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

Cell Metab. 2013 Oct 1;18(4):519-32. doi: 10.1016/j.cmet.2013.09.010.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Caspases / deficiency
  • Caspases / genetics
  • Caspases / metabolism
  • Caspases, Initiator
  • Cognition / physiology
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Glucose Intolerance
  • Hippocampus / metabolism
  • Immunity, Innate
  • Inflammasomes / metabolism*
  • Interleukin-1 / metabolism
  • Mice
  • Mice, Knockout
  • Motor Activity / physiology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Interleukin-1 / deficiency
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction
  • Transcriptome

Substances

  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Inflammasomes
  • Interleukin-1
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pycard protein, mouse
  • Receptors, Interleukin-1
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Caspase 1

Associated data

  • GEO/GSE43034