Fat gets a bad rap. Thanks to decades of trendy weight-loss plans extolling the virtues of low-fat diets, many Americans are under the misconception that all fats are bad for you, and anything fat-free is inherently healthy. The truth is, because fat makes up most of the structural elements found in each of the human body’s trillions of cells, our bodies actually require a certain amount of fat to be normally constructed and function properly. However, all fats are not the same.

Omega-3 polyunsaturated fatty acids: The skinny on essential fats 

A particularly important family of fats helping to maintain optimal cellular health are called polyunsaturated fatty acids (PUFAs). Often referred to as “healthy fats”, PUFAs are distinguished at the molecular level from saturated and monounsaturated fatty acids by the presence of at least 1 double bond between carbons within their fatty acid chain (refer to the images of different types of fat below to see what these structural differences actually look like).  Depending on the position of a fat’s first double bond, PUFAs can be named as one of 2 sub-families: omega-3 fatty acids or omega-6 fatty acids. 

Omega-3 PUFAs, particularly family members EPA and DHA, are most commonly found within cell membranes, and are removed from these membranes each day in order to contribute to a number of physiological processes critical for maintaining daily normal, foundational activity.  For example, a large body of research shows that deficiencies in these important fats have been linked to features associated with a prolonged inflammatory response (cellular stress that continues on for abnormally long periods).^1,2 Despite growing evidence that deficiencies in EPA and DHA may contribute to poor health, suboptimal levels are common among those eating a standard Western diet characterized by a low intake of fish and seafood, and a high intake of processed foods, saturated fats, and a substantial excess of omega-6-laden vegetable oils. 

This article focuses primarily on the features and functions of omega-3 PUFAs. However, in order to appreciate their biological significance to cells and therefore general heath, it’s helpful to understand the difference between omega-3 and omega-6 fatty acids, and how these two families of fatty acids interact.  

Omega-3s and omega-6s: PUFA sources 

Alpha-linolenic acid (ALA) is the parent fatty acid of the omega-3 family, and through a complex series of metabolic reactions gives rise to the long-chain fats eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Because ALA is required for cells to function normally but cannot be synthesized by the body, it is called an essential fatty acid. ALA must be consumed through dietary sources including:

• Flaxseeds, camelina seeds, perilla seeds, chia seeds, hemp
• Canola oil, flaxseed oil, walnut oil  
• Walnuts, pecans 

Although EPA and DHA can be synthesized from ALA, their conversion rates are so low that they are considered conditionally essential or necessary nutrients. This means that EPA and DHA are physiologically necessary for balanced, normal cell structure and function, and therefore ultimately necessary for optimal health.³ Because the body is extremely limited in its ability to convert EPA and DHA from ALA, it is generally recommended^4,5 that EPA and DHA be obtained directly through dietary sources including: 

• Cold-water fatty fish (tuna, sardines, salmon, mackerel)
• Fish oil (EPA+DHA supplements) 
• Plant-based sources like algae or algae oil 

Linoleic acid (LA) is the parent fatty acid of the omega-6 family and is transformed through a complex series of metabolic reactions into the long-chain omega-6 fatty acid arachidonic acid (AA) and other omega-6 PUFAs.  Similar to ALA, linoleic acid (LA) cannot be made by the body and is therefore called an essential fatty acid that must be obtained from the diet.  Primary sources of LA include certain vegetable oils (soybean, corn, safflower, canola), nuts and seeds, avocados, and animal meats. While “vegetable” oils may sound nutritious, keep in mind that most of the foods containing vegetable oils contain fatty acids that have been structurally changed in some way. As a result, foods containing these altered oils (e.g., baked goods, fried foods, chips and other packaged snacks, etc.) may have limited health benefits compared to fats in their native state. 

Although LA and AA serve important structural and physiological functions—especially for optimal skin health and during early brain development^6,7—when consumed in great excess these fatty acids can contribute to a host of detrimental health effects.^2,8 Conversely, a tremendous amount of research shows that consuming an equal balance of omega-3 and omega-6 fats can help balance omega-6 and omega-3 levels in cells and tissues.  When balanced, these fats may help to improve cell structure and function, and ultimately contribute to a wide variety of health benefits.   

Importantly, because both classes of fatty acids compete for the same enzymes needed to synthesize their PUFA derivatives, an increase in the content of omega-3 within a cell typically occurs at the expense of omega-6, and vice versa.² Understanding how the amount and type of fats consumed in the diet affects the amount and type of fats making up your cells is very important, as these fats may influence many aspects of health in both the short- and long-term. 

