Life Extension Magazine®

Issue: Feb 2018

Fish oil, NAD+, AMPK, and Immune

Fish oil, NAD+, AMPK, and Immune

Fish oil

Fish, long chain omega-3 polyunsaturated fatty acids consumption, and risk of all-cause mortality: a systematic review and dose-response meta-analysis from 23 independent prospective cohort studies.

BACKGROUND AND OBJECTIVES: The consumption of fish and long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) may influence the risk of all-cause mortality, but the findings have been inconsistent. The current systematic review and meta-analysis is to clarify the association between fish and long chain n-3 PUFA consumption with risk of all-cause mortality. METHODS AND STUDY DESIGN: Studies published before March 2017 were identified through electronic searches using PubMed, Scopus and Web of Science database. We included prospective cohort studies that reported relative risks with 95% CI of all-cause mortality for fish and long chain n-3 PUFA consumption. Results were combined using a random effects model. RESULTS: Twenty-three prospective cohorts with a total of 1,035,416 participants were included. Twenty-two pooled studies involving 985,126 participants indicated that fish intake was associated with 6% (RR: 0.94; 95% CI: 0.90, 0.98) reduction in risk of all-cause mortality. Six studies with 430,579 participants investigated the association between long chain n-3 PUFA and all-cause mortality risk, the relative risk for highest versus lowest category was 0.86 (95% CI: 0.80, 0.93). Doseresponse analysis suggested that the risk of all-cause mortality was reduced by 7% (RR: 0.93; 95% CI: 0.88, 0.99) for every 0.2 g per day increment in long chain n-3 PUFA consumption. CONCLUSIONS: Current meta-analysis indicates that both fish and long chain n-3 PUFA consumption are inversely associated with risk of all-cause mortality. These findings could have public health implications with regard to lowering risk of all-cause mortality through dietary interventions.

Asia Pac J Clin Nutr. 2017;26(5):939-956

Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events.

We reviewed available evidence for cardiovascular effects of n-3 polyunsaturated fatty acid (PUFA) consumption, focusing on long chain (seafood) n-3 PUFA, including their principal dietary sources, effects on physiological risk factors, potential molecular pathways and bioactive metabolites, effects on specific clinical endpoints, and existing dietary guidelines. Major dietary sources include fatty fish and other seafood. n-3 PUFA consumption lowers plasma triglycerides, resting heart rate, and blood pressure and might also improve myocardial filling and efficiency, lower inflammation, and improve vascular function. Experimental studies demonstrate direct anti-arrhythmic effects, which have been challenging to document in humans. n-3 PUFA affect a myriad of molecular pathways, including alteration of physical and chemical properties of cellular membranes, direct interaction with and modulation of membrane channels and proteins, regulation of gene expression via nuclear receptors and transcription factors, changes in eicosanoid profiles, and conversion of n-3 PUFA to bioactive metabolites. In prospective observational studies and adequately powered randomized clinical trials, benefits of n-3 PUFA seem most consistent for coronary heart disease mortality and sudden cardiac death. Potential effects on other cardiovascular outcomes are less-well-established, including conflicting evidence from observational studies and/or randomized trials for effects on nonfatal myocardial infarction, ischemic stroke, atrial fibrillation, recurrent ventricular arrhythmias, and heart failure. Research gaps include the relative importance of different physiological and molecular mechanisms, precise dose-responses of physiological and clinical effects, whether fish oil provides all the benefits of fish consumption, and clinical effects of plant-derived n-3 PUFA. Overall, current data provide strong concordant evidence that n-3 PUFA are bioactive compounds that reduce risk of cardiac death. National and international guidelines have converged on consistent recommendations for the general population to consume at least 250 mg/day of long-chain n-3 PUFA or at least 2 servings/week of oily fish.

J Am Coll Cardiol. 2011 Nov 8;58(20):2047-67

Omega-3 fatty acids and inflammatory processes: from molecules to man.

Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor g. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.

