Senolytics plus STING inhibition synergistically suppress inflammaging and restore youthful immunity
Hypothesis
Combining senolytic dasatinib+quercetin (D+Q) with a pharmacological inhibitor of the cGAS‑STING pathway will reduce senescent immune cell burden and circulating cf‑mtDNA more effectively than D+Q alone, leading to durable restoration of naïve T‑cell pools and lower inflammaging markers.
Mechanistic Rationale
- Senescent immune cells secrete cf‑mtDNA that activates cGAS‑STING in neighboring cells, driving paracrine senescence and SASP amplification [6].
- D+Q cleaves senescent cells but leaves 30‑70% residual cells that can be reactivated by stress, releasing more cf‑mtDNA [9].
- Blocking STING signaling prevents cf‑mtDNA‑induced NF‑κB activation, breaking the senescence‑inflammation feedback loop [7].
- Dasatinib and quercetin also have senescence‑independent anti‑inflammatory actions [8]; adding a STING inhibitor targets the upstream nucleic‑acid sensor, complementing those effects.
Testable Predictions
- In aged mice (20‑24 mo), D+Q + STING inhibitor (e.g., H‑151) will reduce senescent CD4+ T‑cell frequency (flow cytometry for p16^INK4a^ or SA‑β‑gal) by >50% compared with D+Q alone (p<0.01).
- Serum cf‑mtDNA levels will drop to youthful levels (<2‑fold increase over 6‑mo controls) only in the combination group.
- Naïve CD4+ T‑cell output (CD62L^hi^CCR7^+) will increase by ≥30% relative to baseline, whereas D+Q alone yields ≤15% increase.
- Clinical read‑outs: lower IL‑6, TNFα, and CXCL8 plasma concentrations; improved glucose tolerance; enhanced vaccine‑specific antibody titers after a novel antigen challenge.
- If the combination fails to surpass D+Q alone on any of these endpoints, the hypothesis is falsified.
Experimental Design (brief)
- Four groups: vehicle, D+Q alone, STING inhibitor alone, D+Q+STING inhibitor.
- Treatment duration 8 weeks, with assessments at baseline, week 4, week 8, and 4 weeks post‑washout.
- Endpoints: flow cytometry for senescence markers, qPCR for cf‑mtDNA, Luminex cytokine panel, metabolic assays, and immunization with OVA.
Potential Impact
Confirming synergy would justify combined senolytic‑immunomodulatory regimens for inflammaging‑driven diseases and refine dosing schedules to avoid incomplete clearance.