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Life Extension Magazine October 2011


Effect of fish oil on arrhythmias and mortality: systematic review.

OBJECTIVE: To synthesise the literature on the effects of fish oil-docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)-on mortality and arrhythmias and to explore dose response and formulation effects. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, the Cochrane Library, PubMed, CINAHL, IPA, Web of Science, Scopus, Pascal, Allied and Complementary Medicine, Academic OneFile, ProQuest Dissertations and Theses, Evidence-Based Complementary Medicine, and LILACS. Studies reviewed Randomised controlled trials of fish oil as dietary supplements in humans. DATA EXTRACTION: The primary outcomes of interest were the arrhythmic end points of appropriate implantable cardiac defibrillator intervention and sudden cardiac death. The secondary outcomes were all cause mortality and death from cardiac causes. Subgroup analyses included the effect of formulations of EPA and DHA on death from cardiac causes and effects of fish oil in patients with coronary artery disease or myocardial infarction. DATA SYNTHESIS: 12 studies totalling 32 779 patients met the inclusion criteria. A neutral effect was reported in three studies (n=1148) for appropriate implantable cardiac defibrillator intervention (odds ratio 0.90, 95% confidence interval 0.55 to 1.46) and in six studies (n=31 111) for sudden cardiac death (0.81, 0.52 to 1.25). 11 studies (n=32 439 and n=32 519) provided data on the effects of fish oil on all cause mortality (0.92, 0.82 to 1.03) and a reduction in deaths from cardiac causes (0.80, 0.69 to 0.92). The dose-response relation for DHA and EPA on reduction in deaths from cardiac causes was not significant. CONCLUSIONS: Fish oil supplementation was associated with a significant reduction in deaths from cardiac causes but had no effect on arrhythmias or all cause mortality. Evidence to recommend an optimal formulation of EPA or DHA to reduce these outcomes is insufficient. Fish oils are a heterogeneous product, and the optimal formulations for DHA and EPA remain unclear.

BMJ. 2008 Dec 23;337:a2931

Prevention of sudden cardiac death with omega-3 fatty acids in patients with coronary heart disease: a meta-analysis of randomized controlled trials.

AIM: To systematically review trials concerning the effects of omega-3 fatty acids on sudden cardiac death (SCD), cardiac death, and all-cause mortality in coronary heart disease (CHD) patients.METHODS: PubMed, Embase, and the Cochrane database (1966-2007) were searched. We identified randomized controlled trials that compared dietary or supplementary intake of omega-3 fatty acids with control diet or placebo in CHD patients. Eligible studies had at least 6 months of follow-up data, and cited SCD as an end-point. Two reviewers independently assessed methodological quality. Meta-analysis of relative risk was carried out using the random effect model. RESULTS: Eight trials were identified, comprising 20,997 patients. In patients with prior myocardial infarction (MI), omega-3 fatty acids reduced relative risk (RR) of SCD (RR = 0.43; 95% CI: 0.20-0.91). In patients with angina, omega-3 fatty acids increased RR of SCD (RR = 1.39; 95% CI: 1.01-1.92). Overall, RR for cardiac death and all-cause mortality were 0.71 (95% CI: 0.50-1.00) and 0.77 (95% CI: 0.58-1.01), respectively. CONCLUSIONS: Dietary supplementation with omega-3 fatty acids reduces the incidence of sudden cardiac death in patients with MI, but may have adverse effects in angina patients.

Ann Med. 2009;41(4):301-10

Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review.

