DHA/EPA and ALA for Cardiovascular Disease & All-Cause Mortality

[Ron Put]

Based on a relatively deep dive, I am really starting to question the prevailing view on DHA and EPA. It's starting to look to me that much of the research (including research on the benefits of fish consumption) is industry-sponsored and it doesn't really make sense.  I first started questioning it when it dawned on me that most Blue Zones consume next to no DNA and EPA, from fish or other sources. The Okinawans consumed less than 1% fish in their diet, and the long-living Sardinians, for example, were the hill-dwellers who consumed virtually no fish and very little animal products. The more I dig, the more it seems to me like advertising, including the Omega tests offered by just about everyone nowadays.


Effects of alpha-linolenic acid versus those of EPA/DHA on cardiovascular risk markers in healthy elderly subjects

Results:
Both n-3 fatty acid diets did not change concentrations of total-cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerol and apoA-1 when compared with the oleic acid-rich diet. However, after the EPA/DHA-rich diet, LDL-cholesterol increased by 0.39 mmol/l (P=0.0323, 95% CI (0.030, 0.780 mmol/l)) when compared with the ALA-rich diet. Intake of EPA/DHA also increased apoB concentrations by 14 mg/dl (P=0.0031, 95% CI (4, 23 mg/dl)) and 12 mg/dl (P=0.005, 95% CI (3, 21 mg/dl)) versus the oleic acid and ALA-rich diet, respectively. Except for an EPA/DHA-induced increase in tissue factor pathway inhibitor (TFPI) of 14.6% (P=0.0184 versus ALA diet, 95% CI (1.5, 18.3%)), changes in markers of hemostasis and endothelial integrity did not reach statistical significance following consumption of the two n-3 fatty acid diets.

Conclusions:
In healthy elderly subjects, ALA might affect concentrations of LDL-cholesterol and apoB more favorably than EPA/DHA, whereas EPA/DHA seems to affect TFPI more beneficially.



Adipose tissue α-linolenic acid is inversely associated with insulin resistance in adults

Results: Compared with the lowest tertile, the third tertile (β = -0.13; 95% CI: -0.24, -0.01) of adipose tissue ALA was inversely associated with the HOMA-IR. When stratified by waist circumference, ALA continued to be inversely associated [third tertile: β = -0.17 (95% CI: -0.31, -0.02)] with the HOMA-IR in subjects with a waist circumference ≤88 cm in women or ≤102 cm in men but not in those with a larger waist circumference. No significant association was noted between adipose tissue EPA plus DHA and HOMA-IR.

Conclusions: Higher adipose tissue ALA was inversely associated with insulin resistance in this cohort of healthy adult men and women. This finding appears to be more pronounced in individuals with a normal waist circumference.


Is docosahexaenoic acid synthesis from α-linolenic acid sufficient to supply the adult brain?

This review summarizes evidence that DHA synthesis from ALA can provide sufficient DHA for the adult brain by examining work in humans and animals involving estimates of DHA synthesis and brain DHA requirements. Also, an update on methods to measure DHA synthesis in humans is presented highlighting a novel approach involving steady-state infusion of stable isotope-labeled ALA that bypasses several limitations of oral tracer ingestion. It is shown that this method produces estimates of DHA synthesis that are at least 3-fold higher than brain uptake rates in rats.

[mccoy]

22 hours ago, Ron Put said:

I first started questioning it when it dawned on me that most Blue Zones consume next to no DNA and EPA, from fish or other sources. The Okinawans consumed less than 1% fish in their diet, and the long-living Sardinians, for example, were the hill-dwellers who consumed virtually no fish and very little animal products.

The Sardinians maybe consumed some fish coming from the coast, but probably in negligible amounts. The same seems to apply to the Ikarians. My same reasoning is that there have been so many landlocked populations with no or little access to fish, maybe smallish amounts of freshwater fish. 

On the other side, I still consume lots of ground flaxseed and chia. Some ALAs are bound to be transformed into EPA-DHA, unless a very unfavorable genetic polymorphism occurs.

