Research Article| Volume 75, ISSUE 3, P213-220, September 2006

Omega-3 fatty acids, energy substrates, and brain function during aging


      The maintenance of optimal cognitive function is a central feature of healthy aging. Impairment in brain glucose uptake is common in aging associated cognitive deterioration, but little is known of how this problem arises or whether it can be corrected or bypassed. Several aspects of the challenge to providing the brain with an adequate supply of fuel during aging seem to relate to omega-3 fatty acids. For instance, low intake of omega-3 fatty acids, especially docosahexaenoic acid (DHA), is becoming increasingly associated with several forms of cognitive decline in the elderly, particularly Alzheimer's disease. Brain DHA level seems to be an important regulator of brain glucose uptake, possibly by affecting the activity of some but not all the glucose transporters. DHA synthesis from either α-linolenic acid (ALA) or eicosapentaenoic acid (EPA) is very low in humans begging the question of whether these DHA precursors are likely to be helpful in maintaining cognition during aging. We speculate that ALA and EPA may well have useful supporting roles in maintaining brain function during aging but not by their conversion to DHA. ALA is an efficient ketogenic fatty acid, while EPA promotes fatty acid oxidation. By helping to produce ketone bodies, the effects of ALA and EPA could well be useful in strategies intended to use ketones to bypass problems of impaired glucose access to the brain during aging. Hence, it may be time to consider whether the main omega-3 fatty acids have distinct but complementary roles in brain function.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Prostaglandins, Leukotrienes and Essential Fatty Acids
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Sobocki P.-A.
        • Jonsson B.
        • Wittchen H.-U.
        • Olesen J.
        Costs of disorders of the brain in Europe.
        Eur. J. Neurol. 2005; 12: 1-27
        • Watson G.S.
        • Craft S.
        Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease.
        Eur. J. Pharmacol. 2004; 490: 97-114
        • Petersen K.F.
        • Befroy D.
        • Dufour S.
        • Dziura J.
        • Arlyan C.
        • Rothman D.L.
        • DiPietro L.
        • Cline G.W.
        • Shulman G.L.
        Mitochondrial dysfunction in the elderly: possible role in insulin resistance.
        Science. 2003; 300: 1140-1142
        • Heininger K.
        The cerebral glucose-fatty acid cycle: evolutionary roots, regulation and (patho) physiological importance.
        Int. Rev. Neurobiol. 2002; 5: 105-158
        • Meneilly G.S.
        • Cheung E.
        • Tessier D.
        • Yakura C.
        • Tuokko H.
        The effect of improved glycemic control on cognitive functions in the elderly patient with diabetes.
        J. Gerontol. 1993; 48: M117-M121
      1. S. Hoyer, R. Nitsch, K. Oesterreich, Glucose metabolism as the site of the primary abnormality in early onest dementia of Alzheimer type? J. Neurol. 235 (1988) 143–148.

        • Sokoloff L.
        Measurement of local cerebral glucose utilization and its relation to local functional activity in the brain.
        in: Vranic M. Fuel Homeostasis and the Nervous System. Plenum, New York1991: 21-42
        • Damasio H.
        • Eslinger P.
        • Damasio A.R.
        • Rizzo M.
        • Huang H.K.
        • Demeter S.
        Quantitative computed tomographic analysis in the diagnosis of dementia.
        Arch. Neurol. 1983; 40: 715-719
        • Kalaria R.N.
        • Haril S.I.
        Reduced glucoses transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease.
        J. Neurochem. 1989; 53: 1083-1088
        • Bookheimer S.
        • Strojwas M.H.
        • Cohen M.S.
        • Saunders A.M.
        • Pericak-Vance M.A.
        • Mazzioatta J.C.
        • Small G.W.
        Patterns of brain activation in people at risk for Alzheimer's disease.
        New Engl. J. Med. 2000; 343: 502-503
        • Foster N.L.
        • Chase T.N.
        • Fedio P.
        • Patronas N.J.
        • Brooks R.A.
        • di Chiro G.
        Alzheimer's disease: focal cortical changes shown by positron emission tomography.
        Neurology. 1983; 33: 961-965
        • Duara R.
        • Barker W.W.
        • Cheng J.
        • Yoshii F.
        • Loewenstein D.A.
        • Pascal S.
        Viability of neocortical function shown in behavioral activation state PET studies in Alzheimer's disease.
