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The role of calcium regulation in brain aging: reexamination of a hypothesis

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Abstract

Studies of the central nervous system have a long history; however, it is only recently that we have begun to understand brain function in health and disease states. And, the topic of the aging brain has become a subject of intense study for a short period. At present, the process of normal aging is relatively poorly understood. Although there are a number of theories of aging, no single theory appears to account for most age-dependent brain changes. This review provides a re-evaluation of the “Calcium Hypothesis of Brain Aging” in light of new evidence which supports the proposition that cellular mechanisms, which maintain the homeostasis of cytosol Ca2+ concentration, play a key role in brain aging; and that sustained changes in [Ca2+]i homeostasis provide the final common pathway for age-associated brain changes. This revision of the calcium hypothesis suggests that there is a complex interaction between the amount of [Ca2+]i perturbation and the duration of such deregulation of Ca2+ homeostasis and it proposes that a small disturbance in Ca2+ homeostasis with a sustained increase in [Ca+]i over a long period has similar cell injuring consequences as that produced by a large increase in [Ca2+]i over a shorter period. Although there are several alternative mechanisms through which the regulation of cytosol [Ca2+]i can be disrupted (such as changes in ion channels, extrusion pumps, and sequestration), this review focuses on disruptions in energy metabolism and changes in the structure and function of membranes as the most likely antecedent events which lead to disruption of Ca2+ homeostasis. The principle purpose of this review is to identify scientific opportunities and stimulate further research into cellular mechanisms of brain aging.

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References

  1. Torrey B.B., Kinsella K., Tauber C.M.: An aging world. International population reports series. U.S. Department of Commerce, Bureau of the Census. 78: 95, 1987.

    Google Scholar 

  2. Warner H.R., Butler R.N., Sprott R.L., Schneider E.L.: Modern Biological Theories of Aging. Raven Press, New York, 1987, pp. 1–4.

    Google Scholar 

  3. Finch C.E., Morgan D.G.: RNA and protein metabolism in the aging brain. Ann. Rev. Neurosci. 1989 (In press.).

  4. Truman J.W., Fahrbach S., Kimura K.I.: Hormones and programmed cell death: insights from invertebrate studies. In: Coleman P.D., Higgins G.A., Phelps C.H. (Eds.), Molecular and cellular mechanisms of neuronal plasticity in aging and Alzheimer’s disease. Elsevier, Amsterdam, 1989 (In press).

    Google Scholar 

  5. Landfield P.W.: Personal Communication, 1989.

  6. Khachaturian Z.S.: Towards theories of brain aging. In: Kay D.S., Burrows G.W. (Eds.), Handbook of Studies on Psychiatry and old age. Elsevier, Amsterdam, 1984, pp. 7–30.

    Google Scholar 

  7. Khachaturian Z.S.: Hypothesis on the regulation of cytosol calcium concentration and the aging brain. Neurobiol. Aging 8: 345–346, 1987.

    Article  PubMed  CAS  Google Scholar 

  8. Bartus R.T., Dena R.L., Beer B., Lippa A.S.: The cholinergic hypothesis of geriatric dysfunction. Science 217: 408–417, 1982.

    Article  PubMed  CAS  Google Scholar 

  9. Gibson G.E., Peterson C.: Calcium and the aging nervous system. Neurobiol. Aging 8: 329–343, 1987.

    Article  PubMed  CAS  Google Scholar 

  10. Cheung W.Y.: Calmodulin plays a pivotal role in cellular regulation. Science 207: 19–27, 1979.

    Article  Google Scholar 

  11. Carvahlo A.P.: Calcium in the nerve cell. In: Lajtha A. (Ed.), Handbook of Neurochemistry. Plenum Press, New York, 1982, pp. 69–116.

    Google Scholar 

  12. McGraw C.F., Nachsen D.A., Blaustein M.P.: Calcium movement and regulation in presynaptic nerve terminals. In: Cheung W.Y. (Eds.), Calcium and Cell Function. Academic Press, New York, 1982, pp. 81–110.

