The circadian clock does not merely synchronize metabolism; it times the enzymatic removal of repressive H3K27me3 marks at senescence‑associated secretory phenotype (SASP) loci. We hypothesize that KDM6A/UTX and KDM6B/JMJD3 are recruited to SASP promoters in a CLOCK‑BMAL1‑dependent fashion, creating daily windows of H3K27me3 demethylation. In young tissues this rhythm limits SASP transcription to specific phases, preventing chronic inflammation. With age, dampened clock amplitude reduces KDM6 recruitment, causing loss of rhythmic H3K27me3 erosion and persistent low‑level SASP expression, which fuels inflammaging.

Key mechanistic steps:

• CLOCK‑BMAL1 binds E‑box elements near SASP gene promoters at circadian dawn.
• This binding recruits KDM6A/B complexes via a protein‑protein interface distinct from their catalytic JmjC domains.
• KDM6-mediated H3K27me3 demethylation peaks during the early active phase, allowing transient transcription factor access.
• As circadian amplitude declines, KDM6 occupancy falls, H3K27me3 accumulates aberrantly, and SASP genes become constitutively derepressed.

Testable predictions:

1. ChIP‑seq for KDM6A/B and H3K27me3 in liver and spleen of young (3 mo) vs old (24 mo) mice collected every 4 h over 24 h will show a robust oscillatory KDM6 signal and reciprocal H3K27me3 rhythm in young tissue that flattens with age.
2. Genetic disruption of the CLOCK‑BMAL1 interaction surface on KDM6A (point mutation that preserves demethylase activity) will abolish H3K27me3 oscillations without affecting global H3K27me3 levels, leading to SASP upregulation even in young animals.
3. Pharmacological enhancement of circadian amplitude (e.g., via REV‑ERB agonists) in old mice will restore KDM6 promoter occupancy, reduce basal SASP mRNA, and lower circulating IL‑6 and TNF‑α levels.
4. SASP promoter reporters containing wild‑type E‑boxes will display luciferase rhythms in vitro; mutating the E‑boxes will dampen the rhythm and increase baseline activity.

These experiments directly challenge the view that circadian influence on aging is limited to metabolic pathways and instead position the clock as a gatekeeper of epigenetic silencing at inflammatory loci. If validated, restoring circadian‑KDM6 coupling could represent a geroprotective strategy complementary to senolytics or NAD+ boosters.