[Sibiriak]

On 8/18/2021 at 5:59 AM, Ron Put said:

Based on a relatively deep dive, I am really starting to question the prevailing view on DHA and EPA. It's starting to look to me that much of the research (including research on the benefits of fish consumption) is industry-sponsored and it doesn't really make sense. I first started questioning it when it dawned on me that most Blue Zones consume next to no DNA and EPA, from fish or other sources.

Yeah,  I've been leaning in that direction for some time (and btw, that Jeff Nelson video is pretty good-- blistering attack on  Dr. Joel "Noni Juice" Fuhrman!)

Back in 2017,  I posted this:

Quote

mccoy: What conversion rate might we expect in vegetarians and vegans? Max is about 20% I believe for EPA and 9% for DHA.  If half of max conversion is present, 2% ALAs→ 5600 mg→ 560 mg EPA + 252 mg DHA= 812 EPA+DHA, which is higher than the NIH daily recommended quantity.

----------------

Also, brain DHA might be different than blood DHA.  [...]Maybe the conclusion is that the intricacies of ALAs metabolism are still not perfectly known.

I decided to take another look into the ALA conversion issue,  and the more I look into the more complex and uncertain the whole issue becomes.  It also make me wonder about the wisdom in doing speculative calculations based on such imperfect information.

[As an aside,  it has always struck me as odd from an evolutionary standpoint that humans would NEED to eat fish or fish oil to maintain optimum health.]

As far as the conversion rates are concerned, it appears that the 9% figure for DHA is a real outlier, and that:

Quote

Stable isotope methods have typically resulted in estimates of percent conversion of ALA to DHA being less than 1% of the ingested stable-isotope ALA, although estimates vary widely, ranging from 0–9.2% (Table 1). Also, there is typically no increase in plasma total lipid or phospholipid DHA when ALA intake is increased in humans (reviewed in [10] ;  [11]), supporting the conclusion that DHA synthesis from ingested ALA is not an efficient process in humans.

http://www.sciencedirect.com/science/article/pii/S0163782715000223

But that all may be largely irrelevant when the complexities of  DHA uptake into the brain are taken into consideration.  The following review really gets deep into the issue of ALA conversion and brain DHA requirements.    It’s a must read, imo.

Is docosahexaenoic acid synthesis from α-linolenic acid sufficient to supply the adult brain?

http://www.sciencedirect.com/science/article/pii/S0163782715000223

A few quotes:

 

Quote

Recommendations for daily intake of EPA and DHA for primary prevention of coronary heart disease range from 200 to 3000 mg/d (reviewed in [29]), but we are not aware of any specific recommendations regarding DHA intakes pertaining to the adult brain.

 

Quote

This review critically examines the methodologies used to estimate DHA synthesis from ALA in humans and presents evidence suggesting that DHA synthesis capacity in humans may be greater than previously estimated. Studies measuring DHA synthesis in adult humans will also be reviewed in the context of the brain. Additionally, a novel technique to measure DHA synthesis, that can be used in humans, the steady-state infusion method, is presented and evaluated as a means to determine, for the first time, a quantitative DHA synthesis-secretion rate in adult humans. In 2009, Barcelo-Coblijn and Murphy elegantly argued that ALA is a significant contributor to tissue DHA [25]. Herein, we provide an update of the literature with a focus on brain DHA homeostasis.

 

Quote

Based on the model that plasma unesterified DHA is the major DHA pool that enters the brain, brain DHA uptake rates in the rat can be measured by infusing radiolabeled unesterified-DHA and measuring how much gets incorporated into the brain, after correcting for plasma radioactivity (i.e. brain exposure to radioactivity) and the pool size [62]. More recently, this concept was applied to humans using positron emission tomography to image the incorporation of [1-¹¹C]-DHA into the brain and quantify a rate of DHA uptake into the brain [63]. The rate of DHA uptake into the brain is assumed to be replacing DHA that is consumed in the brain, and therefore, can be used as an estimate for the brain DHA requirement. It has been reported that the brain DHA uptake rate in humans is between 2.4 and 3.8 mg/day [63] ;  [64]. Based on current estimates of ALA consumption in adult males of 1700 mg/day, the percent conversion of ALA to DHA would need to be 0.14–0.22% to match the brain DHA requirement [65]. Therefore, it is possible that even a small amount of DHA synthesis may be sufficient to meet adult brain DHA uptake demands.

