Drivers of age-related inflammation and strategies for healthspan extension

Immunol Rev. 2015 May;265(1):63-74. doi: 10.1111/imr.12295.


Aging is the greatest risk factor for the development of chronic diseases such as arthritis, type 2 diabetes, cardiovascular disease, kidney disease, Alzheimer's disease, macular degeneration, frailty, and certain forms of cancers. It is widely regarded that chronic inflammation may be a common link in all these age-related diseases. This raises the question, can one alter the course of aging and potentially slow the development of all chronic diseases by manipulating the mechanisms that cause age-related inflammation? Emerging evidence suggests that pro-inflammatory cytokines interleukin-1 (IL-1) and IL-18 show an age-dependent regulation implicating inflammasome-mediated caspase-1 activation in the aging process. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome controls the caspase-1 activation in myeloid-lineage cells in several organs during aging. The NLRP3 inflammasome is especially relevant to aging as it can get activated in response to structurally diverse damage-associated molecular patterns (DAMPs) such as extracellular ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals, all of which increase with age. Interestingly, reduction in NLRP3-mediated inflammation prevents age-related insulin resistance, bone loss, cognitive decline, and frailty. NLRP3 is a major driver of age-related inflammation and therefore dietary or pharmacological approaches to lower aberrant inflammasome activation holds promise in reducing multiple chronic diseases of age and may enhance healthspan.

Keywords: IL-1; IL-18; NLRP3; adipose tissue; cytokines; inflammasome; macrophage; sarcopenia; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Aging / immunology*
  • Animals
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Humans
  • Inflammation / immunology*
  • Interleukin-1 / metabolism
  • Myeloid Cells / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein


  • Carrier Proteins
  • Interleukin-1
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Caspase 1