Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging
Open accessAbstract
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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Ablation of Nlrp3 in mice reduced circulating levels of IL-18 and IL-1β and reduced microglial activation and astrogliosis in the hippocampus.
“ablation of Nlrp3 in mice reduced circulating levels of IL-18 and IL-1β and reduced microglial activation and astrogliosis in the hippocampus.”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [73]
The Results sections on peripheral inflammation and hippocampal inflammation report reduced circulating IL-18, reduced microglial activation, and reduced astrogliosis in aged Nlrp3-deficient mice. They do not support a reduction in circulating IL-1β: serum and plasma IL-1β were not measurable in 23-month-old wild-type mice. Page numbers are not provided in our copy. (LLM, conf=0.92)
Experimental — accuracy not yet measuredNlrp3 ablation increased expression of genes related to learning and memory and reduced age-related cognitive decline in wild type mice.
“Nlrp3 ablation also increased expression of genes related to learning and memory and reduced age-related cognitive decline in “wild type” mice [73].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [73]
The Results sections on innate immune activation and healthspan report increased expression of learning- and memory-related genes and protection from age-related cognitive decline in aged Nlrp3-deficient mice. The claim's qualification “in wild type mice” is incorrect: wild-type mice were the comparator, not the mice in which Nlrp3 was ablated. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVarious DAMPs that accumulate throughout an organism's lifespan activate the NLRP3 inflammasome, leading to elevated IL-1β levels associated with aging.
“Various DAMPs that accumulate throughout an organism’s lifespan activate the NLRP3 inflammasome, which leads to elevated IL-1β levels associated with aging [73].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [73]
Inflammaging is driven in part by NLRP3 inflammasome activation.
“Inflammaging is driven in part by NLRP3 inflammasome activation,5–8”
From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [6]
Ablation of the NLRP3 inflammasome protects mice from age-related increases in innate immune activation, alterations in the CNS transcriptome, and astrogliosis, while improving glycemic control and motor performance.
“Ablation of the NLRP3 inflammasome protects mice from age-related increases in innate immune activation, alterations in the CNS transcriptome, and astrogliosis, while improving glycemic control and motor performance (86).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [86]
Strong evidence from mouse studies indicates that blockade of the NLRP3 inflammasome extends healthspan, attenuating multiple age-related degenerative changes linked to inflammageing, including insulin resistance, thymic involution, T cell senescence, bone loss, and physical and cognitive function decline.
“In humans, IL-18 blood levels increase with ageing, and strong evidence from mouse studies indicates that blockade of the NLRP3 inflammasome extends healthspan, attenuating multiple age-related degenerative changes that have been linked to inflammageing, including insulin resistance, thymic involution, T cell senescence, and bone loss as well as physical and cognitive function decline114,117,118.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [114]
IL-1β and IL-18 are important in inflammageing, are produced by the NLRP3 inflammasome, and contribute to ageing-related disease pathology.
“IL-1β and IL-18 are also critical in inflammageing; these cytokines are products of the NLRP3 inflammasome, and contribute to the pathology of ageing-related diseases73.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [73]
Ageing is associated with increased activation of the NLRP3 inflammasome, which is primarily expressed by myeloid immune cells, and a subsequent increase in IL-1β expression.
“Ageing is associated with increased activation of the NLRP3 inflammasome45,107, which is primarily expressed by myeloid immune cells107,108, and a subsequent increase in the expression of IL-1β, which is a major cytokine implicated in promoting ageing-related disease107.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [107]
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Self-citation
- Authors
- Youm, Y.-H., Grant, R. W., McCabe, L. R., Albarado, D. C., Nguyen, K. Y., Ravussin, A., Pistell, P., Newman, S., Carter, R., Laque, A., Münzberg, H., Rosen, C. J., Ingram, D. K., Salbaum, J. M., & Dixit, V. D.
- Affiliations
- Pennington Biomedical Research Center (US)
- Michigan State University (US)
- Louisiana State University (US)
- Maine Medical Center Research Institute (US)
- Corresponding author
- Dixit, Vishwa Deep
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 18
- Issue
- 4
- Pages
- 519-532
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4017327
- OpenAlex
- W2153328565
- Cited by
- 674
- References
- 49
- Citations by year
- 2026: 57 · 2025: 54 · 2024: 65 · 2023: 52 · 2022: 76 · 2021: 62 · 2020: 70 · 2019: 55 · 2018: 52 · 2017: 46 · 2016: 24 · 2015: 39 · 2014: 19 · 2013: 1
- FWCI
- 12.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG043608, AG043608)
- National Institute of General Medical Sciences (P20GM103528)
- National Institute of Allergy and Infectious Diseases (AI105097, R56AI105097, R01AI105097)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090556, DK090556, P30DK020572, P30DK072476)
- National Center for Research Resources (P20-RR02195)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD055528, R01HD055528)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- NLRP3 inflammasome, low-grade inflammation, aging, sterile inflammation, caspase-1, caspase-11, interleukin-1, astrocyte activation, cognitive decline, motor performance, bone loss, thymic atrophy, glycemic control, neuroinflammation, age-related degenerative diseases
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Aging, Animals, Carrier Proteins, Cognition, Cytoskeletal Proteins, Hippocampus, Immunity, Innate, Interleukin-1, Motor Activity, Signal Transduction, Receptors, Interleukin-1, Glucose Intolerance, Mice, Knockout, Caspases, Caspase 1, Apoptosis Regulatory Proteins, Mice, CARD Signaling Adaptor Proteins, Caspases, Initiator, Inflammasomes, Transcriptome
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