Neurochemical Research

, Volume 27, Issue 11, pp 1513–1523 | Cite as

Age-Associated Changes in Central Nervous System Glycerolipid Composition and Metabolism

  • N. M. Giusto
  • G. A. Salvador
  • P. I. Castagnet
  • S. J. Pasquaré
  • M. G. Ilincheta de Boschero


In this review, changes in brain lipid composition and metabolism due to aging are outlined. The most striking changes in cerebral cortex and cerebellum lipid composition involve an increase in acidic phospholipid synthesis. The most important changes with respect to fatty acyl composition involve a decreased content in polyunsaturated fatty acids (20:4n-6, 22:4n-6, 22:6n-3) and an increased content in monounsaturated fatty acids (18:1n-9 and 20:1n-9), mainly in ethanolamine and serineglycerophospholipids. Changes in the activity of the enzymes modifying the phospholipid headgroup occur during aging. Serine incorporation into phosphatidylserine through base-exchange reactions and phosphatidylcholine synthesis through phosphatidylethanolamine methylation increases in the aged brain. Phosphatidate phosphohydrolase and phospholipase D activities are also altered in the aged brain thus producing changes in the lipid second messengers diacylglycerol and phosphatidic acid.

Aging phospholipids central nervous system 


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  1. 1.
    Stubbs, C. D. and Smith, A. D. 1984. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim. Biophys. Acta 779:89-137.Google Scholar
  2. 2.
    Lynch, R. D. 1980. Utilization of polyunsaturated fatty acids by human diploid cells aging in vitro. Lipids 15:412-420.Google Scholar
  3. 3.
    Horrocks, L. A., Van Rollins, M., and Yates, A. J. 1981. Lipid changes in the ageing brain. Pages 601-630, in Thompson, R. S. H. and Davidson, A. N. (Eds.) The Molecular Basis of Neuropathology. Edward Arnold Publishers Ltd., London.Google Scholar
  4. 4.
    López, G. H., Ilincheta de Boschero, M. G., Castagnet, P. I., and Giusto, N. M. 1995. Age-associated changes in the content and fatty acid composition of brain glycerophospholipids. Comp. Biochem. Physiol. 112B:331-343.Google Scholar
  5. 5.
    Rouser, G. and Yamamoto, A. 1968. Curvilinear regression course of human brain lipid composition changes with age. Lipids 3:284-287.Google Scholar
  6. 6.
    Schroeder, F. 1984. Role of membrane lipids asymmetry in aging. Neurobiol. Aging 5:323-333.Google Scholar
  7. 7.
    Sum, G. Y. and Samorajski, T. 1972. Age changes in the lipid composition of whole homogenates and isolated myelin fraction of mouse brain. J. Gerontol. 27:10-17.Google Scholar
  8. 8.
    Sum, G. Y. and Samorajski, T. 1973. Age differences in the acyl group composition of phosphoglycerides in myelin isolated from the brain of rhesus monkey. Biochim. Biophys. Acta 316: 19-27.Google Scholar
  9. 9.
    Giusto, N. M., Roque, M. E., and Ilincheta de Boschero, M. 1992. Effects of aging on the content, composition and synthesis of sphingomyelin in the Central Nervous System. Lipids 27: 835-839.Google Scholar
  10. 10.
    Ruggiero, F. M., Cafagna, F., Petruzzella, V., Gadaleta, M. N., and Quagliariello, E. 1992. Lipid composition in synaptic and non-synaptic mitochondria from rat brains and effect of aging. J. Neurochem. 59:487-491.Google Scholar
  11. 11.
    Farooqui, A. A., Horrocks, L. A., and Farooqui, T. 2000. Glycerophospholipids in brain: Their metabolism, incorporation into membranes, functions and involvement in neurological disorders. Chem. Phys. Lipids 106:1-29.Google Scholar
  12. 12.
    Yu, B. P. 1993. Oxidative damage by free radicals and lipid peroxidation in aging. Pages 57-88 in Byung, P. Yu (Ed.) Free Radicals in Aging. CRC Press, Inc.Google Scholar
  13. 13.
    Ilincheta de Boschero, M. G., Roque, M. E., Salvador, G. A., and Giusto, N. M. 2000. Alternative pathways for phospholipid synthesis in different brain areas during aging. Exp. Gerontol. 35:653-668.Google Scholar
