Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease¹. Multiple factors can contribute to ageing-associated inflammation²; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS–STING signalling pathway, which mediates immune sensing of DNA³, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS–STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS–STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS–STING signalling as a potential strategy to halt neurodegenerative processes during old age.

Objective: This study investigated the effectiveness of liraglutide 3.0 mg daily in combination with a standardized multidisciplinary intervention on body weight and body composition changes in a real‐life setting.Methods: A prospective, observational cohort study design was used. Adult patients with BMI > 35 kg/m², or BMI > 28 kg/m² with greater than or equal to one metabolic comorbidity, were included (n = 54, 65% women). Liraglutide treatment was covered by Swiss health insurance. Clinical and biological data were collected at baseline, 4 months, and 10 months. Body composition was assessed by dual‐energy x‐ray absorptiometry at baseline and 10 months.Results: At 10 months, mean (SD) percentage weight loss (WL%) was −12.4% (5.5%) or −14.1 (6.6) kg. WL% was ≥5% in 87% of patients at 4 months and in 96% at 10 months. WL% was higher in women (−9.5% [3.1%] vs. men −7.2% [2.5%], p = 0.02) at 4 months and persisted at 10 months (−13.7% [5.2%] vs. −9.6% [5.1%], p = 0.006). WL% was associated with baseline percentage fat mass but not with age or BMI. Body composition showed a decrease in fat mass, visceral adipose tissue, and absolute lean mass.Conclusions: In a real‐world setting, liraglutide 3.0 mg led to beneficial changes in WL and body composition, with a greater impact in women.

Introduction: Lipedema is a poorly known condition. Diagnosis is based almost exclusively on clinical criteria, which may be subjective and not always reliable. This study aimed to investigate regional body composition (BC) by dual-energy X-ray absorptiometry (DXA) in patients with lipedema and healthy controls and to determine cut-off values of fat mass (FM) indices to provide an additional tool for the diagnosis and staging of this condition. Methods: This study is a single-center case-control study performed at Lausanne University Hospital, Switzerland. Women with clinically diagnosed lipedema underwent regional BC assessment by DXA. The control group without clinical lipedema was matched for age and body mass index (BMI) at a ratio of 1:2 and underwent similar examination. Regional FM (legs, arms, legs and arms, trunk, android and gynoid FM) was measured in (kg) and divided by FM index (FMI) (kg/m2) and total FM (kg). The trunk/legs and android/gynoid ratios were calculated. For all indices of FM distribution showing a significant difference between cases and controls, we defined the receiver operating characteristic (ROC) curves, calculating the area under the curve (AUC), sensitivity, specificity, and Youden’s index. Types and stages of lipedema were compared in terms of FM indices. Correlation analyses between all FM distribution indices and lipedema stages were performed. Results: We included 222 women (74 with lipedema and 148 controls). Overall, the mean age was 41 years (standard deviation [SD] 11), and mean BMI was 30.9 kg/m2 (SD 7.6). A statistically significant difference was observed for all DXA-derived indices of FM distribution between groups, except for arm FM indices. The ROC curve analysis of leg FM/total FM, as a potential indicator of lipedema, resulted in an AUC of 0.90 (95% confidence interval 0.86–0.94). According to Youden’s index, optimal cut-off value identifying lipedema was 0.384. Sensitivity and specificity were 0.95 and 0.73, respectively. We found no significant differences between lipedema types and stages in terms of FM indices, nor significant correlations between the latter and lipedema stages. Discussion/Conclusion: BC assessment by DXA, and particularly calculation of the leg FM/total FM index, is a simple tool that may help clinicians rule out lipedema in doubtful cases.

