#48

Harvard paper, just published, that cites the paper you mentioned: Non-Esterified Fatty Acid Profiles and Cause-Specific Mortality: The Cardiovascular Health Study 2025

The final population included 1996 participants with a mean age of 78 years. 60.5% were female. Over a median 11-year follow-up period, 1678 participants died. Total fasting NEFA was associated with higher risk of all-cause mortality (aHR per standard deviation: 1.17, 95% CI [1.10–1.23]). Total post-load NEFA was not associated with mortality. Among subclasses, only monounsaturated fatty acid (MUFA) was associated with total mortality (aHR 1.24, 95% CI [1.09–1.41]). For individual NEFAs, nervonic acid (aHR 1.06, 95% CI [1.01–1.12]), petroselaidic acid (aHR 1.21, 95% CI [1.03–1.42]) and eicosapentaenoic acid (aHR 0.90, 95% CI [0.82–0.99]) were associated with all-cause mortality.

Here as well, association with all-cause mortality for EPA, not DHA.

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#49

@adssx People on this forum respect you and listen to you so what you say matters. You are choosing to broadcast a very strong opinion about DHA (and fish oil to a lesser degree) based on a fraction of the deep scientific study over the last 40 years. Many of the studies you are highlighting were of people with advanced CVD. Do these results apply to healthy people? And don’t throw “Mendelian randomization” around like quotes from the Bible…a study is only as good as the design. This is why the body of work matters. Omega 3’s are one of the most research areas in nutritional science.

Omega 3’s are a nutrient. ALA is an “essential” nutrient. EPA and DHA are always found together in nature. EPA and DHA are only not considered “essential” (die without them) because the body can make a small amount from ALA. But the body will put more EPA and DHA into cells if added to the diet. Adding more is associated with lower all cause mortality. And lower inflammation. And faster recovery from exercise. And better immune function. And why wouldn’t we expect benefits from better functioning cells…

I agree that no one should supplement only DHA but I see no reason to fear DHA. Get it by eating fish first or take fish oil that comes with EPA and DHA together as is found in fish. Algae sources can also work if fish is objectionable.

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#50

OK so disclaimer to our silent readers: I’m just a human being, and I often say dumb things, so I might be wrong on this! I actually hope I’m wrong because I supplemented with DHA for a long time (as I followed blindly the advice of some “influencers” without taking the time to properly look at the evidence, and also because the picture is getting worse and worse when you look at the latest evidence) and because I wish DHA could help. So if anyone has strong evidence against what I say: please post it!

Just based on all the latest research. Small low-quality trials or association studies from decades ago have no value when we have larger high-quality RCT (e.g., VITAL-DEP and PreventE4), high quality Mendelian randomization (didn’t exist until a few years ago), and higher quality association studies (adjusted for socio-economic status and comorbidities, with dose–response analysis, etc.).

Not at all. Please read the list again: Vitamin O (Omega 3) for athletes - #4 by adssx

  • PreventE4 was “365 cognitively unimpaired individuals between 55 and 80 (mean age 66)”.
  • VITAL was “20,000 U.S. men and women without cancer or CVD at baseline”. The mechanistic study is in all human being.
  • The Stanford + UCSD paper indeed looked at people “who underwent coronary angiography” so unhealthy. Still, if DHA is detrimental in these people, why would it be beneficial in healthy people? (it might be, but please prove it!)
  • Mendelian randomization studies apply to all people as well
  • The plasma study was done in “289 participants (103 AD patients, 92 MCI patients, and 94 controls)”, so not at all “people with advanced CVD”.
  • Same for the animal studies listed.

Yes, @Neo made good objections about MR studies here: Predicting Alzheimers & Dementia (and minimizing risk) - #623 by Neo

After checking, it seems that these MR studies were well done and that the results are sound (especially when an association, whether positive or negative, was found):

Yes, that’s why in my message I included various types of studies, all showing the null or detrimental effects of DHA supplementation: Vitamin O (Omega 3) for athletes - #4 by adssx

  • Randomized control trials
  • Meta-review of RCTs
  • Mendelian randomization studies
  • Association studies
  • Animal studies
  • Mechanistic studies on humans

Yes, and science moves forward. We should update our practice based on science.

I think one should fear DHA supplementation (dietary is OK, the amount are smaller) and supplement with EPA only if they want to supplement.