BACKGROUND: Epidemio-logic data suggest that omega-3 fatty acids derived from fish oil reduce cardiovascular disease. The clinical benefit of dietary fish oil supplementation in preventing cardiovascular events in both high and low risk patients is unclear.OBJECTIVE: To assess whether dietary supplements of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease cardiovascular events across a spectrum of patients. DATA SOURCES: MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and citation review of relevant primary and review articles. STUDY SELECTION: Prospective, randomized, placebo-controlled clinical trials that evaluated clinical cardiovascular end points (cardiovascular death, sudden death, and nonfatal cardiovascular events) and all-cause mortality in patients randomized to EPA/DHA or placebo. We only included studies that used dietary supplements of EPA/DHA which were administered for at least 1 year. DATA EXTRACTION: Data were abstracted on study design, study size, type and dose of omega-3 supplement, cardiovascular events, all-cause mortality, and duration of follow-up. Studies were grouped according to the risk of cardiovascular events (high risk and moderate risk). Meta-analytic techniques were used to analyze the data. DATA SYNTHESIS: We identified 11 studies that included a total of 39,044 patients. The studies included patients after recent myocardial infarction, those with an implanted cardioverter defibrillator, and patients with heart failure, peripheral vascular disease, and hypercholesterolemia. The average dose of EPA/DHA was 1.8 +/- 1.2 g/day and the mean duration of follow-up was 2.2 +/- 1.2 years. Dietary supplementation with omega-3 fatty acids significantly reduced the risk of cardiovascular deaths (odds ratio [OR]: 0.87, 95% confidence interval [CI]: 0.79-0.95, p = 0.002), sudden cardiac death (OR: 0.87, 95% CI: 0.76-0.99, p = 0.04), all-cause mortality (OR: 0.92, 95% CI: 0.85-0.99, p = 0.02), and nonfatal cardiovascular events (OR: 0.92, 95% CI: 0.85-0.99, p = 0.02). The mortality benefit was largely due to the studies which enrolled high risk patients, while the reduction in nonfatal cardiovascular events was noted in the moderate risk patients (secondary prevention only). Meta-regression failed to demonstrate a relationship between the daily dose of omega-3 fatty acid and clinical outcome. CONCLUSIONS: Dietary supplementation with omega-3 fatty acids should be considered in the secondary prevention of cardiovascular events.

Clin Cardiol. 2009 Jul;32(7):365-72

Consumption of polyunsaturated fatty acids, fish, and nuts and risk of inflammatory disease mortality

BACKGROUND: n-3 (omega-3) Polyunsaturated fatty acids (PUFAs), fish, and nuts can regulate inflammatory processes and responses.OBJECTIVE: We investigated whether dietary intakes of PUFAs [n-3, n-6 (omega-6), and α-linolenic acid], fish, and nuts were associated with 15-y mortality attributed to noncardiovascular, noncancer inflammatory diseases. DESIGN: The analyses involved 2514 participants aged ≥49 y at baseline. Dietary data were collected by using a semiquantitative food-frequency questionnaire, and PUFA, fish, and nut intakes were calculated. Inflammatory disease mortality was confirmed from the Australian National Death Index. RESULTS: Over 15 y, 214 subjects died of inflammatory diseases. Women in the highest tertiles of total n-3 PUFA intake, compared with those in the lowest tertile of intake at baseline, had a 44% reduced risk of inflammatory

disease mortality (P for trend = 0.03). This association was not observed in men. In both men and women, each 1-SD increase in energy-adjusted intake of α-linolenic acid was inversely associated with inflammatory mortality (hazard ratio: 0.83; 95% CI: 0.71, 0.98). Subjects in the second and third tertiles of nut consumption had a 51% and 32% reduced risk of inflammatory disease mortality, respectively, compared with those in the first tertile (reference). Dietary intakes of long-chain n-3 and n-6 PUFAs and fish were not associated with inflammatory disease mortality. CONCLUSIONS: We report on a novel link between dietary intake of total n-3 PUFA and risk of inflammatory disease mortality in older women. Furthermore, our data indicate a protective role of nuts, but not fish, against inflammatory disease mortality.

Am J Clin Nutr. 2011 May;93(5):1073-9

Omega-3 fatty acid supplementation reduces one-year risk of atrial fibrillation in patients hospitalized with myocardial infarction.

