ácido alfa-linolénico (ALA)

Alpha-Linolenic Acid (ALA): A Comprehensive Encyclopedic Reference

1. Identity: Chemical Names, Structure, and Natural Sources

1.1 Nomenclature and Chemical Identity

Alpha-linolenic acid (ALA), also known in scientific literature simply as alpha-linolenic acid, is an n−3 (omega-3) essential fatty acid. In terms of its structure, it is formally named all-cis-9,12,15-octadecatrienoic acid, and in physiological literature it is listed by its lipid number, 18:3 (n−3). It is a carboxylic acid with an 18-carbon chain and three cis double bonds. The first double bond is located at the third carbon from the methyl end of the fatty acid chain. Thus, ALA is a polyunsaturated n−3 (omega-3) fatty acid.

The term alpha-linolenic acid encompasses all fatty acids under the IUPAC nomenclature "(9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid," including, but not limited to, "ALA," "LNA," "linolenic acid," "cis,cis,cis-9,12,15-octadecatrienoic acid," "all-cis-9,12,15-octadecatrienoic acid," and "(9Z,12Z,15Z)-9,12,15-octadecatrienoic acid."

ALA was first discovered in 1887 by an Austrian chemist named Karl Hazura, but its chemical structure was not fully clarified until 1909. The name alpha-linolenic acid comes from the Latin words linum, meaning "flax," and oleic, meaning "pertaining to oil" — referring to its initial isolation from flaxseed oil.

ALA is a regioisomer of gamma-linolenic acid (GLA), an 18:3 (n−6) fatty acid — that is, a polyunsaturated omega-6 fatty acid with three double bonds. These two compounds are distinct entities with different biological roles and should not be confused.

1.2 Essential Fatty Acid Status

ALA is an essential fatty acid found in plants that can be endogenously metabolized to its elongation/desaturation products eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acid n-3 (DPA n-3, 22:5n-3), and docosahexaenoic acid (DHA, 22:6n-3), through a series of desaturation, elongation, and beta-oxidation steps. ALA is essential because of the lack of delta-15 desaturase required for its synthesis in the body.

1.3 Natural Sources

Seed oils are the richest sources of alpha-linolenic acid, notably those of hempseed, chia, perilla, flaxseed (linseed oil), rapeseed (canola), and soybeans. ALA is also found in many seeds and oils including walnuts. Dietary-rich sources of this fatty acid also include Camelina sativa and other plant food sources.

ALA is the most important n-3 source in the diets of people who do not regularly consume oily fish — not only vegetarians and vegans — or who do not take EPA and DHA supplements.

1.4 Common Forms and Preparations

ALA is available in numerous dietary and supplemental forms:

• Flaxseed oil (linseed oil): Cold-pressed oil from Linum usitatissimum seeds, one of the most concentrated plant sources of ALA, available as bottled oil and in softgel capsules.
• Whole and ground flaxseed: Flaxseed and flaxseed oil contain various essential fatty acids but are particularly rich in ALA. Flaxseed (but not flaxseed oil) also has a high fiber content that may have health benefits similar to those of other high-fiber products, along with phytoestrogens.
• Chia seed oil and chia seeds: Among the richest seed oil sources of ALA.
• Walnut oil and walnuts: A dietary source providing notable quantities of ALA.
• Canola and soybean oils: Common cooking oils contributing ALA to the diet at population level.
• Perilla oil: Present in high amounts in perilla oil, among other plant oils.
• Softgel capsules of flaxseed oil: Oral flaxseed oil supplements may be safe for short-term use (up to 6 months) in limited amounts.

Some studies state that ALA remains stable during processing and cooking. However, other studies indicate that ALA might not be suitable for baking as it will polymerize with itself. Some ALA may also oxidize at baking temperatures.

2. Traditional and Historical Use

2.1 Flax (Linum usitatissimum) — The Primary Source Plant

Flaxseeds are known as Linum usitatissimum — the species name meaning "most useful." The flax plant originated in Mesopotamia, and the first records of the culinary use of flaxseeds date from the times of ancient Greece.