    Google Scholar 

  13. Rassmussen H.: The calcium messenger system. N. Engl. J. Med. 314: 1094–1101, 1986.

    Article  Google Scholar 

  14. Rassmussen H.: The calcium messenger system. N. Engl. J. Med. 314: 1164–1170, 1986.

    Article  Google Scholar 

  15. Landfield P.W., Campbell L.W., Hao S., Kerr S.D.: Aging-related increase in voltage-sensitive, inactivating calcium currents in rat hippocampus: implications for mechanisms of brain aging and Alzheimer’s disease. In: Khachaturian Z.S., Cotman C.W., Pettegrew J.W. (Eds.), Calcium, Membranes, Aging and Alzheimer’s Disease. N.Y. Acad. Sci., New York, 1989 (In press).

    Google Scholar 

  16. Miller R.J.: Calcium signaling in neurons, TINS 11: 415–418, 1988.

    Google Scholar 

  17. Blaustein M.P.: Calcium transport and buffering in neurons. TINS 11: 438–448, 1988.

    PubMed  CAS  Google Scholar 

  18. Tsien R.W., Lipscombe D., Madison D.V., Bley K.R., Fox A.P.: Multiple types of neuronal calcium channels and their selective modulation. TINS 11: 431–437, 1988.

    PubMed  CAS  Google Scholar 

  19. Cotman C.W., Geddes J.W.: Amino Acid Receptors, and Alzheimer’s Disease. In: Coleman P.D., Higgins G.A., Phelps C.H. (Eds.), Molecular and Cellular Mechanisms of Neuronal Plasticity in Aging and Alzheimer’s Disease. Elsevier, Amsterdam, 1989 (In press).

    Google Scholar 

  20. Siesjo B.K.: Cell damage in the brain: a speculative synthesis. J. Cerebral. Blood Flow Metab. 1: 155–185, 1981.

    Article  CAS  Google Scholar 

  21. Siesjo B.K., Bengtsson F., Grampp W., Theander S.: Calcium, excitotoxins and neuronal death in brain. In: Khachaturian Z.S., Cotman C., Pettegrew J.W. (Eds.), Calcium, Membranes, Aging and Alzheimer’s Disease. New York Acad. Science, New York, 1989 (In press.).

    Google Scholar 

  22. Kretsinger R.H.: Mechanism of selective signaling by calcium. Neurosci. Res. Prog. Bull. 19: 213–328, 1981.

    Google Scholar 

  23. Levine A.S., Gosnell B.A., Morley J.E.: Alterations in calmodulin levels in tissues from aged animals. J. Geront. 41: 20–23, 1986.

    Article  PubMed  CAS  Google Scholar 

  24. Hansford R.G., Castro F.: Effects of senescence of Ca2+-ion transport by heart mitochondria. Mech. Ageing Deu. 19: 5–13, 1982.

    Article  CAS  Google Scholar 

  25. Vitorica J., Clark A., Machado A., Satrustegui J.: Impairment of glutamate uptake and absence of alterations in the energy transducing ability of old rat brain mitochondria. Mech. Ageing Deu. 29: 255–266, 1985.

    Article  CAS  Google Scholar 

  26. Vitorica J., Satrustegui J.: Involvement of mitochondria in the age-dependent decrease in calcium uptake of rat brain synaptosomes. Brain Res. 378: 36–48, 1986.

    Article  PubMed  CAS  Google Scholar 

  27. Leslie S.W., Chandler L.J., Barr E., Farrar R.P.: Reduced calcium uptake by rat brain mitochondria and synaptosomes in response to aging. Brain Res. 329: 177–183, 1985.

    Article  PubMed  CAS  Google Scholar 

  28. Michaelis M.L.: Ca2+ Handling Systems in Neuronal Aging. In: Khachaturian Z.S., Cotman C., Pettigrew J.W. (Eds.), Calcium Membranes, Aging and Alzheimer’s Disease. N.Y. Acad. Sci., New York, 1989 (In press).

