Hypothesis

Each acute immune response triggers a transient JNK‑AP‑1 burst that, while necessary for pathogen clearance, deposits persistent H3K27ac marks at SASP promoters and accelerates telomere shortening in effector lymphocytes. Over successive infections, these epigenetic and genomic lesions convert protective NK and CD8⁺ T cells into senescent, inflammation‑driving cells that fail to clear senescent neighbors, thereby fueling inflammaging.

Rationale

• JNK phosphorylates c‑Jun/c‑Fos, activating AP‑1, which directly upregulates SASP genes (IL‑6, IL‑1β, TNF‑α)【https://pmc.ncbi.nlm.nih.gov/articles/PMC8350022/】.
• Mitochondrial ROS in stressed cells activates JNK, creating a feed‑forward loop with NF‑κB via TAK1【https://doi.org/10.1101/gad.331272.119】【https://pmc.ncbi.nlm.nih.gov/articles/PMC9783938/】.
• During acute influenza infection, JNK induces TREM1 and amplifies inflammation【https://pmc.ncbi.nlm.nih.gov/articles/PMC12033962/】, showing that protective immunity already engages the JNK‑AP‑1 axis.
• Senescent NK cells show telomere loss, DDR/p53 activation, and reduced T‑bet/Eomes, impairing cytotoxicity【https://pmc.ncbi.nlm.nih.gov/articles/PMC12538774/】.
• Aging drives tissue‑specific H3K27ac accumulation at inflammatory loci, creating epigenetic memory that keeps SASP genes primed【https://doi.org/10.1101/gr.240093.118】.

These observations suggest that the repeated activation of JNK‑AP‑1 during normal immune responses—not just chronic low‑grade inflammation—progressively scars the epigenome and telomeres of effector lymphocytes, pushing them toward a senescent SASP phenotype.

Novel Mechanistic Insight

We propose that JNK‑AP‑1 signaling recruits histone acetyltransferases (e.g., p300/CBP) to enhancers of SASP genes, establishing stable H3K27ac marks that persist after the signal wanes. Simultaneously, JNK‑dependent upregulation of NADPH oxidase (NOX2) increases intracellular ROS during each activation cycle, causing oxidative telomere attrition. The combination of epigenetic priming and telomere dysfunction lowers the threshold for senescence induction upon subsequent stress, converting a cleared effector cell into a senescent, SASP‑secreting cell.

Testable Predictions

1. Epigenetic persistence: Mice subjected to sequential acute infections (e.g., influenza → LPS) will show increased H3K27ac at Il6, Il1b, and Tnf promoters in circulating NK and CD8⁺ T cells compared to naïve controls, detectable by ChIP‑seq 30 days after the final challenge【https://pmc.ncbi.nlm.nih.gov/articles/PMC8350022/】.
2. Telomere shortening: Flow‑FISH analysis will reveal progressive telomere loss in antigen‑experienced lymphocytes that correlates with the number of infection cycles, independent of age【https://pmc.ncbi.nlm.nih.gov/articles/PMC12538774/】.
3. Functional conversion: Lymphocytes from repeatedly challenged mice will exhibit elevated SASP cytokine secretion (IL‑6, IL‑1β) upon ex‑vivo restimulation and reduced cytotoxicity against senescent target cells, reversible by JNK inhibition (SP600125) or p300/CBP blockade (A-485)【https://doi.org/10.1101/gad.331272.119】.
4. In vivo impact: Adoptive transfer of JNK‑hyperactive, infection‑primed lymphocytes into young recipients will accelerate tissue inflammation and senescence markers (p16^INK4a, SA‑β‑gal) compared to transfer of naïve lymphocytes.

Falsifiability

If repeated acute immune challenges fail to increase H3K27ac at SASP loci, do not accelerate telomere attrition in effector lymphocytes, or do not confer a senescent SASP phenotype, the hypothesis would be refuted. Conversely, confirming these links would support the idea that immune system success—through cumulative JNK‑AP‑1 activity—directly fuels aging.