PURPOSE: Current strategies for avoiding atrial fibrillation (AF) are of limited value. We aim to assess the relationship between omega-3 fatty acids (n-3 PUFA) and AF occurrence in post-myocardial infarction (MI) patients. METHODS: A population study, linking hospital discharge records, prescription databases, and vital statistics, was conducted and included all consecutive patients with MI (ICD-9: 410) in six Italian local health authorities over a 3-year period. A propensity score (PS)-based, 5-to-1, greedy 1:1 matching algorithm was used to check consistency of results. Sensitivity analysis was performed to assess the robustness of findings. RESULTS: N-3 PUFA reduced the relative risk of the hospitalization for AF [hazard ratio (HR) 0.19, 95% CI 0.07-0.51] and was associated with a further and complementary reduction in all-cause mortality (HR 0.15, 95% CI 0.05-0.46). PS-based matched analysis and sensitivity analysis confirmed the main results. CONCLUSION: n-3 PUFA reduced both all-cause mortality and incidence of 1-year AF in patients hospitalized with MI.

Eur J Clin Pharmacol. 2008 Jun;64(6):627-34

Blood eicosapentaenoic acid and docosahexaenoic acid as predictors of all-cause mortality in patients with acute myocardial infarction--data from Infarction Prognosis Study (IPS) Registry.

BACKGROUND: Although omega-3 polyunsaturated fatty acids are known to have beneficial effects on cardiovascular diseases, their prognostic value has not been studied prospectively in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The plasma levels of phospholipids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (% of total fatty acids), were measured in 508 patients (365 males; mean age, 63 years) with AMI. Clinical and biomarker predictors of all-cause and cardiovascular mortality were identified by stepwise Cox regression model. During a mean follow-up of 16.1 months, 36 (7.1%) patients died. After controlling for confounding variables, age (hazard ratio (HR): 1.09, P<0.001), renal insufficiency (HR: 2.84, P=0.01) and EPA level (HR: 0.29, P=0.004) were identified as independent predictors of all cause-mortality. When stratified by gender, age (HR: 1.08, P=0.001) and renal insufficiency (HR: 4.49, P=0.003) were predictors of all-cause-mortality in males, whereas EPA level (HR: 0.18, P=0.009) and angiotensin-converting enzyme inhibitor use (HR: 0.24, P=0.03) were identified as predictive of all-cause-mortality in females. CONCLUSIONS: Lower plasma level of EPA, but not DHA, was an independent predictor for all-cause-mortality in patients with AMI, but this relationship was significant only in female patients.

Circ J. 2009 Dec;73(12):2250-7

A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.

BACKGROUND: The benefit of n-3 polyunsaturated fatty acids (PUFA) supplementation for mortality and cardiovascular events after myocardial infarction is well documented, but the effect of n-3 PUFA in Caucasians without established cardiovascular disease is not known. Our aim was to examine the influence of supplementation with eicosapentaenoic acid and docosahexaenoic acid on all-cause mortality and cardiovascular events in elderly men at high-risk of cardiovascular disease. DESIGN: In the Diet and Omega-3 Intervention Trial, 563 Norwegian men, 64-76-year old and 72% without overt cardiovascular disease, were randomized to a 3-year 2×2 factorial designed clinical trial of diet counseling and/or 2.4 g n-3 PUFA supplementation. The n-3 PUFA arm was placebo-controlled (corn oil). METHODS: Demographic parameters and classical risk factors were obtained at baseline. Deaths and cardiovascular events were recorded through 3 years, and the effects of n-3 PUFA-intervention on these outcomes were evaluated in pooled groups of the n-3 PUFA-arm. RESULTS: There were 38 deaths and 68 cardiovascular events. The unadjusted hazard ratios of all-cause mortality and cardiovascular events were 0.57 (95% confidence interval: 0.29-1.10) and 0.86 (0.57-1.38), respectively. Adjusted for baseline age, current smoking, hypertension, body mass index and serum glucose, hazard ratios were 0.53 (0.27-1.04, P=0.063) and 0.89 (0.55-1.45, P=0.641), respectively. CONCLUSION: We observed a tendency toward reduction in all-cause mortality in the n-3 PUFA groups that, despite a low number of participants, reached borderline statistical significance. The magnitude of risk-reduction suggests that a larger trial should be considered in similar populations.

