Elderly and patients affected by chronic diseases face a high risk of muscle loss and impaired physical function. Omega 3 fatty acids (FA) attenuate inflammation and age-associated muscle loss, prevent systemic insulin resistance and improve plasma lipids, potentially impacting on sarcopenia. This paper aims to review recent randomized clinical studies assessing the effects a chronic omega 3 FA supplementation on inflammatory and metabolic profile during conditions characterized by sarcopenia (aging, insulin resistance, type 2 diabetes, chronic renal failure). A comprehensive search of three online databases was performed to identify eligible trials published between 2012 and 2017. A total of 36 studies met inclusion criteria. Omega 3 FA yielded mixed results on plasma triglycerides in the elderly and no effects in renal patients. No changes in systemic insulin resistance were observed. Inflammation markers did not benefit from omega 3 FA in insulin resistant and in renal subjects while decreasing in obese and elderly. Muscle related parameters improved in elderly and in renal patients. In conclusion, in aging- and in chronic disease-associated sarcopenia omega 3 FA are promising independently of associated anabolic stimuli or of anti-inflammatory effects. The evidence for improved glucose metabolism in insulin resistant and in chronic inflammatory states is less solid.
Declined muscle mass, functional status and metabolic demand with advancing age are prevalent in chronic disease states including the metabolic syndrome, type 2 diabetes, cancer and chronic renal failure [1,2,3,4]. These conditions are characterized by the activation of common pathways, which ultimately induce loss of muscle mass either because of blunted muscle protein synthesis or because of accelerated protein breakdown. Systemic low-grade inflammation, which characterizes disease- and age-related muscle decline induces muscle wasting by the activation of multiple pathways . In addition, inflammation-induced insulin resistance may accentuate the metabolic dysfunction in skeletal muscle in the presence of preexisting type 2 diabetes mellitus (T2DM) . Given that skeletal muscle accounts for up to 40% of total body mass, a significant change in its metabolic function may significantly impact systemic glucose disposal. Finally, excess oxidative damage, which is usually associated with inflammation may induce accumulation of dysfunctional proteins and DNA damage in muscle .
Interventions targeted at the correction of the aberrant activation of these pathways are therefore likely to preserve muscle mass and function resulting in improved systemic homeostasis, lifespan and progression of chronic age-related diseases. Clinical studies have shown that in humans specific nutrients can mechanistically interfere with the processes associated with muscle deterioration during aging and chronic diseases. In human and animal studies, omega 3 fatty acids (omega 3 FA) suppress muscle protein degradation , enhance the rate of muscle protein synthesis in response to anabolic stimuli (feeding or physical exercise) [9,10], quench systemic oxidative stress and inflammation [11,12], and improve insulin sensitivity and lipid profile . Despite this evidence, results of clinical studies addressing the beneficial effects of omega 3 to counteract muscle mass decline are less clear-cut.
Therefore, the aim of the current work is to review and discuss the findings from the most recent human studies to determine the effects of omega 3 FA on significant determinants of muscle mass and function, systemic inflammation, metabolic and lipid profile in age-associated chronic diseases as compared to healthy individuals.