Background: Conflicting results have been reported regarding the predictive value of preoperative psychological assessment and weight outcome after bariatric surgery. This might be attributed to different factors affecting early weight loss and long-term weight loss. Herein, we investigated whether preoperative psychiatric profile was associated with preoperative BMI and with both early (1 year) and long-term (5 years) weight loss after Roux-en-Y gastric bypass (RYGB). Methods: Prospective observational cohort study of patients undergoing RYGB between 2013 and 2019. Symptoms related to anxiety, depression, eating disorder, and alcohol use disorders were assessed by employing validated, specific psychometric tests (STAI-S/T, BDI-II, BITE, AUDIT-C) prior to surgery. Pre-operative BMI, early weight loss (1 year), and long-term weight evolution (up to 5 years) were registered. Results: Two hundred thirty six patients (81% women) were included in the present study. Linear longitudinal mixed model showed a significant effect of preoperative high anxiety (STAI-S) on long-term weight outcome, after controlling for gender, age and type 2 diabetes. Patient with high preoperative anxiety score regained weight faster than those experiencing low anxiety (each year percent excess BMI loss (%EBMIL) − 4.02%, ± 1.72, p = 0.021). No other pre-operative psychiatric symptoms have been shown to have an impact on long-term weight loss. In addition, no significant association was found between any of the pre-operative psychiatric variables and pre-operative BMI, or early weight loss (%EBMIL) at 1-year post-RYGB. Conclusion: Herein we identified high anxiety score (STAI-S) as a predictor for long-term weight regain. Thus, long-term psychiatric surveillance of these patients and the development of tailored management tools could serve as a means to prevent weight regain. Graphical

Purpose Visceral adipose tissue (VAT) is associated with cardiometabolic risk factors and insulin resistance. The physiological mechanisms underlying the benefits of Roux-en-Y gastric bypass surgery (RYGB) on glucose metabolism remain incompletely understood. The impact of RYGB on VAT was assessed among three groups of patients stratified by their glucose tolerance before surgery. Methods Forty-four obese women were categorized into normoglycemia (n = 21), impaired glucose tolerance (IGT, n = 18) and diabetes (n = 5) before surgery. Body composition measured by dual-energy X-ray absorptiometry (DXA) was performed before surgery, 6 months and 12 months after. Results The three groups had comparable mean age (mean 38.6 ± SD 9.9) and BMI at baseline (41.9 ± 4.3 kg/m²). After 12 months, total weight loss (mean 35.1% ± 7.5) and excess weight loss (91.1% ± 25.1) were similar between groups. Pre-surgery mean VAT was significantly higher in diabetes (mean 2495 ± 616 g) than in normoglycemia (1750 ± 617 g, p = 0.02). The percentage of VAT to total body fat was significantly higher in diabetes (mean 4.4% ± 0.9) compared to normoglycemia (2.9% ± 0.8, p = 0.003). Twelve months after surgery, VAT loss was significantly greater among patients with diabetes (mean 1927 ± 413 g) compared to normoglycemia (1202 ± 450, p = 0.009). Conclusions RYGB leads to important VAT loss, and this loss is greater in patients with diabetes prior to surgery. As VAT is associated with insulin resistance, this reduction may account for the profound impact of this surgery on glucose metabolism.

Higher mass-normalized net energy cost of walking (NetC_w/kg) and mechanical pendular recovery are observed in obese compared to lean adults. This study aimed to investigate the effect of different classes of obesity on the energetics and mechanics of walking and to explore the relationships between body mass, NetC_w/kg and gait mechanics by using principal component analysis (PCA). NetC_w/kg and gait mechanics were computed in severely obese (SOG; n = 18, BMI = 40.1 ± 4.4 kg·m⁻²), moderately obese (MOG; n = 17, BMI = 32.2 ± 1.5 kg·m⁻²) and normal-weight (NWG; n = 13, BMI = 22.0 ± 1.5 kg·m⁻²) adults during five walking trials (0.56, 0.83, 1.11, 1.39, 1.67 m·s⁻¹) on an instrumented treadmill. NetC_w/kg was significantly higher in SOG compared to NWG (p = 0.019), with no significant difference between SOG and MOG (p = 0.14), nor between MOG and NWG (p = 0.27). Recovery was significantly higher in SOG than in NWG (p = 0.028), with no significant difference between SOG and MOG (p = 0.13), nor between MOG and NWG (p = 0.35). PCA models explained between 17.0% and 44.2% of the data variance. This study showed that: (1) obesity class influences the gait energetics and mechanics; (2) PCA was able to identify two components, showing that the obesity class is associated with lower walking efficiency and better pendulum-like characteristics.