 

Quote

Recently, alternative mechanisms for DHA synthesis have been proposed [84]; [93]; [94] ;  [95]. An experiment performed in baboons determined that the Δ6-desaturase enzyme also has Δ8-desaturase activity [93]. Based on this finding the authors proposed an alternative pathway for DHA synthesis from ALA that functions in parallel with the classical pathway and involves an initial elongation of ALA to 20:3n-3 followed by Δ8-desaturation to make 20:4n-3, which is then desaturated and elongated to become DHA [93]. Another recent study questioned the Δ6-desaturation as the sole rate-limiting step in the synthesis pathway. The authors found that the elongation of DPA n-3 to 24:5n-3 may be another crucial control point in DHA synthesis [94]. This reaction is catalyzed by the enzyme elovl2, and lack of expression of this enzyme in heart is believed to be the reason why heart tissue has very low DHA synthesis rates [96]. These novel insights into DHA synthesis merit further investigation to determine how much they contribute to DHA synthesis in vivo.

 

Quote

While most studies report that plasma and erythrocyte EPA increase with ALA feeding, most do not detect an increase in plasma or erythrocyte DHA [98]; [99]; [100]; [101]; [102]; [103]; [104]; [105]; [106]; [107]; [108]; [109]; [110]; [111]; [112]; [113]; [114]; [115]; [116] ;  [117]. Reviews of these studies have pointed out two important points pertaining to the lack of plasma DHA increases after ALA feeding. Firstly, in humans with low DHA diets (vegans and vegetarians), ALA feeding increases plasma DHA [97]. Additionally, plasma DHA tends to increase to a greater extent when ALA consumption is increased in combination with decreased LNA consumption [10] ;  [11].

 

It should be recognized that these studies only measure DHA in blood lipids (plasma, erythrocytes, or leukocytes) as opposed to tissues. While plasma DHA may be a reliable marker for dietary DHA intake, the applicability of this pool to the brain is not agreed upon. This is because most of these studies measure percent composition of DHA in the esterified blood lipid pools, which are not thought to be available to the brain [62]. A recent rodent study performed in our laboratory highlights this point [66]. We fed rats a diet that was either low in n-3 PUFA (0.25% fatty acids as ALA) or contained either ALA or DHA. After 15 weeks on these diets, levels of DHA in the body and plasma were significantly higher in rats fed DHA compared to rats fed the ALA and control diet (2.4 and 11-fold higher, respectively, for the body and 2 and 5-fold higher, respectively, for plasma). However, brain DHA levels were not different between ALA- and DHA-fed rats, similar to previous studies in rats [19] and non-human primates [20], suggesting that changes in blood DHA concentration do not necessarily reflect the magnitude of changes in brain DHA, with some exceptions [118] ;  [119]. Interestingly, graded ALA deprivation from 4.6% (considered “adequate” to maintain brain function and DHA concentrations) to 0.2% (considered “inadequate” based on decreased DHA concentration and metabolism) of fatty acids in a diet lacking DHA results in decreased brain DHA only when the ALA content of the diet is decreased to 0.8% or lower [120]. This indicates that extreme cases of ALA deprivation are required to affect brain DHA concentrations.

 

