Weiss LA, Barrett-Connor E & von Mn D. Ratio of n6 to n3 fatty acids and bone mineral density in older adults: the Rancho Bernardo Study
Am J Clin Nut, 2005;81(4):934-938

Background: Several lines of evidence suggest that n3 fatty acids reduce the risk of some chronic diseases, including heart disease, diabetes, and cancer. Other research, mainly in animals, also suggests a role in bone health.

Objective: We aimed to investigate the association between the ratio of dietary n6 to n3 fatty acids and bone mineral density (BMD) in 1532 community-dwelling men and women aged 4590 y.

Design: Between 1988 and 1992, dietary data were obtained through self-administered food-frequency questionnaires, and BMD was measured at the hip and spine with the use of dual-energy X-ray absorptiometry. A medical history was obtained and current medication use was validated. Age- and multiple-adjusted linear regression analyses were performed.

Results: There was a significant inverse association between the ratio of dietary linoleic acid to -linolenic acid and BMD at the hip in 642 men, 564 women not using hormone therapy, and 326 women using hormone therapy; these results were independent of age, body mass index, and lifestyle factors.
An increasing ratio of total dietary n6 to n3 fatty acids was also significantly and independently associated with lower BMD at the hip in all women and at the spine in women not using hormone therapy.

Conclusions: A higher ratio of n6 to n3 fatty acids is associated with lower BMD at the hip in both sexes. These findings suggest that the relative amounts of dietary polyunsaturated fatty acids may play a vital role in preserving skeletal integrity in older age.

Stark KD, Park EJ, Maines VA, Holub BJ. Effect of a fish-oil concentrate on serum lipids in postmenopausal women receiving and not receiving hormone replacement therapy in a placebo-controlled, double blind trial. Am J Clin Nutr 2000;72(2):389-394.

BACKGROUND: Omega-3 fatty acid supplementation lowered serum triacylglycerol concentrations in studies in which most of the subjects were male. The effects of omega-3 fatty acid supplementation in postmenopausal women receiving and not receiving hormone replacement therapy (HRT) have received little attention. OBJECTIVE: We sought to determine the effects of a fish-oil-derived omega-3 fatty acid concentrate on serum lipid and lipoprotein risk factors for cardiovascular disease in postmenopausal women receiving and not receiving HRT, with an emphasis on serum triacylglycerol concentrations and the ratio of triacylglycerol to HDL cholesterol.

DESIGN: Postmenopausal women (n = 36) were grouped according to exogenous hormone use and were randomly allocated to receive 8 capsules/d of either placebo oil (control) or n-3 fatty acid-enriched oil (supplement). The supplement provided 2.4 g eicosapentaenoic acid (EPA) plus 1.6 g docosahexaenoic acid (DHA) daily. Serum lipids and the fatty acid composition of serum phospholipids were determined on days 0 and 28.

RESULTS: Supplementation with omega-3 fatty acids was associated with 26% lower serum triacylglycerol concentrations (P < 0.0001), a 28% lower overall ratio of serum triacylglycerol to HDL cholesterol (P < 0.01), and markedly greater EPA and DHA concentrations in serum phospholipids (P < 0.05).

CONCLUSIONS: These results show that supplementation with a fish-oil-derived concentrate can favorably influence selected cardiovascular disease risk factors, particularly by achieving marked reductions in serum triacylglycerol concentrations and triacylglycerol: HDL cholesterol in postmenopausal women receiving and not receiving HRT. This approach could potentially reduce the risk of coronary heart disease by 27% in postmenopausal women.

Maggie Laidlaw and Bruce J Holub. Effects of supplementation with fish oil?derived n-3 fatty acids and gamma-linolenic acid on circulating plasma lipids and fatty acid profiles in women. Am J of Clinical Nutrition, 2003;77(1)37-42

Background:
Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and gamma-linolenic acid (GLA) have lipid-modifying and antiinflammatory properties. The effects of supplement mixtures of these fatty acids on plasma lipids and the fatty acid compositions of serum phospholipids have received little attention.

