Omega-3 fatty acids have been shown to influence a wide range of chronic diseases through their ability to direct eicosanoid metabolism towards anti-inflammatory pathways. Omega-3 fats include long chain omega-3 fats such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly found in fish, and α-linolenic acid (ALA) found in some plant oils.

These fats are well known for their anti-inflammatory effects and benefit to lower serum triglycerides. Additionally, in the diet, fatty fish rich in omega-3 fatty acids have demonstrated cardiovascular protection and may assist in reducing metabolic syndrome and helping to prevent obesity comorbidities. While DHA is found in the highest concentrations in the brain and retina, it can be found in every cell membrane. Hence, DHA is thought to possibly be helpful for cognitive function.

What are omega-3 fatty acids?
Omega-3 fatty acids, as well as omega-6 fatty acids, are considered to be essential because they must be consumed in the diet. The richest dietary sources of omega-3 fatty acids include cold-water fish (sardines, wild salmon, black cod, trout, herring, mackerel), ground flax, chia seeds, walnuts, and hemp hearts. The plant sources provide ALA while the animal sources provide EPA and DHA. ALA can theoretically be converted to EPA and DHA though it’s known to not be the most efficient process. This is especially the case if you have a gene variant involving the enzyme fatty acid desaturase (FADS). Therefore, consuming EPA and DHA directly from foods and/or dietary supplements is the only practical way to increase levels of these fatty acids in the body.

Some research suggests that the balance of omega-6:omega-3 fatty acids to have critical importance in the pathogenesis of many chronic diseases, such as cardiovascular disease and cancer, but the optimal ratio has not been conclusively determined. I, and many others, like to strive for omega-6:omega-3 ratio, ideally 1:1 up to 4:1. A high ratio, particularly noted in the American diet can be 10:1, even 20:1 omega-6: omega-3 fatty acids – this imbalance may play a role in the development of obesity and related diseases. Regardless of the ratio, researchers agree that raising EPA and DHA blood levels is far more important than lowering linoleic acid or arachidonic acid levels, the two types of essential omega-6 fatty acids.

How much do we eat? The American diet includes ~.25 grams omega-3 fatty acids daily compared with the Japanese diet that contains 5-6 grams daily. How much is that in regards to foods?

• 3-ounces wild salmon: 1.6 grams DHA/EPA

• 3-ounces herring: 1.7 grams DHA/EPA

• 3-ounces sardines 0.9 grams DHA/EPA

• 3-ounces black cod/sablefish: 1.5 grams DHA/EPA

• 1 tablespoon ground flax: 1.6 grams ALA

• 1 tablespoon chia seeds: 1.8 grams ALA

• 1 tbsp hemp hearts: 0.9 grams ALA

• ¼ cup walnuts: 2.6 grams ALA

The Dietary Guidelines for Americans recommend consuming the equivalent of ~250 mg/day of EPA and DHA, which corresponds to eating fish twice weekly. The U.S. Food and Drug Administration claims that levels up to 3 grams/day are considered safe; other authorities suggest levels up to 5–6 grams/day are safe.

Cardiovascular Health
Various research studies have shown that higher consumption of fish and higher dietary or serum levels of omega-3 fatty acids are associated with a lower risk of heart failure, coronary disease, and fatal coronary heart disease. Omega-3 fatty acids regulate lipid metabolism, favoring fatty acid oxidation and suppression of lipogenesis, which leads to a favorable lipid profile. Fish oil and other omega-3 supplements lower triglyceride levels and might reduce the risk of some cardiovascular endpoints, especially among people with low dietary omega-3 intakes. The American Heart Association recommends 4 grams daily EPA + DHA to reduce serum triglyceride values; each 1 gram/day of omega-3 fatty acids reduced triglyceride levels by 5.9 mg/dL, and the effect was stronger in people with higher baseline triglyceride levels. It may be that the cardioprotective effect for omega-3 supplementation is stronger for people with existing coronary heart disease than for healthy individuals.

Gut Microbiome
It is well known that our gut microbiome is essential to virtually all aspects of health. In animals, omega-3 fatty acid supplementation was beneficial to restore the gut microbiota and regulate immunity. Various studies have found that EPA and DHA can reverse intestinal microbial dysbiosis by increasing beneficial bacteria species, including Lactobacillus, Bifidobacterium, and protective butyrate-producing bacteria. Furthermore, omega-3 fats decrease the proportions of ‘not so nice’ LPS-producing and mucolytic bacteria in the gut, and they can reduce inflammation as well as oxidative stress.