Flaxseed has a long history of traditional use for health and industrial purposes. Originally cultivated near the Middle East, flaxseed was later used to make linen cloths in ancient Egypt, stews in Ethiopia, and laxatives in ancient Greece.

Historically, linseed oil, derived from flaxseed, was used as a topical demulcent and emollient, as a laxative, and as a treatment for coughs, colds, and urinary tract infections.

In North America, European settlers used flaxseed to make poultices for cuts and burns and oil for paints. Flaxseed was first planted in the United States with the arrival of the early colonists in North America. In the 17th century, flax was first introduced and planted in Canada, the country that is currently the major producer.

Flaxseed — the edible seeds harvested from flax (Linum usitatissimum) plants — was consumed as food by the ancient Greeks and Romans and has reemerged as a possible "superfood" because of its high dietary fiber and omega-3 fatty acid content.

2.2 Notes on Traditional Use of ALA Specifically

It is important to note that traditional uses of flaxseed, walnut, and hemp in ancient cultures were aimed at the whole food or oil, not at isolated ALA — the molecule was not identified until the late 19th century. Traditional preparations therefore encompass the matrix of the whole seed or cold-pressed oil. The traditional health rationale for linseed oil as an emollient, laxative, and anti-inflammatory agent predates any biochemical understanding of its omega-3 content. Today, flaxseed and flaxseed oil supplements are promoted for the heart, brain, and immune system. These products typically contain ALA, an omega-3 fatty acid extracted from flaxseed or flaxseed oil.

3. Key Constituents, Active Compounds, and Mechanisms of Action

3.1 The ALA Molecule

ALA is an 18-carbon polyunsaturated fatty acid containing three double bonds at the 9, 12, and 15 positions, found in green leaves, seed oils (particularly flax), pumpkin seeds, beans, and walnuts — flaxseeds being the richest source.

3.2 Metabolic Conversion to Long-Chain Omega-3s

ALA is metabolized to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by desaturases and elongases in humans. However, the conversion of ALA to EPA and DHA is limited, and these long-chain n−3 PUFAs are mainly provided from dietary sources such as fish and seafood.

ALA is a substrate for the synthesis of the very-long-chain n−3 PUFAs EPA and DHA; however, as noted by Burdge and Calder, the conversion is low: approximately 0.2% to EPA, 0.13% to DPA, and 0.05% to DHA.

The rate-limiting enzyme for the conversion of ALA to EPA and DHA appears to be the polymorphic delta-6-desaturase, and there is an indication that this conversion is reduced by competition with the n-6 PUFA linoleic acid (LA), which is desaturated and elongated by the same enzymes. Consequently, the ratio of n-6/n-3 PUFAs in the diet can dictate how much ALA gets converted to EPA and DHA.

Generally, supplementation with ALA or ALA-rich oils leads to an increase in EPA levels and has no significant effect on DHA or the omega-3 index.

3.3 Oxylipin Pathway and Anti-inflammatory Mechanisms

Studies investigating the cellular mechanisms for ALA's beneficial effects showed that ALA is metabolized to oxylipins through the Lipoxygenase (LOX), the Cyclooxygenase (COX), and the Cytochrome P450 (CYP450) pathways, leading to hydroperoxy-, epoxy-, mono-, and dihydroxylated oxylipins. In several mouse and cell models, it has been shown that ALA and some of its oxylipins, including 9- and 13-hydroxy-octadecatrienoic acids (9-HOTrE and 13-HOTrE), have immunomodulating effects.

The major effects of ALA on metabolic syndrome appear to be through its conversion to more potent EPA and DHA, the impact on the n-3/n-6 ratio, and the consecutive effects on the formation of oxylipins and endocannabinoids, inflammation, insulin sensitivity, and insulin secretion, as well as adipocyte and hepatocyte function.

3.4 Anti-inflammatory and Antioxidant Properties

ALA, an omega-3 polyunsaturated fatty acid extracted from plant sources, has been shown to be one of the anti-inflammatory and antioxidant agents. In cell studies, ALA reduced pro-inflammatory cytokine levels including IFNγ, TNFα, and IL-6.

