Skip to main content
PMC home page
Age logoLink to Age
. 1997 Oct;20(4):201–213. doi: 10.1007/s11357-997-0020-2

Aging and oxygen toxicity: Relation to changes in melatonin

Russel J Reiter 1
PMCID: PMC3455256  PMID: 23604322

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is a chemical mediator produced in the pineal gland and other sites in the body. The melatonin found in the blood is derived almost exclusively from the pineal gland. Since the pineal synthesizes melatonin primarily at night, blood levels of the indole are also higher at night (5–15 fold) than during the day. Some individuals on a nightly basis produce twice as much melatonin as others of the same age. Throughout life, the melatonin rhythm gradually wanes such that, in advanced age, melatonin production is usually at a minimum. Melatonin was recently found to be a free radical scavenger and antioxidant. It has been shown, in the experimental setting, to protect against both free radical induced DNA damage and oxidative stress-mediated lipid peroxidation. Pharmacologically, melatonin has been shown to reduce oxidative damage caused by such toxins as the chemical carcinogen safrole, carbon tetrachloride, paraquat, bacterial lipopolysaccharide, kainic acid, δ-aminolevulinic and amyloid β peptide of Alzheimer’s disease as well as a model of Parkinson’s disease involving the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Additionally, the oxidative damage caused by agents such as ionizing radiation and excessive exercise is reduced by melatonin. Since free radical-induced molecular injury may play a significant role in aging, melatonin’s ability to protect against it suggests a potential function of melatonin in deferring aging and age-related, free radical-based diseases. Besides its ability to abate oxidative damage, other beneficial features of melatonin may be important in combating the signs of aging; these include melatonin’s immune-stimulating function, its sleep-promoting ability, its function as an anti-viral agent, and general protective actions at the cellular level. Definitive tests of the specific functions of physiological levels of melatonin in processes of aging are currently being conducted.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

References

  • 1.Harman D. Aging: A theory based on free radicals and radiation chemistry. J. Gerontol. 1956;11:298–300. doi: 10.1093/geronj/11.3.298. [DOI] [PubMed] [Google Scholar]
  • 2.Harman D. Free radical theory of aging: Origin of life, evolution, and aging. Age. 1980;3:100–102. doi: 10.1007/BF02432267. [DOI] [Google Scholar]
  • 3.Hayflick L. Theories of biological aging. Exp. Gerontol. 1985;20:145–159. doi: 10.1016/0531-5565(85)90032-4. [DOI] [PubMed] [Google Scholar]
  • 4.Rose M.R. The Evolutionary Biology of Aging. New York: Oxford; 1991. [Google Scholar]
  • 5.Harman D. Free radical theory of aging: The “free radical” related diseases. Age. 1983;7:111–131. doi: 10.1007/BF02431866. [DOI] [Google Scholar]
  • 6.Harman D. The aging process: Major risk factor for disease and death. Proc. Natl. Acad. Sci. USA. 1991;88:5360–5633. doi: 10.1073/pnas.88.12.5360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Kehrer J.P. Free radicals, mediators of tissue injury and disease. Crit. Rev. Toxicol. 1993;23:21–48. doi: 10.3109/10408449309104073. [DOI] [PubMed] [Google Scholar]