2.1. Metabolic and Lipid Profile in Healthy, Elderly and Chronic Renal Failure
In healthy subjects, omega 3 supplementation resulted in divergent effects on glucose and lipid reduction depending on the dose of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). Short term supplementation (6 weeks) of different doses omega 3 (600 mg of EPA or 1800 mg EPA or 600 mg DHA daily) was provided to 121 healthy individuals randomly allocated to a 1:1:1:1 ratio, and was compared with an olive oil treatment . Main results from the pairwise placebo comparison suggest that only DHA supplementation significantly affected metabolic profile, reducing post prandial triglyceride (TG) concentration by −52.2 mg/dL (−99.3, −5.0), equal to a −20.0% (−38.7, −1.4) reduction (p < 0.05). DHA also increased postprandial LDL levels by 18.5 mg/dL (10.0, 27.0) (p < 0.01) and postprandial total cholesterol (TC) by 10.9 mg/dL (0.8, 21.0) (p < 0.05. EPA affected metabolic profile only when administered at high dose of 1800 mg, reducing both fasting and post prandial triglyceride-rich lipoprotein (TRL) concentration when expressed as percentage of difference from baseline, respectively by −14.6% (−27.0, −2.2) and −12.6% (−25.2, 0) (p < 0.05) . A study in obese women receiving 360 mg EPA and 1290 mg DHA compared with placebo for 3 months, found reduced triglyceride-rich-lipoprotein levels from 1.48 ± 0.61 mmol/L to 1.22 ± 0.45 mmol/L (p < 0.01), and reduced insulin concentration from 16.10 ± 5.44 µIU/mL to 14.15 ± 4.37 µIU/mL (p < 0.05). No effect was seen on TC, high density lipoproteins (HDL), low density lipoproteins (LDL) and fasting blood glucose (FBG) .
In the elderly omega 3 supplementation showed contrasting results on metabolic profile. Twenty-four elderly women received 360 mg EPA and 1290 mg DHA daily for 12 weeks, or placebo. Omega 3 treatment reduced TG concentration from 1.30 ± 0.14 to 1.01 ± 0.14 mmol/L (−29%) (p < 0.01), while compared with no effects observed in the placebo group . No effects were observed on plasma insulin or FBG. Conversely, a 1860 mg EPA and 1500 mg DHA daily supplementation for 6 months was not effective in lowering TG, HDL, LDL and FBG, in healthy elderly . Fish oil administration was also evaluated with or without vitamin E (vit E) supplementation, and compared to placebo. Seventy-four women transitioning through menopause received 540 mg EPA and 360 mg DHA daily, with or without addition of 400 mg vit E, or a placebo treatment for 3 months. Results indicated a decrease in TC (−5.4% for fish oil only, −7.5% for fish oil and vit E) and LDL concentration (−8.4% for fish oil only, −7.3% for fish oil and vit E) .
Omega 3 supplementation in end-stage renal disease on hemodialysis has been evaluated in different studies. Fifty-two patients received for 6 months 340 mg EPA and 360 mg DHA daily, or a placebo . TC, LDL, TG, serum albumin and urea were unchanged after treatment in both groups . The same data were confirmed in another study, using the same supplementation protocol . In contrast, a different study, assessing the effects of 1080 mg EPA and 720 mg DHA daily compared to placebo for 4 months, demonstrated decreased HDL from 48.47 ± 18.52 to 33.58 ± 7.82 mg/dL (p < 0.01) in the omega 3 treatment group . In this group authors also found decreased TC from 167.4 ± 46.4 to 156.3 ± 57.9 mg/dL (p < 0.05), while post-treatment TG values were not significantly different from baseline, although lower than in placebo group by −29.11 mg/dL (p < 0.05). No difference was observed in FBG, LDL, homeosis model assessment insulin resistance (HOMA-IR), insulin, leptin or adiponectin . No effects of higher doses of omega 3 FA (1914 mg EPA and 957 mg DHA daily supplementation compared to placebo for 12 weeks), were also observed for FBG level and HOMA-IR . A small dose of omega 3, consisting in 80 mg EPA and 120 mg DHA daily for 10 weeks, was compared with a placebo condition using vit E . TC was found to be significantly decreased (p < 0.05) in both the treatment and the placebo group, with no significant difference between groups. No effect or difference was found in TG, HDL or LDL . These results have been partly confirmed also in chronic ambulatory peritoneal dialysis (CAPD) patients using a low dose of omega 3 (540 mg EPA and 360 mg DHA daily for 8 weeks), in which no effect of treatment was found on serum TG, TC, HDL and LDL concentration [24,25]. Results are summarized in Table 1.
