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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 10, 2026
Reviewed October 12, 2026
30 sources · Measured in %

System: Mitochondria & Cellular Energy

Omega-3 indexRed-cell EPA + DHA · HS-Omega-3 Index

In cohorts, people whose red-cell EPA plus DHA sat in the top fifth (above about 6.8 to 8 percent) died at about 15 to 34 percent lower rates than those in the bottom fifth (below about 4.2), but randomized trials of about a gram a day of EPA plus DHA prevented no deaths and no major cardiovascular events, 4 g of purified EPA cut events in one trial while 4 g of EPA plus DHA did not in another, high doses raised atrial fibrillation, and no trial has ever treated anyone to an index target, so the index is best read as a reliable measure of fish and fish-oil intake whose link to outcomes is association, not proof.

The omega-3 index is the share of a red blood cell's fatty acids that is EPA plus DHA, a stable record of the past few months of fish and fish-oil intake. Most routine panels do not include it; the commercial test prints under 4 percent as high risk, 4 to 8 as intermediate and above 8 as low risk, cutpoints proposed in 2004 from sudden cardiac death data. Cohorts of 2,500 to 42,466 people found the lowest mortality at the top of the range; the large supplement trials mostly found nothing, with one exception and one safety signal.

01 · The scale

Where the laboratory range and the evidence sit.

In cohorts, the top fifth of red-cell EPA plus DHA (above about 6.8 to 8 percent) carried about 15 to 34 percent lower all-cause mortality than the bottom fifth (below about 4.2); in randomized trials, about a gram a day of EPA plus DHA changed neither death nor major cardiovascular events, 4 g of purified EPA cut events by a quarter in one trial and 4 g of EPA plus DHA did not in another, and doses above a gram raised atrial fibrillation by about half.

024681012

  1. Printed as high risk by the commercial red-cell test

    0 to 4 % · Harris and von Schacky 2004 cutpoints

  2. Printed as intermediate risk

    4 to 8 % · Harris and von Schacky 2004 cutpoints

  3. Printed as low risk

    8 and above % · Harris and von Schacky 2004 cutpoints

  4. Highest mortality fifth in Framingham (median 3.7)

    0 to 4.2 % · Harris 2018

  5. Typical US adult not taking supplements

    4 to 5 % · Flock 2013; Jackson 2019

  6. Lowest mortality fifth in Framingham (median 7.8); 34 percent lower all-cause death than the lowest fifth

    6.8 and above % · Harris 2018

  7. Median of the top fifth across 10 cohorts (8.3); usual level around the Sea of Japan and in Scandinavia

    8 and above % · Harris 2017; Stark 2016

  8. No randomized trial has treated anyone to an index target at any level; achieved blood levels in STRENGTH predicted no benefit

    0 and above % · Nissen 2021; Abdelhamid 2020

  • Laboratory range
  • Evidence supports
  • Guideline goal or unstudied
  • Higher risk in studies
Scale in %. Percent of total red-cell fatty acids. A plasma omega-3 index is a different test on a lower scale and cannot be read against these numbers. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What Omega-3 index measures.

The omega-3 index is the content of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) in red blood cell membranes, expressed as a percent of total fatty acids. Red cells turn over slowly, so the number reflects long-term intake rather than the last meal: in a controlled feeding study of 58 men, EPA entered red-cell membranes with a half-life of 28 days and reached a steady state after 180 days, and the authors concluded that red cells report intake over the past month or two. In 20 volunteers sampled weekly for six weeks, the within-person variation of red-cell omega-3 content was 4.1 percent, against 15.9 percent in whole plasma and 14.5 percent in plasma phospholipids, and the red-cell value was not altered by a prior meal.1,2,3Grade B

The index was proposed in 2004 by two lipid researchers who assembled published case-control and prevention data and concluded that an index of 8 percent or above went with the greatest protection from coronary death and 4 percent or below with the least. The strongest single dataset behind it was a nested case-control study in the Physicians' Health Study: among apparently healthy men followed up to 17 years, blood long-chain omega-3 levels were compared in 94 who died suddenly as their first sign of heart disease and 184 matched controls, and the adjusted relative risk of sudden death was 0.28 in the third quartile and 0.19 in the fourth, against the lowest quartile. Those are the origins of the 4 and 8 percent lines: a small number of sudden deaths, not a trial.1,4Grade C

Levels follow diet. Americans who do not take supplements average about 4 to 5 percent; in 115 healthy young adults who ate little oily fish, the mean was 4.3 percent with a range of 2.3 to 6.8. Among 3,458 adults, 84 percent of them in the United States, who bought the test themselves, the mean was 5.99 percent, about half took omega-3 supplements and 32 percent reported eating no fish at all. A survey of 298 studies of healthy adults placed red-cell-equivalent EPA plus DHA above 8 percent around the Sea of Japan, in Scandinavia and in populations not fully adapted to Western food habits, and at or below 4 percent across North America, Central and South America, Europe, the Middle East, Southeast Asia and Africa.5,6,7Grade C

03 · Origins

Where it came from, and where it sits in the network.