Biochem Soc Trans. 2017 Oct 15;45(5):1105-1115

Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as “inflammaging.” Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people. The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging. This article reports the main outcomes of this session.

J Gerontol A Biol Sci Med Sci. 2014 Jun;69 Suppl 1:S4-9

Fish oil supplementation and insulin sensitivity: a systematic review and meta-analysis.

BACKGROUND: Fish oil supplementation has been shown to be associated with a lower risk of metabolic syndrome and benefit a wide range of chronic diseases, such as cardiovascular disease, type II diabetes and several types of cancers. However, the evidence of fish oil supplementation on glucose metabolism and insulin sensitivity is still controversial. This meta-analysis summarized the exist evidence of the relationship between fish oil supplementation and insulin sensitivity and aimed to evaluate whether fish oil supplementation could improve insulin sensitivity. METHODS: We searched the Cochrane Library, PubMed, Embase database for the relevant studies update to Dec 2016. Two researchers screened the literature independently by the selection and exclusion criteria. Studies were pooled using random effect models to estimate a pooled SMD and corresponding 95% CI. This meta-analysis was performed by Stata 13.1 software. RESULTS: A total of 17 studies with 672 participants were included in this meta-analysis study after screening from 498 published articles found after the initial search. In a pooled analysis, fish oil supplementation had no effects on insulin sensitivity compared with the placebo (SMD 0.17, 95%CI -0.15 to 0.48, p = 0.292). In subgroup analysis, fish oil supplementation could benefit insulin sensitivity among people who were experiencing at least one symptom of metabolic disorders (SMD 0.53, 95% CI 0.17 to 0.88, p < 0.001). Similarly, there were no significant differences between subgroups of methods of insulin sensitivity, doses of omega-3 polyunsaturated fatty acids (n-3 PUFA) of fish oil supplementation or duration of the intervention. The sensitivity analysis indicated that the results were robust. CONCLUSIONS: Short-term fish oil supplementation is associated with increasing the insulin sensitivity among those people with metabolic disorders.

Lipids Health Dis. 2017 Jul 3;16(1):131

Obesity and the role of adipose tissue in inflammation and metabolism.

Recent discoveries, notably of the hormones leptin and adiponectin, have revised the notion that adipocytes are simply a storage depot for body energy. Instead, adipocytes are also endocrine organs, with multiple metabolic roles in regulating whole-body physiology. Small adipocytes in lean individuals promote metabolic homeostasis; the enlarged adipocytes of obese individuals recruit macrophages and promote inflammation and the release of a range of factors that predispose toward insulin resistance. Exercise activates the AMP-activated protein kinase (AMPK) in muscle and other tissues, a pathway that increases fat oxidation and glucose transport. Importantly, the adipocyte hormones leptin and adiponectin also activate AMPK; remarkably, the same pathway is activated by certain antidiabetic agents such as thiazolidinediones. Increasingly, our understanding of the adipocyte as an endocrine organ is leading to new insights into obesity and health.

Am J Clin Nutr. 2006 Feb;83(2):461S-465S

Chronic inflammation in obesity and the metabolic syndrome.

The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.

Mediators Inflamm. 2010;2010

NAD+

The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity.

As NAD(+) is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38-both NAD(+) consumers-increases NAD(+) bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD(+) precursor with the ability to increase NAD(+) levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD(+) levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.

Cell Metab. 2012 Jun 6;15(6):838-47

Regulation of cell survival and death by pyridine nucleotides.

