Omega-3s: From Inuit to Implementation

While the relationship between the omega-3 fatty acids and age related cognition and retinal function have only recently begun to emerge, the cardio-vascular effects of EPA and DHA have been studied for nearly three decades. Interest in these fatty acids from cold water fish began in the late 1970's when studies revealed that Greenland's indigenous Inuits had a significantly lower rate of heart attack compared with Western control subjects. These observations generated an estimated 5000 studies to explore this and other effects of omega-3 fats, and ultimately led to the American Heart Association's recommendations for regular omega-3 consumption in 2002. Research continues to support the cardio-protective role of these fatty acids as evidenced by the findings of several newly published studies.

Fish Fatty Acids More Effective Than Defibrillators

Omega-3 fatty acids may prevent more sudden deaths than automated external defibrillators (AED) in homes and public places or implanted defibrillators according to results of a study supported by the Centers for Disease Control (1). Researchers compared these preventive strategies in a computer-simulated community of 100,000 people that resembled the population of Olmsted County, Minnesota.

Raising the omega-3 fatty acid levels among the cyber-Olmsted citizens resulted in lowering overall mortality rates by 6.4%. In contrast, AEDs reduced death rates by 0.8% and implanted defibrillators (ICDs) lowered the rates by 3.3%. Three-quarters of the reduction in deaths from increased omega-3 levels would come from raising them among the healthy portion of the population.

Raising blood levels of the omega-3 in people after a heart attack could save 58 lives yearly according to the simulation's predictions, while only 7 lives were saved by AEDs and implanted defibrillators prevented 30 deaths yearly. While heart attack survivors are routinely given omega-3 supplements in some European countries, this is generally not the case in the U.S., though the evidence supports it. According to a study published in the September issue of the Journal of the American Board of Family Medicine, only 17% of family doctors were likely to advise patients - including those who had suffered a heart attack - to take omega-3 supplements (2). There is a great need, the authors concluded, to "improve awareness of this important advice."

Heart Benefits Confirmed In Systematic Review

A recently published systematic review of randomized controlled trials, prospective cohort and case-control studies, concludes that the evidence suggests that fish or fish oil supplements reduces the rates of all cause mortality, cardiac and sudden death, and possibly stroke(3). The evidence was stronger for secondary than primary prevention.

Commissioned by the NIH, the review found that increased consumption of EPA and DHA - but not the omega-3 fatty acid alpha linolenic (ALA) - reduces the rates of these CVD outcomes. Data on the effects of ALA, found in flaxseed and other vegetable oils, were reportedly limited and typically of poor quality.

Future Directions: An Omega-3 Index

A second review published online in August ahead of print in the journal Cardiovascular Research, also concludes that the majority of the evidence supports the benefits of omega-3 intake for heart health. The authors, from Saint Luke's Hospital, University of Missouri-Kansas City School of Medicine, have proposed an omega-3 index as a modifiable risk factor for CVD. The Index measures the sum of EPA+DHA in the membrane of erythrocytes as the percent of all fatty acids in the red blood cell membrane. The authors also determined that membrane EPA+DHA index equal to or exceeding 8% is associated with the greatest cardio-protection. In the future, this measure of EPA/DHA status could help physicians tailor advice to their patients to help them achieve levels of omega-3 scientifically reported to provide CVD benefits.

References

1. Kottke TE, et al. Preventing sudden death with n-3 (omega-3) fatty acids and defibrillators. Am J Prev Med 31:316-23, 2006.
2. Oh RC, et al. The fish in secondary prevention of heart disease (FISH) survey-primary care physicians and omega-3 fatty acid prescribing behaviors. J Am Board Fam Med 19:459-67, 2006.
3. Wang C, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 84:5-17, 2006.

CVD & AMD Share Common Risks, Processes

A Harvard research team led by Dr. Johanna Seddon notes that age-related macular degeneration (AMD) and cardiovascular disease (CVD) share common risk factors, such as smoking and higher body mass index (BMI). They propose that mechanisms involved in developing AMD could be better understood by evaluating biomarkers of CVD. A number of analyses, in fact, have shown that systemic biomarkers for inflammation and artery damage, including C-reactive protein (CRP) and homocysteine (HCY), are related to AMD. Basic research also demonstrates that inflammatory, immune and atherosclerotic processes are related to AMD development.

To further explore mechanisms related to AMD pathogenesis, these researchers evaluated the relationships between CRP, HCY and other known risk or protective factors for AMD in subjects from the original AREDS trial (1). According to Dr. Seddon, the findings indicate that "sick eyes may occur in sick bodies related to smoking, overweight, inadequate nutrient intake, and other unhealthy behaviors".

Study Design

After randomization for AREDS, 934 subjects from two clinical sites underwent blood draws, measurements, photographs of the macula and answered questionnaires. Dietary, behavioral and medical risk, and protective factors for AMD were evaluated for their associations with blood values of CRP and HCY. This original data provided information on intake of fish as well as antioxidants such as vitamins C and E, alpha- and beta-carotene and lutein/zeaxanthin. In addition, serum nutrient values obtained from participants at one of the sites were also evaluated for their association with CRP and HCY. Multivariable regression analyses were performed after adjusting for age, gender and AREDS treatment.