The long-chain omega-3 fats are, for practical purposes, products of the sea. Marine ecosystems account for virtually all production of EPA and DHA, and the standing explanation has been that marine microbes, the microscopic algae of the plankton among them, make them at the base of the food web with methyl-end desaturase enzymes that vertebrates lack, so that fish carry what they ate. A 2018 survey complicated the picture by finding 121 methyl-end desaturase sequences in 80 species of cnidarians, rotifers, mollusks, annelids and arthropods, some acquired by horizontal gene transfer, and by showing that several invertebrates can make omega-3 fats from scratch; the authors call it a fundamental revision of where the world's omega-3 comes from, though the marine base of the food web still stands. Land plants supply the 18-carbon alpha-linolenic acid, and stable-isotope studies in adults show that conversion of it to EPA is limited and to DHA very low, so the red-cell index tracks EPA and DHA eaten preformed, from fish, seafood or supplements.8,9Grade C

DHA's place in the brain has generated an evolutionary hypothesis and a serious objection to it. Crawford and colleagues argued in 1999 that the expansion of the human brain required a plentiful source of preformed DHA, that the savanna offers little of it while the marine food chain is the richest source, and therefore that the transition to modern humans took place at the land-water interface; a later version from Cunnane and Crawford adds that the human infant's unusual layer of body fat stores DHA and fuels the brain with ketones, and that a shore-based diet of fish, shellfish, frogs, birds' eggs and aquatic plants is the richest source of the brain-selective nutrients, iodine and iron foremost among them. Carlson and Kingston replied that the key premise, that making DHA from alpha-linolenic acid is not just inefficient but insufficient, is not well supported, and that much evidence suggests plant-source alpha-linolenic acid is enough for normal brain development in modern humans and presumably in our ancestors. Both positions are hypotheses about the past; neither is a finding about a blood test today.10,11,12Grade C

Humans have also adapted to their omega-3 supply genetically, which is one reason the same diet produces different blood levels in different people. A genome scan of Greenlandic Inuit, whose traditional diet is rich in omega-3 fats, found its strongest signal of selection in the cluster of fatty acid desaturase genes that set polyunsaturated fat levels; the selected alleles altered membrane fatty acid composition and carried large effects on height and weight. Those desaturases are the enzymes that carry alpha-linolenic acid toward EPA, so the index is a product of three things at once: what was eaten, which desaturase variants a person carries, and how fast red cells turn over. It is the marker on this shelf that comes closest to a pure record of diet, which is also its usefulness.13,9Grade C

04 · The laboratory range

What a laboratory calls normal.

Not on most routine panels. The commercial red-cell test prints under 4 percent as high risk, 4 to 8 as intermediate and 8 percent or above as low risk.

Those three bands are the 2004 proposal's cutpoints, carried onto the report as risk categories: high risk at or below 4 percent, intermediate above 4 and below 8, and low risk at or above 8. They are not a population reference interval. When the same group later re-analyzed published data from 10 cohorts of more than 27,000 people, the mean index was 6.1 percent with a standard deviation of 2.1, the hazard ratio for fatal coronary disease was 0.85 per standard deviation, the medians of the lowest and highest fifths were 4.2 and 8.3 percent, and the authors estimated about 30 percent lower fatal coronary risk moving from 4 to 8 and called under 4 and over 8 reasonable therapeutic targets. That is an estimate from observational data by the index's proponents, which is how the printed bands should be read.14,15Grade B

The sample type sets the scale. In the VITAL trial the omega-3 index was measured in plasma rather than red cells, and the mean was 2.67 percent, a number that would read as alarming on the red-cell scale and is not comparable with it. The 17-cohort pooled analysis combined erythrocyte phospholipids, plasma phospholipids, cholesteryl esters and total plasma by standardizing each cohort to its own quintiles, and the global survey converted every blood fraction to red-cell equivalents before mapping it. A result is comparable only with another result from the same sample type and method, which in practice means the same laboratory.16,17,7Grade B

05 · The evidence

What the studies support.

In the Framingham Offspring cohort, 2,500 adults free of cardiovascular disease (mean age 66, 54 percent women) were followed for a median of 7.3 years, during which 350 died and 245 had a cardiovascular event. After adjustment for 18 variables, those in the highest fifth of the omega-3 index (above 6.8 percent, median 7.8) had a 34 percent lower risk of death from any cause and a 39 percent lower risk of incident cardiovascular disease than those in the lowest fifth (below 4.2 percent, median 3.7). When the original cutpoints were tested, the intermediate group (4 to 8) differed from the high-risk group, but the 8 percent and above group, only 10 percent of the sample, did not reach significance (hazard ratio 0.69). The authors wrote that from an observational study they could not conclude that raising the index would have heart benefits or prolong life.14Grade B