    Google Scholar 

  29. Smith D.O.: Non-uniform changes in nerve-terminal calcium homeostasis during aging. Neurobiol. Aging 8: 366–368, 1987.

    Article  PubMed  CAS  Google Scholar 

  30. Fifkova E., Cullen-Dodkstader K.: Age-related changes in the distribution of calcium-containing synaptic vescicles in the terminals of the perforant pathway. Soc. Neurosci. Abstr. 12: 271, 1986.

    Google Scholar 

  31. Fifkova E., Cullen-Dodkstader K.: Calcium distribution in dendritic spines of the dentate varies with age. Brain Res. 376: 357–362, 1986.

    Article  PubMed  CAS  Google Scholar 

  32. Landfield P.W., Pitler T.A.: Prolonged Ca2+ dependent after hyperpolarization in hippocampal neurons of aged rats. Science 226: 1089–1091; 1984.

    Article  PubMed  CAS  Google Scholar 

  33. Landfield P.W., Morgan G.A.: Chronically elevated plasma Mg2+ improves hippocampal frequency potentiation and reversal learning in aged and young rats. Brain Res. 322: 167–171, 1984.

    Article  PubMed  CAS  Google Scholar 

  34. Pettegrew J.W., Minshew N.J., Cohen M.M., Kopp S.J., Glonek T.: P-31NMR changes in Alzheimer’s and Huntington’s disease brain. Neurol. 34: 281, 1984.

    Google Scholar 

  35. Pettegrew J.W., Kopp S.J., Minshew N.J., Glonek T., Feliksik J.M., Tow J.P., Cohen M.M.: 31p NMP studies of phospholipid metabolism in developing and degenerating brain. Neurol. 35: 257, 1985.

    Google Scholar 

  36. Pettegrew J.W., Kopp S.J., Minshew N.J., Glonek T., Feliksik J.M., Tow J.P., Cohen M.M.: 31p Nuclear Magnetic Resonance studies of phosphoglyceride metabolism in developing and degenerating brain: preliminary observations. J. Neuropathol. Exp. Neurol. 46: 419–430, 1987.

    Article  PubMed  CAS  Google Scholar 

  37. Pettegrew J.W., Withers G., Panchalingam K., Post J.F.M.: 31p Nuclear Magnetic Resonance (NMR) spectroscopy of brain in aging and Alzheimer’s disease. J. Neurol. Trans. 24: 261–268, 1987.

    CAS  Google Scholar 

  38. Pettegrew J.W., Moosy J., Withers G., McKeag D., Panchalingam K.: 31p Nuclear Magnetic Resonance study of the brain in Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 47: 235–248, 1988.

    Article  PubMed  CAS  Google Scholar 

  39. Pettegrew J.W., Panchalingam K., Mossy J., Martinez T.A., Rao G., Boiler F.: Correlation of 31p NMR and morphological findings in Alzheimer’s disease. Arch. Neurol. 45: 1093–1096, 1988.

    Article  PubMed  CAS  Google Scholar 

  40. Cutler N.R., Haxby J.V., Duara C.L., Grady C.L., Moore A.M., Parisi J.E., White J., Heston L., Margolin R., Rapoport S.: Brain metabolism as measured with positron emission tomography: Serial assessment in a patient with familial Alzheimer’s disease. Neurol. 35: 1556–1561, 1985.

    Article  CAS  Google Scholar 

  41. Miotto O., Gonalez R.G., Buonanno R., Growdon J.: In vitro 31p NMR spectroscopy detects altered phospholipid metabolism in Alzheimer’s disease. Can. J. Neurol. Sci. 13: 535–539, 1986.

    Google Scholar 

  42. Duara R., Grady C, Haxby J., Sundaram M., Cutler N.R., Heston L, Moore Schlagetr N., Larson S., Rapoport S.: Positron emission tomography in Alzheimer’s disease [18F] 2-fluoro-2-deoxy-D-glucose study in the resting state. Neurol. 36: 879–887, 1984.

