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Old Sun, Dec-16-18, 03:35
s93uv3h s93uv3h is offline
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Default Phospholipid Omega-3's Brain-DHA Advantage - Dr. Rhonda Patrick

from Dr. Rhonda Patrick (FoundMyFitness email):

The Phospholipid Brain-DHA Advantage

There has been a lot of health experts recently advocating strongly for krill oil as an allegedly superior alternative to fish oil as a source for omega-3s. Today we are going to get into the nitty gritty of fish and krill oil and hopefully shed some light on their similarities as well as differences, which may lead to benefits that are actually specific to different tissues in the body.

It's undeniable that the essential omega-3 fatty acids, particularly eicosapentaenoic acid (known as EPA) and docosahexaenoic acid (known as DHA) are extremely important in human physiology. In fact, because fish oil is already one of my single favorite supplements, it's pretty hard for me to even entertain the notion that there's any room for some sort of trade-up from the awesomeness of fish oil. However, there may be some truth to it within very specific contexts.

Omega-3 fatty acids are essential fatty acids and are required by the human body. They cannot be synthesized by our bodies and must be obtained from the diet. One study using data from the National Center for Health Statistics looked into the most common dietary, lifestyle, or metabolic risk factors influencing early mortality found that low intake of omega-3 fatty acids was one of the top dietary factors that had the largest influence on mortality and it accounted for around 80,000 to 100,000 deaths in 2005 alone. [1]
Some of the Omega-3 Benefits
But... before we dive into krill oil and a comparison between it and fish oil, let's briefly go over just a few of the established benefits of EPA and DHA that are generalizable:

Supplementation with EPA and DHA omega-3 fatty acids has been shown to:

Lower all-cause mortality.

Prevent telomere shortening (a biological measure of aging) (read more.)

Improve learning and memory.

Delay brain aging by repairing damage and preventing atrophy.

Reduce inflammation, immune system hyperactivity that damages tissues and can also initiate cancer

Positively affect cholesterol profile by increasing HDL and lowering triglycerides.

Increase cell membrane fluidity including in neurons, which is critical for the action of neurotransmitters including norepinephrine, which has been shown to play a very important role in focus and attention.

On the topic of cell membrane fluidity and norepinephrine, it plays a very important role in many, many different cellular functions. However, just to make it a little bit more tangible one particular example worth mentioning is the fact that DHA is necessary for the adrenergic receptor (found in the cell membrane) to be able to bind to norepinephrine so that norepinephrine can induce a biological response in the brain.

Norepinephrine, in particular, has been shown to play a very important role in focus and attention. See my video on hyperthermic conditioning to learn more about norepinephrine in the context of sauna use. Neurotransmission, however, isn't the only place where membrane fluidity is critical. In fact, many other cell types also have proteins (like receptors) bound to the membrane will likely have their function impeded by a membrane that is too rigid.

So whether we're talking about omega-3 in the context of mortality or in the context of brain function, omega-3 is awesome & extremely important. Let's now turn to the original thrust of this article and dive into a comparison between fish oil and krill oil. These are the two most common sources.​

Now, I know what you're thinking: there is no way omega-3 can do all of that stuff, I must be trying to sell you on some kinda snake oil! I hope so. I hope so, my friend. And that is because I'm a fan of irony: Snake oil, real snake oil at least, has actually been found to be a fat that is rich in omega-3 fatty acids. In fact, Chinese snake oil has been found to have even more of the anti-inflammatory goodness known as eicosapentaenoic acid than fish oil: on average snake oil is about 20% EPA, which is about 2% more than fish oil at 18%. [2]

Krill Oil's Differentiating Characteristics
There are a few key characteristics that differentiate krill oil, which has omega-3 in phospholipid form, from fish oil.

Krill oil has a higher a bioavailability due to most of its EPA and DHA fatty acids being attached to phospholipids, unlike the omega-3 fatty acids in fish oil which are either found in a triglyceride or ethyl ester form.

One of the phospholipids found in krill oil (and fish) has been found to be the almost exclusive source for the brain in recent mouse, rat, and piglet studies. This phospholipid, known as phosphatidylcholine, is generally not found in molecularly distilled fish oil although it is produced in the body.