Eur J Cardiovasc Prev Rehabil. 2010 Oct;17(5):588-92

Systems biology and longevity: an emerging approach to identify innovative anti-aging targets and strategies.

Human aging and longevity are complex and multi-factorial traits that result from a combination of environmental, genetic, epigenetic and stochastic factors, each contributing to the overall phenotype. The multi-factorial process of aging acts at different levels of complexity, from molecule to cell, from organ to organ systems and finally to organism, giving rise to the dynamic “aging mosaic”. At present, an increasing amount of experimental data on genetics, genomics, proteomics and other -omics are available thanks to new high-throughput technologies but a comprehensive model for the study of human aging and longevity is still lacking. Systems biology represents a strategy to integrate and quantify the existing knowledge from different sources into predictive models, to be later tested and then implemented with new experimental data for validation and refinement in a recursive process. The ultimate goal is to compact the new acquired knowledge into a single picture, ideally able to characterize the phenotype at systemic/organism level. In this review we will briefly discuss the aging phenotype in a systems biology perspective, showing four specific examples at different levels of complexity, from a systemic process (inflammation) to a cascade-process pathways (coagulation) and from cellular organelle (proteasome) to single gene-network (PON-1), which could also represent targets for anti-aging strategies.

Curr Pharm Des. 2010;16(7):802-13

Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches.

A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers (“inflamm-ageing”). This status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation (“inflamm-ageing”) will be discussed in this review in the context of its onset/progression leading to site-restricted and systemic effects. Moreover, some of the possible strategies and therapies to counteract the different sources of molecular mediators which lead to the age-related inflammatory phenotype will be presented.

Curr Pharm Des. 2010;16(6):609-18

Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids.

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are precursors of potent lipid mediators, termed eicosanoids, which play an important role in the regulation of inflammation. Eicosanoids derived from n-6 PUFAs (e.g., arachidonic acid) have proinflammatory and immunoactive functions, whereas eicosanoids derived from n-3 PUFAs [e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] have anti-inflammatory properties, traditionally attributed to their ability to inhibit the formation of n-6 PUFA-derived eicosanoids. While the typical Western diet has a much greater ratio of n-6 PUFAs compared with n-3 PUFAs, research has shown that by increasing the ratio of n-3 to n-6 fatty acids in the diet, and consequently favoring the production of EPA in the body, or by increasing the dietary intake of EPA and DHA through consumption of fatty fish or fish-oil supplements, reductions may be achieved in the incidence of many chronic diseases that involve inflammatory processes; most notably, these include cardiovascular diseases, inflammatory bowel disease (IBD), cancer, and rheumatoid arthritis, but psychiatric and neurodegenerative illnesses are other examples.

Nutr Rev. 2010 May;68(5):280-9

The essential fatty acids omega-6 and omega-3: from their discovery to their use in therapy.

