The effects of obesity superimposed with aging in female mouse model

BACKGROUND AND AIM: People worldwide are living longer and the prevalence of overweight and obesity is growing at an alarming rate. Moreover, obesity has proved to be typically more prevalent among women, who usually live longer than men. Based on these evidences and considering that obesity leads to body health consequences in a way resembling aging, the aim of this study is to evaluate whether obesity superimposed with aging worsens the agedependent changes at peripheral, systemic and central level in female mice. METHODS: The 4-week-old C57BL/6J female mice were fed with standard diet (SD, 10% of energy from fat) or high fat diet (HFD, 60% of energy from fat) for 8, 20, or 36 weeks. After the exposure to the diet, animals were weighted and fasting metabolic parameters (glucose, triglycerides, cholesterol, insulin, leptin) were measured in blood. The gastrointestinal transit was analyzed by the intestinal distribution of high molecular weight fluorescein isothiocyanate dextran (FITC-dextran 70 kDa). The number of fecal pellets was evaluated during 1-hour collection period, and then the fecal water content was calculated. The integrity of intestinal barrier was assessed functionally by plasma level measurement of low molecular weight FITC-dextran 4 kDa after oral gavage and by evaluation of tight junctions occludin (western blot) and zonulin-1 (ELISA) expression level. To investigate the systemic inflammation, the following serum parameters were measured by ELISA: IL-1β, IL-6, IL-23, IL-10. Levels of Aβ1-42 amyloid (ELISA), p-Tau, SIRT1, occludin and zonulin-1 (western blot) were evaluated in hippocampus. RESULTS: In female mice, long-term HFD consumption resulted in an obese phenotype and accelerated age-dependent changes in cholesterol, glucose, insulin and leptin serum levels. Obese aged mice showed delayed intestinal transit, decreased gastric emptying, constipation, reduction in fecal water and increased intestinal permeability earlier and in an enhanced extent compared to SD aged mice. Moreover, obesity caused a further release of systemic inflammatory cytokines, previously observed during aging. Finally, HFD exposition had detrimental effects on brain barrier integrity, increased levels of Aβ1-42 amyloid and decreased SIRT1 expression in hippocampus. CONCLUSION: Our results demonstrated that chronic HFD exposure worsened metabolic alterations, gastrointestinal dysfunctions and systemic inflammation observed in aged SD animals. Moreover, HFD intake caused alterations of brain barrier integrity at early time when compared to old SD mice, possibly accelerating comorbidities at central nervous system. In conclusion, obesity superimposed with aging would accelerate or aggravate the process of aging itself