Long-chain and very long-chain polyunsaturated fatty acids in ocular aging and age-related macular degeneration

Retinal long-chain PUFAs (LC-PUFAs, C12-C22) play important roles in normal human retinal function and visual development, and some epidemiological studies of LC-PUFA intake suggest a protective role against the incidence of advanced age-related macular degeneration (AMD). On the other hand, retinal very long-chain PUFAs (VLC-PUFAs, Cn>22) have received much less attention since their identification decades ago, due to their minor abundance and more difficult assays, but recent discoveries that defects in VLC-PUFA synthetic enzymes are associated with rare forms of inherited macular degenerations have refocused attention on their potential roles in retinal health and disease. We thus developed improved GC-MS methods to detect LC-PUFAs and VLC-PUFAs, and we then applied them to the study of their changes in ocular aging and AMD. With ocular aging, some VLC-PUFAs in retina and retinal pigment epithelium (RPE)/choroid peaked in middle age. Compared with age-matched normal donors, docosahexaenoic acid, adrenic acid, and some VLC-PUFAs in AMD retina and RPE/choroid were significantly decreased, whereas the ratio of n-6/n-3 PUFAs was significantly increased. All these findings suggest that deficiency of LC-PUFAs and VLC-PUFAs, and/or an imbalance of n-6/n-3 PUFAs, may be involved in AMD pathology. Retinal long-chain PUFAs (LC-PUFAs, C12-C22) play important roles in normal human retinal function and visual development, and some epidemiological studies of LC-PUFA intake suggest a protective role against the incidence of advanced age-related macular degeneration (AMD). On the other hand, retinal very long-chain PUFAs (VLC-PUFAs, Cn>22) have received much less attention since their identification decades ago, due to their minor abundance and more difficult assays, but recent discoveries that defects in VLC-PUFA synthetic enzymes are associated with rare forms of inherited macular degenerations have refocused attention on their potential roles in retinal health and disease. We thus developed improved GC-MS methods to detect LC-PUFAs and VLC-PUFAs, and we then applied them to the study of their changes in ocular aging and AMD. With ocular aging, some VLC-PUFAs in retina and retinal pigment epithelium (RPE)/choroid peaked in middle age. Compared with age-matched normal donors, docosahexaenoic acid, adrenic acid, and some VLC-PUFAs in AMD retina and RPE/choroid were significantly decreased, whereas the ratio of n-6/n-3 PUFAs was significantly increased. All these findings suggest that deficiency of LC-PUFAs and VLC-PUFAs, and/or an imbalance of n-6/n-3 PUFAs, may be involved in AMD pathology. The biochemical profile of FAs in human retina was first reported over 45 years ago when Futterman and Andrews (1Futterman S. Andrews J.S. The fatty acid composition of human retinal vitamin A ester and the lipids of human retinal tissue.Invest. Ophthalmol. 1964; 3: 441-444PubMed Google Scholar) identified five major FAs in human retina, including docosahexaenoic acid (DHA, 22:6n-3), arachidonic acid (AA, 20:4n-6), stearic acid (SA, 18:0), oleic acid (OA, 18:1), and palmitic acid (PA, 16:0), all of which belong to the long-chain FA (LC-FA, C12-C22) family. Subsequent studies demonstrated that DHA and AA are the major components of human and vertebrate retinal long-chain PUFAs (LC-PUFAs), and the highest content of LC-PUFAs is found in human and vertebrate retinal rod outer segment membranes (2van Kuijk F.J. Buck P. Fatty acid composition of the human macula and peripheral retina.Invest. Ophthalmol. Vis. Sci. 1992; 33: 3493-3496PubMed Google Scholar, 3Martinez M. Ballabriga A. Gil-Gibernau J.J. Lipids of the developing human retina: I. Total fatty acids, plasmalogens, and fatty acid composition of ethanolamine and choline phosphoglycerides.J. Neurosci. Res. 1988; 20: 484-490Crossref PubMed Scopus (73) Google Scholar, 4Anderson R.E. Lipids of ocular tissues. IV. A comparison of the phospholipids from the retina of six mammalian species.Exp. Eye Res. 1970; 10: 339-344Crossref PubMed Scopus (163) Google Scholar). Their high content and specific tissue distribution suggest that LC-PUFAs have an important functional role in the retina. Human clinical studies and animal studies involving dietary manipulation in rats (5Benolken R.M. Anderson R.E. Wheeler T.G. Membrane fatty acids associated with the electrical response in visual excitation.Science. 1973; 182: 1253-1254Crossref PubMed Scopus (249) Google Scholar, 6Wheeler T.G. Benolken R.M. Anderson R.E. Visual membranes: specificity of fatty acid precursors for the electrical response to illumination.Science. 