Pyridine nucleotides (PNs), such as NAD(H) and NADP(H), mediate electron transfer in many catabolic and anabolic processes. In general, NAD(+) and NADP(+) receive electrons to become NADH and NADPH by coupling with catabolic processes. These electrons are utilized for biologically essential reactions such as ATP production, anabolism and cellular oxidation-reduction (redox) regulation. Thus, in addition to ATP, NADH and NADPH could be defined as high-energy intermediates and “molecular units of currency” in energy transfer. We discuss the significance of PNs as energy/electron transporters and signal transducers, in regulating cell death and/or survival processes. In the first part of this review, we describe the role of NADH and NADPH as electron donors for NADPH oxidases (Noxs), glutathione (GSH), and thioredoxin (Trx) systems in cellular redox regulation. Noxs produce superoxide/hydrogen peroxide yielding oxidative environment, whereas GSH and Trx systems protect against oxidative stress. We then describe the role of NAD(+) and NADH as signal transducers through NAD(+)-dependent enzymes such as PARP-1 and Sirt1. PARP-1 is activated by damaged DNA in order to repair the DNA, which attenuates energy production through NAD(+) consumption; Sirt1 is activated by an increased NAD(+)/NADH ratio to facilitate signal transduction for metabolic adaption as well as stress responses. We conclude that PNs serve as an important interface for distinct cellular responses, including stress response, energy metabolism, and cell survival/death.

Circ Res. 2012 Aug 17;111(5):611-27

PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.

SIRT1 regulates energy homeostasis by controlling the acetylation status and activity of a number of enzymes and transcriptional regulators. The fact that NAD(+) levels control SIRT1 activity confers a hypothetical basis for the design of new strategies to activate SIRT1 by increasing NAD(+) availability. Here we show that the deletion of the poly(ADP-ribose) polymerase-1 (PARP-1) gene, encoding a major NAD(+)-consuming enzyme, increases NAD(+) content and SIRT1 activity in brown adipose tissue and muscle. PARP-1(-/-) mice phenocopied many aspects of SIRT1 activation, such as a higher mitochondrial content, increased energy expenditure, and protection against metabolic disease. Also, the pharmacologic inhibition of PARP in vitro and in vivo increased NAD(+) content and SIRT1 activity and enhanced oxidative metabolism. These data show how PARP-1 inhibition has strong metabolic implications through the modulation of SIRT1 activity, a property that could be useful in the management not only of metabolic diseases, but also of cancer.

Cell Metab. 2011 Apr 6;13(4):461-468

Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)?

Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent deacetylase that is at the pinnacle of metabolic control, all the way from yeast to humans. SIRT1 senses changes in intracellular NAD(+) levels, which reflect energy level, and uses this information to adapt the cellular energy output such that it matches cellular energy requirements. The changes induced by SIRT1 activation are generally (but not exclusively) transcriptional in nature and are related to an increase in mitochondrial metabolism and antioxidant protection. These attractive features have validated SIRT1 as a therapeutic target in the management of metabolic disease and prompted an intensive search to identify pharmacological SIRT1 activators. In this review, we first give an overview of the SIRT1 biology with a particular focus on its role in metabolic control. We then analyze the pros and cons of the current strategies used to activate SIRT1 and explore the emerging evidence indicating that modulation of NAD(+) levels could provide an effective way to achieve such goals.

Pharmacol Rev. 2012 Jan;64(1):166-87

Poly(ADP-ribose) metabolism in brain and its role in ischemia pathology.

The biological roles of poly(ADP-ribose) polymers (PAR) and poly(ADP-ribosyl)ation of proteins in the central nervous system are diverse. The homeostasis of PAR orchestrated by poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG) is crucial for cell physiology and pathology. Both enzymes are ubiquitously distributed in neurons and glia; however, they are segregated at the subcellular level. PARP-1 serves as a “nick sensor” for single- or double-stranded breaks in DNA and is involved in long and short patch base-excision repair, while PARG breaks down PAR. The stimulation of PARP-1 and PAR formation can activate proinflammatory transcription factors, including nuclear factor kappa B. However, hyperactivation of PARP-1 can result in depletion of NAD/ATP, and in PAR-dependent mitochondrial pore formation leading to release of apoptosis inducing factor and cell death. The role of PAR as a death signaling molecule in brain ischemia-reperfusion and inflammation as well as the effect of gender and aging is presented in this review. Modulating the PAR level through pharmacological or genetic intervention on PARP-1/PARG activity and gene expression should be a valuable way for neuroprotective strategy.

