Bioavailability of α-linolenic acid from flaxseed diets as a function of the age of the subject

Abstract

Background:

Dietary flaxseed may have beneficial cardiovascular effects. An aged population has a higher incidence of cardiovascular disease, but they may react differently to flaxseed in the diet.

Objective:

To investigate the response, over a period of 4 weeks, of subjects aged 18–29 or 45–69 years to a diet containing the same amount of α-linolenic acid (ALA) (6 g) introduced in the form of ground flaxseed (30 g) or flaxseed oil.

Results:

All subjects who received flaxseed oil showed a significant increase in plasma ALA and eicosapentaenoic acid (EPA) concentrations over the course of this study. Subjects who received ground flaxseed in the 18–29-year-old group showed a statistically significant increase in their plasma ALA levels, and although there was a trend in the same direction for the 45–69-year-old subjects, this did not achieve statistical significance. The diets induced no major changes in platelet aggregation, plasma total cholesterol, low-density lipoprotein or high-density lipoprotein cholesterol levels in any of the groups. Younger subjects showed a decrease in triglyceride (TG) values compared with older subjects. There were no significant side effects that caused compliancy issues.

Conclusion:

Subject age does not seem to be a major determining factor in influencing ALA absorption from a flaxseed-supplemented diet nor in the metabolism of ALA to EPA in the groups fed flaxseed oil. Concerns about side effects in older subjects administered a higher fiber load in a flaxseed-supplemented diet are not justified. However, younger but not older subjects showed a beneficial decrease in circulating TGs due to flaxseed supplementation.

Introduction

Flaxseed contains one of the richest plant sources of the ω-3 polyunsaturated fatty acid, α-linolenic acid (ALA). ALA is believed to be one of the dietary factors responsible for providing significant protective effects against the incidence of myocardial infarcts and its complications (de Lorgeril et al., 1994, 1999; Erkkilä et al., 2003). Dietary flaxseed, therefore, may be an effective dietary agent to achieve decreases in infarcts and death. However, clinical trials to prove this have not been attempted to date. In experimental work, dietary flaxseed has shown anti-arrhythmic (Ander et al., 2004) and anti-atherogenic actions (Dupasquier et al., 2006, 2007). This would suggest that initiating a larger clinical trial to investigate the cardiovascular benefits of dietary flaxseed is warranted. However, before initiating large, expensive clinical work in patient populations that are primarily >45 years of age, it is important to investigate the differences, if any exist, in the response of older subjects to a diet supplemented with ground flaxseed or flaxseed oil. We know little regarding the response of older subjects to foods that contain higher doses of flaxseed. This may be a problem. It is possible that the absorption of the healthy ALA from flaxseed may be very different in more aged populations. In addition and just as importantly, because of the high content of fiber and oil, flaxseed may not be tolerated as well in the gastrointestinal tract of older people in comparison with young individuals. Therefore, the purpose of this study was to examine the differences in responses of younger and older healthy subjects to a diet supplemented with flaxseed. We have also delivered the same amount of ALA (6 g) in this study in the form of milled flaxseed or flaxseed oil to identify any differences in the responses of the two aged groups to the two different dietary options of flaxseed.

Materials and methods

Study design

This is a double-blinded, randomized, controlled study. The study design was approved by the University of Manitoba Research Ethics Board and the St Boniface General Hospital Research Review Committee. Two groups of apparently healthy subjects without any chronic disease were studied. None of them were using cholesterol-lowering drugs, hypertension drugs, anti-histamines or hormone therapy. One group was composed of subjects between 18 and 29 years of age (10 men and 10 women) and the second was composed of subjects from 45 to 69 years of age (10 men and 10 women). Each subject signed a written informed consent before any study related to screening procedures. Subjects were not allowed to ingest supplementary vitamins or oils or salad dressing containing oils during the course of the study or for 1 month before the start of the study. Their food consumption was not monitored or controlled except as stated above. This study was conducted for 4 weeks and subjects were free to withdraw from participation in this study at any time, for any reason, without penalty.