  14. 14.
    Farooqui, A. A., Yang, H. C., and Horrocks, L. A. 1995. Plasmalogens, phospholipases A2 and signal transduction. Brain. Res. Rev. 21:152-161.Google Scholar
  15. 15.
    Brosche, T. 1997. Plasmalogen phospholipid facts and theses to their antioxidative qualities. Arch. Gerontol. Geriatr. 25:73-81.Google Scholar
  16. 16.
    Lohner, K. 1996. Is the high propensity of ethanolamine plasmalogens to form non-lamellar lipid structures manifested in the properties of biomembranes? Chem. Phys. Lipids 81:167-184.Google Scholar
  17. 17.
    Favrelere, S., Stadelmann-Ingrand, S., Huguet, F., De Javel, D., Piriou, A., Tallineau, C., and Durand, G. 2000. Age-related changes in ethanolamine glycerophospholipid fatty acid levels in rat frontal cortex and hippocampus. Neurobiol. Aging 21: 653-660.Google Scholar
  18. 18.
    Koide, H., Ogita, K., Kikkawa, U., and Nishizuka, Y. 1992. Isolation and characterization of the epsilon subspecies of protein kinase C from rat brain. Proc. Natl. Acad. Sci. USA 89:1149-1153.Google Scholar
  19. 19.
    Noremberg, K. and Strosznajder, J. 1986. Modification of GABA and calcium uptake by lipids in synaptosomes from normoxic and ischemic brain. Neurochem. Int. 8:59-64.Google Scholar
  20. 20.
    Axelrod, J., Burch, R. M., and Jelsema, C. L. 1988. Receptor-mediated activation of phospholipase A via GTP-binding proteins: arachidonic acid and its metabolites as second messengers. Trends Neurosci. 11:117-122.Google Scholar
  21. 21.
    Lynch, M. and Voss, K. L. 1990. Arachidonic acid increases inositol phospholpid metabolism and glutamate release in synaptosomes prepared from hippocampal tissue. J. Neurochem. 55: 215-221.Google Scholar
  22. 22.
    Samochocki, M. and Strosznajder, J. 1993. Modulatory action of arachidonic acid on GABAA/chloride channel receptor function in adult and aged brain cortex. Neurochem. Int. 23:261-267.Google Scholar
  23. 23.
    Ilincheta de Boschero, M. G., López, G. H., Castagnet, P. I., and Giusto, N. M. 2000. Differential incorporation of precursor moieties into cerebral cortex and cerebellum glycerophospholipids during aging. Neurochem. Res. 25:875-884.Google Scholar
  24. 24.
    Terracina, L., Brunetti, M., Avellini, L., De Medio, G., Trovarelli, G., and Gaiti, A. 1992. Arachidonic acid and palmitic acid utilization in aged brain areas. Mol. Cell Biochem. 115:35-42.Google Scholar
  25. 25.
    Kanfer, J. N. 1972. Base-exchange reactions of the phospholipids in rat brain particles J. Lipid. Res. 13:468-476.Google Scholar
  26. 26.
    Vance, J. E. 1998. Eukaryotic lipid-biosynthetic enzymes: The same but not the same. Trends Biochem. Sci. 23:423-428.Google Scholar
  27. 27.
    Verhrastky, A. and Toescu, E. C. 1998. Calcium and neuronal ageing. Trends Neurosci. 21:2-7.Google Scholar
  28. 28.
    Hanahisa, Y. and Yamaguchi, M. 1997. Increase in calcium content and calcium++-ATPase activity in the brain of fasted rats: Comparison with different ages. Mol. Cell Biochem. 17:127-132.Google Scholar
  29. 29.
    Kishimoto, J., Tsuchiya, T., Cox, H., Emson, P., and Nakayama, Y. 1998. Age-related changes of calbindin-D28k, calretinin, and parvalbumin mRNAs in the Hamster brain. Neurobiol. Aging 19:77-82.Google Scholar
  30. 30.
    Baimbridge, K., Celio, M., and Rogers, J. 1992. Calcium-binding proteins in the nervous system. Trends Neurosci. 15:303-307.Google Scholar
  31. 31.
    Holbook, P. and Wurtman, R. 1988. Presence of base-exchange activity in rat brain nerve endings: Dependence on soluble substrate concentration and effect of cations. J. Neurochem. 50:156-162.Google Scholar
  32. 32.
    Mozzi, R. and Porcellati, G. 1979. Conversion of phosphatidyl-ethanolamine to phosphatidylcholine in rat brain by the methylation pathway. FEBS Lett. 100:363-366.Google Scholar
  33. 33.