2.2. Metabolic and Lipid Profile in Impaired Glucose Metabolism (IGM) and T2DM
Impaired glucose metabolism (IGM) patients with coronary artery disease received 1800 mg EPA daily compared with placebo treatment for 6 months . Results indicate an increase in HDL concentration by 2.0 mg/dL (−3.0, 8.0) (p = 0.05), and a decrease in fasting TG by −24.0 mg/dL (−54.0, −3.0) (p < 0.01) after omega 3 supplementation No effect was found for TC, LDL, HOMA-IR, Hb1Ac and FBG . A higher dose including also DHA, consisting in 2388 mg EPA and 1530 mg DHA, was given daily to IGM patients for 9 months, and compared to placebo . Despite the higher dose, no effect was found on FBG, fasting EGB, insulin concentration, HOMA-IR during hyperinsulinaemic-euglycemic-euaminoacidaemic clamp. Nevertheless, omega 3 treatment increased total protein disposal by 9.6% and endogenous whole-body protein turnover by 10.4% under insulin-stimulated conditions (p < 0.01).
In T2DM, supplementation of 1000 mg EPA and 1000 mg DHA daily for 3 months was compared with a placebo group . No effects were seen on insulin concentration, HbA1c, C peptide, TC, LDL, HDL, leptin and adiponectin. At baseline, omega 3 group showed significantly higher TG levels than placebo, and those levels decreased after treatment from 1.79 mmol/L (1.8, 2.41) to 1.48 mmol/L (0.91, 2.08) although without reaching significant difference from placebo group . Higher doses of EPA, consisting in 1548 mg EPA and 828 mg DHA daily for 2 months, compared to placebo, decreased HbA1c from 7.90 ± 0.2% to 7.25 ± 0.17% (p < 0.01), while in the placebo group HbA1c increased (p < 0.05) . In another study, a dose of 1240 mg EPA and 840 mg DHA daily for 10 weeks, decreased retinol binding protein 4 by −10.85 ± 1.62 μg/mL (p < 0.01) compared with placebo . Omega 3 treatment (750 mg EPA and 2000 mg DHA) has been also associated with or without 15 mg pioglitazone (Pio) daily for 24 weeks . HbA1c decreased significantly (p < 0.05) after omega 3 treatment by −7 mmol/mol (1, 13) compared with placebo and Pio groups (p < 0.05). In contrast, FBG increased after omega 3 treatment by 1.07 mmol/L (0.18, 2.02), but it was significantly different only from Pio (p < 0.05). No difference was observed in TC, HDL, LDL, NEFA, leptin, adiponectin or TG in none of the groups . Diabetic patients with non-alcoholic steatohepatitis received 2160 mg EPA and 1440 mg DHA daily, or placebo, for 48 weeks . Compared to baseline levels, FBG and HOMA-IR increased in omega 3 treatment (from 129.9 ± 36.5 to 150.4 ± 43.7 mg/dL and from 12.0 ± 6.8 to 16.1 ± 10.3 respectively, p < 0.05), with no effect in the placebo group. HbA1c also tended to increase from 6.7 ± 0.9 to 7.5 ± 2.2 (p = 0.059). No difference was found in TG, TC, and HDL .
Patients with T2DM or metabolic syndrome participated to a study investigating omega 3 treatment with 3580 mg EPA and 2440 mg DHA daily, botanical oil, or corn oil for 8 weeks . Omega 3 supplementation increased HDL from 40.7 ± 2.8 to 43.6 ± 2.8 mg/dL (p < 0.01), decreased TG from 187.2 ± 22.0 to 156.8 ± 14.7 mg/dL (p < 0.05), increased insulin from 19.1 ± 4.5 to 24.6 ± 6.8 mg/dL (p < 0.05), and slightly reduced HbA1c from 7.42 ± 0.33 to 7.20 ± 0.32 (p = 0.05). No effect was found on TC, LDL, leptin, FBG, and HOMA-IR . Treatment of metabolic syndrome patients with 1800 mg EPA and 1200 mg DHA daily was also associated with or without 10 mL of extra virgin oil for 90 days . Omega 3 treatment without olive oil had no effect on TG, TC, HDL, LDL, FBG, insulin and HOMA-IR; nevertheless, in association with olive oil it reduced TC and LDL (p < 0.05) . Omega 3 supplementation of 1800 mg EPA and 1200 mg DHA was also associated with or without 29 g of kinako or placebo for 90 days, finding decreased TG, increased TC, LDL, FBG, fasting insulin, and HOMA-IR, with no effect on HDL . Results are summarized in Table 2.