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#51

Are any of these studies involving DHA only supplementation? I’m not aware of any studies of DHA supplementation. I’ve only seen separate studies EPA compared to studies of EPA plus DHA, with inferences drawn about DHA. How many other differences were in the studies that could confound the possible “DHA offsets EPA benefits somewhat” hypothesis? It is far from clear.

EPA and DHA are found together in nature and the longest lived people have been eating it that way forever. Supplements are not ideal but better than nothing. That said I see no reason to take DHA only supplements or EPA only supplements. I eat fish. I also take fish oil to get a high omega index. That is what I think the science supports.

I have no idea about brain health effects from omega 3’s but lower chronic inflammation cannot be a bad thing for brain function. Omega 3’s are not a silver bullet to cure whatever is wrong with a person. Omega 3’s are a nutrient that the body expects and will use to function better. A high amount of EPA and DHA in RBC membranes has been shown to be associated with better health and longer life in humans. It s true that no one knows if it is causal but you got do what you can with what you have.

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#52

Please Joseph, just read: Vitamin O (Omega 3) for athletes - #4 by adssx

#53

As you like association studies @约瑟夫_拉维尔: Novel Classification of Cardiovascular Disease Subtypes Reveals Associations Between Mortality and Polyunsaturated Fatty Acids: Insights from the United Kingdom Biobank Study 2024

They clustered people into 3 CVD subtypes based on some biomarkers:

Principal component analysis and k-means clustering were used to determine the CVD subtype. Variables included age, body mass index, waist–hip ratio, diastolic blood pressure, systolic blood pressure, total cholesterol, total triglycerides, high-density lipoprotein-cholesterol, apolipoprotein B:apolipoprotein A1, glycated hemoglobin, creatinine, albumin, C-reactive protein, white blood cell count, platelet count, and hemoglobin concentration.
Three distinct CVD subtypes were identified, with cluster 3 characterized by older age, male gender, and low high-density lipoprotein-cholesterol, having the highest risk of mortality. Clusters 2 and 3 had the highest DHA and ω-6/ω-3 ratios, respectively, compared with Cluster 1.
Cluster 1 consisted of the youngest individuals with elevated levels of ApoB:ApoA1, TC, TG, SBP, and DBP. Cluster 2 predominantly comprised females (77.9%) with the lowest BMI, WHR, TG, creatinine, C-reactive protein, WBC, and hemoglobin concentration, while having the highest levels of HDL-cholesterol. Cluster 3 primarily consisted of males (72.7%) who were older, with a higher BMI, WHR, and HbA1c, and a lower TC, HDL-cholesterol, and PLT.

They adjusted for:

  1. sociodemographic factors, including gender and household income (less than £18,000, £18,000 to £30,999, £31,000 to £51,999, £52,000 to £100,000 and greater than £100,000);
  2. socioeconomic status, including Townsend deprivation index;
  3. lifestyle habits, including smoking status (never, former, and current), alcohol status (never, former, and current), and physical activity (low, moderate, and high);
  4. comorbidities, including hypertension and diabetes; 5) drug use, including cholesterol-lowering medication use, antihypertensive drugs use, insulin treatment, and aspirin use.

Results:

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In multivariate models, we found significant nonlinear relationships between total PUFAs, ω-3, and DHA and risk of all-cause, CVD, and IHD mortality (all P for nonlinearity < 0.05). There was an inverse L-shaped exposure–response relationship between these PUFAs and risk of all-cause mortality, whereas there was a U-shaped exposure–response relationship for risk of CVD and IHD mortality. In the absence of these PUFAs, risk of the outcome increases. Within a specific range, higher ω-3 and DHA concentrations are associated with a reduced risk of outcomes [hazard ratio (HR) < 1.0]. However, once PUFAs reach a specific threshold level, risk stabilizes and no longer continues to decrease or even increase. Cluster 1 displayed the lowest HR under similar exposure levels in all-cause mortality (Figure 10).
We found significant linear relationships between ω-6 and LA and risk of the studied outcomes (all P for linearity < 0.05). High level of these PUFAs were associated with low risk of all-cause and CVD mortality but were associated with an increased risk of IHD mortality.
Our findings suggest that the mortality rates of ω-3 and DHA with CVD and IHD begin to trend upward at high intakes (fourth quartile array). The possible reason for this is that excess ω-3 and DHA may be predisposing factors for atrial fibrillation

So, even this association study confirms that higher might not be better, especially for DHA. The potential inconsistency with previous studies is, I guess, that this one adjusted for many factors, especially income and education. Rich people eat more fish, and if you don’t account for that, the omega-3 index is just a wealth index. Physical exercise might also help to absorb omega 3, so it’s good that this study adjusted for “physical activity (low, moderate, and high)”.

