Long Chain Omega-3 Fatty Acids Reduce Risk of Progression to Advanced Age-Related Macular Degeneration

Currently over 2% of UK adults suffer from age-related macular degeneration (AMD) [1], which causes progressive loss of central vision. However, prevalence is estimated to rise by one third by 2020 [1] due to the increasing proportion of elderly individuals within the population. As the condition cannot be cured, there is great interest in the contribution dietary components may have in preventing loss of visual function. A recently published study by Wu et al. suggested that high intake of ɑ-linolenic acid increased risk of intermediate AMD yet was not associated with the advanced form, but that the observed effect may have been modified by the amount of the trans form in the diet [2]. From discussing their results in the context of wider research it has been concluded that no recommendation should be made to reduce dietary intake of ɑ-linolenic acid, yet limiting consumption of the trans form may be beneficial. It has also been found that increased intake of long chain omega-3 fatty acids, sourced from oily fish, may reduce risk of advancement of AMD.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in those aged over 50 years in the developed world [3], currently affecting almost 600,000 people in the UK [4]. The disease results from damage to photoreceptor cells in the macula, the region of the retina used for seeing fine detail, colour and directly in front [5]; it therefore results in image distortion and changes in visual acuity and contrast sensitivity [4]. Although peripheral vision is not affected, and so total blindness does not occur, symptoms of AMD can significantly affect quality of life [6].

Drusen formation, or the focal deposition of debris such as lipids, naturally occurs with age [3] due to dysfunction of the retinal pigment epithelium. However, numerous drusen or clusters of large deposits are associated with AMD [7]. Early and intermediate AMD are often asymptomatic, with only minor vision loss [8], but 5-15% of cases will progress to advanced AMD [8], of which there are two forms. Dry AMD, or central geographic atrophy (GA), involves retinal thinning and the gradual degeneration of photoreceptor cells, with areas of hypopigmentation from RPE cell loss and hyperpigmentation at drusen peripheries from compensatory cell proliferation [7]. This causes gradual vision loss that can take up to 10 years to affect daily life [4]. In contrast, wet or neovascular AMD can cause vision deterioration within days without immediate treatment [4] as it is characterised by growth of abnormal blood vessels underneath the retina, which can leak, swell and cause macula scarring [5].  As there is no cure for AMD, treatment relies on making use of remaining vision or reducing further growth of blood vessels [5]. This makes research into methods of prevention is of importance.

It is believed that RPE dysfunction results from chemical and light induced oxidative damage to photoreceptor cells [9] so nutrients with antioxidant activity have been widely discussed. The primary focus tends to be on vitamins C, E, and the carotenoids lutein and zeaxanthin, which are present in the lens and retina, as they can react with free radicals produced by light absorption [9], potentially slowing progression to advanced AMD [10]. It has also been suggested that omega-3 fatty acids (n-3 PUFA) may be implicated in the aetiology of AMD due to their high concentrations in the retina [9]. Although long chain n-3 PUFA, particularly docosahexaenoic acid (DHA), have been inversely associated with AMD risk, there are vast inconsistencies within findings regarding the shorter chain n-3 PUFA ɑ-linolenic acid (ALA). In a recently published study by Wu et al. the link between ALA intake and risk of intermediate and advanced AMD was investigated, with further analysis dividing data into two time periods, pre- and post-2002, to identify whether the amount of trans ALA in the diet may have affected results [2]. This review will discuss the conclusions obtained within the wider literature to evaluate whether dietary n-3 PUFA intake is of significance to risk of AMD.

Method

Study population

Subjects were selected from the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Participants had provided information regarding lifestyle and disease outcomes every 2 years and food frequency questionnaires (FFQ) every 4 years. The study population included only those ≥50 years and individuals were censored at age 90 years.

AMD ascertainment

Details of diagnosis, treatment and visual acuity were obtained from opticians following reporting of AMD onset by participants. Photos and optical coherence tomography were also reviewed. Intermediate and neovascular AMD, and central geographic atrophy (GA), were defined based on presence of typical signs in ≥1 eye.

