Franny Jongbloed

147 6 MORBID OBESITY, BARIATRIC SURGERY AND T-CELL AGING INTRODUCTION Obesity (BMI >30) is a risk factor for a wide variety of diseases including hypertension, liver steatosis and cancer 1 . The metabolic syndrome (MetS), characterized by biochemical dysregulation of triglycerides, high-density lipoprotein (HDL) cholesterol, glucose, blood pressure and increase in abdominal waist circumference increases this risk 2 . MetS in the context of obesity is associated with the development of a chronic subclinical systemic inflammatory state 3 . Major players in the development of this inflammatory milieu are adipocytokines, adipokines and cytokines produced by white adipocytes that closely regulate lipid metabolism and the inflammatory response 4 . Adipocytokines contribute to the development of insulin resistance and production of reactive oxygen species 3,5,6 . Immunological changes also have been linked to the reduced lifespan seen in morbidly obese patients 7 . The link between chronic (sub)clinical inflammation and advancing age, a phenomenon called ‘inflammaging’, leads to accelerated aging and frailty 8 . This inflammaging might present itself via a decrease in circulating naive T-cells as well as an increase in more mature T-cells, such as terminally differentiated effector memory RA (EMRA) T-cells. The pro-inflammatory state in morbid obese patients resembles that of inflammaging seen in older people, as the production of adipocytokines leads to impairment of the T-cell system 3 . Total T-cell numbers as well as cytotoxic CD8 + and CD4 + T-cells are reported to be positively associated with BMI and the prevalence of MetS by some authors 9-11 , but not by others 12,13 . Studies investigating the full T-cell differentiation status in obesity in relation to obesity with or without MetS are currently lacking. Cytomegalovirus (CMV) prevalence ranges from 30-100% and depends on socio- economic and ethnic background 14 . CMV leaves a clear fingerprint on circulating T-cells, which resembles T-cell aging. A decreased CD4 + /CD8 + ratio, a more differentiated memory T-cell compartment and expansion of T-cells lacking expression of the costimulatory molecule CD28 have been associated with CMV-seropositivity and attrition of telomeres in T-cells 15-19 . Therefore, we considered CMV-seropositivity as a separate entity in our study. Validated biomarkers for human T-cell aging are reduced numbers of circulating recent thymic emigrants (RTE) as representatives of thymic involution, an enhanced T-cell differentiation status, and attrition of telomeres 15,20,21 . Telomeres are small DNA repeats located at the end of chromosomes that protect from fusion but shorten with each cell division 22 . Several studies find that BMI is inversely correlated with telomere length in T-cells 22,23 . However, this has not been established in all studies 22,24 .The effect of MetS on T-cell aging has not yet been investigated. MV)