Mol Neurobiol. 2010 Jun;41(2-3):187-96

Introduction to poly(ADP-ribose) metabolism.

Poly(ADP-ribosyl)ation is a posttranslational modification of proteins in eukaryotic cells catalysed by a family of NAD+ ADP-ribosyl transferases, the poly(ADP-ribose) polymerases (PARPs). PARP-encoding genes now constitute a superfamily of at least 18 members encoding proteins that share homology with the catalytic domain of the founding member, PARP-1. Poly(ADP-ribose) metabolism is of central importance in a wide variety of biological processes including maintenance of genomic stability, DNA repair, transcriptional regulation, centromere function, modulation of telomere length, regulation of proteasomal protein degradation, regulation of endosomal vesicle trafficking and apoptosis. The life cycle of poly(ADP-ribose) is discussed in the following section. In addition, an overview of the genes and proteins involved in poly(ADP-ribose) metabolism and their possible cellular function is provided.

Cell Mol Life Sci. 2005 Apr;62(7-8):721-30

Poly(ADP-ribosyl)ation and aging.

Poly(ADP-ribosyl)ation is a DNA strand break-driven post-translational modification of proteins catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1), with NAD+ serving as substrate. Poly(ADP-ribosyl)ation is triggered by DNA strand breaks, is functionally associated with DNA repair pathways and is a survival factor for cells under low to moderate levels of genotoxic stress. We have previously described a positive correlation between poly(ADP-ribosyl)ation capacity of mononuclear blood cells with longevity of mammalian species. Our comparison of purified recombinant human and rat PARP-1 revealed that this correlation might be explained in part by evolutionary sequence divergence. We have also developed molecular genetic approaches to modulate the poly(ADP-ribosyl)ation status in living cells. Our results revealed that PARP-1 acts as a negative regulator of DNA damage-induced genomic instability, the latter being known as an important driving force for carcinogenesis. Our recent data obtained in transgenic mice with selective expression of a dominant negative version of PARP-1 in basal skin keratinocytes indicate that PARP-1 activity suppresses skin papilloma formation in a two-stage skin carcinogenesis protocol. It is tempting to speculate that increased poly(ADP-ribosyl)ation capacity in long-lived species might help retard the accumulation of DNA damage and of mutations and thus slow down the rate of aging and of carcinogenesis more efficiently as compared with short-lived animals.

Exp Gerontol. 2004 Nov-Dec;39(11-12):1599-601

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.

Nicotinamide riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD+ metabolism in humans. We report that human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD+, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD+ repletion.

Nat Commun. 2016 Oct 10;7:12948

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice.

Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type II diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.

Sci Rep. 2016 May 27;6:26933

AMPK

Flow Mediated Dilatation as a Biomarker in Vascular Surgery Research.

Endothelial dysfunction is one of the hallmarks of atherogenesis, and correlates with many cardiovascular risk factors. One of the features of endothelial dysfunction is the loss of nitric oxide (NO) bioavailability, resulting in derangements in the vasodilatory response of the vessel wall. Flow mediated dilatation (FMD) of the brachial artery is an accepted method for non-invasive assessment of systemic endothelial function. FMD is examined extensively in the context of cardiovascular research, and has been utilised as a routine assessment in large cohorts such as the Framingham Heart Study, Young Finns Study, and Gutenberg Heart Study. However, FMD is less known in the context of vascular surgery research, despite the similarities between the underpinning disease mechanisms. This review will provide a summary of FMD in terms of its history of development and the conduct of the test in research settings. It will further highlight the key literature of FMD as a biomarker for vascular surgeons, particularly in the context of abdominal aortic aneurysms and lower limb peripheral arterial disease.

J Atheroscler Thromb. 2017 Aug 1;24(8):779-787

VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial.