        J. Cereb. Blood Flow Metab. 1992; 12: 927-934
        • Reiman E.M.
        • Chen K.
        • Alexander G.E.
        • Caselli R.J.
        • Bandy D.
        • Osborne D.
        • Saunders A.M.
        • Hardy J.
        Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.
        Proc. Natl. Acad. Sci. USA. 2004; 101: 284-289
        • Reiman E.M.
        • Chen K.
        • Alexander G.E.
        • Caselli R.J.
        • Bandy D.
        • Osborne D.
        • Saunders A.M.
        • Hardy J.
        Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism.
        Proc. Natl. Acad. Sci. USA. 2005; 102: 8299-8302
        • Grant W.
        Dietary links to Alzheimer's disease.
        Alzheimer's Dis. Rev. 1997; 2: 42-55
        • Kalmijn S.
        • Launer L.J.
        • Ott A.
        • Witteman J.C.
        • Hofman A.
        • Breteler M.M.
        Dietary fat intake and the risk of incident dementia in the Rotterdam Study.
        Ann. Neurol. 1997; 42: 776-782
        • Conquer J.A.
        • Tierney M.C.
        • Zecevic J.
        • Bettger W.J.
        • Fisher R.H.
        Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia and cognitive impairment.
        Lipids. 2000; 35: 1305-1312
        • Barberger-Gateau P.
        • Letenneur L.
        • Deschamps V.
        • Peres K.
        • Dartigues J.F.
        • Renaud S.
        Fish, meat, and risk of dementia: A cohort study.
        Brit. Med. J. 2002; 325: 932-933
        • Heude B.
        • Ducimetiere P.
        • Berr C.
        Cognitive decline and fatty acid composition of erythrocyte membranes—The EVA Study.
        Am. J. Clin. Nutr. 2003; 77: 803-808
        • Morris M.C.
        • Evans D.A.
        • Bienias J.L.
        • Tangney C.C.
        • Bennett D.A.
        • Wilson R.S.
        • Aggarwal N.
        • Schneider J.
        Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease.
        Arch. Neurol. 2003; 60: 940-946
        • Morris M.C.
        • Evans D.A.
        • Tangney C.C.
        • Bienias J.L.
        • Wilson R.S.
        Fish consumption and cognitive decline with age in a large community study.
        Arch. Neurol. 2005; 62: 1-5
        • Tully A.M.
        • Roche H.M.
        • Doyle R.
        • Fallon C.
        • Bruce I.
        • Lawlor B.
        • Coakley D.
        • Gibney M.J.
        Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study.
        Brit. J. Nutr. 2003; 89: 483-489
        • Maclean C.H.
        • Issa A.M.
        • Newberry S.J.
        • Mojica W.A.
        • Morton S.C.
        • Garland R.H.
        • Hilton L.G.
        • Traina S.B.
        • Shekelle P.G.
        Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases.
        Evidence Rep.—Technol. Assess. 2005; 114: 1-66
        • Laurin D.
        • Verreault R.
        • Lindsay J.
        • Dewailly E.
        • Holub B.J.
        Omega-3 fatty acids and risk of cognitive impairment and dementia.
        J. Alzheimer's Dis. 2003; 5: 315-322
        • Soderberg M.
        • Edlund C.
        • Kristensson K.
        • Dallner G.
        Fatty acid composition of brain phospholipids in aging and in Alzheimer's disease.
        Lipids. 1991; 26: 421-425
        • Ximenes da Silva A.
        • Lavialle F.
        • Gendrot G.
        • Guesnet P.
        • Alessandri J.M.
        • Lavialle M.
        Glucose transport and utilization are altered in the brain of rats deficient in n-3 polyunsaturated fatty acids.
        J. Neurochem. 2002; 81: 1-10
        • Pifferi F.
        • Roux F.
        • Langelier B.
        • Alessandri J.M.
        • Vancassel S.
        • Jouin M.
        • Lavialle M.
        • Guesnet P.
        n-3 polyunsaturated fatty acid deficiency reduces the expression of both isoforms of the brain glucose transporter GLUT1 in rats.
        J. Nutr. 2005; 135: 2241-2246
        • Borkman M.
        • Storlien L.H.
        • Pan D.A.
        • Jenkins A.B.
        • Chisholm D.J.
        • Campbell L.V.
        The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids.