Quote

It is possible that though plasma esterified DHA is unchanged with chronic increases in ALA feeding, dietary ALA may be sufficient to maintain brain DHA concentrations, possibly via the plasma unesterified fatty acid pool. The plasma unesterified fatty acid pool is 10–100-fold smaller than the esterified pools [89]; [121] ;  [122] and is maintained largely via the adipose (fasting state) and hydrolysis from plasma lipoproteins (post-prandial) [123]. Also, the DHA concentration of the plasma unesterified fatty acid pool decreases only when extreme n-3 PUFA deprivation occurs [120]. Moreover, few studies have examined the effect of increasing dietary DHA intake on unesterified DHA concentrations in humans, with some studies reporting an increase and others reporting no increase [76]; [121]; [124]; [125]; [126] ;  [127]. Adipose, the tissue that maintains plasma unesterified fatty acid concentrations, has been estimated to contain 1–4 and 20–50 g of DHA in the infant [128] ;  [129] and adult [130], respectively. Using the previously measured brain DHA uptake rate of 3.8 mg/day in adult humans, it can be calculated that adult human adipose contains enough DHA to supply the brain for 14–36 years. It is important to note that the estimate for how long adipose DHA can supply the brain is an overestimate because DHA released from the adipose is used by other tissues as well as the brain. Therefore, to determine the actual amount of time that adipose DHA can supply the brain, the proportion of DHA that is released from the adipose and taken up into the brain (brain-body partition coefficient) must be determined.

Quote

There is considerable debate as to whether the human capacity to synthesize DHA from ALA is sufficient to meet brain DHA requirements. This debate has been further complicated by lack of agreement regarding the brain DHA requirement, and methodological inconsistencies in attempts to quantify the rate of DHA synthesis from ALA. The IOM did not assign a dietary reference intake for DHA, and other recommendations for DHA and EPA intake pertain to cardiovascular disease prevention [27]; [29]; [174] ;  [175] and not specifically to support the brain, in part reflecting uncertainty in the role of dietary DHA in maintaining brain DHA. Fortunately, an estimate of human brain DHA uptake is now available (2.4–3.8 mg/day [63] ;  [64]), and novel approaches to measure whole-body DHA synthesis from serum ALA using steady-state isotope infusion will allow for quantitative comparison of DHA synthesis rates to brain DHA uptake rates, as done previously in rats [66]. This approach will supplement previous measurements of DHA synthesis from ingested stable isotope ALA, which provide estimates of DHA synthesis from postprandial ALA, and produce a more complete understanding of DHA homeostasis in humans.Despite limitations in comparing rates of DHA synthesis and brain DHA uptake rates in humans to date, there is considerable evidence from animals showing that brain DHA levels are similar when fed ALA as the only n-3 PUFA as opposed to DHA or ALA+DHA, as reviewed extensively by [65], although there are some exceptions [119] possibly related to dose-, duration-, and species-specific effects. The brain has mechanisms whereby it can conserve DHA that may explain similar brain DHA between DHA- and ALA-fed rats [176].

 

See also:

The effect of linoleic acid on the whole body synthesis rates of polyunsaturated fatty acids from α-linolenic acid and linoleic acid in free-living rats

http://www.sciencedirect.com/science/article/pii/S0955286315003502

Whole body synthesis rates of DHA from α-linolenic acid are greater than brain DHA accretion and uptake rates in adult rats

http://www.jlr.org/content/55/1/62.full

Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain

https://www.nature.com/articles/srep15791

Edited August 19, 2021 by Sibiriak

[Ron Put]

13 hours ago, Sibiriak said:

I decided to take another look into the ALA conversion issue,  and the more I look into the more complex and uncertain the whole issue becomes.  It also make me wonder about the wisdom in doing speculative calculations based on such imperfect information.

[As an aside,  it has always struck me as odd from an evolutionary standpoint that humans would NEED to eat fish or fish oil to maintain optimum health.]

Yeah, it doesn't make much sense, especially as there is no good evidence that vegans or vegetarians who don't take supplements are more susceptible to dementia or cognitive decline than heavy fish eaters.

The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study

Abstract

We investigated the relationship between animal product consumption and evidence of dementia in two cohort substudies. The first enrolled 272 California residents matched for age, sex, and zip code (1 vegan, 1 lacto-ovo-vegetarian, and 2 'heavy' meat eaters in each of 68 quartets). This design ensured a wide range of dietary exposure. The second included 2,984 unmatched subjects who resided within the Loma Linda, California area. All subjects were enrolled in the Adventist Health Study. The matched subjects who ate meat (including poultry and fish) were more than twice as likely to become demented as their vegetarian counterparts (relative risk 2.18, p = 0.065) and the discrepancy was further widened (relative risk 2.99, p = 0.048) when past meat consumption was taken into account. There was no significant difference in the incidence of dementia in the vegetarian versus meat-eating unmatched subjects. There was no obvious explanation for the difference between the two substudies, although the power of the unmatched sub-study to detect an effect of 'heavy' meat consumption was unexpectedly limited. There was a trend towards delayed onset of dementia in vegetarians in both substudies.