Results

Higher levels of serum antioxidants vitamin C and lutein/zeaxanthin and higher fish intake (a source of omega-3 fats) were associated with lower serum CRP levels. CRP levels decreased 2 milligrams per litre for every 1000 microgram per decilitre increase in blood levels of lutein/zeaxanthin. A 0.2 milligram per litre decrease in CRP was also associated with more than 2 servings of fish weekly.

Increased BMI and smoking were associated with increased CRP, while serum alpha-carotene, dietary intake of antioxidants and vitamin B6 were associated with lower levels of plasma HCY. Levels of HCY were observed to be higher in those with hypertension. While serum vitamin E was linked to lower concentrations of HCY, it was unexpectedly linked to higher levels of CRP.

Comments

Factors reported to be related to AMD, namely antioxidants, smoking, BMI, HCY (2) and fish intake, are also associated with inflammatory, immune, or other CVD mechanisms. These results are consistent with previous findings associating smoking, BMI, and the biomarkers CRP and interleukin-6 with AMD in a different study cohort of AMD patients (3).

The relationship between fish intake, BMI, and levels of inflammatory markers have been previously reported in other "non-ocular" study populations. These data support and expand on these associations. The positive link between higher vitamin E and CRP deserves further study, according to the authors. This finding disagrees with the recent Rotterdam study, which found that vitamin E significantly lowered AMD risk [EduFacts Vol.6 No.1].

Overall, the Harvard study adds to a growing body of data showing a protective effect of antioxidants such as lutein/zeaxanthin, and omega-3 fats against AMD.

References

1. Seddon JM et al. C-reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration. Nutrition 22:441-43, 2006.
2. Seddon JM et al. Evaluation of homocysteine and risk of age-related macular degeneration. Am J Ophthalmol 141:201-3, 2006.
3. Seddon JM et al. Progression of age-related macular
   degeneration: prospective assessment of C-reactive protein, interleukin-6, and other cardiovascular biomarkers. Arch Ophthalmol 123:774-82, 2005.

EPA & DHA: Beyond Heart & Brain Benefits

The long chain fats in fish oil, EPA and DHA, are best known for their cardiovascular benefits. They help guard arteries by quelling chronic inflammation, keeping levels of triglycerides in check, and making vessels more elastic. Factor in their ability to improve electrical communication between heart cells and prevent arrhythmia, and it's easy to understand why omega-3s are a standard part of cardiac care in European countries.

The evidence for an Omega-3 role in fending off mental aging is also increasing [see the February 2007 and December 2006 newsletter issues]. Several new areas of potential benefit for these fatty acids are also emerging: visual, prostate and colon health.

Preventing Retinopathy?

In addition to being studied in the AREDS-2 trial for AMD, the omega-3s may help protect against retinopathy, a deterioration of the retina that affects about 4 million diabetics and 40,000 premature infants. This disease is a 2-part process that starts with a loss of blood vessels. With the vessel loss, the retina becomes oxygen deprived and reacts by spurring new vessel growth. However, the low-oxygen triggered vessels grow abnormally and are malformed, leaky and over-abundant.

Collaborating researchers from the NEI, Harvard, the University of Göteborg in Sweden and other institutions, recently examined the effects of omega-3 and omega-6 in an animal model of retinopathy (1). Animals were fed EPA and DHA from fish oil, or arachidonic acid - an omega-6 typically found in meats and dairy, and made in the body from other fats present in many vegetable oils. The investigators found that mice on the omega-3 diet initially lost 40-50% less retinal vessels compared to the omega-6 group. As a result, the omega-3 fed group had a 40-50% reduction in abnormal vessel growth.

One of the study's authors said: "If clinical trials find that supplementing with omega-3 s is as effective in protecting humans against retinal disease as demonstrated by the findings of this study, this cost effective intervention could benefit millions of people".

Better Colon Health?

Findings from a new study published in the American Journal of Epidemiology, add to a growing body of science linking omega-3 and fatty fish consumption to a reduced risk of colorectal cancer (2). Scottish researchers examined the type and amounts of fats in the diets of 1,455 subjects with colorectal cancer and the same number of matched healthy individuals.

Increased intake of EPA was associated with a 41% reduction in risk, while a 37% lower risk was linked to DHA intake, comparing highest against lowest average intakes. The omega-3s have been shown to reduce the body's inflammatory response (3). This is very important, because chronic inflammation is believed to be the culprit in about 20% of all cancers.

Healthier Prostates?

In addition to colorectal cancer, prostate cancer is also believed to be influenced by chronic inflammation. The incidence of prostate cancer has been increasing over the past 15 years, with over a half million new cases diagnosed every year worldwide.

Higher intake of the omega-3s DHA and EPA could cut the risk of developing this cancer by 40% according to a new study from Harvard (4). The investigators compared blood levels of fatty acids in 476 men with prostate cancer and the same number of healthy controls. The results tally with other studies reporting that regular intake of fatty fish like salmon is associated with a prostate-protective effect.

References

1. Connor KM, et al. Increased dietary intake of 3-poly-unstaturated acids reduces pathological retinal angiogenesis. Nature Medicine 13:868-874, 2007.
2. Theodoratou E, et al. Dietary fatty acids and colorectal cancer: a case-control study. American Journal of Epidemiology 166:181-195, 2007.
3. Wada M, et al. Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products. Journal of Biological Chemistry 282: 22254-66. 2007.
4. Chavarro JE, et al. A prospective study of polyunsaturated fatty acid levels in blood and prostate cancer risk. Cancer Epidemiology, Biomarkers and Prevention. 16:1364-70 ,2007.

