EDITORS NOTE: I (Will) recently did a video on ARA which discusses a recent study that found ARA had positive effects on strength and muscle mass readers will want to check out. The results of this study will be covered HERE and in a future article by Monica. This excellent article below by Monica discusses the safety of ARA supplements and possible health benefits that set the record straight on this fatty acid…
In part 1 I outlined the background to the “ARA is bad” theory, and presented studies that have refuted this notion. Part 1 also explains the importance of distinguishing the different omega-6 fatty acids, LA and ARA, and describes the bell-shaped relationship between ARA and EPA + DHA in cell membranes.
In this part you will learn about safety aspects and potential health benefits (!) of ARA supplementation…
Safety and Health Effects of ARA supplementation
With the bad reputation that ARA has, let’s start by looking at safety data. On a typical modern diet (that includes meat, eggs and fish) the average intake of ARA is approximately 100–200 mg ARA per day.[1-5] Several studies have investigated safety aspects of ARA supplementation in different populations.
When healthy volunteers were given over 7 times the usual intake of ARA (i.e. 1500 to 1700 g ARA per day, compared to usual intake of 200 mg ARA per day) in a 7 week controlled feeding study, no effects on platelet aggregation, bleeding times, the balance of vasoactive metabolites, serum lipid levels, or immune response were observed.[6-10] Likewise, in a recent study on healthy men aged 26-60 years, supplementation with 840 mg ARA per day for 4 weeks had no effect on any metabolic parameter or platelet function.
A study in healthy Japanese men and women aged 55-70 investigated whether ARA supplementation affects clinical parameters involved in cardiovascular, inflammatory, and allergic diseases. Subjects were supplemented with ARA-enriched oil (240 or 720 mg ARA per day) or placebo for 4 weeks, followed by a 4-week washout period. The fatty acid contents of plasma phospholipids, clinical parameters, and AA metabolites were determined at baseline, 2, 4, and 8 weeks. It was found that ARA content in plasma phospholipids in the ARA supplemented groups increased dose-dependently and was almost the same at 2 weeks and at 4 weeks. The elevated ARA content decreased to nearly baseline during a 4-week washout period. Contrary to expectations, during the supplementation and washout periods, no changes were observed in plasma phospholipid EPA and DHA content. There were no changes in clinical blood parameters related to cardiovascular, inflammatory and allergic diseases.
Can ARA supplementation possibly have beneficial health promoting effects?
While ARA is most known for giving rise to pro-inflammatory, vasoconstrictive, and/or pro-aggregatory eicosanoids (such as PGE2, thromboxane A2, and leukotriene B4), ARA also produces eicosanoids that are anti-inflammatory and/or anti-aggregatory (such as prostacyclin, lipoxin A4 [13, 14] and epoxyeicosatrienoic acids ).
Thus, the ARA-derived prostaglandin PGE2 is not a clear-cut pro-inflammatory “devil”. More specifically, PGE2 also inhibits production of some inflammatory cytokines TNF-alpha and IL-1 in immune cells (macrophages and monocytes) and inflammatory leukotrienes , and induces production of inflammation resolving lipoxin A4. 74, 75
As these studies demonstrate, PGE2 from ARA acts as both a pro- and anti-inflammatory agent, and may be responsible for helping to turn off and “resolve” inflammation through the inhibition of 5-lipoxygenase and the production of lipoxins. There is accumulating evidence that lipoxins are promising therapeutic agents for inflammatory disorders leading to tissue damage. It is notable that ARA supplementation dose-dependently increases production of lipoxin A4. Further, it is possible that the pro-resolving effect of ARA-derived eicosanoids may work in concert with the resolvins from EPA and DHA, and protectins from DHA.
Because resolution of inflammation is a distinct process from anti-inflammatory processes , and because ARA gives rise to both inflammatory/anti-inflammatory and pro-resolving lipid mediators, the statement that ARA is “bad” due its involvement in the initiation of inflammation is a flawed over-simplification that is blatantly incorrect. Also this data indicated that the anti-inflammatory effects of dietary fish oil may not be mediated through a simple substitution of one family of eicosanoids for another.
A Science Advisory from the American Heart Association (AHA) acknowledged an additional potentially beneficial role of ARA ; it’s conversion to epoxy-eicosatrienoic acids by cytochrome P450. These compounds are fatty acid epoxides that have potent vasodilator properties by inducing relaxation of vascular smooth muscle cells.