3.5 Neuroprotective Mechanisms

The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in the brain and involve the transcription factor nuclear factor kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), a major neuroprotective protein in the brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF.

Inadequate dietary ALA leads to reductions in both visual acuity thresholds and electroretinogram A- and B-wave responses, which is accompanied by a decrease in brain and retina DHA and an increase in docosapentaenoic acid (DPA, 22:5n−6). This decrease in DHA reflects the limited conversion of ALA to DHA. The DHA content of neural membrane phospholipids modulates the activities of several signaling pathways in the brain and is critical for normal retinal function. Thus, these findings suggest that an inadequate ALA intake decreases the availability of DHA for incorporation into neural membranes.

4. Scientific Evidence by Area of Use

4.1 Cardiovascular Disease

4.1.1 Overview and Meta-analytic Evidence

A meta-analysis of 27 original studies, including 251,049 individuals and 15,327 CVD events, found that higher ALA exposure is associated with a moderately lower risk of CVD, with an overall pooled relative risk (RR) of 0.86 (95% CI: 0.77, 0.97). In observational studies, higher ALA exposure was thus associated with a moderately lower risk of CVD.

Results were generally consistent for dietary and biomarker studies but were not statistically significant for biomarker studies. However, the high unexplained heterogeneity highlights the need for additional well-designed observational studies and large randomized clinical trials to evaluate the effects of ALA on CVD.

4.1.2 Randomized Controlled Trials

Three randomized controlled trials (RCTs) — the AlphaOmega trial, the Prevención con Dieta Mediterránea (PREDIMED) trial, and the Lyon Diet Heart Study — all showed benefits of diets high in ALA on cardiovascular-related outcomes, but the AlphaOmega trial, which was specifically designed to evaluate ALA effects, only showed a trend for benefit.

RCTs have shown that dietary ALA reduced total cholesterol, LDL cholesterol, triglycerides, and blood pressure, and epidemiologic studies and some trials have also shown an anti-inflammatory effect of ALA, which collectively account, in part, for the cardiovascular benefits of ALA. A meta-analysis reported a trend toward diabetes risk reduction with both dietary and biomarker ALA.

4.1.3 Short-term Trials on Lipids and Biomarkers

Short-term trials (6–12 weeks) in generally healthy participants mostly showed no or inconsistent effects of ALA intake (1.2–3.6 g/d) on blood lipids, low-density lipoprotein oxidation, lipoprotein(a), and apolipoproteins A-I and B. Studies of ALA in relation to inflammatory markers and glucose metabolism yielded conflicting results.

A randomized, double-blind, crossover study in Japanese men examined flaxseed oil (a rich source of ALA) versus corn oil supplementation. Flaxseed oil supplementation was associated with a significant decrease in small dense LDL (sd-LDL) concentrations at 4 and 12 weeks, whereas corn oil supplementation had no effect. Moreover, sd-LDL concentrations were significantly lower in the flaxseed oil period than in the corn oil period at 4 weeks. Among subjects with triglyceride concentrations above 100 mg/dL, flaxseed oil supplementation markedly reduced sd-LDL concentrations.

4.1.4 Observational Evidence on Myocardial Infarction

With regard to clinical cardiovascular outcomes, there is observational evidence for a protective effect against nonfatal myocardial infarction. In one studied population, ALA intake assessed by a 135-item food frequency questionnaire ranged from 1.1 to 2.4 g/d (mean 1.6 g/d). Dietary ALA was inversely associated with nonfatal MI, with odds ratios indicating a 39% reduced risk for approximately a 0.6-g/d difference in intake. The relationship between ALA and MI was nonlinear and mainly confined to the lowest levels of intake. Dietary ALA intake correlated well with ALA in adipose tissue, plasma, and erythrocytes, but poorly with biomarkers of EPA and DHA, suggesting a direct cardioprotective effect of ALA rather than via conversion to long-chain n-3 fatty acids.