  • 8.Ames B.N., Shigenaga M.K. Oxidants are a major contributor to cancer and aging. In: Halliwell H., Aruoma O., editors. DNA and Free Radicals. London: Ellis Harwood; 1993. pp. 1–18. [Google Scholar]
  • 9.Reiter R.J., Tan D.X., Poeggeler B., Menendez-Pelaez A., Chen L.C., Saarela S. Melatonin as a free radical scavenger: Implications for aging and age-related diseases. Ann. N.Y. Acad. Sci. 1994;719:1–12. doi: 10.1111/j.1749-6632.1994.tb56817.x. [DOI] [PubMed] [Google Scholar]
  • 10.Reiter R.J. Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J. 1995;9:526–533. [PubMed] [Google Scholar]
  • 11.Halliwell B., Gutteridge J.M.C. Oxygen toxicity, oxygen radicals, transitional metals and disease. Biochem. J. 1984;219:1–14. doi: 10.1042/bj2190001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Kehrer J.P., Smith C.V. Free radicals in biology: Sources, reactivities and roles in the etiology of human disease. In: Frei B., editor. Natural Antioxidants in Human Health and Disease. San Diego: Academic Press; 1994. pp. 25–62. [Google Scholar]
  • 13.Sies H. Strategies of antioxidative defense. Eur. J. Biochem. 1993;215:213–219. doi: 10.1111/j.1432-1033.1993.tb18025.x. [DOI] [PubMed] [Google Scholar]
  • 14.McCord J.M., Omar B.A. Sources of free radicals. Toxicol. Indust. Health. 1993;9:23–37. doi: 10.1177/0748233793009001-204. [DOI] [PubMed] [Google Scholar]
  • 15.Fridovich I. Superoxide dismutases: An adaptation to a paramagnetic gas. J. Biol. Chem. 1989;264:7761–7764. [PubMed] [Google Scholar]
  • 16.Tyler D.D. Polargraphic assay and intracellular distribution of superoxide dismutase in rat liver. Biochem. J. 1975;147:493–504. doi: 10.1042/bj1470493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Curnutte J.T., Babior B.M. Chronic granulomatous disease. Adv. Human Genet. 1987;16:229–297. doi: 10.1007/978-1-4757-0620-8_4. [DOI] [PubMed] [Google Scholar]
  • 18.Colton C.A., Gilbert D.L. Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett. 1987;223:284–288. doi: 10.1016/0014-5793(87)80305-8. [DOI] [PubMed] [Google Scholar]
  • 19.Schreck R., Bauerle R.A. A role for oxygen radicals as second messengers. Trends Cell Biol. 1991;1:39–42. doi: 10.1016/0962-8924(91)90072-H. [DOI] [PubMed] [Google Scholar]
  • 20.Fridovich I. The biology of oxygen radicals. Science. 1978;201:875–880. doi: 10.1126/science.210504. [DOI] [PubMed] [Google Scholar]
  • 21.Diplock A.T. Antioxidants and free radical scavengers. In: Rice-Evans C.A., Burdan R.H., editors. Free Radical Damage and its Control. Amsterdam: Elsevier; 1994. pp. 113–130. [Google Scholar]
  • 22.Lejeune J. Pathogenesis of mental deficiency in Parkinson’s disease. J. Med. Genet. 1990;7(Suppl.):20–30. doi: 10.1002/ajmg.1320370705. [DOI] [PubMed] [Google Scholar]
  • 23.Bowling A.C., Schulz J.B., Brown R.H., Jr., Beal M.F. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J. Neurochem. 1993;61:2322–2325. doi: 10.1111/j.1471-4159.1993.tb07478.x. [DOI] [PubMed] [Google Scholar]
  • 24.Olanow C.W. Oxidative reactions in Parkinson’s disease. Neurology. 1990;40(Suppl.3):32–37. [PubMed] [Google Scholar]
  • 25.Boveris A., Oshino N., Chance B. The cellular production of hydrogen peroxide. Biochem. J. 1972;128:617–630. doi: 10.1042/bj1280617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Chance B., Sies H., Boveris A. Hydroperoxide metabolism in mammalian organs. Physical Rev. 1979;59:527–605. doi: 10.1152/physrev.1979.59.3.527. [DOI] [PubMed] [Google Scholar]
