The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

Youm, Yun‐Hee; Kanneganti, Thirumala‐Devi; Vandanmagsar, Bolormaa; Zhu, Xuewei; Ravussin, Anthony; Adijiang, Ayinuer; Owen, John S.; Thomas, Michael J.; Francis, Joseph; Parks, John S.; Dixit, Vishwa Deep

doi:10.1016/j.celrep.2011.11.005

Cited by 134 publications

(142 citation statements)

References 49 publications

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“…These pathways have been shown to play an important role in aging and age-related disorders Cutler and Mattson 2001). Specifically, the sphingosine-linked fatty acids like ceramides serve as "damage-associated molecular patterns" (DAMPs) that are increased in aged tissue and cause inflammatory damage via the activation of Nlrp3 inflammasome (Vandanmagsar et al 2011;Youm et al 2012). Our data have revealed specific fatty acids in these pathways for which levels in blood serum may correlate with age-related decline in organ function.…”

Section: Discussionmentioning

confidence: 97%

Chronic caloric restriction partially protects against age-related alteration in serum metabolome

Guzman

Fahey

et al. 2012

AGE

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Calorie restriction (CR) remains the most robust metabolic intervention to extend lifespan and improve healthspan in several species. Using global and targeted mass spectrometry-based metabolomics approaches, here we show that chronic CR prevents age-related changes in specific metabolic signatures. Global metabolomic analysis using ultra-performance liquid chromatography-tandem mass spectrometry detected more than 7,000 metabolites in sera from ad-libitum-fed young, aged, and aged C57BL/6 mice maintained on 40 % CR. Multivariate statistical analysis of mass spectrometry data revealed a clear separation among the young, aged, and aged-CR mice demonstrating the potential of this approach for producing reliable metabolic profiles that discriminate based on age and diet. We have identified 168 discriminating features with high statistical significance (p≤0.001) and validated and quantified three of these metabolites using targeted metabolite analysis. Calorie restriction prevented the age-related alteration in specific metabolites, namely lysophosphatidylcholines (16:1 and 18:4), sphingomyelin (d18:1/12:0), tetracosahexaenoic acid, and 7α-dihydroxy-4-cholesten-3-one, in the serum. Pathway analysis revealed that CR impacted the age-related changes in metabolic byproducts of lipid metabolism, fatty acid metabolism, and bile acid biosynthesis. Our data suggest that metabolomics approach has the potential to elucidate the metabolic mechanism of CR's potential anti-aging effects in larger-scale investigations.

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Section: Discussionmentioning

confidence: 97%

Chronic caloric restriction partially protects against age-related alteration in serum metabolome

Guzman

Fahey

et al. 2012

AGE

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“…109 Moreover, IL-1 receptor antagonist reverses stroke-induced peripheral immunosuppression in patients, demonstrating that IL-1 activity is-at least partially-responsible for stroke-induced immunosuppression. 109,110 As Youm et al (2012) demonstrated, 111 agerelated increase in 'lipotoxic danger signals' such as free cholesterol and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy.…”

Section: Different Organs Modulate Autoimmune Mechanisms In the Centrmentioning

confidence: 99%

“…Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy. 111 Thus, it could be speculated that this mechanism also contributes to the massive apoptosis of thymic cells observed after severe stroke. 23 Interestingly, there are arguments for a bi-directional communication between the mammalian immune system and the bacteria on body surfaces.…”

Section: Different Organs Modulate Autoimmune Mechanisms In the Centrmentioning

confidence: 99%

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

Trendelenburg

2014

J Cereb Blood Flow Metab

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Analogous to Toll-like receptors, NOD-like receptors represent a class of pattern recognition receptors, which are cytosolic and constitute part of different inflammasomes. These large protein complexes are activated not only by different pathogens, but also by sterile inflammation or by specific metabolic conditions. Mutations can cause hereditary autoinflammatory systemic diseases, and inflammasome activation has been linked to many multifactorial diseases, such as diabetes or cardiovascular diseases. Increasing data also support an important role in different central nervous diseases such as stroke. Thus, the current knowledge of the functional role of this intracellular 'master switch' of inflammation is discussed with a focus on its role in ischemic stroke, neurodegeneration, and also with regard to the recent data which argues for a relevant role in other organs or biologic systems which influence stroke incidence or prognosis.

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“…Emerging evidence indicates that immunemetabolic interactions control several aspects of the thymic involution process and age-related inflammation (13). We have shown that byproducts of thymic fatty acids and lipids result in accumulation of "lipotoxic DAMPs" (damage-associated molecular patterns), which triggers innate immune-sensing mechanisms such as inflammasome activation that link aging to thymic demise (15). Immune-metabolic interactions within the aging thymus produce a local proinflammatory state that directly compromises the thymic stromal microenvironment, thymic lymphopoiesis, and serves as a precursor of systemic immune dysregulation in the elderly (5,8).…”

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confidence: 99%

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

Youm

Horváth

Mangelsdorf

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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101

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Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against agerelated thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT.

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The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

Cited by 134 publications

References 49 publications

Chronic caloric restriction partially protects against age-related alteration in serum metabolome

Chronic caloric restriction partially protects against age-related alteration in serum metabolome

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

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