Dietary assessment

A 131 item FFQ was initially completed in 1986 in the HPFS and 1984 in the NHS and was modified to reflect changing diets for further assessment. Daily nutrient intake was calculated using data from the USDA Nutrient Database and adjustment for total energy was performed.

Statistical analysis

Participants were included in the analysis from age 50 years to diagnosis of AMD, death, loss to follow-up or end of follow-up. Cumulative average ALA intake was calculated using all FFQs up to the start of each 2 year risk interval and categorised into quintiles. Hazards ratios for intermediate and advanced AMD were estimated using Cox proportional hazards regression, stratified for age and year of the questionnaire cycle and adjusting for various risk factors.

Stratified analysis was conducted to estimate associations pre- and post-2002 due to changes in major food sources of ALA, specifically a reduction in trans ALA intake.

Results

Subject characteristics

A total of 75,889 women and 38,961 men were analysed in the study. 2219 incident AMD cases were confirmed in women (1209 intermediate, 1010 advanced) and 726 cases in men (380 intermediate, 346 advanced). 96% of advanced AMD was neovascular.

Individuals with higher ALA intake had a higher healthy-eating score. ALA was correlated with linoleic acid (LA) but weakly correlated with eicosapentaenoic acid (EPA) or DHA. ALA intake increased 50% in the NHS and 29% in the HPFS from start of study to follow-up.

Results of statistical analysis

Comparing those in the highest to lowest quintiles of ALA intake, a positive association between ALA and intermediate AMD was observed. In individual cohorts, the positive association was only statistically significant in the NHS. Plant sourced ALA was more strongly associated with intermediate AMD than animal-sourced ALA in the HPFS when comparing extreme quintiles. There was no significant association between advanced AMD and ALA or LA.

A positive association between LA intake and intermediate AMD was attenuated after adjustment for ALA, as were positive associations with cis 18:1, cis 18:2, trans 18:2 and saturated fat. Whereas trans 18:1, trans 18:2 and total trans fatty acids were significantly associated with advanced AMD after adjustment for ALA.

When stratified by time, intake of ALA was positively associated with intermediate AMD before but not after 2002. There was no significant association with advanced AMD in either time period.

Discussion

The study by Wu et al. concluded that intake of ALA was positively associated with intermediate AMD [2], suggesting a diet high in n-3 PUFAs may increase risk of onset. When analysed by time period, the association was only significant before 2002. Prior to this time the prevalence of the trans form in the diet was considerably higher [2]. The trans isomer of n-3 PUFA has been shown to impact visual functioning [11], and to be associated with increased risk of AMD [12], therefore it could be questioned whether it was due to this that the positive association was observed rather than being an effect of ALA. The difference between individuals in intakes of the trans and cis forms of n-3 PUFA within studies may offer an explanation as to some of the inconsistencies that exist.

Although Wu et al. found no association between ALA and advanced AMD [2], which potentially reflects the non-continuous progression from intermediate AMD to the advanced form [2], it has been observed that high plasma total n-3 PUFA is associated with a reduced risk of late atrophic AMD [13] and low intake of n-3 PUFA being associated with increased risk of neovascular AMD [14]. In the case of neovascular AMD, this finding could be as a consequence of the antithrombotic and hypolipidemic effects of long chain n-3 PUFA [15] as it is believed that atherosclerosis of blood vessels supplying the choroid and retina may contribute to AMD risk [16]. This means dietary fats related to CHD are often though to also be of significance in the aetiology of AMD [16]. However, the positive association between ALA and AMD, yet negative association with CHD, disputes this as a general assumption [12].