  • 27.Jain A., Martensson J., Stole E., Auld P.A.M., Meister A. Glutathione deficiency leads to mitochondrial damage in brain. Proc. Nat. Acad. Sci. USA. 1991;88:1913–1917. doi: 10.1073/pnas.88.5.1913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Gerschmann R., Gilbert D.L., Nye S.W., Dwyer P., Fenn W.O. Oxygen poisoning and X-irradiation: A mechanism in common. Science. 1954;119:623–626. doi: 10.1126/science.119.3097.623. [DOI] [PubMed] [Google Scholar]
  • 29.Moncada S., Palmer R.M.I., Higgs E.A. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol. Rev. 1991;43:109–142. [PubMed] [Google Scholar]
  • 30.Radi R., Bedsman J.S., Buch K.M., Freeman B.A. Peroxynitrite oxidation by sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J. Biol. Chem. 1991;266:4244–4250. [PubMed] [Google Scholar]
  • 31.Van der Vliet M., O’Neill C.A., Halliwell B., Cross C.E., Kaun H. Aromatic hydroxylation and nitration of phenylalanine and tyrosine by peroxynitrite: Evidence for hydroxyl radical production from peroxynitrite. FEBS Lett. 1994;339:89–92. doi: 10.1016/0014-5793(94)80391-9. [DOI] [PubMed] [Google Scholar]
  • 32.Laurindo F.R.M., de Luz P.L., Uint L., Rocha T.F., Jaeger R.G., Lopes E.A. Evidence for superoxide radical-dependent coronary vasopasm after angioplasty in intact dogs. Circulation. 1991;83:1705–1715. doi: 10.1161/01.cir.83.5.1705. [DOI] [PubMed] [Google Scholar]
  • 33.Spector A. The lens and oxidative stress. In: Sies H., editor. Oxidative Stress, Oxidants and Antioxidants. San Diego: Academic Press; 1993. pp. 529–558. [Google Scholar]
  • 34.Wendel A., Niehorster M., Tregs G. Interactions between reactive oxygen and mediators of sepsis and shock. In: Sies H., editor. Oxidative Stress, Oxidants and Antioxidants. San Diego: Academic Press; 1993. pp. 685–594. [Google Scholar]
  • 35.Schwartz C.J., Valente A.J. The pathogenesis of atherosclerosis. In: Frei B., editor. Natural Antioxidants in Human Health and Disease. San Diego: Academic Press; 1994. pp. 287–302. [Google Scholar]
  • 36.Poeggeler B., Reiter R.J., Tan D.X., Chen L.D., Manchester L.C. Melatonin, hydroxyl radical-mediated oxidative damage and aging. J. Pineal Res. 1993;14:151–158. doi: 10.1111/j.1600-079X.1993.tb00498.x. [DOI] [PubMed] [Google Scholar]
  • 37.Harman D. Free radical theory of aging: Alzheimer’s disease pathogenesis. Age. 1995;18:97–119. doi: 10.1007/BF02436085. [DOI] [Google Scholar]
  • 38.Harman D. Free-radicals and age-related diseases. In: Yu B.P., editor. Free Radicals and Aging. Boca Taton: CRC Press; 1993. pp. 205–222. [Google Scholar]
  • 39.Shigenaga, M.K., Ames, B.N.: Oxidants and mitochondrial decay in aging, in Natural Antioxidants in Human Health and Disease, edited by Frei, B., 1994, pp. 63–106.
  • 40.McCay C.M., Crowell M.F., Manard L.A. The effect of retarded growth upon the length of life-span and upon ultimate body size. J. Nutr. 1935;10:63–75. [PubMed] [Google Scholar]
  • 41.Kristal B.S., Yu B.P. Aging and its modulation by dietary restriction. In: Yu B.P., editor. Modulation of Aging Processes by Dietary Restriction. Boca Raton: CRC Press; 1994. pp. 1–36. [Google Scholar]