4.1.5 Blood Pressure

ALA has shown protective effects against hypertension, contributing to balancing blood pressure through customary diet. According to the 2009 EFSA statement, dietary ALA may contribute to reducing the risk of CVDs, thanks to anti-hypertensive, anti-atherosclerotic, and cardioprotective effects.

4.1.6 Overall Evidence Characterization

While some studies confirm an important association between daily ALA intake and a significant reduction in CVD risk, others indicate that there is no strong correlation. A dose-dependent dietary intake of ALA appears to be associated with a reduced risk of CVD. Some studies confirm that adherence to the Mediterranean diet, with the addition of ALA at correct intake levels, has positive and beneficial effects on significantly reducing ischemic heart disease (IHD), cardiac death, and nonfatal acute MI. Although some studies are significant and vouch for the effectiveness of ALA on CVD, further clinical trials are needed to confirm the relationship between ALA intake at different doses and CVD events.

The clinical trial evidence for ALA is not as extensive as that for EPA + DHA; however, there have been CVD event benefits reported. Those that have been reported for EPA + DHA are stronger because only EPA + DHA differed between the treatment and control groups, whereas in the ALA studies there were diet differences beyond ALA between the treatment and control groups. Current perspective is that increasing dietary ALA will decrease CVD risk; however, randomized controlled clinical trials are necessary to confirm this.

4.2 Inflammation and Inflammatory Markers

There is evidence in humans that supplementation of ALA in the diet is associated with an improved lipid profile, a reduction in the inflammatory biomarker C-reactive protein (CRP), and a reduction in cardiovascular diseases and all-cause mortality.

In cell model research, DHA and ALA consistently showed anti-inflammatory and antioxidative effects, while EPA's beneficial effect was more pronounced under inflammatory conditions, emphasizing the importance of PUFA type and context in managing vascular inflammation. However, this work is largely preclinical and cannot be directly extrapolated to clinical outcomes.

4.3 Neurological and Cognitive Health

The role of ALA in cognition is in the early stages but shows promising evidence of counteracting cognitive impairment.

ALA plays an important role in brain function and protection, as well as exhibiting anti-inflammatory and neuroplastic properties.

In preclinical (animal/cell) models, ALA significantly improved memory and synaptic functions in amyloid-beta (Aβ)-treated mouse brains. These results indicated that ALA could be an applicable intervention in neuroinflammation, apoptotic cell loss, amyloidogenesis, and memory dysfunction via inhibition of TLR4 and its downstream targets. These findings are in animal and cell models and have not been replicated in human clinical trials.

Previous studies have indicated that ALA exhibits neuroprotective effects against in vivo brain damage induced by kainic acid and nerve agents. ALA also promotes synaptic plasticity and exhibits antidepressant activity in vivo. In neurodegenerative diseases such as Alzheimer's disease, ALA treatment has been shown to attenuate inflammation and improve cell viability in glial cell models.

Alpha-linolenic acid, the precursor of the majoritarian brain component DHA, has emerged as a potential novel brain-protective agent, acting via blood-brain barrier (BBB) functionality. This evidence is currently theoretical and mechanistic; large human RCTs in cognitive outcomes are lacking.

4.4 Diabetes and Metabolic Syndrome

A meta-analysis reported a trend toward diabetes risk reduction with both dietary and biomarker ALA. For metabolic syndrome and obesity, however, the evidence for ALA benefits is inconclusive.

Animal studies have shown effects of ALA on insulin sensitivity and glucose metabolism. The major effects of ALA on metabolic syndrome appear to be through its conversion to more potent EPA and DHA, the impact on the n-3/n-6 ratio, and the consecutive effects on the formation of oxylipins and endocannabinoids, inflammation, insulin sensitivity, and insulin secretion, as well as adipocyte and hepatocyte function. Whether these pathways translate into clinically significant effects in humans requires further investigation.

4.5 Cancer — Prostate Cancer Risk

The relationship between ALA and prostate cancer has been studied extensively and remains one of the most debated safety topics in ALA research. The evidence is mixed and does not support a definitive conclusion in either direction.

