Randomized, Double-Blind, Placebo-Controlled Trial to Test the Effects of a Nutraceutical Combination Monacolin K-Free on the Lipid and Inflammatory Profile of Subjects with Hypercholesterolemia.

BACKGROUND: Nutraceutical combinations (NCs) against hypercholesterolemia are increasing in the marketplace. However, the availability of NCs without monacolin K is scarce even though the statin-intolerant population needs it. METHODS: This study is a parallel-group, randomized, placebo-controlled, double-blind trial. We evaluated the effects of the NC containing phytosterols, bergamot, olive fruits, and vitamin K2 on lipid profile and inflammatory biomarkers in 118 subjects (mean age ± SD, 57.9 ± 8.8 years; 49 men and 69 women) with hypercholesterolemia (mean total cholesterol ± SD, 227.4 ± 20.8 mg/dL) without clinical history of cardiovascular diseases. At baseline and 6 and 12 weeks of treatment, we evaluated lipid profile (total, LDL and HDL cholesterol, and triglycerides), safety (liver, kidney, and muscle parameters), and inflammatory biomarkers such as hs-CRP, leukocytes, interleukin-32, and interleukin-38 and inflammatory-microRNAs (miRs) miR-21, miR-126, and miR-146a. RESULTS: Compared to the placebo, at 6 and 12 weeks, NC did not significantly reduce total cholesterol (p = 0.083), LDL cholesterol (p = 0.150), and triglycerides (p = 0.822). No changes were found in hs-CRP (p = 0.179), interleukin-32 (p = 0.587), interleukin-38 (p = 0.930), miR-21 (p = 0.275), miR-126 (p = 0.718), miR-146a (p = 0.206), myoglobin (p = 0.164), and creatine kinase (p = 0.376). Among the two reported, only one adverse event was probably related to the nutraceutical treatment. CONCLUSIONS: The evaluated nutraceutical combination did not change serum lipid profile and inflammatory parameters, at least not with the daily dose applied in the present study.

Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and ß-caryophyllene association on human endothelial and monocytic cells.

A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and can contribute to fuel the inflammaging. We investigated both the anti-SASP and anti-inflammatory activities of a nutritional supplement, namely Fenoxidol™, composed of turmeric extract bioCurcumin (bCUR), Polydatin (the natural glycosylated precursor of Resveratrol-RSV), and liposomal ß-caryophyllene (BCP), in two human cellular models, such as the primary endothelial cell line, HUVECs and the monocytic cell line, THP-1. Replicative and Doxorubicin-induced senescent HUVECs, both chosen as cellular models of SASP, and lipopolysaccharides (LPS)-stimulated THP-1, selected as a model of the inflammatory response, were treated with the three single natural compounds or with a combination of them (MIX). In both senescent HUVEC models, MIX treatment significantly reduced IL-1ß and IL-6 expression levels and p16ink4a protein, and also increased SIRT1 protein level, as well as downregulated miR-146a and miR-21 expression, two of the so-called inflamma-miRNAs, more effectively than the single compounds. In THP-1 cells stimulated with LPS, the MIX showed a significant effect in decreasing IL-1ß, IL-6, TNF-α, and miR-146a expression levels and Caspase-1 activation, in association with an up-regulation of SIRT1 protein, compared to the single compounds. Overall, our results suggest that the three analysed compounds can have a combined effect in restraining SASP in senescent HUVECs as well as the inflammatory response in LPS-stimulated THP-1 cells.

Plasma levels of interleukin-38 in healthy aging and in type 2 diabetes.

Plasma levels of interleukin (IL)-38 were evaluated in patients with type 2 diabetes (T2DM) and healthy controls. Plasma IL-38 was higher in T2DM patients and positively related to waist/hip ratio, HbA1c, uric acid, liver function tests, triglycerides and total proteins. Patients suffering from diabetic nephropathy had the highest IL-38 levels.

Pleiotropic effects of polyphenols on glucose and lipid metabolism: Focus on clinical trials.

Epidemiological evidence from observational studies suggests that dietary polyphenols (PPs) - phytochemicals found in a variety of plant-based foods - can reduce the risk of developing type 2 diabetes mellitus (T2DM). Clinical trials have also indicated that PPs may help manage the two key features of T2DM, hyperglycemia and dyslipidemia. Since the incidence of T2DM is dramatically increasing worldwide, identifying food-based approaches that can reduce the risk of developing it and help manage its main risk factors in early-stage disease has clinical and socioeconomic relevance. After a brief overview of current epidemiological data on the incidence of T2DM in individuals consuming PP-rich diets, we review the evidence from clinical trials investigating PP-enriched foods and/or PP-based nutraceutical compounds, report their main results, and highlight the knowledge gaps that should be bridged to enhance our understanding of the role of PPs in T2DM development and management.

