Hypothesis

Intermittent senolytic dosing combined with timed omega-3 supplementation restores vaccine‑induced germinal center responses in older adults by suppressing lymphoid SASP and promoting resolution pathways.

Mechanism

Senescent T follicular helper (Tfh) cells accumulate in secondary lymphoid organs with age and secrete IL‑6 and other SASP factors that disrupt follicular dendritic cell networks, impairing B cell affinity maturation 14. Senolytics such as dasatinib + queretin (D+Q) eliminate these senescent Tfh cells, reducing IL‑6 driven inflammation 56. Omega‑3 derived resolvins and protectins actively counteract NF‑κB signaling and promote macrophage‑mediated clearance of apoptotic senescent cells, further lowering tissue SASP 8. When given intermittently (e.g., one 3‑day cycle every 4 weeks) senolytics avoid cumulative toxicity while allowing immune reconstitution; omega‑3 supplementation timed 24 h after each senolytic dose enhances resolvin production during the inflammatory rebound phase, creating a window where SASP is suppressed and resolution pathways dominate.

Testable Predictions

1. Older adults receiving the combined intermittent regimen will show a ≥2‑fold increase in hemagglutination inhibition titers after influenza vaccination compared with placebo.
2. Peripheral blood frequencies of CXCR5^+PD‑1^+ Tfh cells and serum IL‑6 will decrease significantly after each senolytic cycle, while resolvin levels (RvD1, RvE1) will rise.
3. Lymph node ultrasound will reveal increased follicular dendritic cell network density correlating with improved germinal center B cell (CD19^+CD38^lowIgD^−) frequencies.
4. No increase in grade ≥ 2 adverse events will be observed versus senolytic‑only or omega‑3‑only arms, confirming the safety of intermittent dosing.

Experimental Design

A double‑blind, placebo‑controlled, 2 × 2 factorial trial in participants aged ≥ 65 years (n = 200) will randomize to: (A) senolytic (D+Q) 100 mg + 250 mg orally for 3 consecutive days every 28 days, (B) matched placebo; (C) high‑dose omega‑3 ethyl esters 4 g daily, (D) olive oil placebo. All arms receive standard quadrivalent influenza vaccine 7 days after the first senolytic/placebo dose. Primary outcome: vaccine HAI titer at day 28. Secondary outcomes: flow cytometry of circulating Tfh cells, serum IL‑6, resolvins, lymph node imaging, and adverse event monitoring over 6 months. Statistical analysis will use mixed‑effects models to test interaction between senolytic and omega‑3.

Significance

If confirmed, this approach would provide a translatable, low‑cost strategy to reverse immunosenescence‑related vaccine failure, directly linking senocyte clearance with pro‑resolution lipid mediators to restore adaptive immunity in the elderly.