  • 42.Keaney J.F., Jr., Frei B. Antioxidant protection of low-density lipoprotein and its role in the prevention of atherosclerotic vascular disease. In: Frei B., editor. Natural Antioxidants in Human Health and Disease. San Diego: Academic Press; 1994. pp. 303–354. [Google Scholar]
  • 43.Byers, T., Guerrero, N.: Epidemiologic evidence for vitamin C and E in cancer prevention. Am. J. Clin. Nutr. 62(Suppl): 13855–13935, 1995. [DOI] [PubMed]
  • 44.Brivba K., Sies H. Non enzymatic antioxidant defense systems. In: Frei B., editor. Natural Antioxidants in Human Health and Disease. San Diego: Academic Press; 1994. pp. 107–128. [Google Scholar]
  • 45.Niki, E., Noguchi, N., Tsuchihashi, H., Gotoh, N.: Interaction among vitamin C, vitamin E, and β-carotene. Am. J. Clin. Nitr. 62(Suppl): 1322S–1326S, 1995. [DOI] [PubMed]
  • 46.Matsuo M. Age-related alterations in antioxidant defense. In: Yu B.P., editor. Free Radicals and Aging. Boca Raton: CRC Press; 1993. pp. 143–182. [Google Scholar]
  • 47.Reiter R.J., Melchiorri D., Sewerynek E., Poeggeler B., Barlow-Walden L.R., Chuang J.I., Ortiz G.G., Acuña-Castroviejo D. A review of the evidence supporting melatonin’s role as an antioxidant. J. Pineal Res. 1995;18:1–11. doi: 10.1111/j.1600-079X.1995.tb00133.x. [DOI] [PubMed] [Google Scholar]
  • 48.Ianas O., Olnescu R., Badescu I. Melatonin involvement in oxidative stress. Rom. J. Endocrinol. 1991;29:147–153. [PubMed] [Google Scholar]
  • 49.Tan D.X., Chen L.D., Poeggeler B., Manchester L.C., Reiter R.J. Melatonin: A potent, endogenous hydroxyl radical scavenger. Endocrine J. 1993;1:57–60. [Google Scholar]
  • 50.Sies, H., Stahl, W.: Vitamins E and C, β-carotene, and other carotenoids as antioxidants. Am. J. Clin. Nutr. 62(Suppl.): 1315S–1321S, 1995. [DOI] [PubMed]
  • 51.Pieri, C., Marra, M., Moroni, F., Recchioni, R., Marcheselli, F.: Melatonin: A peroxyl radical scavenger more effective than vitamin E. Life Sci. 55: PL271–PL27, 1994. [DOI] [PubMed]
  • 52.Pieri C., Moroni M., Marra M., Marcheselli F., Recchioni R. Melatonin as an efficient antioxidant. Arch. Gerontol. Geriatr. 1995;20:159–165. doi: 10.1016/0167-4943(94)00593-V. [DOI] [PubMed] [Google Scholar]
  • 53.Scaiano J.C. Exploratory laser flash photolysis study of free radical reactions and magnetic field effects in melatonin chemistry. J. Pineal Res. 1995;19:189–195. doi: 10.1111/j.1600-079X.1995.tb00188.x. [DOI] [PubMed] [Google Scholar]
  • 54.Marshall K.A., Reiter R.J., Poeggeler B., Auroma O.I., Halliwell B. Evaluation of the antioxidant activity of melatonin in vitro. Free Rad. Biol. Med. 1996;21:307–315. doi: 10.1016/0891-5849(96)00046-9. [DOI] [PubMed] [Google Scholar]
  • 55.Chan T.Y., Tang P.C. Characterization of the antioxidant effects of melatonin and related indoleamines in vitro. J. Pineal Res. 1996;20:187–191. doi: 10.1111/j.1600-079X.1996.tb00257.x. [DOI] [PubMed] [Google Scholar]
  • 56.Reiter R.J. Oxygen radical detoxification processes during aging: The functional importance of melatonin. Aging Clin. Exp. Res. 1995;7:340–351. doi: 10.1007/BF03324344. [DOI] [PubMed] [Google Scholar]
  • 57.Reiter R.J. Antioxidant actions of melatonin. Adv. Pharmacol. 1997;38:103–117. doi: 10.1016/S1054-3589(08)60981-3. [DOI] [PubMed] [Google Scholar]
  • 58.Reiter R.J., Pablos M.I., Agapito T.T., Guerrero J.M. Melatonin in the context of the free radical theory of aging. Ann. N.Y. Acad. Sci. 1996;786:362–378. doi: 10.1111/j.1749-6632.1996.tb39077.x. [DOI] [PubMed] [Google Scholar]