A number of studies have shown a positive association between dietary, plasma, or red blood cell levels of alpha-linolenic acid and prostate cancer. Other studies have demonstrated either no association or a negative association.

The relation between ALA and prostate cancer is inconsistent across studies. Data were pooled from 8 case-control and 8 prospective studies. The summary estimate revealed that high ALA dietary intakes or tissue concentrations are weakly associated with prostate cancer risk (relative risk [RR]: 1.20; 95% CI: 1.01, 1.43).

After adjustment for publication bias, however, there was no association between ALA and prostate cancer (RR: 0.96; 95% CI: 0.79, 1.17). Studies examining the relation between ALA and prostate cancer have produced inconsistent findings. High ALA intakes or high blood and adipose tissue concentrations of ALA may be associated with a small increased risk of prostate cancer. However, these conclusions are qualified because of the heterogeneity across studies and the likelihood of publication bias.

Importantly, a 2010 meta-analysis of prospective studies found that subjects who consumed more than 1.5 g/day of ALA compared with subjects who consumed less than 1.5 g/day had a significantly decreased risk of prostate cancer (RR = 0.95; 95% CI: 0.91–0.99). The findings support a weak protective association between dietary ALA intake and prostate cancer risk, but further research is needed to conclude on this question.

The limitations of studies in this area include the assumption that dietary or plasma alpha-linolenic acid levels are positively associated with prostate tissue alpha-linolenic acid levels, and measurement errors of dietary, plasma, and red blood cell alpha-linolenic acid levels. More research is needed before it can be concluded that there is a definitive association between alpha-linolenic acid and prostate cancer.

4.6 Retinal and Visual Function

Inadequate dietary ALA leads to reductions in both visual acuity thresholds and electroretinogram A- and B-wave responses, which is accompanied by a decrease in brain and retina DHA. The DHA content of neural membrane phospholipids modulates the activities of several signaling pathways in the brain and is critical for normal retinal function. These findings suggest that an inadequate ALA intake decreases the availability of DHA for incorporation into neural membranes.

5. Body Systems and Health Areas Associated with ALA

Based on the available evidence, ALA has been studied and associated with the following body systems and health areas:

• Cardiovascular system: ALA is an essential fatty acid of the omega-3 series known for its cholesterol-lowering effect and is considered one of the alternative systems to drug therapy to minimize the risk of CVDs.
• Nervous system / Brain: ALA plays an important role in brain function and protection as well as exhibiting anti-inflammatory and neuroplastic properties.
• Immune / Inflammatory system: ALA is metabolized to oxylipins through the LOX, COX, and CYP450 pathways, producing hydroperoxy-, epoxy-, mono-, and dihydroxylated oxylipins that exert immunomodulating effects.
• Endocrine / Metabolic system: ALA has effects on the formation of oxylipins and endocannabinoids, inflammation, insulin sensitivity, and insulin secretion, as well as adipocyte and hepatocyte function.
• Visual system: ALA, as a precursor to DHA, is critical for maintaining normal retinal and brain DHA levels.
• Reproductive system: Some studies of the use of flaxseed during pregnancy suggest it is possibly unsafe, though the evidence is not conclusive.

6. Dosage Forms and Dosages Reported in Studies

6.1 Established Dietary Reference Values

Experts have not established recommended amounts for omega-3 fatty acids other than for ALA. The amount needed depends on age and sex.

The Institute of Medicine (IOM) established an Acceptable Macronutrient Distribution Range (AMDR) for omega-3s (as ALA) of 0.6 to 1.2% of energy for children and adults aged 1 year and older. The IOM also noted that about 10% of the AMDR can be consumed as EPA and/or DHA.

Current recommendations for ALA are based on an Adequate Intake and have remained at 1.1–1.6 g/d, despite evidence suggesting cardiovascular benefits at amounts above 2 g/d (0.6%–1% total energy).