        New Engl. J. Med. 1993; 328: 238-244
        • Katayama Y.
        • Katsumata T.
        • Muramatsu H.
        Effect of long term administration of ethyl eicosapentaenote (EPA-E) on local cerebral blood flow and glucose utilization in stroke-prone spontaneously hypertensive rats (SHRSP).
        Brain Res. 1997; 761: 300-305
        • Jayasooriya A.P.
        • Weisinger R.S.
        • Weisinger H.S.
        Dietary omega-3 fatty acid supply influences mechanisms controlling body weight and glucose metabolism.
        Asia Pac. J. Clin. Nutr. 2004; 13: S51
        • Newman R.E.
        • Bryden W.L.
        • Kirby A.C.
        Dietary n-3 and n-6 fatty acids alter avian glucose metabolism.
        Brit. J. Poultr. Sci. 2005; 46: 104-113
        • Cunnane S.C.
        α-Linolenate in human nutrition.
        in: Muir A. Westcott N. Flax: The Genus Linum. Harcourt Academic, 2003: 150-180
        • Pawlosky R.J.
        • Hibbeln J.R.
        • Novotny J.A.
        • Salem Jr, N.
        Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans.
        J. Lipid. Res. 2001; 42: 1257-1265
        • Brenna J.T.
        Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man.
        Curr. Opin. Clin. Nutr. Metab. Care. 2002; 5: 127-132
        • McCloy U.
        • Pencharz P.B.
        • Ross R.J.
        • Cunnane S.C.
        Metabolism of 13C-unsaturated fatty acids in healthy women.
        J. Lipid Res. 2004; 45: 474-485
        • Vermunt S.H.
        • Mensink R.P.
        • Simonis A.M.
        • Hornstra G.
        Effects of age and dietary n-3 fatty acids on the metabolism of [13C] alpha-linolenic acid.
        Lipids. 1999; 34: S127
        • Dolecek T.A.
        Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial.
        Proc. Soc. Exp. Biol. Med. 1992; 200: 177-184
        • Cunnane S.C.
        Dietary sources and metabolism of α-linolenate.
        in: Thompson L.U. Cunnane S.C. Flaxseed in Human Nutrition. second ed. AOCS Press, Champaign, IL2003: 63-91
        • Zhao G.
        • Etherton T.D.
        • Martin K.R.
        • West S.G.
        • Gillies P.J.
        • Kris-Etherton P.M.
        Dietary alpha-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women.
        J. Nutr. 2004; 134: 2991-2997
        • Owen O.E.
        • Morgan A.P.
        • Kemp H.G.
        Brain metabolism during fasting.
        J. Clin. Invest. 1967; 46: 1590-1595
        • Adam P.A.J.
        • Raiha N.
        • Rahiala E.L.
        • Kekomaki EL E.L.
        Oxidation of glucose and d-beta-hydroxybutyrate by the early human fetal brain.
        Acta Paediatr. Scand. 1975; 64: 17-24
        • Edmond J.
        Ketone bodies as precursors of sterols and fatty acids in the developing rat.
        J. Biol. Chem. 1974; 249: 72-80
        • Bougneres P.F.
        • Lemmel C.
        • Ferre P.
        • Bier D.M.
        Ketone body transport in the human neonate and infant.
        J. Clin. Invest. 1986; 77: 42-48
        • Robinson A.
        • Williamson D.
        Physiological role of ketone bodies as substrates and signals in mammalian tissues.
        Physiol. Rev. 1980; 60: 143-187
        • Patel M.S.
        • Owen O.E.
        Development and regulation of lipid synthesis from ketone bodies by rat brain.
        J. Neurochem. 1975; 28: 109-114
        • Hahn P.
        • Novak M.
        How important are carnitine and ketones for the newborn infant?.
        Fed. Proc. 1985; 44: 2369-2373
        • Suzuki M.
        • Suzuki M.
        • Sato K.
        • Dohi S.
        • Sato T.
        • Matsuura A.
        • Hiraide A.
        Effect of β-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats.
        Jpn. J. Pharmacol. 2001; 87: 143-150
        • Veneman T.
        • Mitrakou A.
        • Mokan M.
        • Cryer P.
        • gerich J.
        Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycaemia in normal humans.
        Diabetes. 1994; 43: 1311-1317
        • Amiel S.A.
        • Archibald H.R.
        • Chusney G.
        • Williams A.J.K.