  • 59.Pierrefiche G., Laborit H. Oxygen radicals, melatonin and aging. Exp. Gerontol. 1995;30:213–227. doi: 10.1016/0531-5565(94)00036-3. [DOI] [PubMed] [Google Scholar]
  • 60.Sewerynek E., Melchiorri D., Chen L.D., Reiter R.J. Melatonin reduces both basal and bacterial lipopolysaccaride-induced lipid peroxidation in vitro. Free Rad. Biol. Med. 1995;19:903–909. doi: 10.1016/0891-5849(95)00101-3. [DOI] [PubMed] [Google Scholar]
  • 61.Daniels W.M.U., Reiter R.J., Melchiorri D., Sewerynek E., Pablos M.I., Ortiz G.G. Melatonin counteracts lipid peroxidation induced by carbon tetrachloride but does not restore glucose-6-phosphatase activity. J. Pineal Res. 1995;19:1–6. doi: 10.1111/j.1600-079X.1995.tb00164.x. [DOI] [PubMed] [Google Scholar]
  • 62.Melchiorri D., Reiter R.J., Attia A.M., Hara M., Burgos A., Nistico G. Potent portective effect of melatonin on in vivo paraquat induced oxidative damage in rats. Life Sci. 1995;56:83–89. doi: 10.1016/0024-3205(94)00417-Q. [DOI] [PubMed] [Google Scholar]
  • 63.Tan D.X., Poeggeler B., Reiter R.J., Chen L.D., Chert S., Manchester L.C., Barlow-Walden L.R. The pineal hormone melatonin inhibits DNA adduct formation induced by the carcinogen safrolein vivo. Cancer Lett. 1993;70:65–71. doi: 10.1016/0304-3835(93)90076-L. [DOI] [PubMed] [Google Scholar]
  • 64.Tan D.X., Reiter R.J., Chen L.D., Poeggeler B., Manchester L.C., Barlow-Walden L.R. Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole. Carcinogenesis. 1994;15:215–218. doi: 10.1093/carcin/15.2.215. [DOI] [PubMed] [Google Scholar]
  • 65.Vijayalaxmi, Reiter R.J., Sewerynek E., Poeggeler B., Leal B.Z., Meltz M. Marked reduction of radiation-induced micronuclei in human blood lymphoocytes pretreated with melatonin. Radiat. Res. 1995;143:102–106. doi: 10.2307/3578932. [DOI] [PubMed] [Google Scholar]
  • 66.Cagnoli C.M., Atabay C., Kharlamov E., Mavez H. Melatonin protects neurons from singlet oxygen-induced apoptosis. J. Pineal Res. 1995;18:222–226. doi: 10.1111/j.1600-079X.1995.tb00163.x. [DOI] [PubMed] [Google Scholar]
  • 67.Abe M., Reiter R.J., Orhii P.B., Hara M., Poeggeler B. Inhibitory effect of melatonin on cataract formation in newborn rats: Evidence for an antioxidative role for melatonin. J. Pineal Res. 1994;17:94–100. doi: 10.1111/j.1600-079X.1994.tb00119.x. [DOI] [PubMed] [Google Scholar]
  • 68.Menendez-Pelaez A., Poeggeler B., Reiter R.J., Barlow-Walden L.R., Pablos M.I., Tan D.X. Nuclear localization of melatonin in different mammalian tissues: Immunocytochemical and radioimmunoassay evidence. J. Cell. Biochem. 1993;53:372–382. doi: 10.1002/jcb.240530415. [DOI] [PubMed] [Google Scholar]
  • 69.Costa E.J. X., Harzer Lopez R., Lamy-Freund M.T. Permeability of pure lipid bilayers to melatonin. J. Pineal Res. 1995;19:123–126. doi: 10.1111/j.1600-079X.1995.tb00180.x. [DOI] [PubMed] [Google Scholar]
  • 70.Shida C.S., Castrucci A.M.L., Lamy-Freund M.T. High melatonin solubility in water. J. Pineal Res. 1994;16:198–201. doi: 10.1111/j.1600-079X.1994.tb00102.x. [DOI] [PubMed] [Google Scholar]
  • 71.Giusti P., Gusella M., Lipartiti M., Milani D., Zhu W., Vicini S., Manev H. Melatonin protects primary cultures of cerebellar granule neurons from kainate but not from N-methyl-D-aspartate excitotoxicity. Exp. Neurol. 1995;133:39–46. doi: 10.1016/0014-4886(95)90005-5. [DOI] [PubMed] [Google Scholar]
