Circulating Neurofilament Light Chain Levels Increase with Age and Are Associated with Worse Physical Function and Body Composition in Men but Not in Women.

This study aimed to assess the relationship between age-related changes in Neurofilament Light Chain (NFL), a marker of neuronal function, and various factors including muscle function, body composition, and metabolomic markers. The study included 40 participants, aged 20 to 85 years. NFL levels were measured, and muscle function, body composition, and metabolomic markers were assessed. NFL levels increased significantly with age, particularly in men. Negative correlations were found between NFL levels and measures of muscle function, such as grip strength, walking speed, and chair test performance, indicating a decline in muscle performance with increasing NFL. These associations were more pronounced in men. NFL levels also negatively correlated with muscle quality in men, as measured by 50 kHz phase angle. In terms of body composition, NFL was positively correlated with markers of fat mass and negatively correlated with markers of muscle mass, predominantly in men. Metabolomic analysis revealed significant associations between NFL levels and specific metabolites, with gender-dependent relationships observed. This study provides insights into the relationship between circulating serum NFL, muscle function, and aging. Our findings hint at circulating NFL as a potential early marker of age-associated neurodegenerative processes, especially in men.

Organoids: An Emerging Tool to Study Aging Signature across Human Tissues. Modeling Aging with Patient-Derived Organoids.

The biology of aging is focused on the identification of novel pathways that regulate the underlying processes of aging to develop interventions aimed at delaying the onset and progression of chronic diseases to extend lifespan. However, the research on the aging field has been conducted mainly in animal models, yeast, Caenorhabditis elegans, and cell cultures. Thus, it is unclear to what extent this knowledge is transferable to humans since they might not reflect the complexity of aging in people. An organoid culture is an in vitro 3D cell-culture technology that reproduces the physiological and cellular composition of the tissues and/or organs. This technology is being used in the cancer field to predict the response of a patient-derived tumor to a certain drug or treatment serving as patient stratification and drug-guidance approaches. Modeling aging with patient-derived organoids has a tremendous potential as a preclinical model tool to discover new biomarkers of aging, to predict adverse outcomes during aging, and to design personalized approaches for the prevention and treatment of aging-related diseases and geriatric syndromes. This could represent a novel approach to study chronological and/or biological aging, paving the way to personalized interventions targeting the biology of aging.

Phytate Intake, Health and Disease: "Let Thy Food Be Thy Medicine and Medicine Be Thy Food".

Phytate (myo-inositol hexakisphosphate or InsP6) is the main phosphorus reservoir that is present in almost all wholegrains, legumes, and oilseeds. It is a major component of the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets. Phytate is recognized as a nutraceutical and is classified by the Food and Drug Administration (FDA) as Generally Recognized As Safe (GRAS). Phytate has been shown to be effective in treating or preventing certain diseases. Phytate has been shown to inhibit calcium salt crystallization and, therefore, to reduce vascular calcifications, calcium renal calculi and soft tissue calcifications. Moreover, the adsorption of phytate to the crystal faces can inhibit hydroxyapatite dissolution and bone resorption, thereby playing a role in the treatment/prevention of bone mass loss. Phytate has a potent antioxidation and anti-inflammatory action. It is capable of inhibiting lipid peroxidation through iron chelation, reducing iron-related free radical generation. As this has the effect of mitigating neuronal damage and loss, phytate shows promise in the treatment/prevention of neurodegenerative disease. It is reported that phytate improves lipid and carbohydrate metabolism, increases adiponectin, decreases leptin and reduces protein glycation, which is linked with macrovascular and microvascular diabetes complications. In this review, we summarize the benefits of phytate intake as seen in in vitro, animal model, epidemiological and clinical trials, and we also identify questions to answer in the future.

Daily phytate intake increases adiponectin levels among patients with diabetes type 2: a randomized crossover trial.