2.3. Inflammation and Oxidative Stress in in Healthy, Elderly and Chronic Renal Failure
In healthy individuals, 6 week omega 3 daily supplementation with 600 mg EPA or 1800 mg EPA or 600 mg DHA was compared with placebo . Among the inflammatory markers, only Lp-PLA2 concentration was reduced by EPA in a dose-dependent manner with a non significant decrease of −13.0 ng/mL (−28.3, 2.2) compared with placebo in the low dose treatment, and −21.4 ng/mL (−34.9, −7.8) in the high dose treatment (p < 0.05 vs. placebo), while no effect was seen in the DHA or placebo groups. Other inflammatory markers as hsCRP, TNF-α, IL-6, VCAM-1, ICAM-1 and fibrinogen were unaffected by the dose or type of treatment . Compared to placebo, administration of 1000 mg EPA and 400 mg DHA daily for 18 weeks failed to demonstrate any effect on inflammatory status expressed as hsCRP and IL-6 concentrations in a healthy population, although hsCRP levels at baseline were significantly higher in the omega 3 group than in placebo . Again, different doses of combined EPA and DHA (i.e., 300, 600, 900 and 1800 mg daily for 5 months in healthy individuals) did not result in any difference from placebo or in a dose-response effect on IL-6, TNF-α and CRP levels . In another study, obese women received 360 mg EPA and 1290 mg DHA daily for 3 months . Compared with placebo, reduced sVCAM-1 (from 576.86 ± 114.59 to 553.36 ± 130.25 ng/mL, p < 0.01), sPECAM-1 (from 71.25 ± 12.11 to 65.27 ± 8.99 ng/mL, p < 0.01), and hsCRP (from 3.16 ± 1.99 to 2.52 ± 1.57 mg/mL, p < 0.05) were observed in the treatment group. Difference was not significant between post treatment effect compared with placebo, or in IL-6 .
Elderly individuals with mild cognitive impairment received either 720 mg EPA and 480 mg DHA daily for 6 months, or placebo . Compared to placebo, the treatment group showed reduced levels of IL-6 (−34.94 ± 46.18 pg/mL, p < 0.05), TNFα (−5.91 ± 9.03 fmol/mL, p < 0.05), and a tendency for reduced sPLA2 (−113.58 ± 249.81 ng/L, p = 0.052). No significant difference was observed in IL-10, COX and LOX . Oxidative stress was studied in women transitioning through menopause receiving 540 mg EPA and 360 mg DHA daily, with or without addition of 400 mg vit E, or a placebo treatment for 3 months. Following EPA and DHA supplementation TBARS levels increased by 0.05 ± 0.01 μg/L, compared with both placebo (p < 0.01) and EPA and DHA with vit E (p < 0.05) .