Cancer
While some studies have found that higher intake and/or blood levels of omega-3s were associated with a lower risk of certain cancers, the outcomes of human studies are not overly positive. It’s very possible that the anticancer effects of omega-3 fatty acids are dose-dependent; preclinical studies often use high concentrations, and the consumption of omega-3 fatty acids in most countries is too low to yield a protective effect. In the VITAL trial, omega-3 supplementation of 1 gram daily (containing 460mg EPA and 380 mg DHA) had no significant effect on cancer incidence, cancer mortality rates, or the development of breast, prostate, or colorectal cancers. Nonetheless, a cohort study of over 35,000 post-menopausal US women suggested that taking omega-3 supplements was associated with a 32% reduction in breast cancer risk, although other cohort studies are not consistent in this relationship. A meta-analysis of prospective cohort studies did not show an association between omega-3 fatty acid intake and colorectal risk and efforts to associate omega-3 fatty acid intake with prostate cancer risk are mixed. The risk of endometrial cancer was significantly reduced in women with a BMI <25 who had a greater intake of omega-3 fatty acids (EPA, DPA, DHA). Data from the WHEL study suggested that consuming more than .73 grams daily of EPA and DHA from food reduced breast cancer events and all-cause mortality. Additionally, a recent analysis indicated that lower ratio of omega-6/omega-3 fatty acids is associated with a reduced risk of breast cancer in Asian countries, more so than in Western countries. There may be multiple mechanisms at play. All in all, the anti-inflammatory and anticancer effects of omega-3 fatty acids do lead to inhibition of cell proliferation and apoptosis, or programmed cancer cell death.

Omega-3 Fatty Acids may Ameliorate Side Effects of Chemotherapy
Observational data suggest that omega-3 fats are associated with less fatigue in breast cancer patients undergoing chemotherapy. Additionally, encouraging findings indicate that diets high in omega-3 fatty acids and low in added sugar content may be protective against the cognitive side effects associated with chemotherapy, possibly working through mechanisms associated with inflammation, oxidative stress, and neural protection. Overall, high amounts of sucrose and fructose seem to impair memory, while omega-3 fatty acids appear to be protective.

Omega-3 Fatty Acids and Cancer Treatments
Omega-3 fatty acids may enhance clinical benefit of doxorubicin, cisplatin and vincristine. Additionally, EPA enhances the apoptotic and cancer cell inhibiting effects of oxaliplatin + 5-FU. A recent melanoma trial found that lower omega-3 fatty acid and lower fiber consumption was linked to a poorer response to immunotherapy conferring a plausible protective effect of omega-3 fatty acids.

Peripheral Neuropathy
Research has demonstrated that the production of proinflammatory cytokines which induce neuropathy is reduced by EPA and DHA, in particular DHA. Omega-3 fatty acids have been shown to be effective in reducing neuropathy from paclitaxel and oxaliplatin. A randomized, double-blind placebo controlled trial found that 70% of those who consumed 640 mg omega-3 fatty acids (54% DHA and 10% EPA) three times a day did not experience peripheral neuropathy compared with 40.7% for those who did not consume omega-3 fatty acids. The study was small but suggested a benefit without adverse effects. Recommended dosage for chemotherapy induced peripheral neuropathy is 600mg-2000 mg daily.

Blood Sugar & Insulin Resistance
Despite strong evidence in animal studies, human research is mixed regarding omega-3 fats and insulin resistiance. This meta-analysis demonstrated that fish oil supplementation did not improve insulin sensitivity overall though in a subgroup analysis among participants with metabolic disorders, fish oil supplementation reduced the risk of insulin resistance by 47%. In another trial, omega-3 fatty acids (1,200 mg DHA + EPA) for 12 weeks appeared to improve insulin sensitivity and reduce triglyceride levels in individuals with a high risk of type 2 diabetes. These benefits may occur due to the omega-3 fatty acids effect to reduce adipose tissue inflammation. Furthermore, this trial suggested that fish oil exerts positive effects on fasting insulin. Overall, however, the research is weak; omega-3 fatty acids seem to have little effect on type 2 diabetes or measures of glucose metabolism including insulin resistance, including hemoglobin A1C, fasting glucose, or insulin.

Body Weight
A high omega-6 fatty acid intake and a high omega-6/omega-3 ratio are associated with weight gain in both animal and human studies. Research indicates that increasing the intake of omega-3 fatty acids by 0.3–3.0 grams/day is effective for reducing body weight and improving body composition in humans. These findings, however, are from short-term studies (3–12 weeks in duration) and have for the most part shown that omega-3 fatty acids promote modest reductions in body weight and improvements in body composition when taken either alone, or in conjunction with an energy restricted diet. It does seem that omega-3 fatty acids are particularly helpful in reducing visceral fat, the fat that surrounds internal organs. One theory is that high omega-6 fatty acids increase leptin resistance and insulin resistance, whereas omega-3 fatty acids lead to homeostasis and weight loss. Another mechanism may be that omega-3 fatty acids enhance satiety and hence may lead to reduced food intake. The most evidence points to omega-3 fatty acids having the effect to modulate gene expression related to enhanced fat oxidation and reduced fat deposition.