AREDS Reports Numbers 20 and 22

Dietary data was collected from participants when they enrolled in the AREDS trial so that investigators could later examine the relationship of AMD case groups with intake levels of individual nutrients.

To explore these relationships, AREDS subjects were divided into four groups based on increasing severity of drusen or type of AMD. The dietary information from those four groups was then compared with that from AREDS participants categorized as being 'free' of AMD. AMD-free was defined as having no drusen or less than 15 small drusen. Nutrient intake values were adjusted for energy intake then stratified into quintiles.

Results of the analyses were published in the May and September issues of the journal Archives of Ophthalmology. The first of these case-control studies reports on the relationship of dietary lipids and AMD (1), while the second study assessed whether nutrients such as carotenoids, vitamins A, C and E and others, were related to AMD risk (2).

Omega-3 and Fish Intake Lower AMD Risk

The researchers found that only higher intake of total long chain omega-3 and fish (the primary dietary source of EPA and DHA), were linked to a decreased likelihood of having neovascular AMD. Benefit was not seen for the other AMD groups.

Arachidonic acid was the only dietary lipid directly associated with neovascular AMD prevalence. Participants getting the most arachidonic acid in their diets were 54% more likely to have late AMD. Arachidonic acid, an omega-6 fat abundant in meat and dairy, is a precursor for inflammatory eicosinoids.

No statistically significant relationships were seen for other dietary lipids such as the monounsaturates, found in olive oil for example, or saturated fats.

It's interesting to note that the omega-3 fat alpha-linolenic acid, found in flaxseed oil for example, was associated with decreased AMD risk only when it was included along with EPA and DHA as part of the total intake of long chain polyunsaturated fats. Assessed alone, alpha-linolenic was not related to AMD. Alpha-linolenic acid must first be metabolized to EPA to provide anti-inflammatory activity, and this conversion is only 10-20% effective.

Comparing the highest to lowest quintiles, those consuming the most total omega-3 fats were about 39% less likely to have neovascular AMD. Risk reduction for greater fish intake was the same. A 46% lower chance of having late AMD was linked with the highest consumption of DHA.

EPA, DHA and arachidonic acid are major fatty acids in the diet. Both arachidonic acid and DHA (which can be formed from EPA), are key components of retinal photoreceptor outer segments and vascular tissue. While all three of these lipids are essential, a better balance of EPA and DHA to arachidonic acid is recommended for cardiovascular health. This study strongly suggests that improving that balance can favorably influence retinal health as well.

Only Lutein / Zeaxanthin Independently Linked to AMD

Higher dietary intake of lutein and zeaxanthin was independently associated with a reduced likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen. No other nutrients were independently related to AMD.

After adjusting for total energy intake and other non-nutritional risk factors, subjects consuming the highest amount of lutein and zeaxanthin were 35% less likely to have neovascular AMD and 55% less likely to have geographic atrophy than those eating the least. Those whose diets provided the most of these two carotenoids also had a 26% reduced likelihood of having large or extensive drusen.

The findings from both of these AREDS case-control studies are, in part, the basis for testing 10 mg of lutein, 2 mg of zeaxanthin, 650 mg EPA and 350 mg of DHA in the AREDS 2 trial currently underway.

References

1. AREDS Report No. 20: The relationship of dietary lipid intake and age-related macular degeneration in a case-control study. Arch Ophthalmol 125:671-9, 2007.
2. AREDS Report No. 22: The relationship of dietary carotenoids with age-related macular degeneration in a case-control study. Arch Ophthalmol 125:1225-32, 2007.

AREDS 2 Slated to Get Underway

One of the most influential studies of the past decade is about to have a sequel. The Age-Related Eye Disease Study (AREDS), published in late 2001, was the first large-scale trial to demonstrate that supplementation with antioxidant nutrients can help slow the progression of age-related macular degeneration (AMD) and it's associated vision loss.

AREDS found that a combination of vitamins C, E, beta-carotene, zinc and copper lowered the risk of advanced AMD by 25% in high-risk patients. No effects of this antioxidant combination were observed in people without signs of the disease or with early AMD. Subjects without AMD didn't receive zinc - a mineral that also lowered the risk of AMD progressing when given alone to higher risk patients.

Lutein, Zeaxanthin and Omega-3 Fatty Acids

Now, researchers at the National Eye Institute (NEI) are gearing up to assess the impact of other nutrients that have emerged as potentially beneficial since the first AREDS study began: lutein, zeaxanthin and the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Lutein and zeaxanthin are thought to shield the macula and retina from oxidative stress generated by exposure to light.

EPA and DHA, fatty acids that are present in cold-water fish, also play important roles in the eye. According to a review by the NEI, these fatty acids lessen the effects of exposure to light, stress, inflammation and other factors. DHA is also a major component of photoreceptors (rods and cones).