Objective:
The objective was to determine the effects of different levels of GLA supplementation together with a constant intake of EPA plus DHA on the triacylglycerol-lowering effect of EPA plus DHA alone and on the fatty acid patterns (eicosanoid precursors) of serum phospholipids.

Design:
Thirty-one women were assigned to 1 of 4 groups, equalized on the basis of their fasting triacylglycerol concentrations. They received supplements providing 4 g EPA+DHA (4:0, EPA+DHA:GLA; control group), 4 g EPA+DHA plus 1 g GLA (4:1), 2 g GLA (4:2), or 4 g GLA (4:4) daily for 28 d. Plasma lipids and fatty acids of serum phospholipids were measured on days 0 and 28.

Results:
Plasma triacylglycerol concentrations were significantly lower on day 28 than on day 0 in the 4:0, 4:1, and 4:2 groups. LDL cholesterol decreased significantly (by 11.3%) in the 4:2 group. Dihomo-gamma-linolenic acid increased significantly in serum phospholipids only in the 4:2 and 4:4 groups; however, total n-3 fatty acids increased in all 4 groups.

Conclusions:
A mixture of 4 g EPA+DHA and 2 g GLA favorably altered blood lipid and fatty acid profiles in healthy women.
On the basis of calculated PROCAM values, the 4:2 group was estimated to have a 43% reduction in the 10-y risk of myocardial infarction.

Whalley LJ, Fox HC, Wahle KW, et al. Cognitive aging, childhood intelligence, and the use of food supplements: Possible involvement of n-3 fatty acids. Am J Clin Nutr 2004;80:1650-1657.

BACKGROUND:
Food supplement use is widely promoted, but little is known about the cognitive effects of food supplements.

OBJECTIVE:
We examined the effects of food supplement use on cognitive aging.

DESIGN:
This was an observational study of subjects born in 1936 whose mental ability was tested in 1947 and who were followed up in 2000-2001, at which time cognition, diet, food supplement use, and risk factors for vascular disease were assessed.
In a nested case-control study, fish-oil users were matched with nonusers, and cognitive function was related to erythrocyte n-3 fatty acid composition.

RESULTS:
Childhood intelligence quotient (IQ) did not differ significantly by category of food supplement use (ie, none, fish oil, vitamins, and other).

At the age of 64 y, cognitive function was higher in food supplement users than in nonusers before adjustment for childhood IQ. After adjustment for childhood IQ, digit symbol (mental speed) test scores were higher in food supplement users.

Fish-oil supplement users consumed more vitamin C and vegetable and cereal fiber than did non-supplement-users. In a nested case-control study, erythrocyte membrane n-3 content was higher in fish-oil supplement users than in nonusers, but cognitive function did not differ significantly between groups.

Total erythrocyte n-3 fatty acids and the ratio of docosahexaenoic acid to arachidonic acid was associated with better cognitive function in late life before and after adjustment for childhood IQ.

CONCLUSIONS:
Food supplement use and erythrocyte n-3 content are associated with better cognitive aging.
If associations with n-3 content are causal, optimization of n-3 and n-6 fatty acid intakes could improve retention of cognitive function in old age.

PMID: 15585782

Miljanovi B, Trivedi KA, et al. Relation between dietary n3 and n6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clinical Nutrition, 2005;82(4):887-893.

Background: Dry eye syndrome (DES) is a prevalent condition, but information on risk or protective factors is lacking.

Objective: We aimed to determine the association between the dietary intake and ratio of n3 and n6 fatty acids (FAs) and DES occurrence.

Design: Of the 39876 female health professionals in the Womens Health Study (WHS), 32470 women aged 4584 y who provided information on diet and DES were cross-sectionally studied. We assessed FA intakes by using a validated food-frequency questionnaire and assessed DES by using self-reports of clinically diagnosed cases. Of the sample, 1546 (4.7%) subjects reported DES. We used logistic regression models to estimate the odds ratios (ORs) and 95% CIs to describe the relation of FA intake with DES.