1975; 188: 1312-1314Crossref PubMed Scopus (290) Google Scholar) have shown that LC-PUFAs are important for the development and function of the central nervous system, particularly the visual system (7Greiner R.S. Moriguchi T. Hutton A. Slotnick B.M. Salem Jr, N. Rats with low levels of brain docosahexaenoic acid show impaired performance in olfactory-based and spatial learning tasks.Lipids. 1999; 34: S239-S243Crossref PubMed Google Scholar). DHA prevented photoreceptor apoptosis caused by oxidative damage (8Rotstein N.P. Politi L.E. German O.L. Girotti R. Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors.Invest. Ophthalmol. Vis. Sci. 2003; 44: 2252-2259Crossref PubMed Scopus (139) Google Scholar) and promoted differentiation of developing photoreceptors in culture (9Rotstein N.P. Politi L.E. Aveldano M.I. Docosahexaenoic acid promotes differentiation of developing photoreceptors in culture.Invest. Ophthalmol. Vis. Sci. 1998; 39: 2750-2758PubMed Google Scholar). DHA also has significant effects on photoreceptor membranes and neurotransmitters involved in the signal transduction process, rhodopsin activation, rod and cone development, neuronal dendritic connectivity, and functional maturation of the central nervous system (10Uauy R. Hoffman D.R. Peirano P. Birch D.G. Birch E.E. Essential fatty acids in visual and brain development.Lipids. 2001; 36: 885-895Crossref PubMed Scopus (358) Google Scholar). Low plasma and blood cell lipid DHA have been linked to increased risk of poor visual and neural development in infants and children (11Hibbeln J.R. Davis J.M. Steer C. Emmett P. Rogers I. Williams C. Golding J. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study.Lancet. 2007; 369: 578-585Abstract Full Text Full Text PDF PubMed Scopus (766) Google Scholar, 12Innis S.M. Friesen R.W. Essential n-3 fatty acids in pregnant women and early visual acuity maturation in term infants.Am. J. Clin. Nutr. 2008; 87: 548-557Crossref PubMed Scopus (165) Google Scholar). Depletion of DHA, AA, or eicosapentaenoic acid (EPA) from the retina interferes with normal neurogenesis, neurological function, and visual signaling pathways, impairs vision and visual learning tasks, and leads to an abnormal electroretinogram (13Alessandri J.M. Guesnet P. Vancassel S. Astorg P. Denis I. Langelier B. Aid S. Poumes-Ballihaut C. Champeil-Potokar G. Lavialle M. Polyunsaturated fatty acids in the central nervous system: evolution of concepts and nutritional implications throughout life.Reprod. Nutr. Dev. 2004; 44: 509-538Crossref PubMed Scopus (230) Google Scholar, 14Weisinger H.S. Vingrys A.J. Sinclair A.J. The effect of docosahexaenoic acid on the electroretinogram of the guinea pig.Lipids. 1996; 31: 65-70Crossref PubMed Scopus (96) Google Scholar, 15Uauy R. Peirano P. Hoffman D. Mena P. Birch D. Birch E. Role of essential fatty acids in the function of the developing nervous system.Lipids. 1996; 31: S167-S176Crossref PubMed Google Scholar, 16Connor W.E. Neuringer M. Reisbick S. Essential fatty acids: the importance of n-3 fatty acids in the retina and brain.Nutr. 1992; PubMed Scopus Google Scholar, M. W.E. C. fatty acid deficiency and visual in Clin. PubMed Scopus Google Scholar, M. W.E. S. and functional effects of and fatty acid deficiency on retina and brain in Sci. PubMed Scopus Google Scholar, M. Anderson W.E. The of n-3 fatty acids for the development and function of the retina and Nutr. 1988; PubMed Scopus Google Scholar, J. Williams I. for of acid in the of the Nutr. PubMed Scopus Google Scholar). is that LC-PUFAs play an essential role in the development of vision human early W.E. Neuringer M. Reisbick S. Essential fatty acids: the importance of n-3 fatty acids in the retina and brain.Nutr. 1992; PubMed Scopus Google Scholar, E. S. D. J.M. study of dietary and the risk of age-related macular J. Clin. Nutr. 2001; PubMed Scopus Google Scholar). human some epidemiological studies of intake on the of advanced age-related macular degeneration suggest a protective E. S. D. J.M. study of dietary and the risk of age-related macular J. Clin. Nutr. 2001; PubMed Scopus Google Scholar, E. fatty acid intake and incidence of age-related macular degeneration and central a cohort study from the Eye J. Clin. Nutr. PubMed Scopus Google Scholar, N. S.M. C. dietary intake and age-related macular degeneration in the in Eye an study of the Ophthalmol. PubMed Scopus Google Scholar, J. D. M. N. Salem N. A high fatty acid retinal in a of macular J. Full Text Full Text PDF PubMed Scopus Google Scholar, The role of long-chain fatty acids in health and of the Eye Res. PubMed Scopus Google Scholar, J.M. S. B. fatty