This is also interesting, even though Gregger can be overly enthusiastic in his extrapolations at times:

Where are the Lowest Rates of Alzheimer’s in the World?

[Saul]

On 8/19/2021 at 1:10 PM, Ron Put said:

I decided to take another look into the ALA conversion issue,  and the more I look into the more complex and uncertain the whole issue becomes.  It also make me wonder about the wisdom in doing speculative calculations based on such imperfect information.

[As an aside,  it has always struck me as odd from an evolutionary standpoint that humans would NEED to eat fish or fish oil to maintain optimum health.]

Yes; Sibiriac said that.

The likelihood is that ancient hominids lived near the sea; it's quite likely that consumption of fish and shellfish were a large part of their diet. The high w3's in their diet probably led to development of our large brains.

At any rate, ilarge chain w3's are needed by human nutrition; true, as Michael rae has noted, most (but not all) people can convert short chain w3's, such as ALA, to DHA/EPA.

But our ancient ancestors were not vegan.

  --  Saul

[Dean Pomerleau]

22 minutes ago, Saul said:

The likelihood is that ancient hominids lived near the sea;

I'm glad you put it this way rather than suggesting the Aquatic Ape Hypothesis again! 😉

--Dean 

[Ron Put]

2 hours ago, Saul said:

The likelihood is that ancient hominids lived near the sea; it's quite likely that consumption of fish and shellfish were a large part of their diet. The high w3's in their diet probably led to development of our large brains.

At any rate, ilarge chain w3's are needed by human nutrition; true, as Michael rae has noted, most (but not all) people can convert short chain w3's, such as ALA, to DHA/EPA.

Not necessarily what "the science" says:
 

But be that as it may, I have been trying to find compelling evidence for direct DHA and EPA intake, and there is none that I see. Including any evidence requiring fish consumption. Of course, there are rare cases where someone may have impaired conversion, but that's like saying that we should all take insulin because some are Type 1 diabetics.

[Saul]

Ancient Hominids did not get their w3's from flaxseed.

  --  Saul

[Mike41]

She mentioned the reduceit study 4 grams of omega 3 

https://jamanetwork.com/journals/jama/fullarticle/2777450

not all good as it raises atrial fib risk quite significantly.

 

Edited August 22, 2021 by Mike41

[mccoy]

We should not forget that ancient hominids probably had a very short life compared to today's standardsds and that their diet was optimized toward survival and reproduction.

In this sense, omega 3s might not be necessary for survival and reproduction, but they may be necessary for longevity and healthspan. 

[Ron Put]

Thanks for the video, Mike.

mccoy, you make a good point, which is why I don't dwell on diets that claim to be based in evolution. But at the same time, most populations with extreme pre-medical intervention longevity do not appear to consume significant quantities of fish or other DHA and EPA sources, if at all.

And the majority of studies promoting fish or supplementation appear to be industry-sponsored, as are the bevvy of proprietary tests that are supporting it (I've taken three of those :)

So, I am wondering, just as I was wondering about EVOO...

[mccoy]

On 8/29/2021 at 12:55 AM, Ron Put said:

But at the same time, most populations with extreme pre-medical intervention longevity do not appear to consume significant quantities of fish or other DHA and EPA sources, if at all.

Ron, I'm playing the devil's advocate here, but the blue zones populations are pools of genetically selected individuals found in isolated areas, where the same genetic pool could not be diluted. They are developments of specific protective genetic setups. Their dietary regime has its importance but probably does not govern, ditto for other factors. omega 3s or not, they would have regardlessly displayed extreme longevity, most probably.

Edited August 30, 2021 by mccoy