AIM: Adiponectin, a major adipokine secreted by adipose tissue, has been shown to improve insulin sensitivity. Myo-inositol hexaphosphate (phytate; InsP6) is a natural compound that is abundant in cereals, legumes, and nuts that has demonstrated to have different beneficial properties in patients with diabetes type 2. METHODS: We performed a randomized crossover trial to investigate the impact of daily consumption of InsP6 on serum levels of adiponectin, TNF-alpha, IL-6, and IL-1beta in patients with type 2 diabetes mellitus (T2DM; n = 39). Thus, we measure serum levels of these inflammatory markers, classic vascular risk factors, and urinary InsP6 at baseline and at the end of the intervention period. RESULTS: Patients who consumed InsP6 supplements for 3 months had higher levels of adiponectin and lower HbA1c than those who did not consume InsP6. No differences were found in TNF-alpha, IL-6, and IL-1beta. CONCLUSION: This is the first report to show that consumption of InsP6 increases plasma adiponectin concentration in patients with T2DM. Consequently, our findings indicate that following a phytate-rich diet has beneficial effects on adiponectin and HbA1c concentrations and it could help to prevent or minimize diabetic-related complications.

Age-standardized incidence, mortality rate, and trend changes of thyroid cancer in the Balearic Islands during the 2000-2020 period: a population-based study.

Objective: Global thyroid cancer (TC) incidence is growing worldwide, but great heterogenicity exists among published studies, and thus, population-specific epidemiological studies are needed to adequate health resources and evaluate the impact of overdiagnosis. Methods: We conducted a Public Health System database retrospective review of TC incident cases from 2000 to 2020 in the Balearic Islands region and evaluated age-standardized incidence rate (ASIR), age at diagnosis, gender distribution, tumor size and histological subtype, mortality rate (MR), and cause of death. Estimated annual percent changes (EAPCs) were also evaluated and data from the 2000-2009 period were compared to the 2010-2020 period when neck ultrasound (US) was routinely performed by clinicians at Endocrinology Departments. Results: A total of 1387 incident cases of TC were detected. Overall, ASIR (×105) was 5.01 with a 7.82% increment in EAPC. A significant increase in the 2010-2020 period was seen for ASIR (6.99 vs 2.82, P < 0.001) and age at diagnosis (52.11 vs 47.32, P < 0.001) compared to the 2000-2009 period. A reduction in tumor size (2.00 vs 2.78 cm, P < 0.001) and a 6.31% increase in micropapillary TC (P < 0.05) were also seen. Disease-specific MR remained stable at 0.21 (×105). The mean age at diagnosis for all mortality groups was older than survivors (P < 0.001). Conclusion: The incidence of TC has grown in the 2000-2020 period in the Balearic Islands, but MR has not changed. Beyond other factors, a significant contribution of overdiagnosis to this increased incidence is likely due to changes in the routine management of thyroid nodular disease and increased availability of neck US.

GDF15 and ACE2 stratify COVID-19 patients according to severity while ACE2 mutations increase infection susceptibility.

Coronavirus disease 19 (COVID-19) is a persistent global pandemic with a very heterogeneous disease presentation ranging from a mild disease to dismal prognosis. Early detection of sensitivity and severity of COVID-19 is essential for the development of new treatments. In the present study, we measured the levels of circulating growth differentiation factor 15 (GDF15) and angiotensin-converting enzyme 2 (ACE2) in plasma of severity-stratified COVID-19 patients and uninfected control patients and characterized the in vitro effects and cohort frequency of ACE2 SNPs. Our results show that while circulating GDF15 and ACE2 stratify COVID-19 patients according to disease severity, ACE2 missense SNPs constitute a risk factor linked to infection susceptibility.

Role of Advanced Glycation End Products on Aortic Calcification in Patients with Type 2 Diabetes Mellitus.

The aim of this study was to evaluate the relationship between serum levels of advanced glycation end products (AGEs) and abdominal aortic calcification (AAC) in patients with type 2 diabetes mellitus (DM2). This was a prospective cross-sectional study. One-hundred and four consecutive patients with DM2 were given lateral lumbar X-rays in order to quantify abdominal aortic calcification (AAC). Circulating levels of AGEs and classical cardiovascular risk factors were determined. Clinical history was also registered. Patients with higher AGEs values had higher grades of aortic calcification and higher numbers of diabetic-related complications. Multivariate logistic regression analysis showed that being older, male and having high levels of AGEs and triglycerides were the independent risk factors associated to moderate-severe AAC when compared to no-mild AAC. Our results suggest that AGEs plays a role in the pathogenesis of aortic calcifications. In addition, the measurement of AGEs levels may be useful for assessing the severity of AAC in the setting of diabetic complications.

Phytate Decreases Formation of Advanced Glycation End-Products in Patients with Type II Diabetes: Randomized Crossover Trial.