ARA supplementation is gaining increasing attention. An experimental study showed that ARA supplementation ameliorates diabetes , and it has been suggested that ARA acts as an anti-diabetic molecule . Thus, ARA supplementation may possibly help prevent development of diabetes and it consequences in high-risk populations.[26, 27] In addition, ARA supplementation has been shown to significantly protect against the teratogenic action of high blood sugar levels (hyperglycemia).
It has been demonstrated that people over 56 years of age, compared with young adults in their 20s, have a lower amount of ARA in red blood cell phospholipids, after controlling for the potential influence EPA+DHA intake. One study found in healthy elderly men that supplementing with 600 mg ARA per day for 1 month not only significantly increased in ARA content in serum phospholipids, but also improved measures of cognitive function compared with olive oil placebo. This is in line with findings from animal studies. In aged rats, brain levels of ARA and DHA are depleted and memory is impaired (measured by long-term potentiation, the neurophysiological correlate of memory), and restoring brain ARA levels was found to improve memory.
Another study supplemented Japanese elderly individuals aged over 65 years with 240 mg ARA per day + 240 mg DHA per day for 3 months, and demonstrated improved blood flow in the microcirculation of the heart muscle. Thus, ARA and DHA may be beneficial in preventing and/or improving age-related declines in brain and cardiovascular function. This is supported by findings that EPA, DHA, and ARA all may be of benefit in dementia and Alzheimer’s disease by up-regulating gene expression related to neurogenesis, improving neurotransmission and nerve cell communication, elevating endothelial nitric oxide (eNO) production and enhancing brain levels of the neurotransmitter acetylcholine.
Experimental data indicates that ARA or PGE2 prevents gene expression of lipogenic (fat synthesizing) genes in the liver and fat cells.[35, 36] A recent intriguing experimental study showed that ARA, or some of its lipid metabolites, promotes resistance to starvation by acting as signals of reduced food availability, and consequently trigger a fasting program that extends life span, even in an abundant food regimen. It is especially notable that elevated levels of ARA, but not EPA, activate autophagy, which is a physiological process that promotes life span extension by clearing cellular damage.[38-41] By showing that AA can activate autophagy and extend longevity without caloric restriction, these study authors argue that increasing levels of ARA may contribute to life span extension.
What about the omega-6/omega-3 ratio?
Since ARA is an omega-3 fatty acid, you may wonder if supplementing with it might screw up the omega-6/omega-3 ratio in the diet by elevating it. There answer is no. Even when supplementing with 1.5 g ARA per day, this won’t add much to the omega-6 load in your diet. Most of the omega-6 we ingest comes from LA. Typical LA intakes in US adults ranges from approximately 12 to 17 g/d for men and 9 to 11 g/d for women (in contrast, the total n-3 fatty intake for men and women is only 1.3 to 1.8 g/d and 1.0 to 1.2 g/d, respectively) , which is about ten times the amount of ARA you would get from an effective ARA supplementation dose.
Even more importantly, the omega-6/omega-3 ratio is futile. The ratio of omega-6/omega-3 fats in most modern diets is in excess of 10:1, and a ratio of 4:1 or lower has been suggested as optimal for health promotion and disease prevention.[43-48] The suggestion of an optimal omega-6/omega-3 ratio is based on old studies suggesting that high intakes of LA lead to reduced conversion of ALA to EPA due to competition between LA and ALA for the enzyme (delta-6 desaturase) that converts these fatty acids to their respective longer-chain fatty acids (ARA and EPA), resulting in increased tissue ARA levels and reduced EPA and DHA levels.[43, 45, 49] Support for the hypothesis that a high intake of LA inhibits the conversion of ALA to EPA comes from a study by showing that a dietary LA/ALA ratio (omega-6/omega-3 ratio) of 2:1  or 4:1  as compared with 10:1 results in a higher plasma phospholipid EPA levels. But because the conversion of ALA to EPA and especially DHA is so inefficient even at low omega-6/omega-3 ratios and high ALA intakes [50, 52-54], this argument is moot. For example, with a background diet high in saturated fat conversion ALA is approximately 6% for EPA . With a diet rich in n-6 PUFA, conversion is reduced by 40 to 50%. Even at a 6% conversion rate, to achieve an effective dose of EPA (e.g. 2.5 g), one would have to consume over 40 g of ALA! That would require 6 tbsp flaxseed oil or 16 oz (450 g) walnuts (7.2 g ALA per tbsp flaxseed oil, 2.5 g ALA per 28.35 g walnuts). And you’d be lucky if your body produces any significant amount of DHA out of that mega load![50, 54]
Another problem with the omega-6/omega-3 is that it does not distinguish between the different omega-6 (LA, GLA, ARA) and omega-3 fatty acids (ALA, EPA, DHA), which all have different effects (albeit sometimes overlapping), and the ratio can be changed in many different ways [56-68]. Also, the omega-6/omega-3 does not say anything about absolute tissue levels of each individual omega-6 and omega-3 fatty acids, which is likely the factor that matters the most.[68, 69] Therefore, comprehensive reviews by leading nutrition researchers have concluded that the omega-6/omega-3 ratio is misleading and not useful.[69, 70] Hence, it makes more sense to look at the ARA/EPA ratio (or the ARA/EPA+DHA ratio), and especially their absolute tissue levels.[71, 72]
Should I supplement with both ARA and fish oil?