Two larger datasets agree on direction and shrink the size. In the Women's Health Initiative Memory Study, 6,501 women aged 65 to 80 were followed for a median of 14.9 years, 1,851 died, and each standard deviation higher index carried a hazard ratio of 0.92 (99 percent confidence interval 0.85 to 0.98) for death. In the FORCE consortium's pooled analysis of 17 cohorts, 42,466 people were followed for a median of 16 years with 15,720 deaths; comparing the top with the bottom fifth of circulating EPA plus DHA, all-cause mortality was 15 to 18 percent lower, with hazard ratios of 0.87 for all-cause, 0.85 for cardiovascular, 0.89 for cancer and 0.88 for other death per interquintile range, and no association at all for the plant omega-3, alpha-linolenic acid (0.99). For EPA the curve was steeper across the lower blood levels with little additional difference at higher ones.18,17Grade B

The brain data are thinner and mixed. In 1,111 postmenopausal women from the same memory study, a one standard deviation higher index at baseline went with 2.1 cubic centimeters more total brain volume and 50 cubic millimeters more hippocampal volume on MRI eight years later, with the top quartile 159 cubic millimeters larger in the hippocampus than the bottom, and no relation to ischemic lesion volume. But in 2,157 cognitively normal women aged 65 and older tested annually for a median of 5.9 years, there were no differences in cognitive performance at baseline or in the rate of cognitive change between the high and low tertiles of red-cell EPA plus DHA. A larger hippocampus on a scan and no measurable difference in thinking are both true findings, and neither is a trial.19,20Grade C

At about a gram a day, the trials were null. VITAL randomized 25,871 US adults (men 50 and older, women 55 and older) to 1 g a day of marine omega-3 or placebo for a median of 5.3 years: major cardiovascular events had a hazard ratio of 0.92 (0.80 to 1.06), invasive cancer 1.03, cardiovascular death 0.96 and death from any cause 1.02; total myocardial infarction, a secondary endpoint, was 0.72 (0.59 to 0.90). In the subset with blood at one year, the plasma omega-3 index rose from 2.67 to 4.13 percent, and fish intake modified the effect on mortality (interaction p = 0.017), with a hazard ratio of 0.87 in low fish eaters and 1.19 in high. ASCEND randomized 15,480 people with diabetes and no cardiovascular disease to 1 g a day or olive oil for a mean of 7.4 years: serious vascular events occurred in 8.9 versus 9.2 percent (rate ratio 0.97) and death in 9.7 versus 10.2 percent (0.95).16,17,21Grade A

Pooled, the picture is a small coronary effect and no effect on dying. The 2020 Cochrane review of 86 randomized trials and 162,796 people found little or no effect of long-chain omega-3 on all-cause mortality (risk ratio 0.97, 0.93 to 1.01, high-certainty evidence), cardiovascular events (0.96) or stroke (1.02), a possible reduction in cardiovascular mortality (0.92) and in coronary death (0.90, low certainty, 334 treated to prevent one) and coronary events (0.91, 167 treated to prevent one), a 15 percent dose-dependent fall in triglycerides, and no difference by dose or duration. A separate meta-analysis of 13 trials and 127,477 people, excluding REDUCE-IT, found rate ratios of 0.92 for myocardial infarction, 0.92 for coronary death, 0.93 for cardiovascular death and 0.97 for total cardiovascular disease, with risk falling linearly with dose.22,23Grade A

At 4 g a day, two trials in similar patients disagreed. REDUCE-IT gave 4 g of icosapent ethyl, a purified EPA, or placebo to 8,179 statin-treated patients with triglycerides of 135 to 499 mg/dL and established disease or diabetes, for a median of 4.9 years: the primary composite fell from 22.0 to 17.2 percent (hazard ratio 0.75, 0.68 to 0.83) and cardiovascular death from 5.2 to 4.3 percent (0.80), while hospitalization for atrial fibrillation or flutter rose from 2.1 to 3.1 percent and serious bleeding from 2.1 to 2.7 percent (p = 0.06); the manufacturer funded the trial. STRENGTH gave 4 g of an EPA plus DHA carboxylic acid or corn oil to 13,078 statin-treated patients at high risk with high triglycerides and low HDL and was stopped early for futility: the primary endpoint occurred in 12.0 versus 12.2 percent (0.99, 0.90 to 1.09), gastrointestinal side effects in 24.7 versus 14.7 percent, and atrial fibrillation in 2.2 versus 1.3 percent (hazard ratio 1.69).24,25,26Grade A

No trial has randomized anyone to reach an omega-3 index and followed what happened; the closest test is a secondary analysis of STRENGTH. Among 10,382 participants with fatty acid levels at baseline and 12 months, those who reached the top tertile of achieved plasma EPA on treatment had a hazard ratio of 0.98 (0.83 to 1.16) against corn oil, and the top tertile of DHA 1.02 (0.86 to 1.20); sensitivity analyses using changes in red blood cell EPA and DHA gave the same answer. Reaching a high blood level on a 4 g EPA plus DHA product brought neither benefit nor harm. The American Heart Association's 2017 advisory, which by design made no recommendation from observational data, gave no recommendation for the general population, called supplementation reasonable after coronary disease and in heart failure with reduced ejection fraction, and found it not indicated for people with diabetes or prediabetes.27,28Grade A

The safety signal is atrial fibrillation. Across 7 cardiovascular outcome trials and 81,210 participants (mean age 65, weighted follow-up 4.9 years), marine omega-3 supplements raised the risk of atrial fibrillation with a hazard ratio of 1.25 (1.07 to 1.46): 1.49 (1.04 to 2.15) in trials testing more than 1 g a day and 1.12 (1.03 to 1.22) in trials testing 1 g or less, with the hazard rising 1.11 per additional gram. The signal survived the removal of REDUCE-IT, the one trial without DHA.26Grade A

06 · What moves it

The levers with evidence behind them.