The National Health and Nutrition Examination Survey (NHANES) from 2011–2012 reported that most children and adults consume the recommended amounts of omega-3s as ALA. The average intake of ALA from food is 1.59 grams per day for females and 2.06 grams per day for males aged 20 and older.

6.2 Doses Used in Clinical Trials

• Short-term lipid/biomarker trials: ALA intake in short-term trials (6–12 weeks) in generally healthy participants ranged from 1.2–3.6 g/d.
• Cardiovascular risk reduction evidence base: The evidence demonstrates that consumption of 2–3 g/d of ALA reduces the risk of CHD in primary and secondary prevention studies.
• Flaxseed as a food: Research concluded that up to 50 g high-ALA flaxseed per day is palatable, safe, and may be nutritionally beneficial in humans by raising n-3 fatty acids in plasma and erythrocytes and by decreasing postprandial glucose responses.
• Animal study dosages (not directly applicable to humans): In mouse studies, ALA was administered at 60 mg/kg per oral for 6 weeks.
• Efficient dietary sources: Among edible oils, flaxseed oil requires only 2–3 g/day to meet ALA recommendations of the NIH. Flaxseed and chia seeds are among the most efficient sources, requiring only 5–7 g/day of the whole seed to meet recommendations.

7. Safety Considerations and Interactions

7.1 General Tolerability

Limited amounts of flaxseed (especially flaxseed lignan extract or mucilage) or oral flaxseed oil supplements may be safe for use in the short-term (up to 6 months). Higher doses of flaxseed or flaxseed oil supplements may cause uncomfortable digestive symptoms including bloating, fullness, and diarrhea.

ALA has a very wide safety margin in preclinical and available human research.

7.2 Anticoagulant and Antiplatelet Drug Interactions

There are theoretical reasons to suspect that flaxseed or flaxseed oil might interact with other drugs, such as anticoagulant or antiplatelet drugs.

Laboratory and animal studies, as well as preliminary research in people, suggest that flaxseeds and flaxseed oil have antiplatelet and anticoagulant (blood-thinning) effects. Rare cases of increased bleeding and prolonged blood clotting time linked with flaxseed consumption have been reported in people taking blood thinners such as aspirin and warfarin.

7.3 Blood Pressure Medications

With respect to blood pressure medicines: flaxseed may lower blood pressure, so taking flaxseed or flaxseed oil along with medicines that lower blood pressure might lower blood pressure to a level that is not healthy.

7.4 Diabetes Medications

With respect to diabetes medicines: flaxseed may lower blood sugar. Taking flaxseed along with diabetes medicines might lower blood sugar too much. The same is true if flaxseed is taken along with other medicines that have the potential to lower blood sugar.

7.5 Estrogenic / Hormonal Interactions

Flaxseed may hinder the effects of estrogen. This interaction is attributed predominantly to the lignan content of whole flaxseed rather than to ALA itself, though these compounds co-occur in the same preparations.

7.6 Raw and Unripe Flaxseed

Raw or unripe flaxseeds should not be consumed; they may contain potentially toxic compounds. Cyanogenic glycosides (linamarin, linustatin, neolinustatin) were found at highest levels in extracted flaxseed mucilage but were not detected in baked muffins containing 150 g flaxseed/kg.

7.7 Pregnancy

Some studies of the use of flaxseed during pregnancy suggest it is possibly unsafe, but the evidence is not conclusive.

7.8 Prostate Cancer Risk Signal

As noted in Section 4.5, the relationship between ALA and prostate cancer risk remains unresolved. Studies examining the relation between ALA and prostate cancer have produced inconsistent findings. High ALA intakes or high blood and adipose tissue concentrations of ALA may be associated with a small increased risk of prostate cancer; however, these conclusions are qualified because of the heterogeneity across studies and the likelihood of publication bias.

7.9 Oxidative Stability

ALA is an essential n-3 acid highly susceptible to oxidation. Flaxseed oil in particular should be stored in opaque containers, refrigerated, and not used past its expiration date to minimize rancidity and potential formation of lipid oxidation products.

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