You also asked “Do these results apply to healthy people?”: here they “constructed a subtype model of cardiovascular patients” “according to patient baseline characteristics”. They identified 3 clusters that I would call “young unhealthy” (1), “healthy” (2, mostly females), and “old unhealthy” (3). The results were similar across these clusters.

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2g/day of DHA for 2 years has no impact on cognition or hippocampal volume
#54

As a rule of thumb, Dr. Stanfield has been recommending EPA to DHA in a 2:1 ratio. After looking at the results of these various studies, I may even want to try for a higher ratio of EPA to DHA. It does appear that DHA is the red-headed stepchild of the Omega 3 family. A bit of DHA is probably OK, but you want to limit supplementation to mostly EPA if possible. Eating fish is probably the best way to supplement Omega 3s.

I’m glad that @adssx has brought these facts up about DHA, but it seems like it’s become a crusade now. :wink:

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#55

I suspect that it’s partially designed to stimulate opposition. I do that myself sometimes - I will crusade on some issue, because I want people to challenge my idea/findings. Sometimes, if you just casually present something without really pushing it, it just gets ignored. And some ideas/findings are too important to be ignored, like EPA and DHA because it’s pushed so much by influencers and so many people supplement. It’s important to thoroughly discuss it, and hopefully reach some more justified practices with better evidence. For that it is useful to challenge people to present their best opposing arguments and findings. At least that’s how I take it :grin:.

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#56

That’s exactly the reason. I’m pushing for people to provide alternative explanations and challenge what started as a question ( Omega 3 makes me depressed: why? ) but what is now, I think, a fact: supplemental DHA is detrimental to your health. So far, no one has provided any valid objections. I hope one of the “influencers” I contacted will get back to me. I have low expectations.

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#57

I feel bad for @adssx for pulling together so much information and spending so much time on this, just for people to not read his posts thoroughly and instead just quickly criticize and keep to their pre-conceived notions of the what is right. I hope we can do better in the future.

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#58

I think many , like myself, find the information very helpful and will help guide my supplementation strategy.

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#59

A few people messaged me directly and told me switched to EPA-only or were considering doing so. That being said: I might be wrong. Mitchell Lee from Ora Biomedical made an intro to Matt Kaeberlein (his cofounder) to discuss EPA vs DHA so I hope Matt will get back to me. It would be good to know his thoughts.

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#60

I have not tried to analyse the information in any detail, but I have shifted to taking only EPA. As far as I can tell on a superficial scanning of the information there is clearly an argument against DHA supplementation.

My own personal results with fish oil is that I noticed a benefit from supplementation with a mixture a few years ago. Hence I have now stuck to an EPA only version possibly for a few months now. I have not checked exactly when I changed to EPA.

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#61

Chinese paper, just published, not sure if it has any value though: EPA but not DHA improve systemic IR through activating muscle IL-6/AMPK pathway in high-fat diet-fed mice 2025

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#62

The last remaining argument in favor of DHA is some association studies such as this one from 2024: Circulating Docosahexaenoic Acid and Risk of All-Cause and Cause-Specific Mortality 2024

Massive association study:

We analyzed data from UK Biobank, which included 117,702 subjects with baseline plasma DHA levels and 12.7 years of follow-up between April 2007 and December 2021. Associations with risk for mortality endpoints were analyzed categorically by quintile of DHA plasma levels.