    Google Scholar 

  43. Jagust W.J., Friedland R.P., Koss E., Ober B.A., Mathis C.A., Huesman R.H., Budinger T.F.: Progression of regional cerebral glucose metabolic abnormalities in Alzheimer’s disease. J. Neurol 37: 156, 1987.

    Article  Google Scholar 

  44. Haxby J.V., Grady C.L., Koss E., Friedland R.P., Rapoport S.I.: Heterogeneous metabolic and neuropsychological patterns in dementia of the Alzheimer’s type: Cross-sectional and longitudinal studies. Neurol. 37: 159, 1987.

    Google Scholar 

  45. Beradi A., Haxby J.V., Grady C.L., Rapoport S.I., Asymmetrics of brain glucose consumption and memory performance in mild dementia of the Alzheimer type and in healthy aging. Neurol. 37: 160, 1987.

    Google Scholar 

  46. Berent S., Foster N.L., Gilman S., Hichwa R., Lehtinen S.: Patterns of cortical 18F-FDG metabolism in Alzheimer’s and progressive supranuclear palsy patients are related to the types of cognitive impairments. Neurol 37: 172, 1987.

    Google Scholar 

  47. Friedland R.P., Jagust W.J., Budinger T.F., Koss E., Ober B.A.: Consistency of temporal parietal cortex hypometabolism in probable Alzheimer’s disease (AD): Relationships to cognitive decline. Neurol 37: 224, 1987.

    Google Scholar 

  48. Horwitz B., Grady C.L., Schlagter N.L., Duara R., Rapoport S.I.: Intercorrelations of regional cerebral glucose metabolic rats in Alzheimer’s disease. Brain Res. 407: 294–306, 1987.

    Article  PubMed  CAS  Google Scholar 

  49. Rapoport S.I., Horwitz B., Haxby J., Grady C.L.: Alzheimer’s disease: Metabolic uncoupling of associative brain regions. Can. J. Neurol Sci. 13: 540–545, 1986.

    PubMed  CAS  Google Scholar 

  50. Kanfer J.N., McCartney D.G.: Phosphatase and Phospholipase Activity in Alzheimer Brain Tissues. In: Wurtman R.J., Corkin S., Growdn J.H., (Eds.), J. Neurol Trans. Topics in the Basic and Clinical Science of Dementia. Springer-Verlag, New York, 1987, pp. 183–188.

    Google Scholar 

  51. Nishizuka Y.: Studies and perspectives of protein kinase C. Science 233: 305–312, 1986.

    Article  PubMed  CAS  Google Scholar 

  52. Lacal J.C., Moscat J., Aaronson S.: Novel source of 1, 2-diacylglycerol elevated in cells transformed by Haras oncogene. Nature 330: 269–271, 1987.

    Article  PubMed  CAS  Google Scholar 

  53. Scheibel A.B.: Dendritic Changes in Senile and Presenile Dementias. In: Katzman R. (Ed.), Congenital and Acquired Cognitive Disorders. Raven Press, New York, 1979, pp. 107–124.

    Google Scholar 

  54. Geddes J.W., Monaghan D.T., Cotman C.W., Lott I.T., Kim R.C., Chui H.C.: Plasticity of hippocampal circuitry in Alzheimer’s disease. Science. 230: 1179–1181, 1985.

    Article  PubMed  CAS  Google Scholar 

  55. Buell S.J., Coleman P.D.: Dendritic growth in the aged human brain and failure of growth in senile dementia. Science 206: 854–856, 1979.

    Article  PubMed  CAS  Google Scholar 

  56. Buell S.J., Coleman P.D.: Quantitative evidence for selective dendritic growth in normal human aging but not in senile dementia. Brain Res. 241: 23–41, 1981.

    Article  Google Scholar 

  57. Pettegrew J.W.: Molecular Insights into Alzheimer’s Disease. In: Khachaturian Z.S., Cotman C, Pettegrew J.W. (Eds.), Calcium, Membranes, Aging and Alzheimer’s Disease. N.Y. Acad. Sci., New York, 1989 (In press).