BACKGROUND: Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma. METHODS AND RESULTS: We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4,159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL-apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P:=0.04), apoCIII in VLDL+LDL (RR 2.3, P:=0.04), and apoE in HDL (RR 1.8, P:=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P:=0.03), was not related to coronary events (RR 1.3, P:=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results. CONCLUSIONS: The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.

Circulation. 2000 Oct 17;102(16):1886-92

Opening a new lipid “apo-thecary”: incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk.

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) represent the cornerstone of drug therapy to reduce low-density lipoprotein (LDL) cholesterol and cardiovascular risk. However, even optimal statin management of LDL cholesterol leaves many patients with residual cardiovascular risk, in part because statins are more effective in reducing LDL cholesterol than apolipoprotein B (Apo B). Apo B may be a better marker of atherogenic risk than LDL cholesterol because Apo B measures the total number of all atherogenic particles (total atherosclerotic burden), including LDL, very low-density lipoprotein, intermediate-density lipoprotein, remnant lipoproteins, and lipoprotein(a). To determine whether Apo B is a better indicator of baseline cardiovascular risk and residual risk after lipid therapy compared with LDL cholesterol, a MEDLINE search of the literature published in English from January 1, 1975, through December 1, 2010, was conducted. On the basis of data from most population studies, elevated Apo B was more strongly associated with incident coronary heart disease than similarly elevated LDL cholesterol. Apo B was also a superior benchmark (vs LDL cholesterol) of statins’ cardioprotective efficacy in both primary-prevention and secondary-prevention trials. To minimize cardiovascular risk among persons with hypercholesterolemia or dyslipidemia, the best available evidence suggests that intensive therapy with statins should be initiated to achieve the lowest possible Apo B level (with adequate drug toleration) and then other therapies (eg, niacin, bile acid resins, ezetimibe) added to potentiate these Apo B-lowering effects. In future consensus lipid-lowering treatment guidelines, Apo B should be considered as an index of residual risk, a potential parameter of treatment efficacy, and a treatment target to minimize risk of coronary heart disease.

Mayo Clin Proc. 2011 Aug;86(8):762-80

Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans: a randomized, double-blind, crossover trial.

Hesperidin is the predominant polyphenol consumed from citrus fruits and juices. However, hesperidin is proposed to have limited bioavailability due to the rutinoside moiety attached to the flavonoid. The aim of this study was to demonstrate in human subjects that the removal of the rhamnose group to yield the corresponding flavonoid glucoside (i.e., hesperetin-7-glucoside) will improve the bioavailability of the aglycone hesperetin. Healthy volunteers (n=16) completed the double-blind, randomized, crossover study. Subjects randomly consumed hesperetin equivalents supplied as orange juice with natural hesperidin (“low dose”), orange juice treated with hesperidinase enzyme to yield hesperetin-7-glucoside, and orange juice fortified to obtain 3 times more hesperidin than naturally present (“high dose”). The area under the curve (AUC) for total plasma hesperetin of subjects consuming hesperetin-7-glucoside juice was 2-fold higher than that of subjects consuming the “low” dose hesperidin juice [3.45+/-1.27 vs. 1.16+/-0.52 mmol/(L.h), respectively, P>0.0001]. The AUC for hesperetin after consuming the hesperetin-7-glucoside juice was improved to the level of the “high” dose hesperidin juice [4.16+/-1.50 mmol/(L.h)]. The peak plasma concentrations (C(max)) of hesperetin were 4-fold higher (2.60+/-1.07 mmol/L, P<0.0001) after subjects consumed hesperetin-7-glucoside juice compared with those consuming “low” dose hesperidin juice (0.48 +/- 0.27 mmol/L), and 1.5-fold higher than those consuming “high” dose hesperidin juice (1.05+/-0.25 mmol/L). The corresponding T(max) was much faster (0.6+/-0.1 h, P<0.0001) after subjects consumed hesperetin-7-glucoside juice compared with “low” dose (7.0+/-3.0 h) and “high” dose (7.4+/-2.0 h) hesperidin juices. The results of this study demonstrated that the bioavailability of hesperidin was modulated by enzymatic conversion to hesperetin-7-glucoside, thus changing the absorption site from the colon to the small intestine. This may affect future interventions concerning the health benefits of citrus flavonoids.