Results: After adjustment for demographic factors, hormone therapy, and total fat intake, the OR for the highest versus the lowest quintile of n3 FAs was 0.83 (95% CI: 0.70, 0.98; P for trend = 0.05). A higher ratio of n6 to n3 FA consumption was associated with a significantly increased risk of DES (OR: 2.51; 95% CI: 1.13, 5.58) for >15:1 versus <4:1 (P for trend = 0.01). In addition, tuna consumption [1 serving was 113 g (4 oz)] was inversely associated with DES (OR: 0.81; 95% CI: 0.66, 0.99 for 24 servings/wk; OR: 0.32; 95% CI: 0.13, 0.79 for 56 servings/wk versus 1 serving/wk; P for trend = 0.005).

Conclusions: These results suggest that a higher dietary intake of n3 FAs is associated with a decreased incidence of DES in women. These findings are consistent with anecdotal clinical observations and postulated biological mechanisms.

Lu M, Cho E, et al. Prospective Study of Dietary Fat and Risk of Cataract Extraction among US Women. Am J of Epidemiology, 2005; 161(10):948-959

The authors examined prospectively the association between dietary fat intake and cataract extraction in adult women from the Nurses' Health Study.

A total of 71,083 women were followed prospectively for up to 16 years between 1984 and 2000.

Dietary fat was assessed by repeated food frequency questionnaires. Incident cases of cataract extraction were determined by a biennial questionnaire.

The multivariate-adjusted relative risk for the highest compared with the lowest quintile of total fat intake was 1.10 (95% confidence interval (CI): 0.99, 1.22; ptrend = 0.01).

Women in the highest quintile of long-chain omega-3 fatty acid had a 12% lower risk of cataract extraction compared with those in the lowest quintile (relative risk = 0.88, 95% CI: 0.79, 0.98; ptrend = 0.02).

Total fish intake was inversely associated with cataract (for intake of 3/week vs. <1/month: relative risk = 0.89, 95% CI: 0.81, 0.98; ptrend = 0.01).

The authors' findings suggest that higher intake of long-chain omega-3 fatty acid (eicosapentaenoic acid and docosahexaenoic acid) and consumption of fish may modestly reduce the risk of cataract

Hu F, Cho E, et al. Fish and Long-Chain -3 Fatty Acid Intake and Risk of Coronary Heart Disease and Total Mortality in Diabetic Women. Circulation 2003;107:1852-1857.

Background Although several prospective cohort studies have found an inverse association between fish consumption and risk of coronary heart disease (CHD) or sudden cardiac death in the general population, limited data are available among diabetic patients.

Methods and Results We examined prospectively the association between intake of fish and -3 fatty acids and risk of CHD and total mortality among 5103 female nurses with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Between 1980 and 1996 (45 845 person-years of follow-up), we documented 362 incident cases of CHD (141 CHD deaths and 221 nonfatal myocardial infarctions) and 468 deaths from all causes. Compared with women who seldom consumed fish (<1 serving/mo), the relative risks (RRs) (95% CI) of CHD adjusted for age, smoking, and other established coronary risk factors were 0.70 (0.48 to 1.03) for fish consumption 1 to 3 times per month, 0.60 (0.42 to 0.85) for once per week, 0.64 (0.42 to 0.99) for 2 to 4 times per week, and 0.36 (0.20 to 0.66) for 5 or more times per week (P for trend=0.002). Higher consumption of fish was also associated with a significantly lower total mortality (multivariate RR=0.48 [0.29 to 0.80] for 5 times per week [P for trend=0.005]). Higher consumption of long-chain -3 fatty acids was associated with a trend toward lower incidence of CHD (RR=0.69 [95% CI 0.47 to 1.03], P for trend=0.10) and total mortality (RR=0.63 [95% CI, 0.45 to 0.88], P for trend=0.02).