    Google Scholar 

  58. Urry D.W., Chang D.K., Prasad K.U.: On the Mechanism whereby Phosphorylation modulates Protein Folding: Revelance to Protein Tangles and Plaques of Alzheimer’s Disease. In: Khachaturian Z.S., Cotman C., Pettigrew J.W. (Eds.), Calcium, Membranes, Aging and Alzheimer’s Disease. N.Y. Acad. Sci., New York, 1989 (In press).

    Google Scholar 

  59. Yeagle P.L.: Regulation of Membrane Function through Composition, Structure and Dynamics. In: Khachaturian Z.S., Cotman C, Pettegrew J.W. (Eds.), Calcium, Membranes, Aging and Alzheimer’s Disease. N.Y. Acad. Sci., New York, 1989 (In press).

    Google Scholar 

  60. Landfield P.W., Waymire J., Lynch G.: Hippocampal aging and adrenocorticoids: a quantitative correlation. Science 202: 1098–1101, 1978.

    Article  PubMed  CAS  Google Scholar 

  61. Landfield P.W., Baskin R., Pitler T.: Brain-aging correlates:] retardation by hormonal-pharmacological treatments. Science 214: 581–585, 1981.

    Article  PubMed  CAS  Google Scholar 

  62. Sapolsky R.M.: A mechanism for glucocorticoid toxicity in the hippocampus: Increased neuronal vulnerability of metabolic insult. J. Neurosci. 5: 1128–1332, 1985.

    Google Scholar 

  63. Sapolsky R.M.: Glucocorticoids, Hippocampal Damage and the Glutamatergic Synapse. In: Coleman P.D., Higgins G.A., Phelps C.H. (Eds.), Molecular and Cellular Mechanisms of Neuronal Plasticity in Aging and Alzheimer’s Disease. Elsevier, Amsterdam, 1989 (In press).

    Google Scholar 

  64. Sapolsky R.M.: Glucocorticoid toxicity in the hippocampus: Synergy with kainic acid. Neuroendocrinology 43: 386–392, 1986.

    Article  Google Scholar 

  65. Sapolsky R.M.: Glucocorticoid toxicity in the hippocampus: Reversal by supplementation with brain fuels. J. Neurosci. 6: 2240–2246, 1986.

    PubMed  CAS  Google Scholar 

  66. Sapolsky R.M., Armanini M., Packan D., Tombaugh G.: Stress and glucocorticoids in aging. Endocr. Metab. Clinics. 16: 965–981, 1987.

    CAS  Google Scholar 

  67. Horner H., Sapolsky R.M.: Glucocorticoids decrease glucose transport in cultured hippocampal neurons. Soc. Neurosci. Abst. 372: 11, 1988.

    Google Scholar 

  68. Kerr D., Landfield P.W.: A corticosteroid-sensitive component of the hippocampal calcium-dependent afterhyperpolarization increases with aging. Soc. Neurosci. Ab. 509.17.

  69. Hoyer S., Oesterreich K., Wagner O.: Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type. J. Neural. Transm. 75: 227–232, 1989.

    Article  PubMed  CAS  Google Scholar 

  70. Hoyer S., Nitsch R.: Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J. Neural. Transm. 75: 227–232, 1989.

    Article  PubMed  CAS  Google Scholar 

  71. Hanneberry R.C., Movelli A., Cox J.A., Lysko P.G.: Neurotoxicity at the NMDA Receptor in Energy-Compromised Neurons: an Hypothesis for Cell Death in Aging and Disease. In: Khachaturian Z.S., Cotman C, Pettegrew J.W. (Ed.), Calcium, Membranes, Aging and Alzheimer’s Disease. N Y. Acad. Sci. New York, 1989 (In press).