What is listed here has been tested. The size of each effect, and the size of the study, are in the sentence, so a small effect reads as a small effect.

  • Oily fish, by servings a week

    raises it by about half a point per intake category

    Among 3,458 adults who tested themselves, each step up in reported fish intake raised the index by 0.50 to 0.65 points. The odds of an index of 8 percent or more were 44 percent in people eating three or more servings a week and taking a supplement, 10 percent in people eating two fish meals a week with no supplement, and 2 percent in people doing neither. The Framingham investigators estimated that moving from their lowest-fifth median (3.7) to their highest (7.8) would take about 1,300 mg more EPA plus DHA a day, roughly a 100 g serving of farmed salmon daily or four standard fish-oil capsules. Self-reported intake in a self-selected sample, so the shape is more reliable than the numbers.6,14Grade C

  • EPA plus DHA supplements, by dose

    raises it in proportion to dose; about a gram a day to move from about 4 to 8

    In a five-month randomized trial, 115 healthy adults aged 20 to 45 who ate little oily fish took 0, 300, 600, 900 or 1,800 mg a day of EPA plus DHA from a starting index of 4.3 percent. The 300 mg group reached a median of 6.1, the 900 mg group 7.6 (interquartile range 6.6 to 8.3) and the 1,800 mg group 9.9 (8.9 to 10.5); no one on 600 mg or less reached 8. Dose explained 68 percent of the response, and by body weight the authors estimated 0.9 g a day for a 55 kg person, 1.2 g for 75 kg and 1.5 g for 95 kg to go from 4.3 to 8. Pooling 1,422 people from 14 trials, a mean of 1,983 mg a day for a mean of 13.6 weeks raised the index from 4.9 to 8.1 percent; the model predicted that 850 mg a day of an ethyl-ester product would bring a person starting at 4.9 to about 6.5, and triglyceride-form supplements raised the index about one point more than ethyl esters gram for gram. These are population models of a biomarker, not a dose for any reader; the dose that raised atrial fibrillation in trials sits in this range.5,29,26Grade B

  • Time

    the number lags intake by months

    Because the index is a red-cell measurement, it answers slowly. EPA entered red-cell membranes with a half-life of 28 days and reached a steady state after 180 days in the 18-month feeding study, the dose-response trial ran five months as the approximate time for membrane composition to reach a new steady state, and the pooled supplementation trials averaged 13.6 weeks. A retest sooner than about three months after a change in diet or supplements reads the transition, not the result.2,5,29Grade B

  • Starting level and body weight

    a lower start and a lighter body respond more

    People with a lower baseline index gained more from the same dose, and dose per kilogram of body weight predicted the response better than dose alone; older age and more physical activity also predicted slightly larger rises in the five-month trial. In the pooled trials, only baseline index, dose and chemical form (ethyl ester or triglyceride) were significant predictors, together explaining 62 percent of the variation in response.5,29Grade C

  • Plant omega-3 (flax, chia, walnuts)

    raises EPA a little and DHA not at all

    Alpha-linolenic acid, the plant omega-3, is converted to EPA only to a limited extent and to DHA hardly at all in stable-isotope studies, somewhat more in women than in men, and raising its intake for weeks to months increases EPA in red cells without increasing DHA. In the 17-cohort pooled analysis, circulating alpha-linolenic acid had no association with mortality (hazard ratio 0.99) while the marine fatty acids did, and in the Cochrane review increasing it made little or no difference to all-cause mortality (risk ratio 1.01). A plant-based diet needs an algal or fish source to move the index.9,17,22Grade B

  • Prescription omega-3 products

    raise it and lower triglycerides; a physician's decision

    Prescription EPA plus DHA or EPA-only products at 4 g a day lower triglycerides by 30 percent or more in people with very high triglycerides, and the EPA plus DHA forms raise LDL cholesterol in that setting while EPA alone did not. The 2019 American Heart Association advisory calls them an effective and safe option for lowering triglycerides, alone or with a statin. Whether one belongs in a particular person's care, and at what dose, is a prescriber's decision that weighs the triglyceride benefit against the atrial fibrillation and bleeding signals above.30,24Grade A

07 · Reading it well

Caveats, and what belongs with a physician.