    Crews, F., Hirata, F., and Axelrod, J. 1980. Identification and properties of methyltransferases that synthetize phosphatidylcholine in rat brain synaptosomes. J. Neurochem. 34:1194-1498.Google Scholar
  34. 34.
    Crews, F. T., Calderini, G., Battistella, A., and Toffano, T. 1981. Age-dependent changes in the methylation of phospholipids. Brain Res. 229:256-259.Google Scholar
  35. 35.
    Tacconi, M. and Wurtman, R. 1985. Phosphatidylcholine produced in rat synaptosomes by N-methylation is enriched in polyunsaturated fatty acids. Proc. Natl. Acad. Sci. 82:4828-4831.Google Scholar
  36. 36.
    Butterwith, S. C., Martin, A., and Brindley, D. N. 1984. Can phosphorylation of Phosphatidate Phosphohydrolase by a cyclic AMP-dependent mechanism regulate its activity and subcellular distribution and control hepatic glycerolipid synthesis? Biochem. J. 222:487-493.Google Scholar
  37. 37.
    Sturton, R. G. and Brindley, D. N. 1980. Factors controlling the metabolism of Phosphatidate by Phosphohydrolase and Phospholipase A type activities. Effects of magnesium, calcium and amphiphilic cationics drugs. Biochim. Biophys. Acta 619:494-505.Google Scholar
  38. 38.
    Martin, A., Gomez-Muñoz, A., Jamal, Z., and Brindley, D. N. 1991. Characterization and assay of Phosphatidate Phosphohydrolase. Methods Enzymol. 197:553-563.Google Scholar
  39. 39.
    Sciorra, V. A. and Morris, A. J. 1999. Sequential actions of Phospholipase D and Phosphatidic acid Phosphohydrolase 2 b generate diglyceride in mamalian cells. Mol. Biol. Cell 1:3863-3876.Google Scholar
  40. 40.
    Fleming, I. N. and Yeaman S. J. 1995. Subcellular distribution of N-ethylmaleimide-sensitive and-insensitive Phosphatidic acid Phosphohydrolase in rat brain. Biochim. Biophys. Acta 1254:161-168.Google Scholar
  41. 41.
    Jamdar, S. C. and Cao, W. F. 1994. Properties of Phosphatidate Phosphohydrolase in rat adipose tissue. Biochem. J. 301:793-799.Google Scholar
  42. 42.
    Hooks, S. B., Ragan, S. P., and Lynch, K. R. 1998. Identification of a novel human Phosphatidic acid Phosphatase type 2 isoform. FEBS Lett. 472:188-192.Google Scholar
  43. 43.
    Roberts, R., Sciorra, V. A., and Morris, A. J. 1998. Human type 2 Phosphatidic Acid Phosphohydrolases. Substrate specificity of the type 2a, 2b, and 2c enzymes and cell surface activity of the 2a isoform. J. Biol. Chem. 273:22059-22067.Google Scholar
  44. 44.
    Billah, M. M. and Arthes, J. C. 1990. The regulation and cellular functions of phosphatidylcholine hydrolysis. Biochem J. 269:281-291.Google Scholar
  45. 45.
    Jamal, Z., Martin, A., Gomez-Muñoz, A., and Brindley, D. N. 1991. Plasma membrane fraction from rat liver contain a Phosphatidate Phosphohydrolase distinct from That in the endoplasmic reticulum and cytosol. J. Biol. Chem. 266:2988-2996.Google Scholar
  46. 46.
    Brindley, D. N. and Waggoner, W. 1998. Mammalian Lipid Phosphate Phosphohydrolases. J. Biol. Chem. 273:24281-24284.Google Scholar
  47. 47.
    Pasquaré, S. J., Ilincheta de Boschero, M. G., and Giusto, N. M. 2001. Aging promotes a different phosphatidic acid utilization in cytosolic and microsomal fractions from brain and liver. Exp. Gerontology 36:1387-1401.Google Scholar
  48. 48.
    Farooqui, A. A., Rammchan, K. W., and Horrocks, L. A. 1989. Isolation, characterization, and regulation of Diacylglycerol Lipases from the bovine brain. Ann. NY Acad. Sci. 559:25-36.Google Scholar
  49. 49.
    Gorraci, G., Francescangeli, E., Horrocks, L. A., and Porcellati, G. 1981. The reverse reaction of cholinephosphotransferase in rat brain microsomes. A new pathway for degradation of phosphatidylcholine. Biochim. Biophys. Acta 664:373-379.Google Scholar
  50. 50.
    Brindley, D. N., Abousalham, A., Kikuchi, Y., and Wang, C. N. 1996. Cross-talk between the bioactive glycerolipids and sphingolipids in signal transduction. Biochem. and Cell Biol. 71: 469-476.Google Scholar
  51. 51.