Myo-inositol hexaphosphate (phytate; IP6) is a natural compound that is abundant in cereals, legumes, and nuts and it has the ability to chelate metal cations. The binding of IP6 to transition metals suggests that it could be used for the treatment of metal-catalyzed protein glycation, which appears to trigger diabetes-related diseases. Our in vitro studies showed that IP6 reduced the formation of Fe3+-catalyzed advanced glycation end-products (AGEs). This led us to perform a randomized cross-over trial to investigate the impact of the daily consumption IP6 on protein glycation in patients with type 2 diabetes mellitus (T2DM; n = 33). Thus, we measured AGEs, glycated hemoglobin (HbA1c), several vascular risk factors, and urinary IP6 at baseline and at the end of the intervention period. Patients who consumed IP6 supplements for 3 months had lower levels of circulating AGEs and HbA1c than those who did not consume IP6. This is the first report to show that consumption of IP6 inhibits protein glycation in patients with T2DM. Considering that AGEs contribute to microvascular and macrovascular complications in T2DM, our data indicates that dietary supplementation with IP6 should be considered as a therapy to prevent the formation of AGEs and therefore, the development of diabetes-related diseases in patients with T2DM.

Diabetes mellitus and cardiovascular clinical characteristics of Spanish women with stable ischaemic heart disease: Data from the SIRENA study.

The relationship between diabetes and the cardiovascular clinical characteristics of Spanish women with stable ischaemic heart disease was studied in a nationwide cross-sectional study. Diabetes was related to a higher burden of risk factors, comorbidity, multivessel disease and coronary surgery.

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.

BACKGROUND: Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes. We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both. METHODS: We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites in 18 countries. Eligible patients were aged at least 18 years (or at least 20 years in Japan) and diagnosed with type 2 diabetes, with insufficient glycaemic control (HbA1c 7·0-10·5% [53·0-91·0 mmol/mol]) despite stable treatment with metformin, thiazolidinediones, or both. We randomly assigned participants (2:2:1:1) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0·5 mg once weekly plus oral sitagliptin placebo once daily, subcutaneous semaglutide 1·0 mg once weekly plus oral sitagliptin placebo once daily, oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0·5 mg once weekly, or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1·0 mg once weekly. The two oral sitagliptin 100 mg groups (with semaglutide placebo 0·5 mg and 1·0 mg) were pooled for the analyses. The primary endpoint was change in HbA1c from baseline to week 56, assessed in the modified intention-to-treat population (all randomly assigned participants who received at least one dose of study drug); change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint. Safety endpoints included adverse events and hypoglycaemic episodes. This trial is registered with ClinicalTrials.gov, number NCT01930188. FINDINGS: Between Dec 2, 2013, and Aug 5, 2015, we randomly assigned 1231 participants; of the 1225 included in the modified intention-to-treat analysis, 409 received semaglutide 0·5 mg, 409 received semaglutide 1·0 mg, and 407 received sitagliptin 100 mg. Mean baseline HbA1c was 8·1% (SD 0·93); at week 56, HbA1c was reduced by 1·3% in the semaglutide 0·5 mg group, 1·6% in the semaglutide 1·0 mg group, and 0·5% with sitagliptin (estimated treatment difference vs sitagliptin -0·77% [95% CI -0·92 to -0·62] with semaglutide 0·5 mg and -1·06% [-1·21 to -0·91] with semaglutide 1·0 mg; p<0·0001 for non-inferiority and for superiority, for both semaglutide doses vs sitagliptin). Mean baseline bodyweight was 89·5 kg (SD 20·3); at week 56, bodyweight reduced by 4·3 kg with semaglutide 0·5 mg, 6·1 kg with semaglutide 1·0 mg, and 1·9 kg with sitagliptin (estimated treatment difference vs sitagliptin -2·35 kg [95% CI -3·06 to -1·63] with semaglutide 0·5 mg and -4·20 kg [-4·91 to -3·49] with semaglutide 1·0 mg; p<0·0001 for superiority, for both semaglutide doses vs sitagliptin). The proportion of patients who discontinued treatment because of adverse events was 33 (8%) for semaglutide 0·5 mg, 39 (10%) for semaglutide 1·0 mg, and 12 (3%) for sitagliptin. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 73 (18%) who received semaglutide 0·5 mg, 72 (18%) who received semaglutide 1·0 mg, and 30 (7%) who received placebo, and diarrhoea was reported in 54 (13%) who received semaglutide 0·5 mg, 53 (13%) who received semaglutide 1·0 mg, and 29 (7%) who received placebo. Seven (2%) patients in the semaglutide 0·5 mg group, two (<1%) in the semaglutide 1·0 mg group, and five (1%) in the sitagliptin group had blood-glucose confirmed hypoglycaemia. There were six fatal events (two in the semaglutide 0·5 mg group, one in the semaglutide 1·0 mg group, and three in the sitagliptin group); none were considered likely to be related to the trial drugs. INTERPRETATION: Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin, thiazolidinediones, or both, and had a similar safety profile to that of other GLP-1 receptor agonists. Semaglutide seems to be an effective add-on treatment option for this patient population. FUNDING: Novo Nordisk A/S.