The index has a commercial origin. The scientist who proposed it in 2004 is affiliated with the laboratory that sells the HS-Omega-3 Index test, as the author affiliations of the Framingham paper record, and the same group wrote the 10-cohort re-analysis that endorsed the 4 and 8 percent targets, the fish-intake study built from the laboratory's own customers, and the pooled supplementation model. The science is peer-reviewed and much of it is independent, but the cutpoints a reader sees on the report were set and defended by people with a stake in the test. This entry cites their peer-reviewed papers and nothing from the company.14,15,6,29Grade C

Method and sample type change the number. Red cells vary least within a person (4.1 percent week to week against about 15 percent for plasma), but studies have measured whole plasma, plasma phospholipids, cholesteryl esters and erythrocytes, and a plasma index runs on a lower scale (mean 2.67 percent in VITAL). Trends are meaningful only on the same test from the same laboratory, and a single result from a different method cannot be placed on the red-cell bands.3,7,16Grade B

The index measures intake more reliably than it proves benefit. The dose-response trial was designed to validate it as a biomarker of EPA plus DHA consumption, which it is. The mortality associations in cohorts are adjusted for education, occupation, smoking, activity and the rest, but people who eat fish differ in ways no model fully captures, and the one trial analysis that asked whether reaching a high blood level on treatment predicted fewer events found that it did not.5,14,27Grade A

The evidence above 8 percent is thin. Only 10 percent of the Framingham cohort sat at 8 or above and that group's lower mortality was not statistically significant; across the 17 pooled cohorts the EPA curve flattened at higher levels; and in VITAL the only hint of benefit for death was in people who ate little fish, with a hazard ratio above 1 in those who ate a lot. If supplements help anyone, the data point to people starting low, not to pushing an already high index higher.14,17,16Grade B

The gap between cohorts and trials has a plausible explanation that is not flattering to supplements. The American Heart Association's advisory writers noted that background fish intake was higher in recent trials than in early ones, so that an added gram a day would produce little measurable benefit in people already eating the recommended one to two weekly servings, and that observational data suggest a nonlinear effect concentrated at the low end. On this reading the cohorts and the trials are both right, and the index's main use is to identify a low intake.28,17Grade B

High-dose supplements are not inert. Atrial fibrillation rose by about half in trials of more than a gram a day and by about a tenth at a gram or less; serious bleeding was 2.7 against 2.1 percent on 4 g of purified EPA, and no excess bleeding was seen at 1 g in VITAL. The habit of taking several grams of fish oil for a better number carries a risk the number itself does not show.26,24,16Grade A

See a physician

  • Taking warfarin, a direct oral anticoagulant or an antiplatelet drug, or with a history of serious bleeding, before starting any omega-3 product above about a gram a day: in the 4 g trial serious bleeding was 2.7 against 2.1 percent.
  • Palpitations, a racing or irregular heartbeat, unexplained breathlessness or lightheadedness while taking an omega-3 supplement, particularly at doses above a gram a day, which raised atrial fibrillation in trials.
  • Triglycerides of about 500 mg/dL or more, where prescription omega-3 at 4 g a day is one of the recognized treatments and the choice between products, and alongside other therapy, is a prescriber's decision.
  • A prior heart attack, known coronary disease or heart failure with reduced ejection fraction, where the cardiology advisory calls supplementation reasonable and the decision belongs with the treating physician rather than a page.
  • Memory or thinking changes that prompted the test: measurable cognitive change deserves a proper evaluation, and no cohort or trial shows that raising the index reverses it.

This page is education, not individual medical advice, and reading it creates no physician-patient relationship.

08 · Open questions

What the literature does not settle.

  • No randomized trial has assigned people to reach a target omega-3 index and followed outcomes; every number on the 4 to 8 scale is an association, and the one analysis of achieved blood levels on treatment found no benefit.
  • Why 4 g of purified EPA reduced events while 4 g of EPA plus DHA did not is unresolved; the two trials differed in formulation, in comparator oil and in the populations enrolled, and the explanation determines whether EPA, DHA or the index as a whole is the thing to measure.
  • Whether benefit is confined to people who start low is suggested by the fish-intake interaction in VITAL and the flattening EPA curve across the pooled cohorts, and has not been tested by a trial that enrolls on a low index.
  • Whether the atrial fibrillation signal applies to fish on the plate, as opposed to concentrated supplements, is unknown; the trials tested capsules and the Cochrane reviewers found little evidence either way about eating fish.
  • Whether a higher index protects the brain is open: a larger hippocampus on MRI in one cohort of older women, no difference in cognitive decline in another, and no trial that measured either against the index.
  • What an index above 8 or 10 percent adds, if anything, is undefined; the cohorts contain few such people and the populations that live there differ in far more than fish.

10

Questions

11 · Sources

30 sources, read in full.

Numbered in the order they appear. Each line says what this page relies on from the paper; the link opens the record at PubMed or the publisher.

  1. 1.

    Harris WS, Von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease?. Preventive Medicine. 2004. PMID 15208005. DOI 10.1016/j.ypmed.2004.02.030.