acid and with age-related macular the of Ophthalmol. PubMed Scopus Google Scholar, D. M. A. M. for the effect of fatty acids on of age-related macular a 2007; PubMed Scopus Google and N. M. of and blood cell lipids with of macular to an Ophthalmol. PubMed Scopus Google Scholar) a protective effect of DHA and intake in disease. Their role in the of inherited retinal degenerations is more R.S. Anderson C. from retinal Vis. Google Scholar). retinal LC-PUFAs have received attention over the very long-chain PUFAs (VLC-PUFAs, Cn>22) A. A. of fatty acids with fatty on by human Google Scholar, M. but is a for of n-3 fatty acids in Eye Res. PubMed Scopus Google Scholar) are also found in mammalian but in a of retina, and brain in a low and their are essential of the A. fatty acids in PubMed Scopus Google Scholar, M.I. A of very fatty acids in from vertebrate Full Text PDF PubMed Google Scholar). DHA, AA, and their VLC-PUFAs are in a normal human A. Polyunsaturated fatty acids and retinal Ophthalmol. of Scopus Google but be from precursors and a biochemical the enzymes of the of very long-chain FAs with and M. but is a for of n-3 fatty acids in Eye Res. PubMed Scopus Google Scholar, J.S. A for very long-chain fatty acid 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google Scholar, Anderson R.E. Retinal very long-chain from studies on Res. Full Text Full Text PDF PubMed Scopus Google Scholar). in the of the very long-chain are associated with macular in the and in due to of function in the VLC-PUFAs are of a a with FA and a more of PUFAs J.S. A for very long-chain fatty acid 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google Scholar). may play important roles in that be by the more and J.S. A for very long-chain fatty acid 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google their and minor abundance them difficult to R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google which that VLC-PUFAs have been since their M.I. A of very fatty acids in from vertebrate Full Text PDF PubMed Google Scholar, A. P. D. A. A. of a of fatty acids in the brain of J. PubMed Scopus Google Scholar). we methods to detect LC-PUFAs and VLC-PUFAs in human retina and retinal pigment epithelium We applied these methods to retinal of LC-PUFAs and VLC-PUFAs, and we their levels in ocular aging and AMD. 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A in the retinal deficiency of 2007; PubMed Scopus Google Scholar, M. M. R. in is associated with forms of macular 2001; PubMed Scopus Google Scholar, J. N. A. M. M. macular caused by a in the Ophthalmol. Vis. Sci. 2001; Google Scholar). in the of the was in retinal lipids are with studies Lipids in human of with rod outer and neural retina.Invest. Ophthalmol. Vis. Sci. 31: Google Scholar, R.E. Benolken R.M. of photoreceptor from PubMed Scopus Google Scholar, P. of the lipid and fatty acid composition of Res. Full Text PDF PubMed Google Scholar) in which was reported that of and also are with in which for of retinal The levels of and in have been reported to have an with J. P. of fatty acids in human Res. 1999; 31: PubMed Scopus Google but for of lipid in retina. AA has been reported to in an in human neural retina G. S. N. C. P. and fatty acid profile of the retina, retinal pigment and the and with tissue fatty acids in human Eye Res. 2008; 87: PubMed Scopus Google but their was from damage is to be involved in AMD age-related macular 2008; PubMed Scopus Google Scholar). The of in DHA to damage oxidative B. S. and Nutr. PubMed Scopus Google Scholar). demonstrated that the oxidative from the lipids DHA and adrenic acid M. M. A. an to the of age-related macular Sci. PubMed Scopus Google are more in ocular from AMD retina from normal retina M. and for age-related macular 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). have been shown to the AMD of AMD J. J. to age-related macular degeneration with and Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. and for age-related macular Full Text Full Text PDF PubMed Scopus Google Scholar). The of in AMD that increased of DHA and adrenic acid that in AMD may to a in DHA and adrenic acid, which is with study C. D.G. degeneration in a with a associated with retinal Full Text Full Text PDF PubMed Scopus Google Scholar, P. by age-related macular degeneration increased in the retinal pigment epithelium and Ophthalmol. 