Diet supply

Flaxseed (ground or flaxseed oil) was included in baked muffins that were offered in two different flavors, namely banana chocolate chip and cranberry orange. The muffins were prepared monthly by the Canadian International Grains Institute in Winnipeg. Subjects received one muffin daily that contained 30 g of ground flaxseed or 6 g of ALA delivered in flaxseed oil (the same amount of ALA found in 30 g of flaxseed). The energy and nutrient composition were balanced in both groups (Table 1).

Table 1 Energy and nutrient composition of the diets

Study procedures

During each visit (week 0, week 4), a 12-h fasting blood draw of 15 ml was collected by venopuncture. In tubes containing 1 mg of EDTA (ethylenediaminetetraacetic acid) (BD, Franklin Lakes, NJ, USA) per ml, 5 ml was used for the analysis of plasma fatty acids and lipid levels. In tubes containing sodium citrate, 10 ml was used for platelet aggregation work.

Plasma fatty acids were measured by gas chromatography as described in detail elsewhere (Dupasquier et al., 2006, 2007). Briefly, blood samples were centrifuged at 1800 × g for 5 min at 4 °C to obtain plasma, and then the plasma fatty acids were derived and then analyzed using a Varian CP-3800 gas chromatograph (Varian Inc., Palo Alto, CA, USA), equipped with a flame ionization detector and Varian CP-Sil 88 capillary column (Varian; 60 m × 0.25 mm × 0.20 μm). A volume of 1 μl of the methyl esters suspended in benzene was injected using an autosampler at a split ratio of 1:50. The flow rate of the helium carrier gas was 1.5 ml/min. The oven temperature was maintained at 80 °C for 1 min, increased by 30 °C/min to 140 °C, then increased by 5 °C/min to 225 °C and maintained at that temperature for 10 min. The total run time for each sample was 30 min. C17:0 was used as the internal standard and the fatty acid contents of the sample were identified by comparison with an authentic standard, GLC-462 (Nu-Chek Prep, Elysian, MN, USA). Plasma cholesterol and triglyceride (TG) levels were measured as described (Dupasquier et al., 2006, 2007).

Platelet aggregation studies (Cardinal and Flower, 1980) were carried out immediately on fresh blood samples. As previously reported (Austria et al., 2008), blood collected in sodium citrate tubes was centrifuged at 100 × g for 15 min to provide the platelet-rich plasma. Collection of this top layer, followed by a subsequent centrifugation of the remaining sample at 2400 × g for 15 min, yielded the platelet-poor plasma. Collagen (2 μg/ml) or thrombin (0.3 U) was used to stimulate aggregation. Platelet-poor plasma served as the blank.

Effects associated with the dietary intervention (that is, gastrointestinal discomfort, diarrhea, excessive gas, etc.) were monitored. The severity of the discomfort was subjectively estimated by the subjects. The severity of AEs (adverse events) was graded following a scale from 0 to 4: grade 0=no AE; grade 1=mild AE; grade 2=moderate; grade 3=severe; and grade 4=AE that requires hospitalization.

Statistical analysis and efficacy data

Statistical significance was determined with one-way ANOVA (analysis of variance) using SAS software (Sigma Stat, SPSS Science Inc., Chicago, IL, USA) followed by Duncan's multiple range post hoc test. Subjects were included in the statistical analysis for efficacy if they had been at least 80% compliant with muffin consumption, donated two blood samples and were 100% compliant with diet and concomitant restrictions as instructed.

Results

In this double-blinded, randomized, controlled trial, we studied the bioavailability of ALA as a function of the age of the subject ingesting the flaxseed. The muffins ingested, which contained either ground flaxseed or flaxseed oil, did not differ significantly with respect to their ALA content or the n-6/n-3 fatty acid ratios (Table 2). The study was completed successfully by 37 of 40 subjects. Two of the three subjects who did not complete the trial did not complete enough of the doses of food to be included in the results. This was not related to any adverse effects. In addition, one subject had to be omitted from the study because the initial ALA plasma value was so high that it strongly suggested that supplements or flaxseed had been ingested before the baseline blood draw.