Inflamm-aging microRNAs may integrate signals from food and gut microbiota by modulating common signalling pathways.

Human gut microbiota, which comprises an extremely diverse and complex community of microorganisms inhabiting the intestinal tract, may be associated with inflammation and age-related chronic health conditions. However, the mechanism underlying this association is only recently beginning to emerge. Transfer and modulation of gene expression by diet-derived microRNAs (miRs) in mammals might be involved in this communication. Through a bioinformatics approach, using on line tools and repositories, we searched for evidences that food-containing miRs, actually involved in the modulation of the inflammatory process, (inflamma-miRs), may contribute to mediate the anti-inflammatory effects exerted by some foods through the modulation of aging-related pathways and gut microbiota composition in a bidirectional communication. Supported by a "Pubmed" search and our previous research, a trio of experimentally validated inflamma-miRs were considered: miR-155, miR-146a and miR-21. Our in silico study supports the hypothesis that these inflamma-miRs could modulate some pathways, such as lysine degradation and lengthening of fatty acids which are involved in the modulation of microbiota composition, i.e. prevotella, ruminococcus and oscillibacter and vice versa. Food homologues to human miR-21, miR-155 and miR-146a were found in cow fat, cow milk, and eggs suggesting that they may be able of targeting, and probably exacerbating, inflammation related pathways. If these data will be experimentally validated, they will further support the relevance of a nutraceutical approach for a healthy aging.

Circulating miR-146a in healthy aging and type 2 diabetes: Age- and gender-specific trajectories.

To evaluate the combined effect of age and glycemic state on circulating levels of the inflamma-miR-146a levels, 188 healthy subjects (CTR) aged 20-104 years and 144 type-2 diabetic patients (T2DM), aged 40-80 years, were analyzed. In CTR subjects, miR-146a levels showed a significant age-related decline. When a gender-stratified analysis was ran, the miR-146a age-related trajectory was confirmed only in men and a negative correlation with PAI-1, uric acid, and creatinine was also observed. In women, miR-146a circulating levels showed negative correlations with azotemia, uric acid, waist/hip ratio and ferritin. A significant miR-146a decline with aging was also observed in T2DM patients. Significant positive correlations were found between miR-146a in diabetic patients and total cholesterol, LDL-C, ApoA1, ApoB, and platelets, and negative correlations with serum iron and ferritin. Notably, miR-146a was significantly overexpressed in T2DM patients treated with metformin. MiR-146a levels were significantly lower in diabetic patients than in age-matched CTR and negatively correlated to both fasting glucose and HbA1c in males. Finally, age-related trajectories for circulating miR-146a levels showed an inverted U-shaped relationship; however, in T2DM patients the trajectory was significantly shifted towards lower levels. Our findings support the hypothesis that miR-146a could be a functional biomarker of healthy/unhealthy aging.

Anti-senescence compounds: A potential nutraceutical approach to healthy aging.

The desire of eternal youth seems to be as old as mankind. However, the increasing life expectancy experienced by populations in developed countries also involves a significantly increased incidence of the most common age-related diseases (ARDs). Senescent cells (SCs) have been identified as culprits of organismal aging. Their number rises with age and their senescence-associated secretory phenotype fuels the chronic, pro-inflammatory systemic state (inflammaging) that characterizes aging, impairing the regenerative ability of stem cells and increasing the risk of developing ARDs. A variegated class of molecules, including synthetic senolytic compounds and natural compounds contained in food, have been suggested to possess anti-senescence activity. Senolytics are attracting growing interest, and their safety and reliability as anti-senescence drugs are being assessed in human clinical trials. Notably, since SCs spread inflammation at the systemic level through pro-oxidant and pro-inflammatory signals, foods rich in polyphenols, which exert antioxidant and anti-inflammatory actions, have the potential to be harnessed as "anti-senescence foods" in a nutraceutical approach to healthier aging. We discuss the beneficial effects of polyphenol-rich foods in relation to the Mediterranean diet and the dietary habits of long-lived individuals, and examine their ability to modulate bacterial genera in the gut.