    English, D., Martin, M., Harvey, K., Akard, L., Allen, R., Widlanski, T. S., García, J., and Siddiqui, R. A. 1997. Characterization and purification of neutrophil ecto-phosphatidic phosphohydrolase. Biochem. J. 324:941-950.Google Scholar
  52. 52.
    Freeman, E. J. 2000. The Ang II-induced growth of vascular smooth muscle cells involves a phospholipase D-mediated signaling mechanism. Arch. Biochem. Biophys. 374:363-370.Google Scholar
  53. 53.
    Singer, W. D., Brown, H. A., and Sternweis, P. C. 1997. Regulation of eukaryotic phosphatidylinositol-specific phospholipase C and phospholipase D. Annu. Rev. Biochem. 66:475-509.Google Scholar
  54. 54.
    Kobayashi, M. and Kanfer, J. N. 1987. Phosphatidylethanol formation via transphosphatidylation by rat brain synaptosomal phospholipase D. J. Neurochem. 48:1597-1603.Google Scholar
  55. 55.
    Massemburg, D., Han, J. S., Liyanage, M., Patton, W. A., Rhee, S. G., Moss, J., and Vaughan, M. 1994. Activation of rat brain phospholipase D by ADP-rybosilation factors 1,5, and 6: Separation of ADP ribosylation factor-dependent and oleate dependent enzymes. Proc. Natl. Acad. Sci. 91:11718-11722.Google Scholar
  56. 56.
    Liscovitch, M., Czarny, M., Fiucci, G., Lavie, Y., and Tang, X. 1999. Localization and possible functions of phospholipase D isozymes. Biochim. Biophys. Acta 1439:245-263.Google Scholar
  57. 57.
    Salvador, G. A., Pasquaré, S. J., Ilincheta de Boscheró, M. G., and Giusto, N. M. 2001. Differential modulation of phospholipase D and phosphatidate phosphohydrolase during aging in rat cerebral cortex synaptosomes. Exp. Gerontol. In Press.Google Scholar
  58. 58.
    Narang, N., Joseph, J. A., Ayyagari, P. V., Gerber, M., and Crews, F. T. 1996. Age-related loss of cholinergic-muscarinic coupling to PLC: Comparison with changes in brain regional PLC subtypes mRNA distribution. Brain Res. 708:143-152.Google Scholar
  59. 59.
    Ayyagari, P. V., Gerber, M., Joseph, J. A., and Crews, F. T. 1998. Uncoupling of muscarinic cholinergic phosphoinositide signals in senescent cerebral cortical and hippocampal membranes. Neurochem. Int. 32:107-115.Google Scholar
  60. 60.
    Toescu, E. C. and Verkhratsky, A. 2000. Parameters of calcium homeostasis in normal neuronal aging. J. Ant. 4:563-569.Google Scholar
  61. 61.
    Brown, D. A. and London, E. 1998. Functions of lipid rafts in biological membranes. Annu. Rev. Cell Dev. Biol. 14:111-136.Google Scholar
  62. 62.
    Topham, M. K. and Prescott, S. M. 1999. Mammalian diacylglycerol kinases, a family of lipid kinases with signaling functions. J. Biol. Chem. 274:11447-11450.Google Scholar
  63. 63.
    Shinomura, T., del Rio, E., Breen, K. C., Downes, C. P., and McLaughlin, M. 2000. Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes. Br J Pharmacol 131:1011-1018.Google Scholar
  64. 64.
    Qian, Z. and Drewes, L. R. 1989. Muscarine acetilcholine receptor regulate phosphatidylcholine phospholipase D in canine brain. J. Biol. Chem. 264:21720-21724.Google Scholar
  65. 65.
    Farooqui, A. A., Liss, L., and Horrocks, L. A. 1990. Elevated activities of lipases and lysophospholipases in Alzheimer's disease. Dementia 1:208-214.Google Scholar
  66. 66.
    Folch, J., Lees, M., and Sloane Stanley, G. H. 1957. A simplified method for isolation and purification of total lipides from animals tissues. J. Biol. Chem. 226:497-509.Google Scholar
  67. 67.
    Rouser, G., Fleischer, S., and Yamamoto, A. 1970. Two dimensional thin layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids 5:494-496.Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • N. M. Giusto
    • 1
  • G. A. Salvador
    • 1
  • P. I. Castagnet
    • 1
  • S. J. Pasquaré
    • 1
  • M. G. Ilincheta de Boschero
    • 1
  1. 1.Instituto de Investigaciones BioquímicasUniversidad Nacional del Sur y Consejo Nacional de Investigaciones Cientificas y TécnicasBahía BlancaArgentina

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