Hypothesis

Hormetic stressors such as intermittent fasting, mild heat shock, or exercise extend lifespan by engaging the replication‑stress response machinery, not by altering histone methylation states. KDM5A/B are recruited to stalled replication forks where they act as scaffolds for CHK1 activation and RRM2 upregulation, a role that does not require their demethylase activity [PMC8181900]. Consequently, the longevity benefit of hormesis should persist when the catalytic domain of KDM5 is inactivated but disappear when the protein is depleted or its protein‑protein interaction surfaces are disrupted.

Testable Predictions

1. Catalytic‑dead rescue – In C. elegans or mouse models expressing a demethylase‑deficient KDM5A/B point mutant (e.g., H604A/H606A in the JmjC domain) on a background of endogenous KDM5 loss, hormetic interventions (e.g., every‑other‑day fasting or voluntary wheel running) will still increase median lifespan compared with wild‑type controls.
2. Scaffold disruption abolishes hormesis – Introducing mutations that prevent KDM5 interaction with CHK1 or RRM2 (identified from structural studies) will block the lifespan extension normally seen with hormesis, even though global H3K4me3 levels remain unchanged.
3. Epigenetic read‑out is dispensable – Chromatin immunoprecipitation sequencing after a hormetic pulse will show no significant change in H3K4me3/H3K27me3 at bivalent promoters in tissues derived from catalytic‑dead animals, yet downstream signaling (phospho‑CHK1, increased dNTP synthesis via RRM2) will be activated.
4. R‑loop/STING axis as a negative comparator – In the same models, hormesis will not provoke R‑loop accumulation or STING‑mediated innate immune activation, contrasting with the phenotype observed upon pharmacological KDM5 inhibition in cancer cells [elifesciences.org/reviewed-preprints/106249].

Mechanistic Rationale

The current literature ties KDM5/6 to cancer‑specific stresses: replication fork stabilization, oxygen sensing, and R‑loop‑driven viral mimicry [science.org/doi/10.1126/science.aaw1026; frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.906662/full]. These activities share a common theme: the enzymes act as platforms that coordinate DNA‑damage signaling and metabolic adaptation. Hormesis, by definition, imposes a low‑grade, transient challenge that stalls replication forks or perturbs nucleotide pools without causing catastrophic damage. Under such conditions, KDM5A/B’s non‑catalytic scaffolding function would be sufficient to amplify checkpoint signaling, boost dNTP supply, and promote a transient pause that allows repair pathways to engage—effects that are known to improve proteostasis and delay senescence.

If the demethylase activity were essential, we would expect global changes in H3K4me3 that correlate with lifespan extension across hormetic paradigms. The absence of such data in the aging literature, coupled with the clear demethylase‑independent role in replication stress, suggests the field has been looking at the wrong enzymatic readout. Testing the predictions above will either uncover a novel, activity‑independent longevity mechanism for KDM5/6 or refute the hypothesis, thereby clarifying whether hormesis truly speaks a language of threat or can be uncoupled from it.