Nutraceutical activation of Sirt1: a review.

The deacetylase sirtuin 1 (Sirt1), activated by calorie restriction and fasting, exerts several complementary effects on cellular function that are favourable to healthspan; it is often thought of as an 'anti-aging' enzyme. Practical measures which might boost Sirt1 activity are therefore of considerable interest. A number of nutraceuticals have potential in this regard.

Nutraceutical Prevention of Diabetic Complications-Focus on Dicarbonyl and Oxidative Stress.

Oxidative and dicarbonyl stress, driven by excess accumulation of glycolytic intermediates in cells that are highly permeable to glucose in the absence of effective insulin activity, appear to be the chief mediators of the complications of diabetes. The most pathogenically significant dicarbonyl stress reflects spontaneous dephosphorylation of glycolytic triose phosphates, giving rise to highly reactive methylglyoxal. This compound can be converted to harmless lactate by the sequential activity of glyoxalase I and II, employing glutathione as a catalyst.

Monounsaturated Fat vs Saturated Fat: Effects on Cardio-Metabolic Health and Obesity.

For over 40 years saturated fat, the fat found primarily in animal foods, was thought to be the main culprit for increasing cholesterol levels and causing heart disease. During this same time vegetable oils were promoted as being heart healthy because they could lower cholesterol. However, recently the evidence implicating saturated fat as being harmful to heart health has been challenged and more studies are beginning to show the harms from consuming industrially produced vegetable oils.

Nutraceuticals/Drugs Promoting Mitophagy and Mitochondrial Biogenesis May Combat the Mitochondrial Dysfunction Driving Progression of Dry Age-Related Macular Degeneration.

In patients with age-related macular degeneration (AMD), the crucial retinal pigment epithelial (RPE) cells are characterized by mitochondria that are structurally and functionally defective. Moreover, deficient expression of the mRNA-editing enzyme Dicer is noted specifically in these cells. This Dicer deficit up-regulates expression of Alu RNA, which in turn damages mitochondria-inducing the loss of membrane potential, boosting oxidant generation, and causing mitochondrial DNA to translocate to the cytoplasmic region.

Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity.

Ferulic acid, a bacterial metabolite of anthocyanins, seems likely to be a primary mediator of the health benefits associated with anthocyanin-rich diets, and has long been employed in Chinese cardiovascular medicine. In rodent studies, it has exerted wide-ranging antioxidant and anti-inflammatory effects, the molecular basis of which remains rather obscure. However, recent studies indicate that physiologically relevant concentrations of ferulic acid can boost expression of Sirt1 at mRNA and protein levels in a range of tissues.

Coenzyme Q10 deficiency can be expected to compromise Sirt1 activity.

For reasons that remain unclear, endogenous synthesis and tissue levels of coenzyme Q10 (CoQ10) tend to decline with increasing age in at least some tissues. When CoQ10 levels are sufficiently low, this compromises the efficiency of the mitochondrial electron transport chain, such that production of superoxide by site 2 increases and the rate of adenosine triphosphate production declines. Moreover, CoQ10 deficiency can be expected to decrease activities of Sirt1 and Sirt3 deacetylases, believed to be key determinants of health span.

Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity-Nutraceutical Options.

In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)-or glucolipotoxicity-can induce a loss of glucose-stimulated insulin secretion (GSIS). This in turn can lead to a chronic state of glucolipotoxicity and a sustained loss of GSIS, ushering in type 2 diabetes. Loss of GSIS reflects a decline in beta cell glucokinase (GK) expression associated with decreased nuclear levels of the pancreatic and duodenal homeobox 1 (PDX1) factor that drives its transcription, along with that of Glut2 and insulin.

Nutraceutical Aid for Allergies - Strategies for Down-Regulating Mast Cell Degranulation.

Interactions of antigens with the mast cell FcεRI-IgE receptor complex induce degranulation and boost synthesis of pro-inflammatory lipid mediators and cytokines. Activation of spleen tyrosine kinase (Syk) functions as a central hub in this signaling. The tyrosine phosphatase SHP-1 opposes Syk activity; stimulation of NADPH oxidase by FcεRI activation results in the production of oxidants that reversibly inhibit SHP-1, up-regulating the signal from Syk.