J Nutr. 2006 Feb;136(2):404-8

Hydrolysis of the rutinose-conjugates flavonoids rutin and hesperidin by the gut microbiota and bifidobacteria.

Flavonols and flavanones are polyphenols exerting many healthy biological activities. They are often glycosylated by rutinose, which hampers absorption in the small intestine. Therefore they require the gut microbiota to release the aglycone and enable colonic absorption. The role of the gut microbiota and bifidobacteria in the release of the aglycones from two major rutinosides, hesperidin and rutin, was investigated. In bioconversion experiments, the microbiota removed rutinose from both rutin and hesperidin, even though complete hydrolysis was not obtained. To investigate whether bifidobacteria can participate to the hydrolysis of rutinosides, 33 strains were screened. Rutin was resistant to hydrolysis by all the strains. Among six tested species, mostly Bifidobacterium catenulatum and Bifidobacterium pseudocatenultum were able to hydrolyze hesperidin, by means of a cell-associated activity. This result is in agreement with the presence of a putative a-l-rhamnosidase in the genome of B. pseudocatenulatum, while most of the available genome sequences of bifidobacteria aside from this species do not bear this sequence. Even though B. pseudocatenulatum may contribute to the release of the aglycone from certain rutinose-conjugated polyphenols, such as hesperidin, it remains to be clarified whether this species may exert a role in affecting the bioavailability of the rutinoside in vivo.

Nutrients. 2015 Apr 14;7(4):2788-800

Immune

Impact of Aging and Cytomegalovirus on Immunological Response to Influenza Vaccination and Infection.

The number of people over the age of 60 is expected to double by 2050 according to the WHO. This emphasizes the need to ensure optimized resilience to health stressors in late life. In older adults, influenza is one of the leading causes of catastrophic disability (defined as the loss of independence in daily living and self-care activities). Influenza vaccination is generally perceived to be less protective in older adults, with some studies suggesting that the humoral immune response to the vaccine is further impaired in cytomegalovirus (CMV)-seropositive older people. CMV is a b-herpes virus infection that is generally asymptomatic in healthy individuals. The majority of older adults possess serum antibodies against the virus indicating latent infection. Age-related changes in T-cell-mediated immunity are augmented by CMV infection and may be associated with more serious complications of influenza infection. This review focuses on the impact of aging and CMV on immune cell function, the response to influenza infection and vaccination, and how the current understanding of aging and CMV can be used to design a more effective influenza vaccine for older adults. It is anticipated that efforts in this field will address the public health need for improved protection against influenza in older adults, particularly with regard to the serious complications leading to loss of independence.

Front Immunol. 2017 Jul 17;8:784

Immunosenescence: Influenza vaccination and the elderly.

Aging is associated with a decline in the normal function of the immune system, both cellular and humoral, which often leads to a state of ‘immunosenescence’. It is necessary that we understand the fundamental cellular and molecular basis of immune senescence and immune responsiveness to prevent age-related diseases, such as viral and bacterial infections, in order to develop appropriate preventative and novel therapeutic measures. Vaccination has been a highly effective prophylactic in protecting vulnerable populations worldwide from many pathogens. Novel vaccine research to enhance protection against these diseases remains a global area of innovation and improvement. This review discusses the impact of immune senescence on the response to influenza vaccines, and the recent progress in translating the knowledge into developing effective influenza vaccines for the elderly to promote healthy aging.

Curr Opin Immunol. 2014 Aug;29:38-42

Prevention of flu episodes with colostrum and Bifivir compared with vaccination: an epidemiological, registry study.