2003; PubMed Scopus Google Scholar) reported that and RPE/choroid from AMD of with age-matched normal which may to increased and n-3 PUFAs oxidative in of the of in AMD may to oxidative of PUFAs and which is with study and M. M. A. an to the of age-related macular Sci. PubMed Scopus Google Scholar, M. and for age-related macular 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. to age-related macular degeneration with and Full Text Full Text PDF PubMed Scopus Google Scholar). oxidative is also to be involved in AMD age-related macular 2008; PubMed Scopus Google Scholar). and and which in a of with the of DHA is to and which by and and T. of in a of 2007; PubMed Scopus Google Scholar, and in their role and in neurological Res. PubMed Scopus Google Scholar). in of DHA in AMD may also be the of The ratio of is increased in AMD ocular tissue with the age-matched normal an imbalance in and in AMD retina. with a retinal n-6/n-3 ratio has a protective effect against C. J. A. S. S. D. dietary intake of fatty acids retinal 2007; PubMed Scopus Google Scholar). All of these suggest that oxidative and play an important role in the of AMD M. of age-related macular Eye Res. PubMed Scopus Google whereas a in DHA and adrenic acid and an in the of and n-6/n-3 may be of AMD. we RPE/choroid we some with more to retina, due to the of blood in RPE/choroid was significantly in the with the and middle that in with to the from the Retinal pigment acid and effects of dietary fatty Ophthalmol. Google Scholar). DHA in RPE/choroid retina may be due to of DHA photoreceptor outer segment lipids E. S. D. J.M. study of dietary and the risk of age-related macular J. Clin. Nutr. 2001; PubMed Scopus Google Scholar, Retinal pigment play a central role in the of docosahexaenoic acid by photoreceptor and Eye Res. 1992; PubMed Scopus Google Scholar, of acid photoreceptors and retinal pigment epithelium by Ophthalmol. Vis. Sci. 34: Google Scholar). DHA and adrenic acid in RPE/choroid were in the normal in the AMD which was to findings in the retina. retina and RPE/choroid is due to of of the photoreceptor outer segment photoreceptor outer segment Retinal pigment acid and effects of dietary fatty Ophthalmol. Google Scholar, D. R.W. of the retinal pigment The Retinal Scholar). and VLC-PUFAs be from and J.S. A for very long-chain fatty acid 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google Scholar, of long-chain fatty Res. 2004; PubMed Scopus Google Scholar) the of and VLC-PUFAs in AMD with age-matched normal is with the of and VLC-PUFAs were significantly in AMD to age-matched normal may be due to the of precursors and in AMD retina or impaired VLC-PUFAs be from the of and enzymes in M. but is a for of n-3 fatty acids in Eye Res. PubMed Scopus Google Scholar, J.S. A for very long-chain fatty acid 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google Scholar) but which in retina, and brain R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google Scholar) levels of VLC-PUFAs are found in of animal of macular a macular that from of the A. A in the retinal deficiency of 2007; PubMed Scopus Google and the in the has been reported to be associated with AMD risk A. J. T. R.E. a role for fatty acid and of the system in the of age-related PubMed Scopus (139) Google Scholar). DHA, more of VLC-PUFAs may also in AMD which VLC-PUFAs in AMD with normal The increased ratio of n-6/n-3 VLC-PUFAs in AMD to normal may also be due to in the levels of their and n-3 and VLC-PUFAs were in all whereas VLC-PUFAs were low that were in but with to retina. The of the photoreceptor outer segment photoreceptor outer segment Retinal pigment acid and effects of dietary fatty Ophthalmol. Google Scholar, D. R.W. of the retinal pigment The Retinal and cell photoreceptors and an of outer Retinal pigment acid and effects of dietary fatty Ophthalmol. Google Scholar, D. R.W. of the retinal pigment The Retinal Scholar). that RPE/choroid may the VLC-PUFAs with retina. RPE/choroid and retina may of VLC-PUFAs in RPE/choroid with to retina is in RPE/choroid R.S. Anderson R.E. Role of macular in the of very fatty Sci. 2008; PubMed Scopus Google Scholar). VLC-PUFAs were the of in AMD RPE/choroid with retinal we have demonstrated that the human retina and RPE/choroid in levels with and that these changes are in AMD are in lipids of the VLC-PUFA in AMD these lipids are in the retina and in the and n-6/n-3 are increased. The for these changes with and to be but may from dietary or of LC-PUFAs and studies with a of AMD the study early and AMD and GC-MS methods study of of VLC-PUFAs in macular and peripheral of the retina. the potential of to retinal VLC-PUFAs and to n-6/n-3 in the and of AMD. We E. and S. for on VLC-PUFAs with arachidonic acid age-related macular degeneration docosahexaenoic acid essential FA eicosapentaenoic acid fatty acid ester acid long-chain FA long-chain of and oleic acid palmitic acid retinal pigment epithelium stearic acid very long-chain