Effects of PUFAs on cell membrane structure and function 

Omega-3s play important roles throughout the body as structural components of cell membranes. When dietary intake is appropriate, both EPA and DHA are common in cell membranes throughout the body. (In contrast, DHA alone can be found in very high concentrations in the retina and the brain, implicating its important role in vision and general nervous system function.)⁹ Cell membranes are made up of 2 layers of a diverse group of similar-shaped molecules called phosholipids, which directly or indirectly influence nearly every aspect of a cell’s daily activity.  After EPA and DHA are consumed through the diet, they  are placed within a membrane phospholipid, where they can affect cellular function by promoting the fluidity, flexibility, and/or the permeability of a membrane.¹⁰ These features are vital to numerous daily cell operations including receiving, processing, and responding to information from nearby cells and messages coming from the surrounding environment.^10,11 Similarly, omega-6 fatty acids are placed within membrane phospholipids, and also can contribute to important structural effects that promote fluidity, flexibility and permeability. 

Some of the most important differences between omega-3 fatty acids (EPA, DHA) and omega-6 fatty acids (such as AA) appear after these fats are removed from cell membranes.  After being removed from cell membranes and deported into a cell’s interior, individual omega-3 and omega-6 fatty acids are converted into potent signaling molecules that help regulate short-term processes that influence how a cell responds to stress. In general:  

• Signaling molecules made from the omega-6 fat arachidonic acid (AA) help initiate processes that may promote short-term cell stress 
• Signaling molecules derived from the omega-3 fats EPA and DHA help initiate processes that may reduce short-term cell stress⁸

Omega-3 research: Evidenced-based health benefits 

Thousands of laboratory and clinical research studies link consumption of EPA and DHA to an array of significant health benefits. The studies highlighted in the next few sections provide an overview of key evidence-based findings and benefits that have been associated with the use of these omega-3 PUFAs.

Omega-3s and Cardiovascular health

A strong body of evidence has demonstrated that EPA and DHA provide benefits for certain aspects of cardiovascular health. Particularly compelling evidence comes from three large, randomized trials. 

1. The Diet and Reinfarction Trial (DART) measured certain cardiovascular factors in 2,033 men and reported that in men who recently experienced a heart attack, omega-3 PUFAs reduced the rates of death from all-causes by up to 29%.¹²
2. The Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico (GISSI-Prevenzione) trial studied 11,324 participants and found that after a year of supplementing with EPA and DHA, the risk of death was 21% less in individuals taking fish oil.¹³
3. The 5-year-long Japan EPA Lipid Intervention Study (JELIS) evaluated 18,645 participants and found that participants taking EPA and a cholesterol-reducing drug (statin) had 19% lower risk of major heart-related problems compared to those taking a statin alone.¹⁴

Other documented benefits of EPA and DHA for heart health include:

• Promoting overall cardiovascular health^15,16
• Helping to maintain normal levels of fats in the blood¹⁷
• Promoting the normal structure and activity of blood vessels^17,18,19
• Helping to maintain a healthy and regular heartbeat²⁰
• Promoting healthy arterial blood flow and the normal functioning of platelets^21,22

Omega-3s & Immune health

Short-term (acute) cell stress responses are a normal and necessary physiological response that begins a very complex process designed to restore damaged body cells and tissues after an injury, infection, illness, or allergic reaction.  If, however, these cell stress responses continue for weeks, months or even years, they can damage both cells and tissues, and may over time contribute to many chronic health problems.^2,8,9

Fatty acids play important roles within this story of short-term and long-term cell stress responses. After removal from cell membranes, the potent signal molecules made from the omega-3 fatty acids EPA and DHA act to help lower cell stress responses. In contrast, after removal from cell membranes, the potent signal molecules made from the omega-6 fatty acid arachidonic acid (AA) act to help raise cell stress responses.  Both are necessary for a normal response to cell stress: when a disturbance occurs, omega-6 signal molecules help the local tissues mobilize and begin the repair work. Importantly, the signal molecules from EPA and DHA help this process to remain within reasonable boundaries and resolve rather quickly (typically within a matter of days).  

A person’s fat intake influences this process by providing the fats that reside within a cell’s membrane, and thus, the ones that will be removed and used.  If omega-6 fatty acids are more abundant within a cell’s membrane, then signal molecules that help promote a cell stress response will be more common. In contrast, if omega-3 fatty acids are more abundant within a cell’s membrane, then signal molecules that help lower a cell stress response will be more common. Research suggests that cells need both fatty acids, but that an abundance of omega-3s is more favorable for maintaining a healthy cell response to stress. In sum, with an appropriate balance of fatty acids in membranes throughout the body, cells have the potential to function more normally.  Because organs are made up of cells, organs will also have the potential to function more normally.  And because normal organ functioning is associated with greater general health, obtaining a sufficient amount of omega-3 fats can help optimize overall health. 

