogens direct suppression of IL-11 transcription--via estrogen receptor- (ER)-mediated interference with NF-{kappa}B/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-{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-/IL-6/IL-1{beta}) [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.

physiology↗