AREDS Analysis

When researchers analyzed the dietary intake of participants in the original AREDS trial, they found that those with the highest intake of DHA had a 50% lower risk of advanced AMD, and those consuming the most EPA had nearly the same 50% decrease in their risk of developing advanced geographic atrophy (a severe form of "dry" AMD). The investigators also studied patients' intake of lutein and zeaxanthin, finding that those with the highest intake had a 50% lower risk of developing new AMD during the trial compared to the control group. For people with high intakes and elevated blood levels of lutein and zeaxanthin, a decreased risk of both neovascular (wet AMD) and dry AMD was observed.

Wet AMD, characterized by leaky blood vessels behind the retina, is considered advanced-stage AMD, while the dry AMD develops slowly over time as light sensitive macular cells degenerate. There are several stages of dry AMD, including early, intermediate and advanced. Dry AMD is more common than the wet form, though wet AMD is usually more severe.

The Next Phase: AREDS 2

The new trial will be a multi-center, randomized study of 4000 participants aged 55 to 80 who have large drusen (yellow-white "spots under the retina) or advanced AMD in one eye. Participants will receive one of four supplements: either placebo, 10 mg of lutein along with 2 mg of zeaxanthin, 1 g of DHA and EPA, or a combination of the lutein, zeaxanthin, DHA and EPA.

AREDS 2 will start recruiting patients in 2006, with a 24-month recruiting period and 5 years of following participants. In addition, the investigators will evaluate a new version of the original AREDS supplements with a reduced level of zinc and without beta-carotene. While the main focus of AREDS II will be on AMD and cataract, the researchers also hope to learn more about the effects of EPA and DHA on mental function.

We won't know the results of AREDS 2 for a number of years. But in the meantime, it makes good sense to keep eating a diet rich in fruits and vegetables for antioxidant nutrients, especially dark green leafy veggies which are good sources of lutein, and to eat fish at least 2-3 times weekly for their heart-healthy omega-3 fats. And if your eye care practitioner has recommended that you take supplements of the original AREDS nutrients, be sure to follow that advice.

References

1. Chew, EY. AREDS links higher intake of DHA, EPA, lutein and zeaxanthin with decreased risk of AMD. Presented at ARVO Minisymposium, Bethesda, Maryland, May, 2005.
2. SanGiovanni JP and Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog in Retinal Eye Res 24:87-138, 2005.

Support for Macular Benefits of Omega-3

Reviewers from the National Eye Institute recently summarized the functions of the omega-3 fatty acids eicosapentenoic acid (EPA) and docosapentaenoic acids (DHA) in retinal tissues. [See EduFacts, Vol. 5 No 7]. According to the reviewers, studies looking at the relationship of the omega-3 fats to the prevalence of advanced AMD have generally observed a protective effect. A new study by Australian researchers adds to this growing body of evidence, and suggests that regularly consuming omega-3 fat, especially from fish, protects against early and late AMD in older individuals (1).

Design and Methods

To assess longitudinal associations between dietary fat and incident AMD, dietary intakes were measured by food frequency questionnaires at baseline in 2895 participants of the Blue Mountains Eye Study (BMES). Since the questionnaires can under- or over-report food consumption, dietary data were verified in a sub- group of participants who completed 4-day weighed food records 3 times over the course of a year. The results were generally in good agreement with the questionnaire data. Seventy five percent of the BMSE cohort (2335 persons) was re-examined after 5 years. Presence of AMD was graded from retinal photographs (Wisconsin ARM Grading System). Logistic regression adjusted for age, sex, vitamin C intake and smoking.

Results

The researchers examined the risk of incident AMD participants in the lowest and highest quintiles of dietary fat intakes with respect to the 60% of the population who represent a moderate, normal intake, or those in the middle 3 quintiles. Participants in the highest vs. the lowest quintiles of omega-3 fat intake had a lower risk of incident early AMD (odds ratio 0.41 [0.22-0.75])

A 40% reduction of incident early ARM was associated with fish consumption at least once a week (odds ratio 0.58 [0.37-0.90]). Consuming fish at least 3 times weekly resulted in about a 70% reduction in the incidence of late AMD (odds ratio 0.25 [0.06-1.00]). (See Table)

When the intake of specific types of fats was calculated, a trend toward increased risk of developing early AMD was noted for people with the lowest intake of monounsaturated fats and omega-3 including alpha-linolenic acid.

Comments

Though several population health studies have linked high dietary fat intake from any source to increased AMD risk, this study found no evidence that dietary fat of any kind raised that risk. The findings are largely in agreement with other studies showing that diets high in omega-3 fatty acids, particularly DHA derived largely from fish, may protect against retinal oxidation and degeneration, according to the authors. They propose that insufficient omega-3 intake could cause abnormal metabolism in the retina and affect cell renewal.