Krill oil contains a special antioxidant called astaxanthin, which is a carotenoid that fish oil does not contain.
Molecular Distillation As A Point of Distinction

It's important to understand that fish oil is usually modified by the process of molecular distillation, which allows EPA and DHA to be concentrated and removes contaminants like mercury. Krill oil is able to circumvent this processing altogether largely due to its lack of contamination characteristic of its position because it sits lower in the food chain.

The omega-3 fatty acids EPA and DHA in fish are mostly in triglyceride form, meaning three fatty acids are bound to a glycerol backbone. Once the fish oil is distilled it is no longer the same substance. After distillation, the EPA and DHA are converted from triglyceride form into ethyl ester form by removing the glycerol backbone and replacing it with an ethanol backbone. At this stage, it can be converted back into a triglyceride form by a process called re-esterification, which adds the glycerol backbone back onto EPA & DHA. [3]

This secondary process of converting EPA and DHA back into triglyceride form is unique to higher-end brands of fish oil (like nordic naturals) and is done to deliberately increase the bioavailability of EPA and DHA fatty acids. Unfortunately, many of the fish oil supplements on the market are left in ethyl ester form after molecular distillation and the bioavailability of EPA and DHA in ethyl ester form is much lower than triglyceride form. [4]

Krill oil contains EPA and DHA that are mostly present in phospholipids, including:




A phospholipid is composed of a fat-soluble diacylglyceride and a water soluble phosphate group attached to an organic molecule (choline, serine, or ethanolamine in the previous examples). What's important to know about the phospholipids in krill oil is that they are more bioavailable than fish oil's triglyceride or estyl ether forms. Phosphatidylcholine, in particular, is very important, but I'll elaborate more on that in a moment.

Bioavailability of Krill Oil vs. Fish Oil

There are two keys areas where omega-3 fatty acids can encounter problems, which affect its bioavailability and use by your tissues.

First, is absorption in the small intestine after ingestion.

Second, is actual transport inside different tissues (such as the brain, heart, and liver) after intestinal absorption.

First let's cover the differences in intestinal absorption of phospholipids (mostly found in krill oil), triglycerides (mostly found in fish oil, if industrially re-esterified), and ethyl esters (mostly found in fish oil, if it wasn't re-esterified).

In order to be absorbed by the small intestine, the EPA and DHA from fish oil present in triglyceride or ethyl ester form must be broken down by pancreatic lipases (enzymes that break down triglycerides) into free omega-3 fatty acids (meaning they are cleaved from their backbone). The EPA and DHA in phospholipids from krill oil are also broken down into free omega-3 fatty acids in small intestine by a different class of enzymes called phospholipases (enzymes that break down phospholipids) but here is the important point: they do not necessarily have to be broken down because they can also form micelles which can be absorbed in their intact form.

Ethyl esters are poor substrates for pancreatic lipases which mean the EPA and DHA in ethyl ester form are not absorbed as well as in triglyceride form (since the ethyl esters are less able to complete the conversion into free fatty acids). While the EPA and DHA in triglycerides are more bioavailable than ethyl esters, they are not more bioavailable than phospholipids. There are two reasons for this:

EPA and DHA in triglycerides can be broken down by gastric lipases in the stomach, which means some of the omega-3 fatty acids in fish oil are lost in the stomach and never make it to the small intestine for absorption into the bloodstream. Unfortunately, the most bioavailable component of fish oil (triglyceride form) is the form that is most susceptible to this, whereas the phospholipids (ie. phosphatidylcholine) found in krill oil are generally not broken down in the stomach. [3]

Krill oil's phospholipids do not necessarily have to be broken down into free fatty acids by phospholipases in the small intestine since they can also be absorbed in their intact form by chylomicrons, which are the lipoproteins responsible for transporting omega-3 in the bloodstream. [5]

***NOTE*** Even though ethyl ester is the least bioavailable form, one trick that can help improve even its bioavailability is to eat it with an accompanying high-fat meal (in other words, a meal rich in triglycerides). [6]

How Much More Bioavailable Is Krill?
About 40%.

