Journal: Clinical science (London, England : 1979)
Although weight loss can usually be achieved by restricting food intake, the majority of dieters regain weight over the long-term. In the hypothalamus, hormonal signals from the gastrointestinal tract, adipose tissue and other peripheral sites are integrated to influence appetite and energy expenditure. Diet-induced weight loss is accompanied by several physiological changes which encourage weight regain, including alterations in energy expenditure, substrate metabolism and hormone pathways involved in appetite regulation, many of which persist beyond the initial weight loss period. Safe effective long-term strategies to overcome these physiological changes are needed to help facilitate maintenance of weight loss. The present review, which focuses on data from human studies, begins with an outline of body weight regulation to provide the context for the subsequent discussion of short- and long-term physiological changes which accompany diet-induced weight loss.
Data showing a remarkable gender difference in life expectancy and mortality, including survival to extreme age, are reviewed starting from clinical and demographic data and stressing the importance of a comprehensive historical perspective and a gene-environment/lifestyle interaction. Gender difference regarding prevalence and incidence of the most important age-related diseases, such as cardiovascular and neurodegenerative diseases, cancer, Type 2 diabetes, disability, autoimmunity and infections, are reviewed and updated with particular attention to the role of the immune system and immunosenescence. On the whole, gender differences appear to be pervasive and still poorly considered and investigated despite their biomedical relevance. The basic biological mechanisms responsible for gender differences in aging and longevity are quite complex and still poorly understood. The present review focuses on centenarians and their offspring as a model of healthy aging and summarizes available knowledge on three basic biological phenomena, i.e. age-related X chromosome inactivation skewing, gut microbiome changes and maternally inherited mitochondrial DNA genetic variants. In conclusion, an appropriate gender-specific medicine approach is urgently needed and should be systematically pursued in studies on healthy aging, longevity and age-related diseases, in a globalized world characterized by great gender differences which have a high impact on health and diseases.
The physical and immunological properties of the human intestinal epithelial barrier in ageing are largely unknown. Ileal biopsies from young (7-12 years), adult (20-40y) and ageing (67-77y) individuals not showing symptoms of gastrointestinal pathologies were used to assess levels of inflammatory cytokines, barrier integrity, and cytokine production in response to microbial challenges. Increased expression of IL-6, but not IFNg, TNF-a and IL-1b was observed during ageing; further analysis showed that CD11c+ dendritic cells (DCs) are one of the major sources of IL-6 in the ageing gut and expressed higher levels of CD40. Up-regulated production of IL-6 was accompanied by increased expression of Claudin-2 leading to reduced transepithelial electric resistance (TEER); TEER could be restored in in vitro and ex-vivo cultures by neutralizing anti-IL-6 antibody. In contrast, expression of Zonula occludens-1, Occludin and Junctional-Adhesion Molecule-A1 did not vary with age and overall permeability to macromolecules was not affected. Finally, cytokine production to different microbial stimuli was assessed in a polarized in vitro organ culture. IL-8 production in response to flagellin declined progressively with age although the expression and distribution of TLR-5 on intestinal epithelial cells remained unchanged. Also, flagellin-induced production of IL-6 was less pronounced in ageing. In contrast, TNF-a production in response to probiotics (VSL#3) did not decline with age; however, in our experimental model probiotics did not down-regulate the production of IL- 6 and expression of Claudin 2. These data suggested that ageing affects properties of the intestinal barrier likely to impact on age-associated disturbances both locally and systemically.
Fully-sedated patients, being treated in the ICU, experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully-sedated ICU patients admitted for acute critical illness (n=3 males, n=3 females; age 63±6 y; APACHE II disease severity-score: 29±2). One leg was subjected to twice-daily NMES of the quadriceps muscle for a period of 7±1 d while the other leg acted as non-stimulated control (CON). Directly before the first and on the morning after the final NMES session, quadriceps muscle biopsies were collected from both legs to assess muscle fiber-type specific cross-sectional area (CSA). Furthermore, phosphorylation status of key proteins involved in the regulation of muscle protein synthesis was assessed, and mRNA expression of selected genes was measured. In the CON leg, type I and type II muscle fiber CSA decreased by 16±9 and 24±7%, respectively (P<0.05). No muscle atrophy was observed in the stimulated leg. NMES increased mTOR phosphorylation by 19% when compared to baseline (P<0.05), with no changes in the CON leg. Furthermore, mRNA expression of key genes involved in muscle protein breakdown either declined (FOXO1; P<0.05) or remained unchanged (MAFBx and MuRF1), with no differences between legs. In conclusion, NMES represents an effective and feasible interventional strategy to prevent skeletal muscle atrophy in critically ill, comatose patients.
T helper (Th)17 immune response participates in allergic lung inflammation and asthma is reduced in the absence of interleukin (IL)-17 in mice. Since IL-17A and IL-17F are induced and bind the shared receptor IL-17RA, we asked whether both IL-17A and IL-17F contribute to house dust mite (HDM) induced asthma. We report that allergic lung inflammation is attenuated in absence of either IL-17A or IL-17F with reduced airway hyperreactivity, eosinophilic inflammation, goblet cell hyperplasia, cytokine and chemokine production as found in absence of IL-17RA. Furthermore, specific antibody neutralization of either IL-17A or IL-17F given during the sensitization phase attenuated allergic lung inflammation and airway hyperreactivity. In vitro activation by HDM of primary dendritic cells revealed a comparable induction of CXCL1 and IL-6 expression and the response to IL-17A and IL-17F relied on IL-17RA signaling via the adaptor protein act1 in fibroblasts. Therefore, HDM-induced allergic respiratory response depends on IL-17RA via act1 signaling and inactivation of either IL-17A or IL-17F is sufficient to attenuate allergic asthma in mice.
Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in LDLR(-/-) mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR(-/-) mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied with a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels, and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction of CVD risk.
Energy balance is not a simple algebraic sum of energy expenditure and energy intake as often depicted in communications. Energy balance is a dynamic process and there exist reciprocal effects between food intake and energy expenditure. An important distinction is that of metabolic and behavioural components of energy expenditure. These components not only contribute to the energy budget directly, but also by influencing the energy intake side of the equation. It has recently been demonstrated that resting metabolic rate (RMR) is a potential driver of energy intake, and evidence is accumulating on the influence of physical activity (behavioural energy expenditure) on mechanisms of satiety and appetite control. These effects are associated with changes in leptin and insulin sensitivity, and in the plasma levels of gastrointestinal (GI) peptides such as glucagon-like peptide-1 (GLP-1), ghrelin and cholecystokinin (CCK). The influence of fat-free mass on energy expenditure and as a driver of energy intake directs attention to molecules emanating from skeletal tissue as potential appetite signals. Sedentariness (physical inactivity) is positively associated with adiposity and is proposed to be a source of overconsumption and appetite dysregulation. The molecular signals underlying these effects are not known but represent a target for research.
Mental clouding is an almost universal complaint among patients with postural tachycardia syndrome (POTS), but remains poorly understood. Thus, we determined whether POTS patients exhibit deficits during neuropsychological testing relative to healthy subjects. A comprehensive battery of validated neuropsychological tests was administered to 28 female POTS patients and 24 healthy subjects in a semi-recumbent position. Healthy subjects were matched to POTS patients on age and gender. Selective attention, a primary outcome measure, and cognitive processing speed were reduced in POTS patients compared to healthy subjects (Ruff 2&7 Speed t-score: 40±9 vs. 49±8; p=0.009; Symbol Digit Modalities Test t-score: 45±12 vs. 51±8; p=0.011). Measures of executive function were also lower in POTS patients (Trails B t-score: 46±8 vs. 52±8; p=0.007; Stroop Word Color t-score: 45±10 vs. 56±8; p=0.001) suggesting difficulties in tracking and mental flexibility. Measures of sustained attention, psychomotor speed, memory function or verbal fluency were not significantly different between groups. This study provides evidence for deficits in selective attention and cognitive processing in patients with POTS, in the seated position when orthostatic stress is minimized. In contrast, other measures of cognitive function including memory assessments were not impaired in these patients, suggesting selectivity in these deficits. These findings provide new insight into the profile of cognitive dysfunction in POTS, and provide the basis for further studies to identify clinical strategies to better manage the mental clouding associated with this condition.
Objective: We sought to quantify the anti-inflammatory effects of two cannabinoid drugs: cannabidiol (CBD) and palmitoylethanolamide (PEA), in cultured cell lines and compared this effect with experimentally inflamed explant human colonic tissue. These effects were explored in acutely and chronically inflamed colon, using inflammatory bowel disease and appendicitis explants. Design: Caco-2 cells and human colonic explants collected from elective bowel cancer, inflammatory bowel disease (IBD) or acute appendicitis resections, and were treated with the following drug treatments: vehicle, an inflammatory protocol of IFNγ and TNFα (10 ng/ml), inflammation and PEA (10µM), inflammation and CBD (10µM), & PEA or CBD alone. PEA, CBD or vehicle were added simultaneously with IFNγ. Nine intracellular signalling phosphoproteins were determined by multiplex. Inflammatory cytokine secretion was determined using ELISA. Receptor mechanisms were investigated using antagonists for CB1, CB2, PPARα, PPARγ, TRPV1 and GPR55. Results: IFNγ and TNFα treatment increased phosphoprotein and cytokine levels in Caco-2 cultures and colonic explants. Phosphoprotein levels were significantly reduced by PEA or CBD in Caco-2 cultures and colonic explants. CBD and PEA prevented increases in cytokine production in explant colon, but not in Caco-2 cells. CBD effects were blocked by the CB2antagonist AM630 and TRPV1 antagonist SB366791. PEA effects were blocked by the PPARα antagonist GW6471. PEA and CBD were anti-inflammatory in IBD and appendicitis explants. Conclusion: PEA and CBD are anti-inflammatory in the human colon. This effect is not seen in cultured epithelial cells. Appropriately sized clinical trials should assess their efficacy.
Diffusion tensor imaging (DTI) metrics such as Fractional Anisotropy (FA) and Mean Diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multi-site, further studies are required to determine whether associations with cognition of similar strength can be detected in a multi-centre setting. 109 patients (mean age=68) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across 6 sites as part of the PRESERVE DTI sub-study. After handling of missing data, 3T-MRI scanning was available from 5 sites on 5 scanner models (Siemens and Philips), alongside neuropsychological and Quality of Life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalised-brain volume, WMH lesion load, and n(o) lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with Global Cognition (standardised β=.268), Mental Flexibility (β=.306), Verbal Fluency (β=.376), and MoCA (β=.273). The magnitudes of these associations were comparable to those previously reported from single-centre studies found in a systematic literature review. In this multi-centre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. This study supports the use of DTI metrics as biomarkers of disease progression in multi-centre studies.