A high intake of polyunsaturated fats (PUFA) alters the degree of unsaturation of lipid membranes [12] and increases susceptibility to peroxidation,  the major pathway attributed to the degeneration of photoreceptors in AMD [17] due to the potential for lipid peroxides to cross link with compounds such as proteins and nucleic acids, affecting the structure and function of tissues [18]. Nonetheless, n-3 PUFAs have been shown to increase macular pigment density in the retina [13], inhibiting peroxidation of long chain n-3 PUFAs by acting as optical filters for blue light [19], which otherwise induces oxidative stress. Additionally, DHA is esterified into phospholipids [20] and constitutes 60% of lipids in retinal photoreceptor cells [18], and is present in highest concentrations in the outer segments. Continuous turnover of cells in the outer segments of photoreceptors occurs during the visual cycle [21] to compensate for oxidative damage [20]. As a result, deficiency in DHA may affect photoreceptor renewal [20], so a constant supply could be considered essential for proper retinal functioning [9]. Studies into long chain n-3 PUFA and risk of AMD support the biological plausibility of their role in visual functioning, with more conclusive findings than those conducted into ALA.  For example, Ding et al. reported that those in the highest quartile of EPA and DHA intake had a 25% decreased risk of AMD [7], and Cho et al. found an inverse relationship with fish consumption, with >4 portions eaten per week resulting in lowest risk of AMD [12].

The well evidenced negative association between risk of AMD and long chain n-3 PUFA, particularly DHA, suggests that ALA should offer similar benefits due to it being a dietary precursor to DHA [21]. However, as <1% of ALA is converted to DHA [22] it is unlikely that increased ALA intake would significantly increase plasma DHA [18]. Furthermore, research into dietary factors affecting risk of AMD is impacted by the role of genetics in its aetiology [18], meaning study participants may display considerable variation in their response.

Impacts

After conducting wider research into the relationship between dietary n-3 PUFA intake and risk of AMD, it could be said that the conclusion made by Wu et al., that ALA intake is positively associated with risk of intermediate AMD [2], requires further investigation before it can be deemed valid. This is due to the inconsistencies that exist between studies and the potentially significant moderating effect of the level of each of the isomeric forms of ALA on results.  It would be essential for this research to be performed prior to making any recommendations to reduce dietary intake of ALA for those at high risk of AMD as the anti-inflammatory nature of ALA, and the protective effects it offers against cardiovascular disease (CVD), fractures and type 2 diabetes [22], suggests decreasing intake may have adverse health effects.  When considering solely ALA, it may be more relevant to advise limiting use of vegetable oils containing high quantities of n-3 PUFAs in frying as this can result in isomerisation and an increase in the amount of the trans form consumed [14].

In addition, long chain n-3 PUFAs have been frequently associated with reduced risk of AMD, therefore it could be said that regular consumption of oily fish or fish oil should be encouraged. Further study into whether individuals with intermediate AMD may benefit from n-3 PUFA supplements may also be warranted as they could have the potential to slow the rate of retinal function degeneration, reducing the impacts on quality of life of sufferers.

---

[1] NHS (2012) Sight problems predicted to rise in UK. URL: http://www.nhs.uk/news/2012/02February/Pages/rise-in-macular-degeneration-eye-problem.aspx [11th June 2017]

[2] Wu, J., Cho, E., Giovannucci, E.L., Rosner, B.A., Sastry, S.M., Schaumberg, D.A., Willett, W.C. (2017) Dietary intake of ɑ-linolenic acid and risk of age-related macular degeneration. The American Journal of Clinical Nutrition, 105(6), 1483-1492.

[3] Rama, D., Jager, M.D., Mieler, W.F., Miller, J.W. (2008) Age-related macular degeneration. The New England Journal of Medicine, 358, 2606-2617.

[4] NHS (2015) Macular degeneration – Symptoms. URL: http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Symptoms.aspx [11th June 2017]

[5] RNIB (2016) Understanding age-related macular degeneration. [pdf] RNIB. Available at: http://www.rnib.org.uk/sites/default/files/APDF-v02-ENG061533%20Understanding%20AMD.PDF [11^th June 2017]

[6] Taylor, D.J., Hobby, A.E., Binns, .M., Crabb, D.P. (2016) How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review. BMJ Open, 6, e011504.