    Review · Proposed red-cell EPA plus DHA as a coronary risk factor; an index of 8 percent or more went with the greatest protection from coronary death and 4 percent or less with the least, from published primary and secondary prevention studies.

  2. 2.

    Katan MB, Deslypere JP, van Birgelen AP, Penders M, Zegwaard M. Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study. Journal of Lipid Research. 1997. PMID 9374124.

    Randomized trial · 58 men fed 0 to 9 g a day of fish oil for 12 months: EPA entered erythrocyte membranes with a half-life of 28 days and reached steady state after 180 days; erythrocytes reflect intake over the past month or two, cholesteryl esters the past week or two, adipose tissue years.

  3. 3.

    Harris WS, Thomas RM. Biological variability of blood omega-3 biomarkers. Clinical Biochemistry. 2010. PMID 19733159. DOI 10.1016/j.clinbiochem.2009.08.016.

    Laboratory method study · 20 volunteers sampled weekly for 6 weeks: within-person coefficient of variation 4.1 percent for red cells, 15.9 for plasma and 14.5 for plasma phospholipids; red-cell value not altered by a meal.

  4. 4.

    Albert CM, Campos H, Stampfer MJ, et al.. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. New England Journal of Medicine. 2002. PMID 11948270. DOI 10.1056/NEJMoa012918.

    Prospective cohort · Nested case-control in the Physicians' Health Study (94 sudden deaths, 184 controls, up to 17 years): adjusted relative risk of sudden death 0.28 in the third and 0.19 in the fourth quartile of blood long-chain omega-3 versus the lowest.

  5. 5.

    Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM. Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. Journal of the American Heart Association. 2013. PMID 24252845. DOI 10.1161/JAHA.113.000513.

    Randomized trial · 115 healthy adults, 0 to 1,800 mg a day for 5 months from a baseline of 4.3 percent: medians 6.1 (300 mg), 7.6 (900 mg) and 9.9 (1,800 mg); no one at 600 mg or less reached 8; dose explained 68 percent of response; by weight about 0.9 to 1.5 g a day to reach 8; US non-supplement users average 4 to 5 percent.

  6. 6.

    Jackson KH, Polreis JM, Tintle NL, Kris-Etherton PM, Harris WS. Association of reported fish intake and supplementation status with the omega-3 index. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2019. PMID 30773210. DOI 10.1016/j.plefa.2019.01.002.

    Cross-sectional study · 3,458 self-testers (84 percent US), mean index 5.99 percent: each fish-intake category added 0.50 to 0.65 points, a supplement 2.2 points; odds of 8 percent or more were 44 percent with 3 or more servings a week plus a supplement, 10 percent with 2 fish meals a week and no supplement, 2 percent with neither.

  7. 7.

    Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Progress in Lipid Research. 2016. PMID 27216485. DOI 10.1016/j.plipres.2016.05.001.

    Review · 298 studies converted to red-cell-equivalent EPA plus DHA: above 8 percent around the Sea of Japan, Scandinavia and populations not adapted to Western diets; 4 percent or less across North and South America, Europe, the Middle East, Southeast Asia and Africa.

  8. 8.

    Kabeya N, Fonseca MM, Ferrier DEK, et al.. Genes for de novo biosynthesis of omega-3 polyunsaturated fatty acids are widespread in animals. Science Advances. 2018. PMID 29732410. DOI 10.1126/sciadv.aar6849.

    Laboratory method study · Marine ecosystems produce virtually all omega-3 long-chain PUFA, attributed to marine microbes with methyl-end desaturases; 121 such desaturase sequences were found in 80 invertebrate species across five phyla, partly by horizontal gene transfer, and several invertebrates make omega-3 PUFA de novo.

  9. 9.

    Burdge GC, Calder PC. Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reproduction Nutrition Development. 2005. PMID 16188209. DOI 10.1051/rnd:2005047.

    Review · Stable-isotope studies: conversion of alpha-linolenic acid to EPA is limited and to DHA very low, greater in women; raising intake increases EPA in erythrocytes and other pools but not DHA.

  10. 10.

    Crawford MA, Bloom M, Broadhurst CL, et al.. Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids. 1999. PMID 10419087. DOI 10.1007/BF02562227.

    Review · The hypothesis that human brain expansion required plentiful preformed DHA, richest in the marine food chain and scarce on the savanna, so that the transition to modern humans took place at the land-water interface.

  11. 11.

    Cunnane SC, Crawford MA. Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution. Journal of Human Evolution. 2014. PMID 24928072. DOI 10.1016/j.jhevol.2014.05.001.

    Review · The shore-based paradigm: a unique fetal fat layer supplies ketones and a DHA reserve, and a shore-based diet (fish, molluscs, crustaceans, frogs, birds' eggs, aquatic plants) is the richest source of brain-selective nutrients, iodine and iron foremost.

  12. 12.

    Carlson BA, Kingston JD. Docosahexaenoic acid, the aquatic diet, and hominin encephalization: difficulties in establishing evolutionary links. American Journal of Human Biology. 2007. PMID 17160979. DOI 10.1002/ajhb.20579.