Table 2 Muffin fatty acid concentrations

Age and baseline body mass index

The mean age of subjects included in the flaxseed oil intervention group was 25.1±3.7 years for the younger group and 49.6±5.1 years for the older individuals. Subjects who received the ground flaxseed had a mean age of 22.5±3.6 years in the younger group and 54.1±6.7 years in the older group. No statistically significant differences were observed when comparing the average ages of these two older age groups or when comparing the ages of the two younger age groups. Body mass index values for the subjects aged 18–29 years who ingested flaxseed oil or ground flaxseed were 22.8±3.4 and 24.8±3.8, respectively. Body mass index values for the two older groups were 24.9±3.7 for those who ingested flaxseed oil and 23.8±1.7 for those who ingested ground flaxseed. Again, no statistically significant differences were observed among any of the groups.

Plasma fatty acids levels

Within 4 weeks, subjects who received flaxseed oil in both age ranges (18–29 and 45–69 years) showed a significant increase in plasma ALA concentrations (P=0.002, P=0.004, respectively) (Figure 1). This was also true for eicosapentaenoic acid (EPA) concentrations (P=0.014, P=0.032, respectively). Subjects aged 45–69 years who consumed flaxseed oil had significantly higher ALA (P=0.001) and EPA (P=0.009) plasma levels than did the 18–29-year-old flaxseed oil group. Docosahexaenoic acid (DHA) and other fatty acid concentrations did not differ from baseline values (Figure 1, Table 3).

Figure 1
figure1

Plasma n-3 fatty acid concentrations following dietary supplementation with ground flaxseed and flaxseed oil for two age groups: 18–29 and 45–69 years. ALA, α-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; Grd, ground flaxseed. *P<0.05 compared with 0 weeks in the same flaxseed source and age group; aP<0.05 compared with ground flaxseed in the same age group.

Table 3 Plasma fatty acid concentrations after 0 and 4 weeks of dietary intervention with ground flaxseed and flaxseed oil in 18–29- and 45–69-year-old age groups

Subjects who received ground flaxseed in the 18–29-year-old group showed a statistically significant improvement in their plasma ALA values (P=0.023) but not EPA or DHA. In the 45–69-year-old ground flaxseed group, plasma ALA was also increased after 4 weeks but this was not statistically significant (P=0.085). EPA, DHA and other fatty acid concentrations did not change compared with baseline values (Figure 1, Table 3).

Subjects aged 18–29 years who consumed flaxseed oil increased their ALA levels more (P=0.001) compared with individuals of the same age who consumed ground flaxseed (Figure 1). This effect was also observed in subjects who consumed flaxseed oil in the 45–69 age group in comparison with those in the same age group who consumed ground flaxseed (P=0.001). No differences were observed in EPA or DHA plasma concentrations in this analysis.

Cholesterol and TG levels

No statistically significant changes in total cholesterol, low-density lipoprotein cholesterol or high-density lipoprotein cholesterol values between groups were detected during the study duration (Table 4). Multiple changes in TG concentrations were observed. Younger subjects included in the ground flaxseed group decreased their TG concentrations by 11% compared with baseline values, whereas in older subjects, it was increased by 13%. The same trend was observed in younger subjects supplemented with flaxseed oil who obtained a significant 20% decrease in blood TG levels versus an increase of 3.5% in the older subgroup. Younger subjects who ingested flaxseed oil decreased their TG values significantly compared with the 45–69 years group supplemented with ground flaxseed (P=0.008) (Table 5).

Table 4 Total cholesterol, LDL-C, HDL-C after 0 and 4 weeks of dietary intervention with ground flaxseed and flaxseed oil in 18–29- and 45–69-year-old age groups
Table 5 Triglyceride values and percentage change from baseline after 0 and 4 weeks of dietary intervention with ground flaxseed and flaxseed oil in 18–29- and 45–69-year-old age groups

Platelet aggregation

Collagen-induced platelet aggregation was significantly inhibited in subjects aged between 45 and 69 years (P=0.02) who ingested flaxseed oil. The rest of the values for platelet aggregation were not statistically different between and within the groups (Table 6).

Table 6 Maximal platelet aggregation and maximal rate of platelet aggregation after 0 and 4 weeks of dietary intervention with ground flaxseed and flaxseed oil in 18–29- and 45–69-year-old age groups

Adverse effects monitoring

There were no adverse side effects reported in any of the groups during this study.