ORs and CIs of Early and Late ARM with Increasing Frequency of Certain Food Types in BMES Participants*
		5-y Incidence, OR (95% CI)
		Early ARM (n = 130)	Late ARM (n = 22)
Margarine
	<1/wk	1.00 (Reference)	1.00 (Reference)
	1-6/wk	.89 (0.57-1.38)	1.55 (0.44-5.40)
	Daily	0.87 (0.58-1.29	0.85 (0.33-2.22)
Butter
	<1/wk	1.00 (Reference)	1.00 (Reference)
	1-6/wk	0.48 (0.22-1.02)	0.82 (0.18-3.76)
	Daily	0.77 (0.48-1.24)	0.85 (0.27-2.66)
Total Fish †
	< 1/mo	1.00 (Reference)	1.00 (Reference)
	≥1/wk	0.48 (0.37-0.90)	0.44 (0.16-1.21)
	≥3/wk	0.62 (0.38-1.03)	0.25 (0.06-1.00)
Nuts
	Never	1.00 (Reference)	1.00 (Reference)
	≥ 1/wk	0.80 (0.52-1.25)	0.82 (0.29-2.34)
	≥ 1/wk	0.79 (0.46-1.34)	0.55 (0.14-2.16)
Abbreviations: ARM, age-related maculopathy; BMES, Blue Mountains Eye Study; CI, confidence interval; OR, odds ratio. *Food types are categorized by frequency of servings. † Includes sardines, tuna, and other fish.

References

1. Chua B, et al. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Archives Ophthalmol 124:981-6, 2006.

DHA and Cell Survival

A paper E-published in March, 2006 reports on the role that the omega-3 fatty acid docosahexaenoic acid (DHA) in fish oil plays in protecting cells in the retina from degenerative diseases like age-related macular degeneration and retinitis pigmentosa (1).

In both of these blinding eye diseases, photoreceptors (rods and cones) degenerate and die. Although this process can be triggered by many different things, one of the most significant protective factors may be the close association of retinal pigment epithelial cells (RPE) and the amount of DHA they contain.

The main role of RPE cells is photoreceptor maintenance. RPE cells conduct the daily shedding, internalization and degradation of the tips of photo-receptor outer segments. Now it appears that RPE cells are also crucial to the survival of photoreceptor cells.

Closer to Solving a Complex Riddle

Both RPE and photoreceptor cells are exposed to potentially damaging factors such as sunlight and high oxygen tension on a daily basis. It's known that antioxidants such as lutein afford some protection, but exactly how these cells avoid harm from these and other factors, has been somewhat of a mystery up to now. However, Nicolas Bazan, MD, PhD, Director of the Neuroscience Center of Excellence at LSU Health Sciences Center in New Orleans, working in col-
laboration with Harvard researchers, has made several important discoveries that are beginning to provide answers to this complex question.

One of the answers is the importance of DHA. RPE cells cope with UV and oxidative stress, as well as trauma, by using antioxidants like vitamin E present in cellular membranes. Part of the RPE cells' response to these insults is to activate the synthesis of a major neuroprotective compound called neuroprotectin D1 or NPD1. Oxidative stress and other triggers turn on genes that lead to inflammation and cell death. NPD1 inhibits these genes. RPE cells contain DHA, which has been found to be the precursor to NPD1.

The DHA - NPD1 Connection

RPE cells regulate the uptake, conservation and delivery of DHA to photoreceptor cells. In addition to stimulating the production of NDP1, DHA promotes protective cell signaling by facilitating the expression of helpful rather than destructive proteins. DHA and NPD1 also decrease the production of damaging free radicals.

DHA is known to be in short supply in patients with retinitis pigmentosa and Usher's syndromes, and an oral supply of DHA has been shown to improve the condition of retinitis pigmentosa patients with chronic progressive neurodegeneration (2). Additionally, studies have found that higher dietary intake of DHA is associated with AMD risk reduction. DHA has been shown to promote the survival and inhibit cell death not only of photoreceptor cells, but also of neurons in an experimental model of Alzheimer's disease.

Other important questions remain, including the identification of another receptor believed to be an important pathway for NPD1, and more information is needed about the signals that control NPD1 formation. It's important to define these initial events, notes Dr. Bazan, since early clinical manifestations of retinal degeneration precedes massive photoreceptor cell death.

References

1. Bazan NG. Review. Cell survival matters: docosahexaenoic acid signaling neuroprotection and photoreceptors. Trends in Nueroscience. [Epub ahead of print], March 30, 2006.
2. Berson EI, et al. Further evaluation of DHA in patients with retinitis pigmentosa receiving vitamin A treatment subgroup analyses. Arch Ophthalmol 122:457-64, 2004.

CVD & AMD Share Common Risks, Processes

A Harvard research team led by Dr. Johanna Seddon notes that age-related macular degeneration (AMD) and cardiovascular disease (CVD) share common risk factors, such as smoking and higher body mass index (BMI). They propose that mechanisms involved in developing AMD could be better understood by evaluating biomarkers of CVD. A number of analyses, in fact, have shown that systemic biomarkers for inflammation and artery damage, including C-reactive protein (CRP) and homocysteine (HCY), are related to AMD. Basic research also demonstrates that inflammatory, immune and atherosclerotic processes are related to AMD development.

To further explore mechanisms related to AMD pathogenesis, these researchers evaluated the relationships between CRP, HCY and other known risk or protective factors for AMD in subjects from the original AREDS trial (1). According to Dr. Seddon, the findings indicate that "sick eyes may occur in sick bodies related to smoking, overweight, inadequate nutrient intake, and other unhealthy behaviors".