[7] Ding, X., Patel, M., Chan, C-C. (2009) Molecular pathology of age-related macular degeneration. Progress in Retinal and Eye Research, 23(1), 1-18.

[8] NIH (2015) Facts about age-related macular degeneration. URL: https://nei.nih.gov/health/maculardegen/armd_facts [11th June 2016]

[9] Raats, M., de Groot, L., van Staveren, W. (2009) Food for the ageing population. Cambridge: Woodhead Publishing Ltd.

[10] NIH (2013) NIH study provides clarity on supplements for protection against blinding eye disease. URL: https://nei.nih.gov/news/pressreleases/050513 [11th June 2017]

[11] Acar, N., Chardigny, J-M., Bonhomme, B., Almanza, S., Doly, M., Sébédio, J-L. (2002) Long-term intake of trans (n-3) polyunsaturated fatty acids reduces the b-wave amplitude of electroretinograms in rats. The Journal of Nutrition, 132(10), 3151-3154.

[12] Cho, E., Hung, S., Willett, W.C., Spiegelman, D., Rimm, E.B., Seddon, J.M., Colditz, G>A., Hankinson, S.E. (2001) Prospective study of dietary fat and the risk of age-related macular degeneration. The American Journal of Clinical Nutrition, 73(2), 209-218.

[13] Merle, B.M.J., Delyfer, M-N., Korobelnik, J-F., Rougier, M-B., Malet, F., Féart, C., Le Goff, M., Peuchant, E., Letenneur, L., Dartigues, J-F., Colin, J., Barberger-Gateau, P., Delcourt, C. (2012) High concentrations of plasma n3 fatty acids are associated with decreased risk for late age-related macular degeneration. The Journal of Nutrition, 143(4), 505-511.

[14] Aoki, A., Inoue, M., Nguyen, E., Obata, R., Kadonosono, K., Shinkai, S., Hashimoto, H., Sasaki, S., Yanagi, Y. (2016) Dietary n-3 fatty acid, ɑ-tocopherol, zinc, vitamin D, vitamin C, and ẞ-carotene are associated with age-related macular degeneration in Japan. Scientific Reports, 6, 20723.

[15] Seddon, J.M., Rosner, B., Sperduto, R.D. (2001) Dietary fat and risk for advanced age-related macular degeneration. Archives of Ophthalmology, 119(8), 1191-1199.

[16] Johnson, E.J., Schaefer, E.J. (2006) Potential role of dietary n-3 fatty acids in the prevention of dementia and macular degeneration. The American Journal of Clinical Nutrition, 83(6), S1494-1498S.

[17] Sin, H.P.Y., Liu, D.T.L., Lam, D.S.C. (2012) Lifestyle modification, nutritional and vitamins supplements for age-related macular degeneration. Acta Ophthalmologica, 91(1), 6-11.

[18] Carneiro, A., Andrade, J.P. (2017) Nutritional and lifestyle interventions for age-related macular degeneration: A review. Oxidative Medicine and Cellular Longevity, Article ID 6469138.

[19] Castro Lima, V., Rosen, R.B., Farah, M. (2016) Macular pigment in retinal health and disease. International Journal of Retina and Vitreous, 2(19).

[20] Querques, G., Forte, R., Souied, E.H. (2011) Retina and omega-3. Journal of Nutrition and Metabolism, Article ID 748361.

[21] Krishnadev, N., Meleth, A.D., Chew, E.Y. (2010) Nutritional supplements for age-related macular degeneration. Current Opinions in Ophthalmology, 21(3), 184-189.

[22] Rajaram, S. (2014) Health benefits of plant-derived ɑ-linolenic acid. The American Journal of Clinical Nutrition, 100(1), 443S-448S.