The Importance of Maintaining a Low Omega-6/Omega-3 Ratio for Reducing the Risk of Autoimmune Diseases, Asthma, and Allergies.

Up until about 100 years ago, the omega-6/3 ratio has been around 4:1 or less. However, the typical Western diet now provides an omega-6/3 ratio of approximately 20:1 in favor of omega-6. This predisposes to supraphysiologic inflammatory responses and perpetuates chronic low-grade inflammation.

High Intakes of Bioavailable Phosphate May Promote Systemic Oxidative Stress and Vascular Calcification by Boosting Mitochondrial Membrane Potential-Is Good Magnesium Status an Antidote?

Chronic kidney disease is characterized by markedly increased risk for cardiovascular mortality, vascular calcification, and ventricular hypertrophy, and is associated with increased systemic oxidative stress. Hyperphosphatemia, reflecting diminished glomerular phosphate (Pi) clearance, coupled with a compensatory increase in fibroblast growth factor 23 (FGF23) secretion are thought to be key mediators of this risk. Elevated serum and dietary Pi and elevated plasma FGF23 are associated with increased cardiovascular and total mortality in people with normal baseline renal function.

Review - Nutraceuticals Can Target Asthmatic Bronchoconstriction: NADPH Oxidase-Dependent Oxidative Stress, RhoA and Calcium Dynamics.

Activation of various isoforms of NADPH oxidase contributes to the pathogenesis of asthma at multiple levels: promoting hypercontractility, hypertrophy, and proliferation of airway smooth muscle; enabling lung influx of eosinophils via VCAM-1; and mediating allergen-induced mast cell activation. Free bilirubin, which functions physiologically within cells as a feedback inhibitor of NADPH oxidase complexes, has been shown to have a favorable impact on each of these phases of asthma pathogenesis. The spirulina chromophore phycocyanobilin (PhyCB), a homolog of bilirubin's precursor biliverdin, can mimic the inhibitory impact of biliverdin/bilirubin on NADPH oxidase activity, and spirulina's versatile and profound anti-inflammatory activity in rodent studies suggests that PhyCB may have potential as a clinical inhibitor of NADPH oxidase.

Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections.

A recent retrospective study has provided evidence that COVID-19 infection may be notably less common in those using supplemental melatonin. It is suggested that this phenomenon may reflect the fact that, via induction of silent information regulator 1 (Sirt1), melatonin can upregulate K63 polyubiquitination of the mitochondrial antiviral-signalling protein, thereby boosting virally mediated induction of type 1 interferons. Moreover, Sirt1 may enhance the antiviral efficacy of type 1 interferons by preventing hyperacetylation of high mobility group box 1 (HMGB1), enabling its retention in the nucleus, where it promotes transcription of interferon-inducible genes.

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer's Pathogenesis-And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder.

Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer's disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid β generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid β on neurons and thereby aiding prevention of AD.

Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients.

Magnesium and vitamin D each have the possibility of affecting the immune system and consequently the cytokine storm and coagulation cascade in COVID-19 infections. Vitamin D is important for reducing the risk of upper respiratory tract infections and plays a role in pulmonary epithelial health. While the importance of vitamin D for a healthy immune system has been known for decades, the benefits of magnesium has only recently been elucidated.

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond.

Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation-including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity-antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide.

The Importance of Maintaining a Low Omega-6/Omega-3 Ratio for Reducing the Risk of Inflammatory Cytokine Storms.

Inflammatory cytokine storms in the lungs are a potential consequence of RNA viruses. One issue that may increase the risk of developing inflammatory cytokine storms in the lungs during viral infections is an imbalance in the dietary omega-6/3 ratio. Indeed, over the past 100 years the omega-6/3 ratio in the Western world has increased from approximately 4:1 to 20:1.

Azithromycin and glucosamine may amplify the type 1 interferon response to RNA viruses in a complementary fashion.

Previous research demonstrates that, in clinically relevant concentrations, azithromycin can boost the ability of RNA viruses to induce type 1 interferon by amplifying the expression and virally-mediated activation of MDA5. O-GlcNAcylation of MAVS, a down-stream target of MDA5, renders it more effective for type 1 interferon induction. High-dose glucosamine administration up-regulates O-GlcNAcylation by increasing the cellular pool of UDP-N-acetylglucosamine.

Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.