Study Design

After randomization for AREDS, 934 subjects from two clinical sites underwent blood draws, measurements, photographs of the macula and answered questionnaires. Dietary, behavioral and medical risk, and protective factors for AMD were evaluated for their associations with blood values of CRP and HCY. This original data provided information on intake of fish as well as antioxidants such as vitamins C and E, alpha- and beta-carotene and lutein/zeaxanthin. In addition, serum nutrient values obtained from participants at one of the sites were also evaluated for their association with CRP and HCY. Multivariable regression analyses were performed after adjusting for age, gender and AREDS treatment.

Results

Higher levels of serum antioxidants vitamin C and lutein/zeaxanthin and higher fish intake (a source of omega-3 fats) were associated with lower serum CRP levels. CRP levels decreased 2 milligrams per litre for every 1000 microgram per decilitre increase in blood levels of lutein/zeaxanthin. A 0.2 milligram per litre decrease in CRP was also associated with more than 2 servings of fish weekly.

Increased BMI and smoking were associated with increased CRP, while serum alpha-carotene, dietary intake of antioxidants and vitamin B6 were associated with lower levels of plasma HCY. Levels of HCY were observed to be higher in those with hypertension. While serum vitamin E was linked to lower concentrations of HCY, it was unexpectedly linked to higher levels of CRP.

Comments

Factors reported to be related to AMD, namely antioxidants, smoking, BMI, HCY (2) and fish intake, are also associated with inflammatory, immune, or other CVD mechanisms. These results are consistent with previous findings associating smoking, BMI, and the biomarkers CRP and interleukin-6 with AMD in a different study cohort of AMD patients (3).

The relationship between fish intake, BMI, and levels of inflammatory markers have been previously reported in other "non-ocular" study populations. These data support and expand on these associations. The positive link between higher vitamin E and CRP deserves further study, according to the authors. This finding disagrees with the recent Rotterdam study, which found that vitamin E significantly lowered AMD risk [EduFacts Vol.6 No.1].

Overall, the Harvard study adds to a growing body of data showing a protective effect of antioxidants such as lutein/zeaxanthin, and omega-3 fats against AMD.

References

1. Seddon JM et al. C-reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration. Nutrition 22:441-43, 2006.
2. Seddon JM et al. Evaluation of homocysteine and risk of age-related macular degeneration. Am J Ophthalmol 141:201-3, 2006.
3. Seddon JM et al. Progression of age-related macular
   degeneration: prospective assessment of C-reactive protein, interleukin-6, and other cardiovascular biomarkers. Arch Ophthalmol 123:774-82, 2005.

A flurry of recent research suggests that there may be ways to improve our odds of preventing Alzheimer's or age-related mental decline through diet and life-style. Here's a look at some of the promising findings.

Mental Exercises for Brain Gain

Lead researchers from Pennsylvania State University report that mental exercise may play a key role in staving off age-related loss of mental agility (1). The research team divided the 2,800+ subjects aged 65 and older into four groups of roughly 700 to receive training in either memory, reasoning or speed of processing, and a control group that received no instruction. Memory training consisted of strategies to remember word lists or texts, such as associating various words, visualizing them or organizing them in specific ways. Reasoning training taught subjects how to spot the pattern in a series of letters or numbers. Processing speed was enhanced by repeated practice in identifying an object on a screen after increasingly shorter visual exposures.

Training Yields Long Term Improvements

Participants were asked to appraise their own skills, and indicate whether the training helped with every-day tasks. Practical skills like finding items in a medicine cabinet were also independently evaluated by the scientists. After training, 87% of the speed trainees, 74% of the reason trainees and 26% of the memory trainees showed immediate improvement.

That advantage over their untrained peers persisted over the next 5 years. Compared to controls, the memory group, for example, was able to remember about 3-4 more words from a list of 12-15. Some who got refresher training 1and 3 years after the initial instruction performed best of all, especially those in the speed-processing group. Tasks like making change for a purchase or reading medication labels were performed more quickly and efficiently.

Most impressively, the training seemed to largely offset the cognitive decline experienced by nearly of the control subjects. By the end of 5 years, a significant gap had opened between those in the instruction groups and controls. According to one of the study's authors, "to drive this effect, you have to practice things you don't necessary like or things you don't regularly practice". In other words, it may not be quite as simple as doing crossword or sudoku puzzles. In the future, the authors hope to make these training programs more widely available. It's not hard to envision mental exercise programs in senior centers nationwide to help prevent mind decline as we age.

Dietary Strategies for Brain Fitness

Research shows that brain levels of DHA decrease with age, and that getting more DHA later in life increases brain content. The December, 2006 issue of Staying Healthy describes a Tufts study which links higher blood levels or intake of DHA (from fish) to a significantly lower risk of Alzheimer's and dementia. A second double-blind study from Sweden found that omega-3 supplements slowed mental decline in people with very mild Alzheimer's, though the group with mild disease was small and no effect was seen in people with more advanced forms (2). In addition, a small study from Japan reports improvements in immediate memory and attention in patients with mild cognitive impairment after taking DHA and arachidonic acid supplements (vs. placebo) for 3 months (3).

Since the Mediterranean diet is abundant in seafood, it's no surprise that it would also show promise in protecting mental function. But that diet's potential benefits may extend beyond its fish content. Scientists report that subjects most closely following a "Med" style diet consisting mostly of vegetables, legumes, fruits, cereals and some fish were almost 40% less likely to develop Alzheimer's than those with the poorest adherence (see the August, 2006 issue).

