Hypothesis

The sustained activation of the JNK‑AP‑1 axis in aging males results from X‑chromosome escape of the histone demethylase KDM5C, which maintains open chromatin at AP‑1‑responsive enhancers of senescence‑associated secretory phenotype (SASP) genes. In females, two X chromosomes buffer KDM5C dosage through compensatory inactivation, limiting its escape‑driven chromatin remodeling. In males, loss of chromosome Y (LOY) exacerbates KDM5C escape, creating a dosage‑sensitive feed‑forward loop that converts transient stress‑induced JNK signaling into chronic AP‑1 activity, driving inflammaging and reducing lifespan.

Predictions

• In mouse models, hematopoietic‑specific overexpression of KDM5C will recapitulate the LOY immune phenotype: increased H3K4me2 demethylation at AP‑1 target loci, heightened basal JNK phosphorylation, and elevated circulating IL‑6/TNF‑α.
• CRISPR‑mediated repression of X‑linked KDM5C in LOY‑male macrophages will reduce AP‑1 transcriptional output (measured by ATAC‑seq and phospho‑c‑Jun) and alleviate SASP secretion without affecting acute JNK responses to stressors.
• Pharmacologic inhibition of KDM5C demethylase activity (e.g., with CPI‑455) will normalize JNK‑AP‑1 signaling in aged male immune cells and extend median lifespan in a LOY‑accelerated aging model.
• Conversely, forced expression of KDM5C in female macrophages will sensitize them to SASP induction, eroding the female longevity advantage.

Falsifiability If KDM5C overexpression fails to increase basal JNK‑AP‑1 signaling or if KDM5C inhibition does not attenuate inflammaging in LOY males, the proposed mechanistic link between X‑escape dosage and chronic JNK signaling would be refuted.

Connection to Prior Work This hypothesis builds on observations that aging induces escape of 19 X‑linked genes in mouse hippocampus [1] and that LOY triggers upregulation of X‑escape genes such as KDM5C in immune cells [2]. It integrates the known role of autosomal MAP3K5 variants in modulating JNK‑dependent longevity [3,4] by proposing an X‑linked epigenetic rheostat that sets the threshold for JNK‑AP‑1 transition from protective to pathological.

[1] https://www.science.org/doi/10.1126/sciadv.ads8169 [2] https://doi.org/10.1101/2025.06.01.25328624 [3] https://pubmed.ncbi.nlm.nih.gov/15820683 [4] https://www.aging-us.com/article/202844/text