Conclusions A higher consumption of fish and long-chain -3 fatty acids was associated with a lower CHD incidence and total mortality among diabetic women

Lox CD. Effects of marine fish oil (omega-3 fatty acids) on lipid profiles in women. Gen Pharmacol,1990; 21(3):295-298.

Cycling women both taking or not taking oral contraceptives and menopausal women on replacement estrogen ingested 3 g daily of marine fish oil for 30 days. Triglycerides decreased in the contraceptive users, cholesterol and LDL increased in the non-contraceptive user; while LDL decreased in the menopausal women. After 14 days removal of the fish oil, lipid profiles generally returned to a pattern generally thought to be harmful. Fish oil appears to alter lipids favorably in women receiving exogenous estrogens compared to natural circulating estrogen.

Timonen M, Horrobin D, et al. Fish consumption and depression: the Northern Finland 1966 birth cohort study. J Affect Disord, 2004;82(3):447-452

BACKGROUND: Since low fish consumption and omega-3 fatty acids have recently been linked with depression, we investigated by means of a large, general population database, whether a low fish consumption is associated with increased risk of developing depression.

METHODS: The Northern Finland 1966 Birth Cohort was followed up prospectively from pregnancy up to the age of 31 years. The data on HSCL-25 depression subscale, doctor-diagnosed life-time depression and fish consumption (during the previous 6 months) of cohort members were obtained by postal questionnaires at the age of 31. The final number of cohort members, whose completed variable information was available in multivariate logistic analyses, was 2721 males and 2968 females.

RESULTS: After adjusting for body mass index, serum total cholesterol level and socioeconomic situation, logistic regression analyses showed that among females the risk of developing depression increased up to 2.6-fold (95%CI 1.4-5.1) among rare fish eaters when compared with regular eaters. In males, there were no significant differences between rare and regular fish eaters for any of the estimates of depression.

LIMITATIONS: The data on life-time fish consumption of cohort members were not available.

CONCLUSIONS: A low frequency of fish consumption was statistically significantly associated with depression in women, but not in men. Possible background-theories behind the gender difference are discussed.

Hu FB, Bronner L, et al. Fish and Omega-3 Fatty Acid Intake and Risk of Coronary Heart Disease in Women. JAMA. 2002;287(14):1815-1821.

CONTEXT: Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD) in men, but limited data are available regarding women.

OBJECTIVE: To examine the association between fish and long-chain omega-3 fatty acid consumption and risk of CHD in women.

DESIGN, SETTING, AND PARTICIPANTS: Dietary consumption and follow-up data from 84,688 female nurses enrolled in the Nurses' Health Study, aged 34 to 59 years and free from cardiovascular disease and cancer at baseline in 1980, were compared from validated questionnaires completed in 1980, 1984, 1986, 1990, and 1994. MAIN

OUTCOME MEASURES: Incident nonfatal myocardial infarction and CHD deaths.

RESULTS: During 16 years of follow-up, there were 1513 incident cases of CHD (484 CHD deaths and 1029 nonfatal myocardial infarctions). Compared with women who rarely ate fish (<1 per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking, and other cardiovascular risk factors, the multivariable relative risks (RRs) of CHD were 0.79 (95% confidence interval [CI], 0.64-0.97) for fish consumption 1 to 3 times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for 2 to 4 times per week, and 0.66 (95% CI, 0.50-0.89) for 5 or more times per week (P for trend =.001). Similarly, women with a higher intake of omega-3 fatty acids had a lower risk of CHD, with multivariable RRs of 1.0, 0.93, 0.78, 0.68, and 0.67 (P<.001 for trend) across quintiles of intake. For fish intake and omega-3 fatty acids, the inverse association appeared to be stronger for CHD deaths (multivariate RR for fish consumption 5 times per week, 0.55 [95% CI, 0.33-0.90] for CHD deaths vs 0.73 [0.51-1.04]) than for nonfatal myocardial infarction.