Lastly, a series of studies conducted at Tufts have shown that diets enriched with antioxidant-rich blueberries, strawberries, cranberries or grape juice can reduce or reverse declines in brain function in laboratory animals.

References

1. Willis SL, et al. Long-term effects of cognitive training on everyday function outcomes in older adults. JAMA 296:2805-14, 2006.
2. Freund-Levi Y, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD Study. Arch Neurol 63:1402-8, 2006.
3. Kotani S, et al. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 56:159-64, 2006.

DHA, Fish Lower Risk for Alzheimer's

Coldwater, fatty fish are a concentrated source of the omega-3 fats docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Population health studies have consistently shown positive health effects from fish consumption and, now, a study published in the November issue of The Archives of Neurology, links greater fish intake to a lower risk of developing Alzheimer's and other dementias (1). And in this study, DHA was most important for cutting risk.

Using data from the Framingham Heart study, researchers followed about 900 healthy participants for an average of more than 9 years. During that time, 99 people developed dementia including 71 cases of Alzheimer's. Researchers quantified the amount of DHA and fish the participants typically consumed by dietary questionnaires, and measured the level of fatty acids in their blood.

DHA Cuts Risk of Dementia by Nearly 50%

The top 25% of study volunteers with the highest blood levels of DHA reduced their risk of developing dementia by 47%. They were about half as likely to develop dementia as the 75% of participants with lower levels of DHA in their blood. The risk reduction was seen even after controlling for other known or suspected risk factors for dementia such as smoking, overweight, high blood pressure and diabetes.

Participants who ate two or more servings of fish weekly reduced their dementia risk by 39%, while those who ate less had no risk reduction.

According to the study's authors, the observation that DHA seems to be key in lowering dementia risk is consistent with earlier data showing high levels of DHA in healthy brain tissue and low levels in the brains of people with Alzheimer's. The next step will be to conduct placebo controlled trials of DHA in people who don't yet have Alzheimer's to see whether DHA can help protect against this disease.

Active Lifestyle Could Protect Against AMD

Exercise may help protect against age-related macular degeneration (AMD) according to the results of a large study supported by the NIH and published in the British Journal of Ophthalmology (2). The authors examined the relationship between physical activity and AMD because heart disease and AMD appear to share common risk factors. And regular exercise, as we all know, is good for the heart and arteries.

Participants in the Beaver Dam Eye Study were followed for 15 years. During that time they were given eye exams periodically, and they filled out questionnaires at the beginning of the study to assess their level of activity. They were asked how many flights of stairs they climbed daily, how many city blocks they walked each day, and how often each week they engaged in physical activity that involved working up a sweat.

Compared with sedentary people, those who participated in regular activity 3 times weekly were less likely to develop wet AMD. Those with an active lifestyle - defined as engaging in an activity that resulted in sweating 3 or more times each week - reduced their risk of wet AMD by 70%. Walking 12 or more blocks daily lowered that risk by 30%.

Walk Daily, Put More Fish on Menu

Can't get to the gym or participate in vigorous exercise? Try walking at least a mile daily. Though each city and each block vary in length, walking 8-12 city blocks is roughly equivalent to a mile. It's certainly good for heart and may help your eyesight as well.

For better mental function as we age, remember that fatty fish is best, and frying fish can cause some deterioration of its DHA content. You can also consider augmenting your intake of DHA and EPA with supplemental fish oil.

References

1. Schaefer EJ, et al. Plasma phosphatidylcholine docosahexaenoic Acid content and risk of dementia and Alzheimer disease: the Framingham Heart study. Arch Neurol. 63:1545-50, 2006.
2. Knudtson MD, et al. Physical Activity and the 15-year Cumulative Incidence of Age-related Macular Degeneration: The Beaver Dam Eye Study. British J of Ophthalmology, published online Oct. 31, 2006.

Diet May Keep Chronic Lung Disorders at Bay

You don't smoke, and you avoid second hand smoke and air pollution as much as possible. Are there other steps you can take to help maintain healthy airways and lung function? Well, research suggests that your diet can influence the risk of chronic bronchitis and asthma, and may lessen symptoms for those who already suffer from such conditions.

Mediterranean-Style Diet Fends Off COPD

Consuming a "Med"-style diet rich in fruits, veggies and fish may halve the risk of chronic obstructive pulmonary disease (COPD), the umbrella term for chronic bronchitis and emphysema (1).

Harvard researchers tracked more than 42,000 male health professionals for 12 years, ranking them by how closely they followed a Med style diet or how much they stuck to a Western dietary pattern. After adjusting for age, smoking and other factors, greater adherence to the Med diet was associated with a 50% decrease in COPD risk compared to men with the lowest adherence. At the same time, men who followed a Western style diet most closely were about four and a half times more likely to suffer from newly diagnosed COPD as those who ate the least from that menu.

The Western diet was defined as one high in processed foods, refined grains, cured and red meats, French fries and deserts. The researchers noted that this diet contains nitrites used to preserve or color foods such as bacon, corned beef, luncheon meats, sausage and ham. Nitrites generate free radical compounds that could contribute to progressive deterioration of pulmonary function. A high-glycemic diet like the Western eating pattern has also been linked to impaired lung function.