There is evidence demonstrating that omega-3 fatty acids are more bioavailable in krill oil.

When identical doses of EPA and DHA were given in either phospholipid form, triglyceride form, or ethyl ester form (molecularly distilled) to humans, EPA and DHA concentrations in plasma cholesterol were shown to be highest when in phospholipid form followed by triglyceride form and, lastly, ethyl ester form. [7]

In line with this, another study in which humans that were given krill oil containing 62.8% of the total amount of omega-3 fatty acids in fish oil, increased their plasma EPA and DHA levels to the same level as those in the fish oil group despite the fact that it was a smaller dose (by 37.2%). [8] Because the EPA and DHA concentrations in plasma cholesterol are indicative of the amount actually being absorbed in the small intestine and into the bloodstream, this suggests that EPA and DHA in phospholipid form is more bioavailable than triglyceride and ethyl ester is the least bioavailable.
DHA from Krill Oil More Readily Transported to Brain Cells

The concentration of EPA and DHA in plasma cholesterol is not necessarily indicative of the amount of these omega-3 fatty acid concentrations inside different cell types. So let's take a closer look at the mechanisms of transport inside different tissues starting with my favorite, the brain.

DHA is the most abundant fatty acid found in the brain, making up 10 to 20% of the brain's total lipid composition, which is 60% by dry weight. [9] Despite the fact that DHA is abundant in the brain, the mechanisms of how DHA crosses the blood-brain barrier have remained unclear for some time, up until recently. As it turns out, something called DHA-lyso-phosphatidylcholine is far more preferred by the brain compared to DHA in its free fatty acid form, which is what we have left over after triglyceride or ethyl ester DHA has been broken down by lipases. [10,11] But what is DHA-lyso-phosphatidylcholine?​

DHA-lyso-phosphatidylcholine is a byproduct of DHA in phosphatidylcholine after it is cleaved (by phospholipases) either in the small intestine or in the bloodstream. Since DHA in phosphatidylcholine is primarily found in krill oil and not fish oil, this means that krill oil is a great source for DHA-lyso-phosphatidylcholine while fish oil is not. [11] It seems as though DHA-lyso-phosphatidylcholine may be really important. In fact, studies have shown that DHA-lyso-phosphatidylcholine accumulates by 10-fold higher amounts in the brain than DHA in free fatty acid form. [10] This isn't a phenomenon specific to just rats, either. Another study demonstrated something very similar in piglets as well: DHA is taken up into developing brains of piglets in phosphatidylcholine far more effectively than DHA in triglyceride form. [12]

A Transporter Specialized for DHA-lysophosphatidylcholine

So what is the mechanism? Why does the brain prefer DHA-lysophosphatidylcholine over DHA in free fatty acid form?

A nature paper published in May 2014 found a specialized DHA transporter (called Mfsd2a) that transports DHA-lysophosphatidylcholine across the blood-brain barrier. They showed that mice engineered to lack this transporter had 60% less DHA in their brain compared to normal mice! [13]

Getting rid of this transporter ONLY affected DHA levels in the brain and not other tissues, such as the heart or liver... which, instead, has been shown to mostly accumulate DHA in its non-esterified form. [10] The one exception is red blood cells, which actually also prefers DHA-lysophosphatidylcholine which makes sense because DHA concentrations in red blood cells tightly correlate to actual DHA levels found in the brain. [14]

This last point actually makes a great argument for using red blood cell omega-3 content as an index for omega-3 sufficiency instead of the more common plasma cholesterol tests, but as of yet this type of test is not widely available on the market.
Krill Oil Has Its Own Antioxidant: Astaxanthin

One other unique aspect of krill oil is that, unlike fish oil, krill oil contains astaxanthin. That isn't to say that fish don't contain astaxanthin, common fish that eat zooplankton, such as salmon, do as well. However, insofar as we're talking about omega-3 supplements: astaxanthin is a carotenoid that is unique to krill oil and is not present in fish oil. Astaxanthin is produced primarily by phytoplankton, which produce the precursors lycopene and beta-carotene; zooplankton graze on phytoplankton and convert some of the beta-carotene to astaxanthin. Fish (such as salmon) and crustaceans (such as krill) eat zooplankton and this is their source of astaxanthin. [15]

Carotenoids, such as astaxanthin, are antioxidants that uniquely sequester a type of oxidation originating from singlet oxygen (which is produced from UV radiation) and they are also strong antioxidants against peroxyl radicals. [16] Singlet oxygen and peroxy radicals are very reactive and can damage lipid membranes, DNA, and proteins in your cells. All of these are fundamental biological causes of aging. (Note: for more information on this please see my video entitled, "Do Antioxidants Cause Cancer?").

