Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging

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Abstract

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 agerelated 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. © 2013 Elsevier Inc.

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Youm, Y. H., Grant, R. W., McCabe, L. R., Albarado, D. C., Nguyen, K. Y., Ravussin, A., … Dixit, V. D. (2013). Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metabolism, 18(4), 519–532. https://doi.org/10.1016/j.cmet.2013.09.010

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