The aim of this study was to evaluate the efficacy of colostrum (ARD Colostrum) in association with the immunomodulator Bifivir in the prevention of flu episodes compared with anti-flu vaccination. The registry groups included no prevention, vaccination, vaccination+immunomodulators, and immunomodulators only. Groups were comparable for age and sex distribution. In the group without prevention there were 8 major episodes and 12 minor episodes out of 34 subjects (8-12/34); in the vaccination group the respective figures were 8-13/38; in the group treated with a combination of vaccination and immunomodulators (ARD Colostrum + Bifivir) the figures were 4-9/33; and in the group treated with immunomodulators only there were 11 viral episodes (3-8) in 36 subjects. The episodes in the vaccination+immunomodulators and immunomodulators only groups were significantly lower compared with the other two groups (P<0.05). The number of episodes registered with the immunnomodulators was significantly lower than those observed in patients using vaccination or no prevention (P<0.05). The number of days of disease was higher in untreated controls compared to the groups treated with immunomodulators (P<0.05) and 2 times higher in the vaccination group compared to the same groups (P<0.05). The average relative costs were significantly lower (2.3 times) in the immunomodulators groups in comparison with the other groups (P<0.05). No problems concerning tolerability or side effects were observed during the study. Compliance was very good. In conclusion, the administration of immunomodulators is very cost effective and appears to be more effective than vaccination to prevent flu.

Panminerva Med. 2010 Dec;52(4):269-75

Probiotic strain Bacillus subtilis CU1 stimulates immune system of elderly during common infectious disease period: a randomized, double-blind placebo-controlled study.

BACKGROUND: Bacillus probiotics health benefits have been until now quite poorly studied in the elderly population. This study aimed to assess the effects of Bacillus subtilis CU1 consumption on immune stimulation and resistance to common infectious disease (CID) episodes in healthy free-living seniors. RESULTS: One hundred subjects aged 60-74 were included in this randomized, double-blind, placebo-controlled, parallel-arms study. Subjects consumed either the placebo or the probiotic (2.10(9) B. subtilis CU1 spores daily) by short periodical courses of 10 days intermittently, alternating 18-day course of break. This scheme was repeated 4 times during the study. Symptoms of gastrointestinal and upper/lower respiratory tract infections were recorded daily by the subjects throughout the study (4 months). Blood, saliva and stool samples were collected in a predefined subset of the first forty-four subjects enrolled in the study. B. subtilis CU1 supplementation did not statistically significantly decrease the mean number of days of reported CID symptoms over the 4-month of study (probiotic group: 5.1 (7.0) d, placebo group: 6.6 (7.3) d, P = 0.2015). However, in the subset of forty-four randomized subjects providing biological samples, we showed that consumption of B. subtilis CU1 significantly increased fecal and salivary secretory IgA concentrations compared to the placebo. A post-hoc analysis on this subset showed a decreased frequency of respiratory infections in the probiotc group compared to the placebo group. CONCLUSION: Taken together, our study provides evidence that B. subtilis CU1 supplementation during the winter period may be a safe effective way to stimulate immune in elderly subjects.

Immun Ageing. 2015 Dec 3;12:24

A new chance of preventing winter diseases by the administration of synbiotic formulations.