CONCLUSION: Among women, higher consumption of fish and omega-3 fatty acids is associated with a lower risk of CHD, particularly CHD deaths.

Erkkilä AT, Matthan NR, et al. Higher plasma docosahexaenoic acid is associated with reduced progression of coronary-artery atherosclerosis in women with established coronary artery disease. J. Lipid Res., doi:10.1194/jlr.P600005-JLR200.

Fish, fish oil supplement, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and in some cases alpha-linolenic acid (ALA) intake have been associated with reduced risk of cardiovascular events and death.

The association between n-3 fatty acids in plasma lipids and progression of coronary-artery atherosclerosis was assessed among women with established coronary artery disease (CAD).

A prospective cohort study involved postmenopausal women (n=228) participating in the Estrogen Replacement and Atherosclerosis trial.

Quantitative coronary angiography was performed at baseline and after 3.2±0.6 (mean±SD) years. Women with plasma phospholipid DHA levels above the median, compared to below, exhibited less atherosclerosis progression as expressed by decline in minimum coronary artery diameter (-0.04±0.02 mm and -0.10±0.02 mm, respectively, P=0.007), or increase in percent stenosis (1.34±0.76% and 3.75±0.74%, respectively, P=0.006) and had fewer new lesions [2.0 (0.5-3.5) % of measured segments (95% confidence interval)] and 4.2 (2.8-5.6)%, respectively, P=0.009] after adjustments for cardiovascular risk factors.

Similar results were observed for DHA in the triglycerides. EPA and ALA in plasma lipids were not significantly associated with atherosclerosis progression.

Consistent with higher reported fish intake, higher levels of plasma triglyceride and phospholipid DHA is associated with less progression of coronary atherosclerosis in postmenopausal women with established CAD.

Mez-Shez N, Gonzz V, et al. Fish Oil (n-3) Polyunsaturated Fatty Acids Beneficially Affect Biliary Cholesterol Nucleation Time in Obese Women Losing Weight. J. Nutr 2001;131:2300-2303

It has been reported that intake of (n-3) polyunsaturated fatty acids (PUFA) reduces the risk of coronary heart disease and decreases biliary cholesterol saturation in the bile of gallstone patients.

We investigated the effect of n-3 PUFA on cholesterol saturation index (CSI) and nucleation time (NT) in obese subjects who were losing weight. This was a double-blind, placebo-controlled clinical trial.

Obese women (n = 35) with a body mass index (BMI) 30 kg/m2, with no prior history of gallstones or cholecystectomy by ultrasound were first studied to ensure absence of stones or biliary sludge. The women were then assigned to a hypocaloric regimen [5.02 MJ (1200 kcal)/d] and to receive 1200 mg/d of ursodeoxycholic acid (UDCA), 11.3 g/d of (n-3) PUFA or a placebo for 6 wk. BMI, CSI and NT were recorded at baseline and at the end of the experimental period.

BMI decreased 5.75 ± 2.7%/mo (range, 1.5?12.42%/MO) during the experiment. The CSI did not change in any of the groups. Cholesterol NT decreased significantly in the UDCA and placebo groups, but not in the (n-3) PUFA group. None of the women had developed gallstones at 6 wk.

These results suggest that (n-3) PUFA maintain the CSI and NT in obese women during rapid weight loss, which probably results in the prevention of cholesterol gallstone formation.

Lopez-Garcia E, Schulze MB, et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr, 2004;134(7):1806-1811

We evaluated the hypothesis that intake of (n-3) fatty acids is inversely associated with biomarkers of inflammation and endothelial activation.

We conducted a cross-sectional study of 727 women from the Nurses' Health Study I cohort, aged 43-69 y, apparently healthy at time of a blood draw in 1990. Dietary intake was assessed by a validated FFQ in 1986 and 1990.

C-reactive protein (CRP) levels were 29% lower among those in the highest quintile of total (n-3) fatty acids, compared with the lowest quintile; interleukin-6 (IL-6) levels were 23% lower, E-selectin levels 10% lower, soluble intracellular adhesion molecule (sICAM-1) levels 7% lower, and soluble vascular adhesion molecule (sVCAM-1) levels 8% lower.