Cognitive Health
Some, but not all, observational studies suggest that diets high in omega-3 fatty acids are associated with a reduced risk of cognitive decline, Alzheimer’s disease, and dementia. Overall, research is not yet sufficient to indicate that omega-3 supplementation affects cognitive function in healthy older adults or in people with Alzheimer’s disease compared to placebo. For people with mild cognitive impairment, omega-3 fats may improve certain aspects of cognitive function, including attention, processing speed, and immediate recall. Lower serum DHA levels are also associated with more cerebral amyloidosis (build-up of protein deposits called amyloids that increase the risk of stroke and dementia) in healthy older adults, whereas higher DHA is correlated with preservation of brain volume. However, a trial published in September 2022 found that higher omega-3 fatty acid levels in the blood were related to better brain structure and cognitive function in predominantly middle-aged men and women without dementia.


Inflammation
It is well known that omega-3 fatty acids inhibit inflammation; DHA plays a role in immune cell signaling pathways critical to inflammation. For humans to elicit an anti-inflammatory response, a total EPA and DHA intake of greater than 2 grams daily seems to be required.

Dietary Supplements
The use of fish oil supplements, rich in omega-3 fatty acids, increased significantly from 1.3% in 1999-2000 to 12% in 2011-2012. Does that mean that you need to be using them? Of course not, but it may be worth considering. Omega-3 fatty acids can be found in several dietary supplement formulations, including fish oil, krill oil, cod liver oil, and vegetarian products that contain algal oil. A typical fish oil supplement provides about 1,000 mg fish oil, containing 180 mg EPA and 120 mg DHA, but doses vary widely. A higher quality, more potent, omega-3 dietary supplement contains 562.5 mg EPA and 437.5 mg DHA in one gelcap [Nordic Naturals ProOmega2000] or even a total of 3400 mg omega-3 fatty acids (1950 mg EPA, 975 mg DHA, 475 mg other omega-3s) in 1 teaspoon [Nordic Naturals ProOmega D-Xtra].

What should you look for? First and foremost, be sure that the product uses molecular distillation to remove any mercury and toxins. If third party tested, even better – someone else is reporting their data, so you’re sure that it’s accurate. The type of omega-3 also matters. Omega-3 fatty acids as re-esterified triglycerides, natural triglycerides, and free fatty acids have somewhat higher bioavailability than ethyl esters. In small print, the bottle will likely state this. If not, it may be a good idea to put that bottle back on the shelf and keep looking. Krill oil contains omega-3 fatty acids primarily as phospholipids, and limited research suggests that these have somewhat higher bioavailability than the omega-3s in fish oil, but they’re also found in lower dosages. Generally speaking, one gelcap may contain 440-500 mg krill oil (40-105 mg EPA, 22-80 mg DHA). Plant-based sources of omega-3 fatty acids from algal oil usually provide around 100–300 mg DHA; some contain EPA as well. These supplements typically contain omega-3s in the triglyceride form.

Generally speaking, fish oil supplements are a source of omega-3 fatty acids and are considered safe (from adverse affects) by the FDA at intakes up to 3 grams daily, and up to 4 grams daily when under the care of a physician who can monitor the potential for abnormal bleeding function. As with most dietary supplements, you do want to discontinue omega-3 supplementation 7-10 days prior to surgery.

Testing Omega-3 Fatty Acid Levels
The omega-3 index is the proportion of long-chain omega-3 fatty acids, EPA and DHA, of all fatty acids on your red blood cell membranes. It reflects the omega-3 status of your body over the previous four months. Ideally, an omega-3 index in the 8-12% range may help to maintain heart, brain, eye, and joint health.

Quest Diagnostics offers a test called OmegaCheck (test code 92701) – this test is generally covered by your medical insurance if ordered by your physician. OmegaCheck measures total and individual omega-3 and omega-6 fatty acids as well as the ratio of omega-6:omega-3 fatty acids.

OmegaQuant is a private company that offers a few omega-3 fatty acid tests; they range from $49-$99.95. The Omega-3 Index Basic Test measures your omega-3 index. The Omega-3 Index Plus Test reports your omega-3 index, ratio of omega-6:omega-3 fatty acids, and trans fat index. The Omega-3 Index Complete Test measures all the fatty acids in the blood, and reports levels of all 24 fatty acids, as well as the Omega-3 index, ratios, and the trans fat index. If you’re interested in viewing a sample report, click here. If at all interested, click HERE to order a kit for a 5% discount. These are blood spot tests that you can run yourself at home; no medical order is required.

Bottom Line
While research is not conclusive on all fronts, evidence suggests that omega-3 fatty acids are beneficial for inflammation, reducing serum triglycerides, cognitive function, improving tolerance to cancer treatments, peripheral neuropathy, and possibly more. Eat dietary sources of omega-3 fatty acids. If you’re open to it, I would include both plant sources and clean, cold-water fish. Consider a supplemental source – and be sure it’s high quality, molecularly distilled, and providing ample omega-3 fatty acids in each cap or teaspoon. Want to be sure you're covering your bases, test Omega Check or OmegaQuant.

With more holidays around the corner, do your best to take care of your mind and body.

In Health,
Natalie