        • Gale E.A.M.
        Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non-glucose fuel.
        Clin. Sci. 1991; 81: 189-194
        • Reger M.
        • Henderson S.T.
        • Hale C.
        • Cholerton B.
        • Baker L.D.
        • Watson G.S.
        • Hyde K.
        • Chapman D.
        • Craft S.
        Effects of beta-hydroxybutyrate on cognition in memory-impaired adults.
        Neurobiol. Aging. 2004; 25: 311-314
        • Freeman J.M.
        • Freeman J.B.
        • Kelly M.T.
        The Ketogenic Diet: A Treatment for Epilepsy.
        third ed. Demos Publications, New York,2000 (p. 236)
        • Musa-Veloso K.
        • Likhodii S.S.
        • Rarama E.
        • Comeau J.J.E.
        • Benoit S.
        • Chartrand D.
        • Carmant L.
        • Lortie A.
        • Liu C.
        • Curtis R.
        • Cunnane S.C.
        Breath acetone and seizure control in children with epilepsy on a ketogenic diet.
        Nutrition. 2006; 22: 1-8
      2. S.C. Cunnane, M.A. Ryan, C.R. Nadeau, R.P. Bazinet, K. Musa-Veloso, U. McCloy, Why is lipid synthesis an integral target of β-oxidized and recycled carbon from polyunsaturates in neonates? Lipids 38 (2003) 477–484.

        • Emmison N.
        • Gallagher P.A.
        • Coleman R.A.
        Linoleic and linolenic acids are selectively secreted in triacylglycerols by hepatocytes from neonatal rats.
        Am. J. Physiol. 1995; 269: R80-R86
        • Likhodii S.S.
        • Musa K.
        • Mendonca A.
        • Dell C.
        • Burnham W.M.
        • Cunnane S.C.
        Dietary fat, ketosis and seizure protection in rats on the ketogenic diet.
        Epilepsia. 2000; 41: 1400-1410
        • Blomqvist G.
        • Thorell J.O.
        • Ingvar M.
        • Grill V.
        • Widen L.
        • Stone-Elander S.
        Use of R-β-[1-11C]hydroxybutyrate in PET studies of regional cerebral uptake of ketone bodies in humans.
        Am. J. Physiol. 1995; 269: E948-E959
        • Blomqvist G.
        • Alvarsson M.
        • Grill V.
        • von Heigne G.
        • Ingvar M.
        • Thorell J.O.
        • Stone-Elander S.
        • Widen L.
        • Ekberg K.
        Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients.
        Am. J. Physiol. 2002; 283: E20-E28
        • Morris A.A.M.
        Cerebral ketone body metabolism.
        J. Inherit. Metab. Dis. 2005; 28: 109-121
        • Fukao T.
        • Lopaschuk G.D.
        • Mitchell G.A.
        Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry.
        Prostaglandins Leukot. Essent. Fatty Acids. 2004; 70: 243-252
        • James M.J.
        • Ursin V.M.
        • Cleland L.G.
        Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n-3 fatty acids.
        Am. J. Clin. Nutr. 2003; 77: 1140-1145
        • Boston P.F.
        • Bennett A.
        • Horrobin D.F.
        • Bennett C.N.
        Ethyl-EPA in Alzheimer's disease; a pilot study.
        Prostaglandins Leukot. Essent. Fatty Acids. 2004; 71: 341-346
        • Yerram N.R.
        • Moore S.A.
        • Spector A.A.
        Eicosapentaenoic acid metabolism in brain microvessel endothelium: effect on prostaglandin formation.
        J. Lipid Res. 1989; 30: 1747-1757
        • Montine T.J.
        • Morrow J.D.
        Fatty acid oxidation in the pathogenesis of Alzheimer's disease.
        Am. J. Pathol. 2005; 166: 1283-1289
        • Chambrier C.
        • Bastard J.P.
        • Rieusset J.
        • Chevillotte E.
        • Bonnefont-Rousselot D.
        • Therond P.
        • Hainque B.
        • Riou J.P.
        • Laville M.
        • Vidal H.
        Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor gamma.
        Obes. Res. 2002; 10: 518-525
        • Berge R.K.
        • Madsen L.
        • Vaagenes H.
        • Tronstad K.J.
        • Gottlicher M.
        • Rustan A.C.
        In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipideamic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation.
        Biochem. J. 1999; 343: 191-197