In contrast, a Med-style diet is rich in beta-carotene, vitamins C and E, polyphenols (bioflavonoids), omega-3s, and essential minerals. It is these antioxidants and polyphenols that appear to offer protection. According to the study authors, their findings are consistent with previous study results suggesting a beneficial effect for antioxidants on COPD - particularly vitamin C and, to a lesser extent, vitamin E.

Fish & Whole-Grains Guard Against Asthma

A study published late last year also supports components of the Med-style diet as helpful for young asthmatics (2). With the assistance of their parents, Dutch public health researchers assessed the diets of nearly 600 children 8-13 years old.

The investigators found that whole grains and fish intake were most closely linked with asthma risk. High intakes of whole grains and fish were associated with a 54% and 66% reduction in the odds of having asthma, respectively. Kids who consumed a high intake of both foods experienced significantly less wheezing. Only 4.2% of children who ate the most grains and fish suffered wheezing, while 20% of those eating the least exhibited this symptom.

It's also worth noting that a diet rich in antioxidants found in fruits and veggies is important for expectant moms. A study conducted by Harvard researchers found that higher maternal intakes of antioxidants during pregnancy decrease the risk for wheezing illnesses in early childhood (3).

Fish Oil Helps Exercisers with Asthma

Exercise is a powerful trigger of asthma symptoms in about 80% of asthmatics. Vigorous exercise can cause airways to narrow, resulting in shortness of breath, wheezing and chest tightness. Recently, researchers from Indiana University tested the ability of fish oil to reduce the severity of these symptoms (4). They found that when asthmatics were given high dose fish oil supplements instead of placebos, they had better pulmonary function and needed to use a bronchodilator less frequently after a bout of exercise.

References

1. Varraso R, et al. Prospective study of dietary patterns and chronic obstructive pulmonary disease among US men. Thorax (Br Med J) E pub online, May 15, 2007.
2. Tabak C, et al. Diet and asthma in Dutch school children (ISAAC-2). Thorax (Br Med J) 61:1048-53, 2006.
3. Litonjua AA, et al. Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age. Am J Clin Nutr 84:903-11, 2006.
4. Mickleborough TD, et al. Protective effect of fish oil supplementation on exercise-induced bronco-constriction in asthma. Chest 129:39-49, 2006.

Chances are that we all know someone who has been diagnosed with coronary heart disease (CHD). It is, after all, one of the most common chronic diseases. Diet is a first line defense for preventing and treating this condition, yet evidence suggests that the benefits of following the Mediterranean diet may outweigh those of low-fat diets often prescribed for people with CHD. In the Lyon Diet Heart Study, for example, the Mediterranean style dietary approach was found to be better than the older American Heart Association's low-fat diet in preventing heart attacks in people with heart disease. It was also more protective against certain cancers.

What is The Mediterranean Diet?

This eating pattern is based on the traditional diets of Greece, Crete and southern Italy. The pattern is similar but varies a bit in the 16 countries that border the Mediterranean Sea due to cultural differences. But here's what the overall pattern looks like: lots of vegetables and fruit, whole grain breads, unrefined cereals and dairy daily, with olive oil as the main source of added fat. It calls for fish, poultry and nuts weekly, with very moderate intake of sweets, eggs and potatoes. Red meat is eaten sparingly, about once a week, but moderate red wine is consumed daily.

Why is This Diet Heart-Healthy?

The fats you get from the Mediterranean diet are important. At least some of the diet's cardio-protective effects are due to the omega-3 fats found in fish. Fish oils have been shown to reduce the rate of heart attack and stroke over the long term. The diet contains a moderate amount of fat, with more coming from fish and less from red meat. It also relies on fats from heart-healthy nuts and olive (or canola) oil as the primary added fat. This type of fat has a more favorable effect on triglycerides and the "good" HDL cholesterol compared to the more typical low-fat diet. Another important benefit comes from whole grains and unrefined cereals. They offer lots of fiber and essential nutrients, as do vegetables and fruits.

Embracing the Mediterranean style diet doesn't mean you have to follow it exactly. For one thing, the number of servings will vary depending on body size, level of activity and overall calorie needs. Including foods from your own culinary heritage can be important too. Certain Asian patterns of eating are actually similar to the Mediterranean diet in that they focus on eating less red meat and more plant-based sources of fat and protein. If you use the pyramid as a general guide, here are a few things to keep in mind:

• Daily physical activity is the foundation of any healthful pyramid. Start by doing what activities you can do, since every little bit helps;
• Most people, especially non-dairy consumers, may need to take supplemental calcium and vitamin D. A healthy diet pyramid designed by Harvard experts also suggests taking a daily multi-supplement;
• While moderate alcohol intake is cardio-protective, daily consumption may not be right for everyone. Red wine can be a trigger for some migraine suffers, for example, and older women at risk for breast cancer are advised to limit alcohol consumption.
• Lastly, if you have an existing disease it's best to follow your health professional/s dietary advice.

References

1. Curtis BM et al. Understanding the Mediterranean diet. Postgrad Med 112:online, 2002
2. Bautista MC et al. The Mediterranean Diet: Is it cardioprotective? Prog Cardiovasc Nurs 20:70-76, 2005.
3. Kinney JM. Challenges to rebuilding the US Food Pyramid. Cur Opin Clin Nutr Metab Care 8:1-7, 2005.