Gut-derived NLRP3 activation programs CD8+ T-cell exhaustion via a succinate‑SUCNR1‑IL‑1β‑TOX axis in aging
The hypothesis is that age‑related gut barrier disruption releases bacterial succinate and other DAMPs that activate the succinate receptor SUCNR1 on lamina propria macrophages, amplifying NLRP3 inflammasome signaling and IL‑1β production. This IL‑1β then acts directly on circulating CD8+ T cells, driving STAT3‑dependent upregulation of the transcription factor TOX and consequent expression of exhaustion markers PD‑1, TIM‑3 and LAG‑3. In other words, gut‑derived succinate provides a specific molecular link that converts systemic inflammaging into irreversible T‑cell dysfunction.
Testable predictions:
- Aged mice will show elevated luminal succinate levels, increased SUCNR1 expression on gut macrophages, and higher caspase‑1 cleavage compared with young controls.
- Oral administration of a non‑absorbable SUCNR1 antagonist (or succinate‑scavenging probiotic) will reduce NLRP3 activation in the gut lamina propria, lower systemic IL‑1β, and decrease the frequency of PD‑1⁺TIM‑3⁺LAG‑3⁺ CD8+ T cells in blood and spleen.
- Adoptive transfer of SUCNR1‑deficient macrophages into aged recipients will blunt the rise in T‑cell exhaustion markers despite an aged microbiome.
- Blocking IL‑1R on T cells (using anakinra) will rescue proliferative capacity and cytokine production (IFN‑γ, IL‑2) of CD8+ T cells from aged mice, even when gut succinate remains high.
Experimental approach:
- Measure fecal and portal vein succinate by LC‑MS in young (3 mo) and aged (24 mo) C57BL/6 mice.
- Flow cytometry of intestinal macrophages for SUCNR1, NLRP3, cleaved caspase‑1, and intracellular IL‑1β.
- Serum IL‑1β and IL‑18 quantification via ELISA.
- Peripheral CD8+ T cells stained for PD‑1, TIM‑3, LAG‑3, TOX, Ki‑67, and intracellular cytokine staining after ex‑vivo stimulation.
- Intervention groups: (a) succinate‑scavenging probiotic (E. coli Nissle engineered to express succinate dehydrogenase), (b) oral SUCNR1 antagonist, (c) IL‑1R antagonist, (d) control.
- Assess functional outcomes: proliferative CFSE dilution, tumor clearance in a subcutaneous melanoma model, and lifespan.
Falsifiability: If SUCNR1 blockade or IL‑1R inhibition fails to reduce PD‑1/TIM‑3/LAG‑3 expression or improve T‑cell function despite confirmed reduction in gut NLRP3 activity, the proposed succinate‑SUCNR1‑IL‑1β‑TOX axis would be refuted. Conversely, a positive result would establish a direct, mechanistic route from gut metabolite signaling to T‑cell exhaustion, supporting a bottom‑up longevity strategy that targets intestinal succinate sensing before attempting neurocentric interventions.