Cell Metabolism
Volume 18, Issue 4, 1 October 2013, Pages 519-532
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Article
Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging

https://doi.org/10.1016/j.cmet.2013.09.010Get rights and content
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Highlights

  • Age-related DAMPs activate canonical Nlrp3 inflammasome without engaging caspase-11

  • Reduction in the Nlrp3 inflammasome activity reduces age-related inflammation

  • Ablation of Nlrp3 inflammasome slows age-related degenerative changes

  • IL-1 partakes in regulating age-related CNS inflammation and functional decline

Summary

Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related “sterile” inflammation in both periphery and brain independently of the noncanonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis. Consistent with the hypothesis that systemic low-grade inflammation promotes age-related degenerative changes, the deficient Nlrp3 inflammasome-mediated caspase-1 activity improved glycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer an innovative therapeutic strategy to lower Nlrp3 activity to delay multiple age-related chronic diseases.

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