Omega-3s, the Brain and mental health 

By weight, over half of the brain is composed of fats (lipids), with DHA representing 10-20% of this fat.⁵ The prevalence of DHA in the brain and other nervous tissues and a wealth of laboratory and clinical research combine to suggest that this molecule plays integral roles during human development, while helping to promote the healthy structure and function of nervous system components throughout life.²⁷ Evidence from clinical trials, observational studies, and meta-analyses have found that EPA and DHA may: 

Omega-3s, Pregnancy and Neonatal development 

• Support healthy brain function and cognitive development in infants and children^28-30
• Help maintain normal levels of attention and focus^31,32
• Support a stable mood and overall mental health^33,34
• Promote healthy brain structure, memory, and neurological functioning into older adulthood^35–39

The life journey begins with fetal development during pregnancy, and similar to adults, a sufficient abundance of omega-3 fatty acids appears to be beneficial for a fetus’s cellular health. Research has found that DHA accumulates rapidly in the brain and retina during the latter part of gestation and during the first several years of postnatal life.  Studies have also found that supplementing with DHA may promote a woman’s chances of carrying a baby to full-term (for more information about DHA during gestational development, refer to “Why Do I Need DHA During Pregnancy?”).  Further evidence suggests that omega-3s, particularly DHA, work to: 

• Help promote a healthy pregnancy^40-42
• Support normal gestation duration and birthweight^42,43
• Support normal fetal development^29,43

Omegas 3 & 6: dosage and ratio 

In light of their respective roles in helping to promote and resolve certain cell stress responses, evidence suggests that the amount of omega-6 and omega-3 fatty acids within cell membranes—commonly referred to as the omega-6:3 ratio—plays a central role in helping to promote healthy cells throughout the body.⁸ Although no optimal omega-6:3 ratio has been determined for everyone (due to differences in gender, age, weight, activity, diet, hormone levels, stress, medications, etc.), research suggests a ratio of 2:1 or 1:1 may provide numerous health advantages.^2,8 If a person’s ratio is high (that is, if their cell membranes contain many more omega-6 fatty acids compared to omega-3 fatty acids), it can be lowered by consuming fewer omega-6 fats and eating more EPA and DHA.  

A simple lab test is the fastest and most efficient way to measure your omega-6:3 index.  A simple finger-prick blood test can be ordered by your health practitioner and used to develop specific nutritional goals and health recommendations.  In the absence of testing, the International Society for the Study of Fatty Acids and Lipids (ISSFAL)⁴⁴ and American Heart Association (AHA)⁴⁵ have provided the following daily recommendations:

While these recommendations are helpful, it is worth noting that research studies using larger doses of omega-3 fatty acids (between 1,000 mg/day and 5,000 mg/day) for treating a variety of health problems reliably demonstrate that higher doses are effective and well tolerated.^26,29,31,45

Omega-3 research: Why the conflicting results?

Although thousands of research studies have demonstrated a strong association between omega-3s and physiological benefits throughout the body, some studies (typically meta-analyses) have reported results that suggest EPA and DHA lack benefits for certain health problems.  These findings (and sensationalized headlines) have led some to question the use of these omega-3 PUFAs.^47-49 While each science-based study merits careful attention, there are a number of evidence-based reasons that explain many of these neutral or negative study outcomes. Notable reasons include: 

Increasing use of pharmaceutical drugs

Many studies include participants who are already taking one or more medications for specific health problems.  Since each drug potently influences cell metabolism in multiple ways over short-time periods, the more subtle influences of EPA and DHA over longer periods of time is often harder to detect.^47,50

Implications of studying health concerns using meta-analyses 

In recent years, meta-analyses have become increasingly common for investigating the effects of clinical research. While large, multi-sample studies can be very informative, they are not without limitations. Differences between study designs (differing dosages, study durations, participant demographics) and increased statistical requirements can dilute out or cover up important physiological processes and make it difficult to detect certain metabolic effects.^51,52

More emphasis on consuming fish and omega-3 sources 

Public health messages emphasizing the health benefits of seafood may have led to greater consumption of omega-3 fatty acids for individuals concerned with their health, thus making it difficult to evaluate the benefits of consuming supplemental EPA and DHA in research studies. Moreover, nearly all studies fail to control for participants’ omega-3 and omega-6 consumption via diet or supplementation.^48,50

Conclusion

To make a long story short, many research studies converge on the findings that omega-3 PUFAs are necessary for maintaining normal, balanced and even optimal cellular and metabolic health. While it’s important that we consume both essential PUFAs, research suggests that consuming sufficient EPA and DHA daily each is integral for foundational health, and that supplementation through dietary sources—including fish oil—can lead to significant health benefits.