    Review · The premise that DHA synthesis from alpha-linolenic acid is insufficient for an encephalizing brain is not well supported; much evidence suggests alpha-linolenic acid from terrestrial sources suffices for normal brain development in modern humans and presumably their ancestors.

  13. 13.

    Fumagalli M, Moltke I, Grarup N, et al.. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science. 2015. PMID 26383953. DOI 10.1126/science.aab2319.

    Prospective cohort · A selection scan in Greenlandic Inuit found its strongest signal in the fatty acid desaturase cluster that determines PUFA levels; the selected alleles modulate membrane fatty acid composition and have large effects on weight and height.

  14. 14.

    Harris WS, Tintle NL, Etherton MR, Vasan RS. Erythrocyte long-chain omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: The Framingham Heart Study. Journal of Clinical Lipidology. 2018. PMID 29559306. DOI 10.1016/j.jacl.2018.02.010.

    Prospective cohort · 2,500 adults, median 7.3 years: highest fifth (above 6.8 percent) versus lowest (below 4.2) had 34 percent lower all-cause mortality and 39 percent lower incident cardiovascular disease; 8 percent and above group (10 percent of sample) hazard ratio 0.69, not significant; authors state an observational study cannot show that raising the index helps.

  15. 15.

    Harris WS, Del Gobbo L, Tintle NL. The Omega-3 Index and relative risk for coronary heart disease mortality: Estimation from 10 cohort studies. Atherosclerosis. 2017. PMID 28511049. DOI 10.1016/j.atherosclerosis.2017.05.007.

    Systematic review and meta-analysis · Across 10 cohorts, mean index 6.1 percent (SD 2.1), hazard ratio 0.85 per SD for fatal coronary disease, medians of lowest and highest fifths 4.2 and 8.3 percent; about 30 percent lower risk estimated from 4 to 8; authors call under 4 and over 8 reasonable therapeutic targets.

  16. 16.

    Manson JE, Cook NR, Lee IM, et al.; VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. New England Journal of Medicine. 2019. PMID 30415637. DOI 10.1056/NEJMoa1811403.

    Randomized trial · 25,871 US adults, 1 g a day, median 5.3 years: major cardiovascular events HR 0.92 (0.80 to 1.06), cancer 1.03, myocardial infarction 0.72, cardiovascular death 0.96, all-cause death 1.02; no excess bleeding; plasma omega-3 index mean 2.67 percent at baseline, 4.13 at one year on treatment; fish intake modified the mortality effect (p = 0.017).

  17. 17.

    Harris WS, Tintle NL, Imamura F, et al.; Fatty Acids and Outcomes Research Consortium (FORCE). Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nature Communications. 2021. PMID 33888689. DOI 10.1038/s41467-021-22370-2.

    Systematic review and meta-analysis · 17 cohorts, 42,466 people, median 16 years, 15,720 deaths: top versus bottom fifth of circulating EPA plus DHA 15 to 18 percent lower all-cause mortality; hazard ratios 0.87 all-cause, 0.85 cardiovascular, 0.89 cancer, 0.88 other; alpha-linolenic acid 0.99; EPA curve steeper at low levels.

  18. 18.

    Harris WS, Luo J, Pottala JV, et al.. Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study. Journal of Clinical Lipidology. 2017. PMID 28391893. DOI 10.1016/j.jacl.2016.12.013.

    Prospective cohort · 6,501 women aged 65 to 80, median 14.9 years, 1,851 deaths: hazard ratio 0.92 (99 percent CI 0.85 to 0.98) per standard deviation of the omega-3 index for total mortality; no association for alpha-linolenic, arachidonic or linoleic acid.

  19. 19.

    Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology. 2014. PMID 24453077. DOI 10.1212/WNL.0000000000000080.

    Prospective cohort · 1,111 postmenopausal women, MRI 8 years after the blood draw: 1 SD higher index correlated with 2.1 cm3 larger total brain volume and 50 mm3 larger hippocampus; top versus bottom quartile 159 mm3; no relation to ischemic lesion volume.

  20. 20.

    Ammann EM, Pottala JV, Harris WS, et al.. ω-3 fatty acids and domain-specific cognitive aging: secondary analyses of data from WHISCA. Neurology. 2013. PMID 24068783. DOI 10.1212/WNL.0b013e3182a9584c.

    Prospective cohort · 2,157 cognitively normal women aged 65 and older, annual testing for a median of 5.9 years: no difference in baseline cognition or rate of cognitive change between high and low tertiles of red-cell DHA plus EPA.

  21. 21.

    ASCEND Study Collaborative Group; Bowman L, Mafham M, et al.. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. New England Journal of Medicine. 2018. PMID 30146932. DOI 10.1056/NEJMoa1804989.

    Randomized trial · 15,480 people with diabetes and no cardiovascular disease, 1 g a day versus olive oil, mean 7.4 years: serious vascular events 8.9 versus 9.2 percent (rate ratio 0.97); death from any cause 9.7 versus 10.2 percent (0.95).