    Google Scholar 

  72. Hanneberry R.C., Novelli A., Vigano A., Reilly A., Lysko P.G.: Energy-related Neurotoxicity at the N-Methyl-D-Aspartate (NMDA) Receptor: A Possible Role in Neurodegenerative Diseases. In: Matsuyama S.S. (Ed.), J. Alzheimer Disease and Associated Disorders 3: 168, 1988.

  73. Kalaria R.N., Harik S.I.: Abnormalities of the glucose transporter at the blood-brain barrier and in the blood-brain barrier in Alzheimer’s disease. Alz. Dis. Assoc. Dis. 2: 238, 1988.

    Article  Google Scholar 

  74. Kalaria R.N., Karik S.I.: Reduced glucose transporter at the blood-barrier and in cerebral cortex in Alzheimer disease. J. Neurochem. (In press).

  75. Topple A., Fifkova E., Cullen-Dockstader K.: Effect of age on blood vessels and neurovascular appositions in the rate dentate fascia. Neurobiology of Aging. 1989, (In press).

  76. Choi D.W.: Calcium-mediated neurotoxicity: relationship to specific channel types and tole in ischemic damage. TINS 10: 465–469, 1988.

    Google Scholar 

  77. Choi D.W., Weiss J.H., Koh J., Christine C.W., Kurth M.C.: Glutamate Neurotoxicity, Calcium and Zinc. In: Khachaturian Z.S., Cotman C., Pettegrew J.W., (Eds.), Calcium, Membranes, Aging and Alzheimer’s Disease. N.Y. Acad. Sci. New York, 1989 (In press).

    Google Scholar 

  78. Landfield P.W.: Increased Calcium Current in Rat Hippocampal Neurons during Aging. In: Morad, Nayler, Kadza, Schramm (Eds.), The Calcium Channel: Structure, Function, and Implications. Springer-Verlag, Berlin, 1988, pp. 465–477.

    Chapter  Google Scholar 

  79. Landfield P.W., Lynch G.: Impaired monosynaptic potentiation in invitro hippocampal slices from aged, memory-deficient rats. J. Gerontol. 32: 523–533, 1977.

    Article  PubMed  CAS  Google Scholar 

  80. Landfield P.W., McGaugh J.L., Lynch G.: Impaired synaptic potentiation process in the hippocampus of aged, memory-deficient rats. Brain Res. 150: 85–101, 1978.

    Article  PubMed  CAS  Google Scholar 

  81. Landfield P.W.: Correlative Studies of Brain Neurophysiology and Behavior during Aging. In: Stein D.G. (Ed.), The Psychobiology of Aging. Elsevier, Amsterdam, 1980, pp. 227–252.

    Google Scholar 

  82. Coleman P.D., Flood D.G.: Neuron number and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol. Aging. 8: 521–545, 1987.

    Article  PubMed  CAS  Google Scholar 

  83. Coleman P.D., Flood D.G., Wadhams A., Rogers K.: Neuronal Plasticity in Normal Aging and Failed Plasticity in Alzheimer’s Disease. In: Coleman P.D., Higgins G.A., Phelps C.H. (Eds.), Molecular and Cellular Mechanisms of Neuronal Plasticity in Aging and Alzheimer’s Disease. Elsevier, Amsterdam, 1989 (In press).

    Google Scholar 

  84. Kater S.B., Mattson M.P., Guthrie P.B.: Calcium-induced neuronal degeneration: A Normal Growth Cone Regulating Signal gone Away. In: Khachaturian Z.S., Cotman C.W., Pettegrew J.W. (Eds.), Calcium, Membranes, Aging and Alzheimer’s Disease. N.Y. Acad. Sci., New York, 1989 (In press).

    Google Scholar 

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  1. Neuroscience and Neuropsychology of Aging Program, National Institute on Aging, National Institute of Health, Bldg 31, Room 5C35, Bethesda, Maryland, 20892, USA

    Zaven S. Khachaturian Ph.D

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Khachaturian, Z.S. The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging Clin Exp Res 1, 17–34 (1989). https://doi.org/10.1007/BF03323872

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