  • 72.Melchiorri D., Reiter R.J., Sewerynek E., Chen L.D., Nistico G. Melatonin reduces kainate induced lipid peroxidation in homogenates of different brain regions. FASEB J. 1995;9:1205–1210. doi: 10.1096/fasebj.9.12.7672513. [DOI] [PubMed] [Google Scholar]
  • 73.Giusti P., Lipartiti M., Franeschini D., Schiavo N., Floreani M., Manev H. Neuroprotection by melatonin from kainate-induced excitotoxicity in rats. FASEB J. 1996;10:891–896. doi: 10.1096/fasebj.10.8.8666166. [DOI] [PubMed] [Google Scholar]
  • 74.Chen L.D., Melchiorri D., Sewerynek E., Reiter R.J. Retinal lipid peroxidation in vitro is inhibited by melatonin. Neurosci. Res. Commun. 1995;17:151–158. [Google Scholar]
  • 75.Sewerynek E., Melchiorri D., Ortiz G.G., Poeggeler B., Reiter R.J. Melatonin reduces H2O2 induced lipid peroxidation in homogenates of different rat brain regions. J. Pineal Res. 1995;19:51–56. doi: 10.1111/j.1600-079X.1995.tb00170.x. [DOI] [PubMed] [Google Scholar]
  • 76.Yamamoto H.A., Tang H.W. Preventive effect of melatonin against cyanide-induced seizures and lipid peroxidation in mice. Neurosci. Lett. 1996;207:89–92. doi: 10.1016/0304-3940(96)12493-9. [DOI] [PubMed] [Google Scholar]
  • 77.Sewerynek E., Abe M., Reiter R.J., Barlow-Walden L.R., Chen L.D., McCabe T.J., Roman L.J., Diaz-Lopez B. Melatonin administration prevents lipopolysaccharide-induced oxidative damage in phenobarbital treated rats. J. Cell. Biochem. 1995;58:436–444. doi: 10.1002/jcb.240580406. [DOI] [PubMed] [Google Scholar]
  • 78.Sewerynek E., Melchorri D., Reiter R.J., Ortiz G.G., Lewinski A. Lipopolysaccaride-induced hepatotoxicity is inhibited by the antioxidant melatonin. Eur. J. Pharmacol. 1995;293:327–344. doi: 10.1016/S0014-2999(95)80090-5. [DOI] [PubMed] [Google Scholar]
  • 79.Sokol R.J., Devereaux M.W., Straka M.S., Everson G. Melatonin attenuates hydrophobic bile acid toxicity to isolated rat hepatocytes. Hepatology (Suppt) 1996;24(4pt.2):338A. [Google Scholar]
  • 80.Vijayalaxmi, Reiter R.J., Meltz M. Melatonin protects human blood lymphocytes from radiation-induced chromosome damage. Mut. Res. 1995;346:23–31. doi: 10.1016/0165-7992(95)90065-9. [DOI] [PubMed] [Google Scholar]
  • 81.Bertuglia S., Marchiafava P.L., Colantuoni A. Melatonin prevents ischemia reperfusion injury in hamster cheek pouch microcirculation. Cardiovasc. Res. 1996;31:947–952. doi: 10.1016/0008-6363(96)00030-2. [DOI] [PubMed] [Google Scholar]
  • 82.Sewerynek E., Reiter R.J., Melchiorri D., Ortiz G.G., Lewinski A. Oxidative damage in the liver induced by ischemia-reperfusion: Protection by melatonin. Hepato-Gastroenterology. 1996;43:898–903. [PubMed] [Google Scholar]
  • 83.Manev H., Uz T., Kharlamov, Joo J.Y. Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J. 1996;10:1546–1551. doi: 10.1096/fasebj.10.13.8940301. [DOI] [PubMed] [Google Scholar]
  • 84.Acuña-Castroviejo D., Coto-Montes A., Monti M.G., Ortiz G.G., Reiter R.J. Melatonin is protective against MPTP-induced striatal and hippocampal lesions. Life Sci. 1996;60:PL23–PL29. doi: 10.1016/S0024-3205(96)00606-6. [DOI] [PubMed] [Google Scholar]
  • 85.Iacoviti, L., Johnston, K., Stull, M.D.: Melatonin rescues developing and/or MPP+ damaged dopamine neurons from cell death in culture. Abst. 26th Ann. Mtg. Soc. Neurosci. 22(pt.1): 742, 1996.