As stated above, ARA supplementation does not affect cell membrane phospholipid levels of EPA or DHA.[9, 11, 12, 73] However, fish oil (both EPA and DHA) reduces blood ARA levels and down-regulates ARA incorporation into tissue membrane phospholipids.[61, 74-76] This is in line with the bell-shaped relationship between ARA and EPA + DHA in cell membranes. Therefore, if you are taking a high-dose fish oil, your tissue levels of ARA may actually be below optimal. Therefore, co-supplementing with ARA and fish oil is a good idea and strongly recommended.
On the other hand, supplementing with ARA without fish oil may raise ARA levels too much. This could potentially have a negative effect in the brain, as ARA might increase production of A-beta amyloid , the molecular key event triggering the development and progress of Alzheimer’s Disease.[78-80] This potential side-effect of too much ARA may be counteracted by DHA (found in fish oil and algae oil), as DHA lowers A-beta amyloid levels.[77, 81]
One study showed that supplementing with an oil blend providing a high daily dose of 3600 mg ARA and 2900 mg DHA for 14 days is safe in healthy men aged 19-39 years is safe. This 1.25:1 ratio is similar to the ARA:DHA ratio in human milk , and the study researchers suggested that the safety of this high dose of ARA was due to it being ingested together with DHA.  Thus, when supplementing with 1500 mg ARA/day with the goal to enhance muscle growth, strength gains and performance (more on that in part 3), it is recommended that you also supplement with fish oil providing a least 1200 mg DHA (you want to make sure you get your EPA also).
ARA supplementation of up to 1.5 g per day is safe for people with no pre-existing inflammatory conditions.
Important take-homes from part 1 and part 2 of this series are:
* ARA is not a universally “bad” fatty acid as previously thought. To the contrary, low ARA levels in tissue membranes have been linked to negative health outcomes.
* Contrary to entrenched belief, you cannot rely on your intake of LA (linoleic acid, the parent omega-6 fatty acid) to get enough ARA, because the conversion of LA to ARA is minimal.
* Always supplement ARA together with fish oil. Higher blood levels of both ARA and omega-3 fatty acids are associated with the lowest level of inflammatory markers.[84, 85] A safe and effective dose of ARA is 1.5 g per day. Combine this with a fish oil supplement providing around 2.5 g EPA and 2.5 g DHA per day.
* Optimal health requires raising the levels of both ARA and EPA+DHA in tissues, and not either one at the expense of the other [86-90] and it is low levels of these three main essential fatty acids that cause harm. [86, 91-97] When it comes to ARA (omega-6) and EPA+DHA (omega-3) the key is collaboration and not antagonism. A good example of this is that ARA has a U-shaped relationship with the risk of heart attack; both too low and to high ARA levels in cell membranes are associated with higher heart attack risk.[98, 99]
* Supplementing with both ARA and fish oil (EPA + DHA) together will provide the best of both worlds because intake of ARA is need to enrich cell membranes with ARA, while intake of EPA + DHA will ensure that the cell membranes level of ARA stays in the healthy range (thanks to the bell-shaped relation between these fatty acids, as outlined above). An omega-3 index (level of EPA+DHA in red blood cells) of 8-11% (which is recommended for cardiovascular health promotion[101-103]) coincides with an ARA level in red blood cell of about 14-15%  (the bottom of the risk U-shape relationship) which is the most protective ARA level for heart disease.
Coming next in part 3…
Previous studies have shown that supplementing with EPA + DHA from fish oil increases muscle protein synthesis. [104, 105] Two studies have been conducted on ARA supplementation, which specifically looked at performance enhancing effects. The latest ARA supplementation study also investigated potential muscle growth stimulating effects of ARA… This will be the topic of part 3 of this series…stay tuned!
EFFECTS OF ARA ON STRENGTH AND MUSCLE MASS COVERED HERE
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