Discussion

Most of the investigations of ALA metabolism in human subjects have focused on groups of relatively young, healthy individuals. Our finding of a significant increase in ALA levels after a dietary supplement of flaxseed is similar to previous reports (Francois et al., 2003; Austria et al., 2008; Harper et al., 2006a, 2006b). For example, Francois et al. (2003) showed that plasma ALA values increased after 2 and 4 weeks of 20 g flaxseed oil supplementation in lactating women aged 28–39 years. Cunnane et al. (1995) found increased plasma ALA in healthy young adults with a mean age of 25±3 years after 2 weeks of supplementation with 50 g of milled flaxseed per day. In our study, subjects from both younger groups obtained significant increases in ALA plasma concentrations as well as those from flaxseed oil in the 45–69-year-old group after only 4 weeks of supplementation. Consistent with a previous study (Austria et al., 2008), flaxseed oil induced greater circulating ALA levels than ground flaxseed at the same concentrations used in this study. These data are in conflict with another report that stated that ALA intake from a flaxseed source did not result in a significant increase in plasma phospholipids in subjects with mean age of 22.7 years (Wallace et al., 2003). It is important to note that in this study by Wallace et al., subjects consumed 3.5 g ALA per day which is only 60% of the dosage used in the present investigation. The results of that study are consistent with work of Kaul et al. (2008), which showed that supplementation of the diet with 1 g/day of ALA as flaxseed oil resulted in only a transient increase in plasma ALA over a 12-week experimental intervention. These studies would suggest that a dose of >4 g/day is required to achieve significant increases in ALA. The dose used in this study was 6 g ALA per day. It is important to recognize that the fiber content of flaxseed may in fact lead to a lower plasma ALA level because of a dilution of the fatty acid content in the intestinal tract by the fiber or through a direct inhibition of fatty acid absorption through an as yet undefined mechanism.

Several studies have investigated flaxseed supplementation in older populations. For example, a significant increase in plasma ALA was found after 12 and 26 weeks of supplementation with 6 g of ALA from flaxseed oil in subjects 49 years of age (Harper et al., 2006a, 2006b). Others (Finnegan et al., 2003a, 2003b) reported an increase in plasma ALA with 4.5 and 9.5 g of ALA per day supplementation after 3 and 6 months in groups with an average age of 50 years. Studies for this age group using ground flaxseed have been carried out in patients with lupus nephritis (Clark et al., 1995, 2001) and in hypercholesterolemic postmenopausal women (Arjmandi et al., 1998; Lemay et al., 2002). In most of these investigations, ALA concentrations were increased after the dietary supplementation. However, although these studies have investigated the response of plasma ALA to dietary flaxseed in healthy adults aged 50 years, a direct comparison of the differently aged populations has not been studied. Our data showed that both age groups effectively absorbed ALA from the flaxseed-supplemented diet when it was presented in an oil form. Significantly higher ALA levels were achieved in the older group. This would show clearly that age is not a limiting factor for the absorption of ALA. However, when ground flaxseed was used, the older subjects did not achieve a statistically significant increase in plasma ALA levels despite achieving, once again, higher ALA levels at the end of the study in comparison with the younger subjects. This appears to be due to slightly higher basal levels of ALA in the older subjects than in the younger subjects. Although not statistically different, this was enough to prevent the ALA values in the older group from achieving statistical significance at the 4-week time point. It may be that the older subjects require a dietary intervention that is longer in duration to observe the beneficial increase in plasma ALA. Alternatively, our sample size may not have been large enough to detect a difference.

The efficiency of the elongation and desaturation process by which ALA can be converted to longer chain n-3 polyunsaturated fatty acids in older subjects is not well established. It is important to remember that ALA can be converted in the body to the cardioprotective ω-3 polyunsaturated fatty acids found in fish oils, EPA and DHA (Metcalf et al., 2003; Harper et al., 2006a, 2006b). We observed an increase in plasma EPA which has been consistent across different studies (Francois et al., 2003; Wallace et al., 2003; Harper et al., 2006a). Dietary supplementation with flaxseed oil induced an increase in EPA within 4 weeks in both age groups. Therefore, subject age does not appear to be a limiting factor for conversion of ALA into EPA. This could be important for secondary prevention trials, in which EPA levels have been associated with decreases in inflammatory and atherosclerotic markers (Zhao et al., 2004; Goyens and Mensink, 2006). Again, the effects in the ground flaxseed-supplemented groups did not achieve statistical significance although similar trends were observed in both age groups. The lack of change in plasma DHA is in agreement with several previous investigations (Francois et al., 2003; Wallace et al., 2003; Austria et al., 2008; Harper et al., 2006a, 2006b). Inter-conversion of the n-3 fatty acids appears to be limited in humans. It may be an inefficient process due in part to the large and increasing amounts of n-6 fatty acids in the diet, which compete for the same enzymes (Arterburn et al., 2006).