  • 86.Pappolla M.A., Sos M., Bick R.J., Omar R.A., Hickson-Bick D.L.M., Reiter R.J., Efthimiopoulos S., Sambamurti K., Robakis N.K. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J. Neurosci. 1997;17:1683–1690. doi: 10.1523/JNEUROSCI.17-05-01683.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Richardson J.S., Zhou Y. Oxidative stress in the production and expression of neurotoxic b-amyloid. Restor. Neurol. Neurosci. 1996;9:207–211. doi: 10.3233/RNN-1996-9402. [DOI] [PubMed] [Google Scholar]
  • 88.Reiter R.J. Pineal function during aging: Attenuation of the melatonin rhythm and its neurobiological consequences. Acta Neurobiol. Exp. 1994;54(Suppl.):31–39. [PubMed] [Google Scholar]
  • 89.Reiter R.J. The pineal gland and melatonin in relation to aging: A summary of the theories and of the data. Exp. Gerontol. 1995;30:199–212. doi: 10.1016/0531-5565(94)00045-5. [DOI] [PubMed] [Google Scholar]
  • 90.Reiter R.J. The aging pineal gland and its physiological consequences. Bio Essays. 1992;14:169–175. doi: 10.1002/bies.950140307. [DOI] [PubMed] [Google Scholar]
  • 91.Touitou Y., Fevre M., Lagugvey M., Carayon A., Boydon A., Reinhart A. Age and mental health related circadian rhythms of plasma levels of melatonin, prolactin, luteinizing hormone and follicle stimulating hormone. J. Endocrinol. 1981;91:467–475. doi: 10.1677/joe.0.0910467. [DOI] [PubMed] [Google Scholar]
  • 92.Iguchi H., Kato K., Ibayashi H. Age-dependent reduction is serum melatonin concentrations in healthy human subjects. J. Clin. Endocrinol. Metab. 1982;55:27–19. doi: 10.1210/jcem-55-1-27. [DOI] [PubMed] [Google Scholar]
  • 93.Nair N.P.V., Haribarasubramanian N., Pilapil C., Isaac I., Thavundayil J.X. Plasma melatonin-An index of brain aging in humans? Biol. Psychiatry. 1986;21:141–150. doi: 10.1016/0006-3223(86)90141-1. [DOI] [PubMed] [Google Scholar]
  • 94.Sack R.L., Lewy A.J., Erb D.L., Vollmer W.M., Singer C.M. Human melatonin production decreases with age. J. Pineal Res. 1986;3:379–388. doi: 10.1111/j.1600-079X.1986.tb00760.x. [DOI] [PubMed] [Google Scholar]
  • 95.Reiter R.J., Craft C.M., Johnson J.E., Jr., King T.S., Richardson B.A., Vaughan G.M., Vaughan M.K. Age-associated reduction in nocturnal melatonin levels in female rats. Endocrinology. 1981;109:1295–1297. doi: 10.1210/endo-109-4-1295. [DOI] [PubMed] [Google Scholar]
  • 96.Pang S.F., Tang F., Tang P.L. Negative correlations of age and levels of pineal melatonin, pineal N-acetylserotonin and serum melatonin in male rats. J. Exp. Zool. 1984;229:41–47. doi: 10.1002/jez.1402290106. [DOI] [PubMed] [Google Scholar]
  • 97.Reiter R.J., Johnson L.Y., Steger R.W., Richardson B.A., Petterborg L.J. Pineal biosynthetic activity and neuroendocrine physiology in the aging hamster and gerbil. Peptides (Suppl. 1) 1980;1:69–77. doi: 10.1016/0196-9781(80)90104-7. [DOI] [Google Scholar]
  • 98.Reiter R.J., Richardson B.A., Johnson L.Y., Ferguson B.N., Dinh D.T. Pineal melatonin rhythm: Reduction in aging Syrian hamsters. Science. 1980;210:1372–1373. doi: 10.1126/science.7434032. [DOI] [PubMed] [Google Scholar]