The results look great, except for CVD mortality (more DHA is not better). The trend is also good, but Q5 is not statistically significantly better than Q3. So it looks like as long as you’re not super low (Q1), you’re good:

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Digging more into the paper, they adjusted for:

Age (years), biological sex (male, female), race (white, mixed, Asian, black), marital status (living with a partner, not living with a partner, other/unknown), employment status (not employed, low activity work, high activity work, strenuous work), education (college or higher, post high school, high school, less than high school, unknown), Townsend Deprivation Index (continuous measure of relative deprivation), physical activity (very low, low, medium, high, very high), smoking status (never, former, current, unknown), alcohol intake (daily, 3-4x/week, 1-2x/week, 1-3x/month, special occasions, never, unknown), Body Mass Index ([BMI] continuous, kg/m2), prevalent dyslipidemia (yes/no), prevalent hypertension (yes/no), prevalent diabetes (yes/no), physical activity (very low, low, medium, high, unknown), self-rated health (excellent, good, fair, poor, unknown), and total circulating omega-6 polyunsaturated fatty acid (PUFA) levels (continuous, % of total fatty acids).

So, they did not adjust for income. We know that income and omega-3 intake are associated: Omega-3 Long-Chain Polyunsaturated Fatty Acids Intake by Ethnicity, Income, and Education Level in the United States: NHANES 2003–2014 2020. It is a first confounding factor. However, they adjusted for education attainment, which is correlated to income.

Other recent association studies that adjusted for income did not find benefits (or even found detrimental effects) for high-dose DHA:

They also show that serum DHA levels are highly correlated with fish oil supplementation:

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There’s a massive healthy user bias here if you don’t adjust for fish oil supplementation: people who take fish oil are likely to be more health conscious. They probably also have a better diet, they might take other supplements, they might go to the doctor more often, they might be wealthier, etc. How come they didn’t adjust for that? Or just show the results stratified by self-reported fish oil use?

I also find the ~18.3% fish oil use in Q1 surprising. It’s self-reported, so maybe these people use a low dose infrequently, but even with low-dose intermittent fish oil supplementation, I would expect most people to be at least in Q2 (omega 3 index around 5%). So maybe other factors impact DHA absorption that are not accounted for? DHA levels might therefore represent something else?

Then, they looked at DHA only. Indeed: “Blood levels of DHA but not EPA were available in ∼25% of the individuals enrolled in the UKBB.” They note:

We focused on DHA in this meta-analysis as it was the only specific omega-3 fatty acid level available in the UKBB because nuclear magnetic resonance technology was not able to reliably measure plasma EPA in this population. Blood levels of DHA but not EPA show strong statistically significant inverse associations with risk of Alzheimer disease. On the other hand, EPA monotherapy has been shown to be effective in reducing risk for major adverse CV events. No similar trials of DHA monotherapy have been undertaken. Levels of EPA+DHA have been shown to be inversely associated with mortality; however, whether EPA or DHA is more strongly associated with improved life expectancy remains uncertain.

So, even them don’t know what’s best between EPA and DHA. I guess that there’s a strong correlation between EPA and DHA levels. What if the best is actually high EPA and average DHA? We just don’t have the data here, and we cannot conclude.

To finish, there’s a risk of bias of the authors. All these association studies are always published by O’Keefe and Harris. O’Keefe is the Chief Medical Officer of Cardiotabs, a nutraceutical company selling omega 3 supplements. Harris works for OmegaQuant, which sells the Omega-3 Index test… What a surprise!

That paper (and other similar ones) is the only argument left in favor of DHA supplementation. And I think for the reasons explained above, it’s not a strong one. Especially when considering all the arguments against.

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#63

I’m one of the people who has switched to EPA as a result of his hard work!!! *raises hand enthusiastically

Until I hear a better idea, for now I’m going to supplement with DHA one day per week because I don’t eat fish. The thought is most of you are consuming some dha in your food, and this would help prevent me from having a deficiency.

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#64

Yes. I think getting rid of all DHA is a mistake. It seems to be a U-shaped curve for this one. However, EPA seems the more the better. So I’ll be increasing my EPA intake and decreasing but not eliminating DHA.

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#65

Just pointing out that they jury may still be out re above

There could be overadjustment bias in those last studies

And given that the current study not only adjusted for education, but ALSO for 4-5 or so other variables that are correlated to income adding income to this study could lead to overadjustment bias here.

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#67

100 mg/day of DHA is probably enough. But you get more than that with just one portion of salmon per week. So no need to supplement.

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#68

Which ones?

I don’t know about overadjustment. In any case the lack of adjustment for income isn’t the worst to me. The worst is the healthy user bias and the lack of presentation of results stratified by fish oil use. What if you don’t have any significant trends anymore when you look at fish oil users only or non fish oil users only? How come they didn’t present that data?