Most studies have reported (Singer et al., 1986; Cunnane et al., 1995; Nestel et al., 1997; Rallidis et al., 2003; Harper et al., 2006b) little or no effect of flaxseed on blood total cholesterol, low-density lipoprotein or high-density lipoprotein. Studies investigating the effect of ALA on fasting TGs are contradictory with an increase (Cunnane et al., 1995), decrease (Singer et al., 1986; Djoussé et al., 2003; Zhao et al., 2004) or no effects (Nestel et al., 1997; Rallidis et al., 2003) reported. In our study, younger subjects obtained more beneficial effects on TGs compared with older subjects independent of the flaxseed source over a 4-week period. However, our study could be limited by the duration of the diet and the amount of ALA administered. Longer studies that administered larger doses to older populations showed that dietary ALA is associated with lower plasma TG concentrations (Djoussé et al., 2003; Zhao et al., 2004).

Only modest changes in platelet aggregation in the older subjects who consumed flaxseed oil were detected. The difference was restricted to one measurement point and all other values did not show any significant changes in any of the other groups. This is consistent with most (Kelly et al., 1993; Freese and Mutanen, 1997; Austria et al., 2008; Finnegan et al., 2003a, 2003b) but not all (Allman et al., 1995) previous reports of flaxseed dietary intervention. This minor change could be useful in special groups of patients in this range of age in which cardiovascular and thrombotic diseases are highly prevalent. Conversely, it could be a concern in subjects with a hemorrhagic predisposition, under anti-thrombotic therapy or undergoing surgical interventions. Others have identified an urgent need for more extensive dose-response studies to assess the association between different doses of ALA and bleeding times (Akabas and Deckelbaum, 2006).

It was a concern at the start of this study that older subjects may be more sensitive to the fiber load found in ground flaxseed and, therefore, may experience more symptoms of diarrhea, bloating and gas. There were no adverse side effects reported in any of the groups during this study. This would suggest that age is not a concern when administering up to 30 g of ground flaxseed or 6 g of flaxseed oil to populations within this age range (18–69 years).

In conclusion, our data provide insight into the delivery of ALA through dietary supplementation with flaxseed in milled and oil forms. The data show that the age of the subject is not an important modulatory factor in influencing circulating levels of ALA. Although one may infer that the circulating concentrations reflect absorption of the ALA from the meal, it is important to recognize that circulating levels of the fatty acids are also influenced by the storage and metabolism of ALA as well. However, with regard to the latter, age did not appear to alter the conversion of ALA to EPA. Age does not appear to influence the appearance of adverse side effects either. However, subject age was an important determining factor in the lowering of TG levels in the blood. Understanding the response to dietary flaxseed as a function of subject age is a critical first step before using flaxseed as a dietary intervention in older patient populations.

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Acknowledgements

This study was supported by Flax2015, CIHR and the St Boniface Hospital and Research Foundation. Drs D Rodriguez-Leyva, MN Chahine and Ms CMC Dupasquier were a Visiting Scientist, Postdoctoral Fellow, and Trainee, respectively, of the Heart and Stroke Foundation of Canada.

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Correspondence to G N Pierce.

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Patenaude, A., Rodriguez-Leyva, D., Edel, A. et al. Bioavailability of α-linolenic acid from flaxseed diets as a function of the age of the subject. Eur J Clin Nutr 63, 1123–1129 (2009). https://doi.org/10.1038/ejcn.2009.41

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Keywords

  • omega-3 fatty acid
  • polyunsaturated fatty acids (PUFAs)
  • platelet aggregation
  • linseed
  • cardiovascular disease
  • aging

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