Mechanistic Rationale

Chronic NLRP3 activation in myeloid cells fuels inflammaging by releasing IL‑1β and IL‑18 [1,2]. It's possible that IL‑1β acts on CD8+ T cells to induce SOCS3, which binds NIK and targets it for proteasomal degradation, thereby suppressing the NIK‑HK2 glycolytic pathway [4]. Loss of NIK destabilizes HK2, reduces glycolysis, and pushes progenitor exhausted (Tpex, TCF1+) cells toward terminal exhaustion (Tex‑term, TCF1‑, high CD39/LAG3/TIM‑3) [5].

Testable Prediction

Aged wild‑type mice treated with the NLRP3 inhibitor MCC950 will show:

• Lower serum IL‑1β levels
• Reduced SOCS3 expression in CD8+ T cells
• Increased NIK protein and HK2 stabilization (measured by decreased ubiquitination)
• Higher extracellular acidification rate (ECAR) indicating enhanced glycolysis
• Greater proportion of Tpex (TCF1+) and lower Tex‑term (TCF1‑ PD‑1hi TIM‑3hi) frequencies
• Improved response to anti‑PD‑1 therapy compared with vehicle controls

Falsifiability

If MCC950 treatment fails to decrease SOCS3 or does not rescue NIK/HK2 glycolytic activity despite lowering IL‑1β, the proposed link between NLRP3‑driven inflammaging and T‑cell metabolic exhaustion is refuted. Conversely, if SOCS3 knockdown in T cells mimics the metabolic and phenotypic benefits of NLRP3 inhibition, the hypothesis gains support.

Connection to Existing Interventions

While IL‑11 blockade and TLR5/7 activation reduce systemic inflammation [6], directly targeting the NLRP3‑NIK‑HK2 axis offers a mechanistic route to preserve the reversible Tpex window before epigenetic fixation occurs.