In 1929 Burr and Burr discovered the essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in unsaturated essential fatty acids as they form the framework for the organism’s cell membranes, particularly the neurones in the brain, are involved in the energy-transformation process, regulate the information flows between cells. Polyunsaturated fatty acids are also precursors of ‘’hormonal’’ molecules, often with opposing effects, prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipossines, resolvines, protectines that regulate immunity, platelet aggregation, inflammation, etc. They showed that raised levels of polyunsaturated fatty acids omega-3 in tissue correlate with a reduced incidence of degenerative cardiovascular disease, some mental illnesses such as depression, and neuro-degenerative diseases such as Alzheimer’s. The balance between omega-3 and omega-6 acids allows the cell membranes to develop with exactly the right flexibility and fluidity, to carry messages between neurones, that is a determining factor in physical and mental well-being and has a profound influence on all the body’s inflammatory responses. The results of a number of scientific studies suggest that omega-3 acids contribute to measuring and restricting inflammatory symptoms, whereas omega-6 acids (and saturated fats) give free range to inflammatory responses and amplify allergic reactions. Today in the Western countries, the ratio of omega-3 acids to omega-6 in the diet is weighted 1:10 in favour of omega-6 to up to 1:25 in some areas, while for proper functioning a 4:1 ratio of omega-6 acids to omega-3 acids is generally considered the optimum. In addition, the type of diet followed in the Western countries is very rich in saturated fats like butter and animal fats, but because of an excessive supply of these less noble fats, the cell membranes lose flexibility and this can affect the way they work. An appropriate supplement can be an efficient, effective and often necessary way to meet the body’s needs, enhance its daily functions and promote health and longevity.

Minerva Pediatr. 2008 Apr;60(2):219-33

Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: a preliminary open trial.

OBJECTIVES: We sought to obtain preliminary data regarding the efficacy of omega-3 fatty acids for major depressive disorder associated with the menopausal transition. Secondary outcomes were assessed for vasomotor symptoms (or hot flashes). METHODS: After a single-blind placebo lead-in, participants received 8 weeks of treatment with open-label omega-3 fatty acid capsules (eicosapentaenoic acid and docosahexaenoic acid, 2 g/d). The Montgomery-Asberg Depression Rating Scale (MADRS) was the primary outcome measure. Hot flashes were monitored prospectively using daily diaries and the Hot Flash Related Daily Interference Scale. Blood samples for plasma pretreatment and posttreatment essential fatty acid assays were obtained. Because of the small sample size, data were analyzed using nonparametric techniques. RESULTS: Of 20 participants treated with omega-3 fatty acids, 19 (95%) completed the study. None discontinued because of adverse effects. The pretreatment and final mean MADRS scores were 24.2 and 10.7, respectively, reflecting a significant decrease in MADRS scores (P < 0.0001). The response rate was 70% (MADRS score decrease of ≥50%), and the remission rate was 45% (final MADRS score of ≤). Responders had significantly lower pretreatment docosahexaenoic acid levels than nonresponders did (P = 0.03). Hot flashes were present in 15 (75%) participants. Among those with hot flashes at baseline, the number of hot flashes per day improved significantly from baseline (P = 0.02) and Hot Flash Related Daily Interference Scale scores decreased significantly (P = 0.006). CONCLUSIONS: These data support further study of omega-3 fatty acids for major depressive disorder and hot flashes in women during the menopausal transition.

Menopause. 2011 Mar;18(3):279-84

Omega-3 polyunsaturated fatty acids and anxiety disorders.

Anxiety disorders are a common group of psychiatric illnesses which have significant personal, family and societal costs. Current treatments have limited efficacy in many patients highlighting a need for new therapeutic approaches to be explored. Anxiety disorders exhibit marked comorbity with mood disorders suggesting the existence of mechanistic similarities. Such a notion is supported by observations that some conventional pharmacotherapies are both effective antidepressants and anxiolytics. As such, given that omega-3 PUFA supplementation may be effective in the treatment of major depressive disorder it is reasonable to propose that they may also possess anxiolytic properties. Experimental data in support of such a hypothesis is currently lacking although reduced abundance of omega-3 PUFA have been reported in patients with anxiety, while supplementation with omega-3 PUFA appears to inhibit activation of the HPA axis and can ameliorate some of the symptoms of anxiety. Clinical investigations carried out to date have, however, involved small numbers of participants. Larger trials using a variety of omega-3 PUFA species in clinically well-defined patients with anxiety will be required to demonstrate a therapeutic role for omega-3 PUFA in these disorders. Given the excellent side effect profile of omega-3 PUFA as well as their strong theoretical rationale, such future trials appear justified.

Prostaglandins Leukot Essent Fatty Acids. 2009 Nov-Dec;81(5-6):309-12