The intake of alpha-linolenic acid was inversely related to plasma concentrations of CRP (beta = -0.55, P = 0.02), Il-6 (beta = -0.36, P = 0.01), and E-selectin (beta = -0.24, P = 0.008) after controlling for age, BMI, physical activity, smoking status, alcohol consumption, and intake of linoleic acid (n-6) and saturated fat.

Long-chain (n-3) fatty acids (eicosapentaenoic and docosahexaenoic) were inversely related to sICAM-1 (beta = -0.11, P = 0.03) and sVCAM-1 (beta = -0.17, P = 0.003).

Total (n-3) fatty acids had an inverse relation with CRP (beta = -0.44, P = 0.007), IL-6 (beta = -0.26, P = 0.009), E-selectin (beta = -0.17, P = 0.004), sICAM-1 (beta = -0.07, P = 0.02), and sVCAM-1 (beta = -0.10, P = 0.004).

These associations were not modified by intake of vitamin E, dietary fiber, trans fatty acids, or by the use of postmenopausal hormone therapy.

In conclusion, this study suggests that dietary (n-3) fatty acids are associated with levels of these biomarkers reflecting lower levels of inflammation and endothelial activation, which might explain in part the effect of these fatty acids in preventing cardiovascular disease.

PMID: 15226473

Essential fats may prevent bone loss. USA Today. Vol. 134, No. 2725, pp 15(1)

Maintaining a proper balance of dietary fats may ward off much of the bone loss associated with postmenopausal osteoporosis, states a study by scientists at the Indiana University School of Medicine, Bloomington, and Purdue University, West Lafayette, Ind.

The researchers found that diets with a low ratio of omega-6 fatty acids to omega-3 fatty acids minimizes the bone loss typically brought on by estrogen deficiency, which is common in post-menopausal females.
Omega-6 is found in foods such as grains and beef, while omega-3 is contained in products like walnuts and salmon.

"Many people don't realize it, but our bones are not static structures," explains Mark Seifert, professor of anatomy and cell biology at Indiana University.
Bones undergo a process called "remodeling," in which they continuously are broken down and rebuilt.
Two types of cells govern this process--bone resorption cells, which remove small portions of bone, and bone building cells, which fill in the gaps.
Estrogen blocks some of the inflammatory compounds associated with bone resorption, which may explain why osteoporosis typically progresses after estrogen levels fall with the onset of menopause.

"Our lab and others have shown that omega-3 fatty acids help promote bone formation," reports Bruce Watkins, professor and director of Purdue's Center for Enhancing Foods to Protect Health. "We also have shown that higher intakes of omega-6 fatty acids lead to an increased production of compounds associated with bone loss."

While both types of fats are essential for human health, diets with a high ratio of omega-6 to omega-3 fatty acids often are associated with cardiovascular disease, cancer, and inflammatory and autoimmune diseases.

A low ratio, however, is believed to promote cardiovascular health, improve memory and, as the study demonstrates, protect bone health.

"We saw in this study that omega-3 fatty acids are associated with a better blood profile of bone health, and with higher bone mineral density, in the absence of estrogen," Watkins notes. "A five-to-one dietary ratio of omega-6 to omega-3 fatty acids led to a conservation of bone mineral content that we didn't see with a 10-to-one ratio."

The average American's dietary ratio is approximately 10 to one, which is inflated by the types of foods people eat and the methods used to produce those foods, especially those containing vegetable oils. "Our foods are different today than they were yesterday," he says. "Omega-6 fatty acids have been an important part of our diet but, over the past 80 years, the human diet has shifted in a way that increased the ratio of omega-6 to omega-3 fatty acids."

The omega-6 fatty acids in today's animal feed incorporate right into the animals' tissues where they become part of the eggs, poultry, meats, and pork served in households and restaurants across the country.