BACKGROUND: The efficacy of probiotics is currently well documented with regard to the improvement of gastrointestinal functions, whereas their potential role in the prevention of infectious respiratory diseases has not been sufficiently analyzed. PURPOSE OF THE STUDY AND METHODS: A 3-stage prospective, randomized, double blind, placebo-controlled study was carried out with several synbiotic preparations containing 3 to 5 strains of Lactobacillus plantarum, Lactobacillus rhamnosus, and Bifidobacterium lactis, lactoferrin and prebiotics such as either FOS (short-chain fructooligosaccharides) or GOS (galactooligosaccharides). The study was performed over 3 different winter seasons between 2003 and 2007, and was aimed at assessing the ability of the different preparations to improve intestinal functions and to increase the body’s defences against respiratory infections. In 2003/04 (stage 1; 237 healthy volunteers) an active formulation (A) containing 3 probiotic strains and FOS was used versus placebo; in 2005/06 (stage 2; 234 healthy volunteers) the same formulation versus a similar preparation enriched with lactoferrin (B), and versus placebo; in 2006/07 (stage 3; 250 healthy volunteers), 2 new synbiotic formulations each containing 5 probiotics and FOS (C) or GOS (D), respectively, versus placebo. RESULTS: In stage 1, bowel functions improved (P=0.004) in terms of reduced bloating and more regular intestinal motility. The length of acute respiratory infection episodes considered as a whole (-0.97 d; P=0.007) and upper respiratory tract infections (URTIs, -1.96 d; P=0.044) were significantly decreased in the synbiotic group. The severity of episodes recorded a statistically significant drop in both episodes considered as a whole (3.21 average score vs. 3.98 in the placebo group, P<0.001) and in URTI (2.56 vs. 3.82; P=0.004) and flu classes (3.80 vs. 4.67, P=0.001). In stage 2, improvement of bowel functions was statistically significant (P=0.005) in synbiotic preparation A. A statistically significant reduction in the number of respiratory tract infections episodes was noted with both the two active formulations (P=0.002 in group A and P=0.003 in group B). The duration of episodes considered as a whole (-1.12 d in one of the 2 active formulation groups; P=0.005), URTIs (-2.08 d in group A; P=0.036) and influenza-like illness episodes (-1.40 d in group A; P=0.049) was significantly decreased in the synbiotic group. A reduction trend in cold episodes was also recorded. The severity of episodes recorded a statistically significant drop in episodes considered as a whole (-0.73 in group A, P=0.003; -0.65 in group B, P=0.004) and in the case of flu (-1.25 in group A, P<0.001; -1.18 in group B, P<0.001). In stage 3, the improvement of bowel functions was confirmed for both active formulations (P<0.001). A significant decrease in the total length of respiratory episodes (-1.51 d; P<0.001 in the group C and -1.39 d; P<0.001 in the group D) and in the length of cough (-3.08 d; P<0.001 in group C; -2.83 d; P<0.001 in group D), cold (-1.02 d; P=0.019 in group C; -1.32 d; P=0.001 in group D) and flu episodes was reported. The severity of episodes recorded a statistically significant drop in regard to episodes considered as a whole, the cold and flu classes in both groups and for cough too in group C. The number of episodes also dropped considerably in terms of overall episodes, cold (group C) and flu. CONCLUSIONS: These results demonstrate that a regular, long-term intake of various synbiotics may improve health by reducing the incidence and severity of respiratory diseases during the cold season.

J Clin Gastroenterol. 2008 Sep;42 Suppl 3 Pt 2:S224-33

Prevalence of high-risk indications for influenza vaccine varies by age, race, and income.

Estimates of the proportions of the population who are at high risk of influenza complications because of prior health status or who are likely to have decreased vaccination response because of immunocompromising conditions would enhance public health planning and model-based projections. We estimate these proportions and how they vary by population subgroups using national data systems for 2006-2008. The proportion of individuals at increased risk of influenza complications because of health conditions varied 10-fold by age (4.2% of children <2 years to 47% of individuals >64 years). Age-specific prevalence differed substantially by gender, by racial/ethnic groups (with African Americans highest in all age groups) and by income. Individuals living in families with less than 200% of federal poverty level (FPL) were significantly more likely to have at least one of these health conditions, compared to individuals with 400% FPL or more (3-fold greater among <2 and 30% greater among >64 years). Among children, there were significantly elevated proportions in all regions compared to the West. The estimated prevalence of immunocompromising conditions ranged from 0.02% in young children to 6.14% older adults. However, national data on race/ethnicity and income are not available for most immunocompromising conditions, nor is it possible to fully identify the degree of overlap between persons with high-risk health conditions and with immunocompromising conditions. Modifications to current national data collection systems would enhance the value of these data for public health programs and influenza modeling.

Vaccine. 2010 Sep 7;28(39):6470-7