Something cool about astaxanthin, in particular, is that it is one of the carotenoids that is easily absorbed into the human bloodstream. Astaxanthin has an amphipathic structure (both water soluble and lipid soluble properties), which allows it to accumulate in cell membranes. This a is a good thing, because DHA, which is very prone to oxidative damage, also accumulates in cell membranes where it is needed to play a critical role for the cell in membrane fluidity.

Many antioxidants, such as glutathione, are produced and used in the soluble portion of the cell but are not present in cell membranes. For this reason, getting a little astaxanthin with your omega-3 fatty acids may be a great way to uniquely protect that DHA as well as other polyunsaturated fats in the cell membrane from oxidation since it is localized to the same membrane region of the cell as DHA.

Astaxanthin may also have other benefits on its own. For example, astaxanthin supplementation all by itself has been shown in humans to improve immune function while decreasing an important marker of inflammation known as c-reactive proteincRP). [17] Astaxanthin also reduced DNA damage, hyperlipidemia, and oxidative stress by suppressing lipid peroxidation and increased HDL. [17-20] Oxidative stress, DNA damage, and inflammation are all important initiators of cancer, which I also talked about at length in my video "Do Antioxidants Cause Cancer?"

Astaxanthin as a supplement has also been shown to increase HDL-cholesterol and decrease triglycerides (suggesting it plays an important role in cardiovascular health), reduce the oxidation of cell membranes which has been known to play a role in skin aging, and been shown to actually improve crow's feet, elasticity, and transepidermal water loss. [21] In conclusion, astaxanthin supplementation may be beneficial for fighting against many degenerative diseases of aging, such as cancer, cardiovascular disease, stroke, diabetes, and neurodegenerative diseases.

Fish Roe (Fish Eggs)
In addition to krill oil, fish roe (fish eggs) are one of the most concentrated forms of DHA in phospholipid form. Fish roe from salmon, herring, pollock, and flying fish contain approximately 38%-75% of their omega-3 fatty acids in phospholipid form, mostly present in phosphatidylcholine.
The omega-3 fatty acids in krill oil appear to have many benefits: the EPA and DHA are more bioavailable as a consequence of phospholipids. One of the most compelling reasons krill oil is superior to fish oil is due to the fact that krill oil is a source of DHA-lysophosphatidylcholine, the preferred form of DHA in the brain. Additionally, krill oil comes with the added bonus of astaxanthin, which may also play a special role in the fight against aging that other antioxidants don't.

One last novel feature that is specific to krill oil and not fish oil is that it is also a great source of other phospholipids such as phosphatidylserine, phosphatidylethanolamine which are abundant in mitochondrial membranes and neuronal cell membranes. In fact, the levels of these phospholipids in mitochondrial membranes and neuronal membranes decrease with age and this has been linked to neurodegenerative diseases such as Alzheimer's and Parkinson's Disease.

How much do I take?

The next question many of you might ask is how much to take. I personally do not take krill oil. Instead, I get my omega-3 in phospholipid form from salmon roe, which I try to eat at least three times per week. I supplement with a fish oil dose to correspond to about 2 grams of EPA and 1 gram of DHA per day based on studies I have read that seemed to suggest this might be a good therapeutic dose. What the ideal amount to supplement with krill oil is: I have no idea. This open for debate and something I'm not sure about.

I'm hoping that with the new discovery of this brain-specific transporter, clinical trials will use krill oil or roe when trying to understand the effects of DHA supplementation on the brain. When I figure more out, I'll let you guys know. Until next time! Thanks for reading.​​​​​​​
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