Public Health Interests
Aging; Immune functions; Obesity
A major goal of my research program is to obtain creative insights that advance knowledge in the field of Immune-Metabolic interactions that drive adiposity and age-related chronic diseases. Our studies focus on understanding the mechanisms and consequences of aberrant immune-cell activation in adipose tissue microenvironment and age-related ectopic adipocyte development in lymphoid microenvironment like thymus and bone marrow. This Laboratory utilizes basic cellular and molecular tools, genetic manipulations including reporter and Cre/Lox mouse models to understand patho-physiology of obesity and aging. In addition, clinical studies are evaluating the impact of caloric excess and caloric restriction on mechanism that impact immune system. The long-term goal of our research is to understand the mechanisms of immune-metabolic crosstalk and to help develop novel approaches to regulate the aberrant immune cell activation as means to enhance healthspan.
Specialized Terms: Immune-Metabolic Interactions; Aging and age-related inflammation; Obesity-associated inflammation and metabolic syndrome; Adipose tissue leukocytosis; Inflammasomes; Thymic involution and approaches for thymic rejuvenation; Neuroendocrine control of immune system
Extensive Research Description
The NIH funded projects in the laboratory are –
R01AG031797 (National Institute on Aging)
Impact of Calorie Restriction on Thymopoiesis in Humans.
The overall goal of this randomized control trial is to study whether salutary and pro-longevity effects of calorie restriction in animal models extend to healthy aging and thymic function in middle aged humans. In this study we are analyzing the ectopic adipocyte development in the thymus using MRI and investigating the mechanism of CR’s effects on thymic function and T cell receptor repertoire diversity in humans.
Impact of Obesity and Weight-Loss Interventions on Immune-Surveillance Mechanisms.
The major goal of this study is to determine the mechanisms that link obesity to T cell function, and T cell receptor repertoire diversity. We are evaluating the neuroendocrine-immune interactions that may drive the salutary effects of various bariatric procedures or calorie restriction on metabolic and immune systems during obesity.
R01AG043608: (National Institute on Aging)
Inflammasomes and the mechanism of thymic demise in aging.
The Nlrp3 inflammasome senses metabolic ‘danger signals’ and, upon assembly, causes caspase-1 activation, which in turn controls the secretion of pro-inflammatory cytokines IL-1β and IL-18. The central hypothesis of this proposal is that age-related thymic lipotoxicity via a canonical Nlrp3 Inflammasome-dependent mechanism induces ‘sterile thymic inflammation’ and induces T cell dysfunction during aging.
R01AG045712: (National Institute on Aging)
Impact of CR on inflammasome mediated immune-metabolic interactions
The overall goal of this project is to understand whether CR’s beneficial anti-inflammatory effects observed in animals are relevant to human physiology. Through analysis of archived blood immune cells and fat tissue samples, the current application will identify clinically relevant mechanisms of regulation of inflammation.
Thymic adipogenesis and age-related thymic demise
With progressive aging, thymus is replaced with ectopic adipocytes and its ability to produce naïve T cells is dramatically diminished. This research project is designed to understand the lineage of adipocytes in aging thymus and to determine the causes and consequences of thymic adiposity and its relationship with immune-senescence.
- Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. Mar;21(3):263-9
- Grant R, Nguyen KY, Ravussin A, Albarado D, Youm YH, Dixit VD. (2014) Inactivation of C/ebp homologous protein-driven immune-metabolic interactions exacerbate obesity and adipose tissue leukocytosis. J Biol Chem. May 16;289(20):14045-55.
- Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Münzberg H, Rosen CJ, Ingram DK, Salbaum JM, Dixit VD. (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. Oct 1;18(4):519-32
- Youm YH, Kanneganti TD, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS and Dixit VD (2012) The NLRP3 Inflammasome Promotes Age-related Thymic Demise and Immunosenescence. Cell Reports 1, 56-68.
- Kanneganti TD & Dixit VD. (2012). Immunological complications of obesity. Nat. Immunol. 19;13(8):707-712
- Vandanmagsar B, Youm YH, Ravussin A, Galgani J, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. (2011) The NLRP3 Inflammasome Instigates Obesity-Induced Inflammation and Insulin Resistance. Nat. Med. 17: 179-188. PMID: 21217695
- Youm YH, Yang H, Amin R, Smith SR, Leff T, Dixit VD. (2010) Thiazolidinedione treatment and constitutive-PPAR? activation induces ectopic adipogenesis and promotes age-related thymic involution. Aging. Cell Apr 1. Aug;9(4):478-89.PMID: 20374200.
- Yang H, Youm YH, and Dixit VD. (2009). Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in the age-related thymic involution. J. Immunol. 183(5):3040-52. PMCID: PMC2731487
- Yang H, Youm YH, Vandanmagsar B, Rood J, Kumar KG, Butler AA and Dixit VD. (2009) Obesity Accelerates Thymic Aging. Blood. 114(18):3803-3812. PMID: 19648267
- Dixit VD, Yang H, Sun Y, Youm YH et al (2007) Ghrelin promotes thymopoiesis during aging. J. Clin. Invest. 117: 2778-2790.
- Dixit VD, Schaffer EM, Pyle RS, Collins GD, et al. (2004) Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest.114:57-66.