Effect of a Multifactorial Weight Loss Intervention on HDL Cholesterol Efflux Capacity and Immunosenescence: A Randomized Controlled Trial.

Objective: Life expectancy and obesity prevalence are increasing worldwide, leading to an increase in the prevalence of cardiovascular disease. High-density lipoprotein (HDL) functionality and immunosenescence play key roles in cardiovascular disease, longevity, and quality of aging. Both molecular hallmarks of aging are impacted by obesity and metabolic syndrome and can be modulated by lifestyle.

Pharmacological and genetic increases in liver NADPH levels ameliorate NASH progression in female mice.

Non-alcoholic steatohepatitis (NASH) is one of the fastest growing liver diseases worldwide, and oxidative stress is one of NASH main key drivers. Nicotinamide adenine dinucleotide phosphate (NADPH) is the ultimate donor of reductive power to a number of antioxidant defences. Here, we explored the potential of increasing NADPH levels to prevent NASH progression.

Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier.

Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice.

The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases.

Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.

Background: Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway.

Results: We identify and validate rs2291007 within a conserved region in the 3'UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters.

Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity.

Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs.

Pomegranate Extract Augments Energy Expenditure Counteracting the Metabolic Stress Associated with High-Fat-Diet-Induced Obesity.

Obesity is associated to a low grade of chronic inflammation leading to metabolic stress, insulin resistance, metabolic syndrome, dislipidemia, cardiovascular disease, and even cancer. A Mediterranean diet has been shown to reduce systemic inflammatory factors, insulin resistance, and metabolic syndrome. In this scenario, precision nutrition may provide complementary approaches to target the metabolic alterations associated to "unhealthy obesity".

Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage.

Background: Frailty is a major age-associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6-P dehydrogenase (G6PD).

Production of Fucoxanthin from Using High Performance Countercurrent Chromatography Retaining Its FOXO3 Nuclear Translocation-Inducing Effect.

is a rich source of fucoxanthin, a carotenoid with several health benefits. In the present study, high performance countercurrent chromatography (HPCCC) was used to isolate fucoxanthin from an extract of . A multiple sequential injection HPCCC method was developed combining two elution modes (reverse phase and extrusion).

Conservation of Aging and Cancer Epigenetic Signatures across Human and Mouse.

Aging and cancer are two interrelated processes, with aging being a major risk factor for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been recently reported. Although many of these observations arise from the use of mouse models, there is a lack of systematic comparisons of human and mouse epigenetic patterns in the context of disease.

LXR stimulates a metabolic switch and reveals cholesterol homeostasis as a statin target in Tasmanian devil facial tumor disease.

Devil facial tumor disease (DFTD) and its lack of available therapies are propelling the Tasmanian devil population toward extinction. This study demonstrates that cholesterol homeostasis and carbohydrate energy metabolism sustain the proliferation of DFTD cells in a cell-type-dependent manner. In addition, we show that the liver-X nuclear receptor-β (LXRβ), a major cholesterol cellular sensor, and its natural ligand 24S-hydroxycholesterol promote the proliferation of DFTD cells via a metabolic switch toward aerobic glycolysis.

Activation of p21 limits acute lung injury and induces early senescence after acid aspiration and mechanical ventilation.

The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS).

Author Correction: Identification and characterization of Cardiac Glycosides as senolytic compounds.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/quercetin.

Senescent cells accumulate with obesity in the white adipose tissue of mice and humans. These senescent cells enhance the pro-inflammatory environment that, with time, contributes to the onset of glucose intolerance and type 2 diabetes. Glucose intolerance in mouse models of obesity has been successfully reversed by the elimination of senescent cells with the senolytic compounds navitoclax or the combination of dasatinib and quercetin (D/Q).

Energy Restriction and Colorectal Cancer: A Call for Additional Research.

Colorectal cancer has the second highest cancer-related mortality rate, with an estimated 881,000 deaths worldwide in 2018. The urgent need to reduce the incidence and mortality rate requires innovative strategies to improve prevention, early diagnosis, prognostic biomarkers, and treatment effectiveness. Caloric restriction (CR) is known as the most robust nutritional intervention that extends lifespan and delays the progression of age-related diseases, with remarkable results for cancer protection.

Yarrow Supercritical Extract Ameliorates the Metabolic Stress in a Model of Obesity Induced by High-Fat Diet.

Nowadays, obesity and its associated metabolic disorders, including diabetes, metabolic syndrome, cardiovascular disease, or cancer, continue to be a health epidemic in westernized societies, and there is an increased necessity to explore anti-obesity therapies including pharmaceutical and nutraceutical compounds. Considerable attention has been placed on the identification of bioactive compounds from natural sources to manage the metabolic stress associated with obesity. In a previous work, we have demonstrated that a CO supercritical fluid extract from yarrow (Yarrow SFE), downregulates the expression of the lipogenic master regulator and its downstream molecular targets and in a tumoral context.

Identification and characterization of Cardiac Glycosides as senolytic compounds.

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification.

The sirtuin family in cancer.

Sirtuins are a family of protein deacylases and ADP-ribosyl-transferases, homologs to the yeast SIR2 protein. Seven sirtuin paralogs have been described in mammals, with different subcellular locations, targets, enzymatic activities, and regulatory mechanisms. All sirtuins share NAD as substrate, placing them as central metabolic hubs with strong relevance in lifespan, metabolism, and cancer development.

High-Throughput Image-Based Screening to Identify Chemical Compounds Capable of Activating FOXO.

FOXO proteins are transcription factors with important roles in the regulation of the expression of genes involved in cell growth, proliferation, differentiation, and longevity. FOXO proteins are active in the nucleus but, upon post-translational modification they form a docking site for 14-3-3 proteins and are translocated to the cytoplasm where they are inactive.We make use of this regulatory mechanism of FOXO proteins to develop an image-based high-throughput screening platform to detect compounds that regulate FOXO3 subcellular localization.

Sirt1 protects from K-Ras-driven lung carcinogenesis.

The NAD-dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K-RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines.

FOXO transcription factors at the interface of metabolism and cancer.

Diabetes refers to a group of metabolic diseases characterized by impaired insulin signalling and high blood glucose. A growing body of epidemiological evidence links diabetes to several types of cancer but the underlying molecular mechanisms are poorly understood. The signalling cascade connecting insulin and FOXO proteins provides a compelling example for a conserved pathway at the interface between insulin signalling and cancer.

Analysis of the advantages of cis reporters in optimized FACS-Gal.

Flow cytometry is a powerful multiparametric technology, widely used for the identification, quantification, and isolation of defined populations of cells based on the expression of target proteins. It also allows for the use of surrogate reporters, either enzymatic or fluorescent, to indirectly monitor the expression of these target proteins. In this work, we optimised the dissociation protocol for the detection of the enzymatic reporter LacZ using the FACS-Gal detection system with the fluorogenic substrate FDG to compare cis- versus trans-positioned reporters efficiency.

Young and Lean: Elimination of Senescent Cells Boosts Adaptive Thermogenesis.

Thermogenesis converts the chemical energy of nutrients into heat, and this is associated to improved metabolic performance. In a previous issue of Cell Metabolism, Berry et al. (2017) reported that the progenitors of thermogenic beige adipocytes lose functionality with aging, and this process can be reversed with strategies that eliminate senescent cells.