During peripheral infection, excessive production of pro-inflammatory cytokines in the aged brain from primed microglia induces exaggerated behavioral pathologies. While the pro-inflammatory cytokine IL-6 increases in the brain with age, its role in microglia priming is not known. This study examined the functional role of IL-6 signaling on microglia priming. Our hypothesis is that IL-6 signaling mediates primed states of microglia in the aged. An initial study assessed age-related alteration in IL-6 signaling molecules; sIL-6R and sgp130 were measured in cerebrospinal fluid of young and aged wild-type animals. Subsequent studies of isolated microglia from C57BL6/J (IL-6) and IL-6 knock-out (IL-6) mice showed significantly less MHC-II expression in aged IL-6 compared to IL-6 counterparts. Additionally, adult and aged IL-6 and IL-6 animals were administered lipopolysaccharide (LPS) to simulate a peripheral infection; sickness behaviors and hippocampal cytokine gene expression were measured over a 24 h period. Aged IL-6 animals were resilient to LPS-induced sickness behaviors and recovered more quickly than IL-6 animals. The age-associated baseline increase of IL-1β gene expression was ablated in aged IL-6 mice, suggesting IL-6 is a key driver of cytokine activity from primed microglia in the aged brain. We employed in vitro studies to understand molecular mechanisms in priming factors. MHC-II and pro-inflammatory gene expression (IL-1β, IL-10, IL-6) were measured after treating BV.2 microglia with sIL-6R and IL-6 or IL-6 alone. sIL-6R enhanced expression of both pro-inflammatory genes and MHC-II. Taken together, these data suggest IL-6 expression throughout life is involved in microglia priming and increased amounts of IL-6 following peripheral LPS challenge are involved in exaggerated sickness behaviors in the aged.

Brain microglia become dysregulated during aging and express proinflammatory cytokines that play a role in cognitive aging. Recent studies suggest the flavonoid luteolin reduces neuroinflammation and improves learning and memory in aged mice. However, if dietary luteolin reduces microglia activity in the brain of senescent mice is not known. We hypothesized that feeding aged mice a diet with luteolin would reduce microglia activity. Adult (3-6 months) and aged (22-24 months) mice were fed American Institute of Nutrition (AIN)-93M or AIN-93M with luteolin (6 g/kg) for 4 weeks and injected intraperitoneally with saline or lipopolysaccharide (LPS) before microglia were isolated and stained for major histocompatibility complex (MHC) class II, interleukin (IL)-1b, and IL-6 for flow cytometry. In saline-treated mice fed control diet, aging increased the proportion of microglia that stained for MHC class II (<3% for adults vs. 23% for aged), IL-1b (<2% for adults vs. 25% for aged), and IL-6 (<2% for adults vs. 25% for aged), indicating an age-related increase in proinflammatory microglia. In saline-treated aged mice fed luteolin, the proportion of microglia that stained for MHC class II, IL-1b, and IL-6 was reduced by nearly half (to 12%, 13%, and 12%, respectively). Interestingly, luteolin significantly reduced the proportion of microglia that stained for IL-1b and IL-6 in LPS-treated adult mice but not aged. Collectively, the results show that a diet supplemented with luteolin inhibited brain microglia activity during aging and activation by LPS in adults. Therefore, luteolin may inhibit neuroinflammation and improve cognition in the otherwise healthy aged by constraining brain microglia.

Social deprivation was associated with low uptake and poor success of insulin intensification and this appeared to be largely mediated via lower educational levels.

No abstract

Aims The rising prevalence of obesity and its associated comorbidities represent a growing public health issue; in particular, obesity is known to be a major risk factor for cardiovascular disease. Despite the evidence behind the efficacy of orlistat in achieving weight loss in patients with obesity, no study thus far has quantified its long-term effect on cardiovascular outcomes. The purpose of this study is to explore long-term cardiovascular outcomes after orlistat therapy. Methods and results A propensity-score matched cohort study was conducted on the nation-wide electronic primary and integrated secondary healthcare records of the Clinical Practice Research Datalink (CPRD). The 36 876 patients with obesity in the CPRD database who had completed a course of orlistat during follow-up were matched on a 1:1 basis with equal numbers of controls who had not taken orlistat. Patients were followed up for a median of 6 years for the occurrence of the primary composite endpoint of major adverse cardiovascular events (fatal or non-fatal myocardial infarction or ischaemic stroke), and a number of secondary endpoints including primary endpoint components individually, the occurrence of new-onset heart failure, coronary revascularization, new chronic kidney disease stage III+ (CKD3+), and all-cause mortality. During the median study follow-up of 6 years, the occurrence of major adverse cardiovascular events was lower in the orlistat cohort [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.66–0.83, P &lt; 0.001]. Patients who took orlistat experienced lower rates of myocardial infarction (HR 0.77; 95% CI 0.66–0.88, P &lt; 0.001) and ischaemic stroke (HR 0.68; 95% CI 0.56 to −0.84, P &lt; 0.001) as well as new-onset heart failure (HR 0.79; 95% CI 0.67–0.94, P = 0.007). There was no differences in revascularization rates (HR 1.12; 95% CI 0.91–1.38, P = 0.27), but a lower rate of both CKD3+ development (HR 0.78; 95% CI 0.73–0.83, P &lt; 0.001) and mortality (HR 0.39, 95% CI 0.36 to −0.41, P &lt; 0.001) was observed. Conclusion In this nation-wide, propensity-score matched study, orlistat was associated with lower rates of overall major adverse cardiovascular events, new-onset heart failure, renal failure, and mortality. This study adds to current evidence on the known improvements in cardiovascular risk factor profiles of orlistat treatment by suggesting a potential role in primary prevention.