LEADER-4: blood pressure control in patients with type 2 diabetes and high cardiovascular risk: baseline data from the LEADER randomized trial.

OBJECTIVE: As glucagon-like peptide-1 receptor agonists lower blood pressure (BP) in type 2 diabetes mellitus (T2DM), we examined BP control in relation to targets set by international bodies prior to randomization in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial. METHODS: We analyzed baseline data from LEADER (NCT01179048), an ongoing phase 3B, randomized, double-blind, placebo-controlled cardiovascular outcomes trial examining the cardiovascular safety of the glucagon-like peptide-1 receptor agonist liraglutide in 9340 people with T2DM from 32 countries [age (all mean ±â€ŠSD) 64 ±â€Š7.2 years, BMI 32.5 ±â€Š6.3 kg/m, duration of diabetes 12.7 ±â€Š8.0 years], all of whom were at high risk for cardiovascular disease (CVD). RESULTS: A total of 81% (n = 7592) of participants had prior CVD and 90% (n = 8408) had a prior history of hypertension. Despite prescription of multiple antihypertensive agents at baseline, only 51% were treated to a target BP of less than 140/85 mmHg and only 26% to the recommended baseline BP target of less than 130/80 mmHg. In univariate analyses, those with prior CVD were prescribed more agents (P < 0.001) and had lower BP than those without (137 ±â€Š18.8/78 ±â€Š10.6 mmHg versus 140 ±â€Š17.7/80 ±â€Š9.9 mmHg; P < 0.001). In logistic regression analyses, residency in North America (64% treated to <140/85 mmHg; 38% treated to <130/80 mmHg) was the strongest predictor of BP control. CONCLUSION: These contemporary data confirm that BP remains insufficiently controlled in a large proportion of individuals with T2DM at high cardiovascular risk, particularly outside North America. Longitudinal data from the LEADER trial may provide further insights into BP control in relation to cardiovascular outcomes in this condition.

Cardiovascular risk profile in Mediterranean patients submitted to bariatric surgery and intensive lifestyle intervention: impact of both interventions after 1 year of follow-up.

BACKGROUND: The aim was to compare obesity-related cardiovascular (CV) risk factors (classic and emerging) and the estimated CV risk at 10 years (calculated by REGICOR) in obese Mediterranean patients submitted to bariatric surgery and intensive lifestyle intervention at baseline and after 1 year of follow-up. METHODS: Patients submitted to bariatric surgery (n = 108) and standardized program of therapeutic changes in lifestyle (n = 90) were retrospectively included. Clinical history, physical examination, and laboratory analysis were routinely determined before weight loss intervention and at 1 year follow-up. RESULTS: Seventy-five percent of the surgery patients had a CV risk lower than 5 % and not one patient had a 10-year CV risk higher than 15 %. The percentage of patients with comorbidities (diabetes and sleep apnea syndrome) was higher in the surgery group. Seventeen of the surgery patients had no comorbidities. The improvement in CV risk profile was significant higher in the surgery group. CV risk benefit of both intervention groups was related to baseline higher CV risk, with type 2 diabetes with poor metabolic control and high cholesterol levels being the most important predictors for surgery patients. Neither body mass index nor excess of weight loss was related to CV risk improvement. CONCLUSIONS: Mediterranean patients undergoing a weight loss intervention have a low CV risk. In comparison with lifestyle intervention, surgery induces a better improvement of CV risk. This benefit is related to estimated CV risk, presence of diabetes, and cholesterol levels at baseline. These observations should be taken into account in order to optimize health resources.