In hemodialysis patients receiving for 6 months 340 mg EPA and 360 mg DHA daily, or a placebo, active treatment decreased vascular cell adhesion molecule (VCAM) from 34.1 ± 31.4 U/mL to 21.3 ± 12.9 U/mL (p < 0.05), while no effects where seen in the placebo group or in ICAM values . In patients receiving 1080 mg EPA and 720 mg DHA daily, compared with placebo for 4 months, no effect was observed on CRP levels . Similarly, no effect on hsCRP and IL-6 were observed in hemodialysis patients receiving higher dose of omega 3 (1914 mg EPA and 957 mg DHA daily), compared with placebo for 12 weeks . Conversely, some effects on inflammatory status were observed in patients treated with 1080 mg EPA and 720 mg DHA daily, compared with placebo, for 4 months . Authors found increased IL-10/IL-6 (by 0.64 ± 1.14 respect to baseline p < 0.01 and to placebo p < 0.05). IL-6 levels were reduced respect to baseline (by −7.53 ± 126.01, p < 0.05), but no difference was observed compared with placebo. No difference was observed respect to baseline or placebo in TNFα, IL-10 and CRP . When omega 3 treatment with 1600 mg EPA and 300 mg DHA was associated with or without 400 IU of α-tocopherol, and compared with placebo for 12 weeks, increased plasma nitric oxide (+31.0 ± 40.0 µmol/L, p < 0.01), and increased total antioxidant capacity (TAC) (+57.6 ± 157.8 mmol/L, p < 0.01) were observed. No effect was seen on hsCRP and glutathione (GSH), while albumin and malnonyldialdehyde (MDA) levels where changed only when EPA and DHA were associated with α-tocopherol . Omega 3 treatment in chronic kidney disease patients with 1840 mg EPA and 1520 mg DHA daily was also associated with or without 200 mg coenzyme Q10 (CoQ) for 8 weeks, and compared to placebo . Oxidative stress was determined by F2-isoprostanes, whose values were reduced after omega 3 treatment (from 1714 to 1215 pmol/L, p < 0.01), with no effect of CoQ and no significant changes in placebo. No effect was seen on hsCRP concentration . Moreover, no effect in inflammatory status, determined with CRP and IL-6, or oxidative stress, expressed as superoxide dismutase (SOD) and GSH, was observed in CAPD patients receiving 540 mg EPA and 360 mg DHA daily for 8 weeks/2 months compared to placebo [24,25]. Results are summarized in Table 3.
2.4. Inflammation and Oxidative Stress in IGM, Diabetes, and Metabolic Syndrome
Patients with IGM allocated either to treatment with 1800 mg EPA daily or to placebo for 3 months, presented in the omega 3 group reduced hsCRP concentrations compared to baseline of −0.01 mg/dL (−0.08, 0.00) (p < 0.01), although the same effect was observed also in the placebo group . No effect on inflammatory status, expressed as IL-1β, IL-6 and hsCRP, was observed with a higher dose of omega 3 consisting in 2388 mg EPA and 1530 mg DHA daily compared to placebo for 9 months .
In T2DM, 1000 mg EPA and 1000 mg DHA daily, compared to placebo for 3 months, did not affect systemic inflammatory status determined by hsCRP, IL-6, and TNFα . Omega 3 treatment effect was also evaluated with separated doses of 1000 mg EPA or 1000 mg DHA daily, and compared with placebo, for 12 weeks . Neither EPA nor DHA significantly affected systemic inflammatory status (determined by CRP) and oxidative stress (determined by MDA) in type 1 diabetes (T1DM) patients. However, MDA increased in the placebo group, and omega 3 may help preventing MDA increase . These results confirm a previous study in which patients received 900 mg EPA daily for 12 weeks and were compared to placebo, showing no effect of treatment in none of the inflammatory markers (i.e., CRP, IL-6 and TNFα) and on oxidative stress (expressed by reactive oxygen species, MDA, GSSG/GSH and SOD . Omega 3 treatment with 750 mg EPA and 2000 mg DHA daily was also associated with or without 15 mg pioglitazone (Pio) for 24 weeks and compared to placebo; none of the treatments showed any effect on oxidative stress expressed by superoxide dismutase activity, TBARS and GSSG/GSH .
Similarly, patients with metabolic syndrome receiving 800 mg EPA and 1200 mg DHA daily with or without the addition of 10 mL extra virgin oil for 90 days showed no effect on CRP levels and oxidative stress markers when compared with placebo . Results are summarized in Table 4.
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