  22. 22.

    Abdelhamid AS, Brown TJ, Brainard JS, et al.. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews. 2020. PMID 32114706. DOI 10.1002/14651858.CD003177.pub5.

    Systematic review and meta-analysis · 86 trials, 162,796 people: long-chain omega-3 had little or no effect on all-cause mortality (RR 0.97, high certainty), cardiovascular events (0.96) or stroke (1.02); cardiovascular mortality 0.92; coronary death 0.90 and coronary events 0.91 (low certainty); triglycerides down about 15 percent; no difference by dose; alpha-linolenic acid mortality 1.01; little evidence on eating fish.

  23. 23.

    Hu Y, Hu FB, Manson JE. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. Journal of the American Heart Association. 2019. PMID 31567003. DOI 10.1161/JAHA.119.013543.

    Systematic review and meta-analysis · 13 trials, 127,477 people, mean 5.0 years; excluding REDUCE-IT, rate ratios 0.92 for myocardial infarction, 0.92 for coronary death, 0.93 for cardiovascular death and 0.97 for total cardiovascular disease, with a linear dose-response.

  24. 24.

    Bhatt DL, Steg PG, Miller M, et al.; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. New England Journal of Medicine. 2019. PMID 30415628. DOI 10.1056/NEJMoa1812792.

    Randomized trial · 8,179 statin-treated patients with triglycerides 135 to 499 mg/dL, 4 g icosapent ethyl, median 4.9 years: primary endpoint 17.2 versus 22.0 percent (HR 0.75), cardiovascular death 4.3 versus 5.2 percent (0.80), atrial fibrillation hospitalization 3.1 versus 2.1 percent, serious bleeding 2.7 versus 2.1 percent; funded by Amarin.

  25. 25.

    Nicholls SJ, Lincoff AM, Garcia M, et al.. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020. PMID 33190147. DOI 10.1001/jama.2020.22258.

    Randomized trial · 13,078 statin-treated high-risk patients, 4 g EPA plus DHA carboxylic acid versus corn oil, stopped early for futility: primary endpoint 12.0 versus 12.2 percent (HR 0.99, 0.90 to 1.09); gastrointestinal adverse events 24.7 versus 14.7 percent.

  26. 26.

    Gencer B, Djousse L, Al-Ramady OT, Cook NR, Manson JE, Albert CM. Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation. 2021. PMID 34612056. DOI 10.1161/CIRCULATIONAHA.121.055654.

    Systematic review and meta-analysis · 7 trials, 81,210 participants, mean age 65, 4.9 years: atrial fibrillation HR 1.25 (1.07 to 1.46); 1.49 above 1 g a day and 1.12 at 1 g or less; 1.11 per additional gram; STRENGTH 2.2 versus 1.3 percent (HR 1.69); signal persisted without REDUCE-IT.

  27. 27.

    Nissen SE, Lincoff AM, Wolski K, et al.. Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial. JAMA Cardiology. 2021. PMID 33993205. DOI 10.1001/jamacardio.2021.1157.

    Randomized trial · 10,382 participants with levels at baseline and 12 months: top tertile of achieved plasma EPA HR 0.98 (0.83 to 1.16) and DHA 1.02 (0.86 to 1.20) versus corn oil; sensitivity analyses on red blood cell EPA and DHA changes similar; neither benefit nor harm.

  28. 28.

    Siscovick DS, Barringer TA, Fretts AM, et al.; American Heart Association. Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the American Heart Association. Circulation. 2017. PMID 28289069. DOI 10.1161/CIR.0000000000000482.

    Guideline · Recommendations from randomized trials only: none for the general population; supplementation reasonable after coronary disease (IIa) and in heart failure with reduced ejection fraction (IIa); not indicated in diabetes or prediabetes (III); notes higher background fish intake (one to two weekly servings) in recent trials and a nonlinear effect concentrated at low intake.

  29. 29.

    Walker RE, Jackson KH, Tintle NL, et al.. Predicting the effects of supplemental EPA and DHA on the omega-3 index. American Journal of Clinical Nutrition. 2019. PMID 31396625. DOI 10.1093/ajcn/nqz161.

    Systematic review and meta-analysis · 1,422 people from 14 trials; mean 1,983 mg a day for 13.6 weeks raised the index from 4.9 to 8.1 percent; dose, baseline and chemical form explained 62 percent of response; 850 mg ethyl ester predicted about 6.5 from 4.9; triglyceride form about 1 point more than ethyl ester.

  30. 30.

    Skulas-Ray AC, Wilson PWF, Harris WS, et al.; American Heart Association. Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation. 2019. PMID 31422671. DOI 10.1161/CIR.0000000000000709.

    Guideline · Prescription EPA plus DHA or EPA-only at 4 g a day lowers triglycerides by 30 percent or more in very high triglycerides (500 mg/dL or more); EPA plus DHA raises LDL cholesterol in that setting, EPA alone did not; an effective and safe option alone or with a statin.

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