Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria
Open accessAbstract
Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson–Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24 −/− mice, which phenocopy the human disease. These data were further corroborated in Lmna G609G/G609G mice, another HGPS animal model. We also showed that pharmacological inhibition of the NLRP3 inflammasome by its selective inhibitor, MCC950, improved cellular phenotype, significantly extended the lifespan of progeroid animals, and reduced inflammasome‐dependent inflammation. These findings suggest that inhibition of the NLRP3 inflammasome is a potential therapeutic approach for the treatment of HGPS.
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The LmnaG609G mouse model closely resembles human phenotypes, including heightened inflammation markers like IL-6, caspase 1, and Nlrp3, increased oxidative stress, persistent DNA damage, and cell cycle arrest.
“Among these models, the LmnaG609G mouse model (featuring the mutation 1827C > T; Gly609Gly) closely resembles human phenotypes.305 This includes heightened inflammation markers like IL-6, caspase 1, and Nlrp3, increased oxidative stress, persistent DNA damage, and cell cycle arrest.306,307”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [307]
The Results section ('Zmpste24-deficient mice exhibit hyperactivated NLRP3 inflammasome'; page not provided) reports NLRP3 inflammasome activation in the heart and, more moderately, the liver of LmnaG609G/G609G mice. It reports higher Nlrp3 and caspase 1 expression specifically in Zmpste24-deficient mice, not those measurements in the Lmna model. The cited passages do not establish elevated IL-6, oxidative stress, persistent DNA damage, or cell-cycle arrest in the Lmna model. (LLM, conf=0.87)
Experimental — accuracy not yet measuredZmpste24 − /− mice exhibit elevated expression of caspase 1 and Nlrp3, severe growth retardation, dilated cardiomyopathy, muscular dystrophy, lipodystrophy and premature death.
“In addition, two independently generated mouse models deficient in the Zmpste24 gene (Zmpste24 − /− mice) also exhibit elevated expression of caspase 1 and Nlrp3, severe growth retardation, dilated cardiomyopathy, muscular dystrophy, lipodystrophy and premature death.307,308”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [307]
The Results section on Zmpste24-deficient mice reports elevated Nlrp3 and caspase 1 expression in heart and liver, but not muscle; the lifespan and body-weight results also support premature death and impaired growth. Our copy does not establish that two independently generated Zmpste24-deficient models exhibit all the listed features, nor does it document dilated cardiomyopathy or muscular dystrophy in these mice. The Introduction mentions lipodystrophy among progeria features, but does not establish it specifically for the Zmpste24-deficient mice. (LLM, conf=0.88)
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- Authors
- González‐Dominguez, A., Montañez, R., Castejón‐Vega, B., Nuñez‐Vasco, J., Lendines‐Cordero, D., Wang, C., Mbalaviele, G., Navarro‐Pando, J. M., Alcocer‐Gómez, E., & Cordero, M. D.
- Affiliations
- University of Glasgow (GB)
- Biomedical Research and Innovation Institute of Cadiz (ES)
- Washington University in St. Louis (US)
- Universidad de Sevilla (ES)
- Corresponding author
- Cordero, Mario D
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2021-08-27
- Volume
- 13
- Issue
- 10
- Pages
- e14012-e14012
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC8495449
- OpenAlex
- W3195843085
- Cited by
- 32
- References
- 24
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 5 · 2021: 2
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- idUS (Universidad de Sevilla) (submittedVersion, cc-by-nc-nd)
- Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, other-oa)
- Funders
- Consejería de Salud, Junta de Andalucía (PI‐0036.2014)
- Progeria Research Foundation (PRF 2021‐ 80)
- HHS | National Institutes of Health (AR068972, AR076758)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- NLRP3 inflammasome, Hutchinson-Gilford progeria syndrome, accelerated aging, caspase-1, MCC950, lifespan extension, dermal fibroblasts, lymphoblasts, inflammation, therapeutic target
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Disease Models, Animal, Humans, Longevity, Progeria, Lamin Type A, Mice, Inflammasomes
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