  • 99.Reiter R.J., Vriend J., Brainard G.C., Matthews S.A., Craft C.M. Reduced pineal and plasma melatonin levels and gonadal atrophy in old hamsters kept under winter photoperiods. Exp. Aging Res. 1982;8:27–30. [Google Scholar]
  • 100.Wetterberg L. Genetic regulation of melatonin excretion in urine. Clin. Genet. 1983;24:399–402. doi: 10.1111/j.1399-0004.1983.tb00093.x. [DOI] [PubMed] [Google Scholar]
  • 101.Waldhauser F., Ehrhart B., Förster E. Clinical aspects of the melatonin action: Impact on development, aging and puberty, involvement of melatonin in psychiatric diseases and importance of neuroimmunoendocrine interactions. Experientia. 1993;49:671–681. doi: 10.1007/BF01923949. [DOI] [PubMed] [Google Scholar]
  • 102.Maestroni G.J.M. The immunoneuroendocrine role of melatonin. J. Pineal Res. 1993;14:1–10. doi: 10.1111/j.1600-079X.1993.tb00478.x. [DOI] [PubMed] [Google Scholar]
  • 103.Masoro E.J. Food restriction in rodents: An evaluation of its role in aging. J. Gerontol. 1988;43:B59–B64. doi: 10.1093/geronj/43.3.b59. [DOI] [PubMed] [Google Scholar]
  • 104.Stokkan K.A., Reiter R.J., Nonaka K.O., Lerchl A., Yu B.P., Vaughan M.K. Food restriction retards aging of the pineal gland. Brain Res. 1991;545:66–72. doi: 10.1016/0006-8993(91)91270-B. [DOI] [PubMed] [Google Scholar]
  • 105.Henden T., Stokkan K.A., Reiter R.J., Nonaka K.O., Lerchl A., Jones D.J. The age-associated reduction in pineal β-adrenergic receptor density is prevented by life-long food restriction in rats. Biol. Signals. 1992;1:34–39. doi: 10.1159/000109343. [DOI] [PubMed] [Google Scholar]
  • 106.Axelrod J. The pineal gland: A neurochemical transducer. Science. 1974;184:1341–1349. doi: 10.1126/science.184.4144.1341. [DOI] [PubMed] [Google Scholar]
  • 107.Reiter R.J., Barlow-Walden L.R., Poeggeler B., Heiden S.M., Clayton R.J. Twenty-four hour urinary excretion of 6-hydroxymelatonin sulfate in Down syndrome subjects. J. Pineal Res. 1996;20:45–50. doi: 10.1111/j.1600-079X.1996.tb00238.x. [DOI] [PubMed] [Google Scholar]
  • 108.Street C.A., Di W.L., Peneston-Bird J.F., Patel S., Sadler P., Silman R.E. The purification and characterization of biological 6-sulfatoxymelatonin and comparison with synthetic 6-sulfatoxy-melatonin. J. Pineal Res. 1996;20:98–114. doi: 10.1111/j.1600-079X.1996.tb00246.x. [DOI] [PubMed] [Google Scholar]
  • 109.Medeiros M.H.G., Marchiori P.E., Bechara E.J.H. Superoxide dimutase, glutathione peroxidase and catalase activities in the erythrocytes of patients with intermittent acute porphyria. Clin. Chem. 1985;31:1673–1676. [PubMed] [Google Scholar]
  • 110.Puy, H., Reybach, J.C., Baudry, P., Callebert, J., Touitou, Y., Nordmann, Y.: Decreased nocturnal plasma melatonin levels in patients with recurrent acute intermittent porphyria attacks. Life Sci. 53:621–627. [DOI] [PubMed]
  • 111.Puy H., Deyback J.C., Bogdan A., Collebert J., Baumgarter M., Voisin P., Nordmann Y., Touitou Y. Increased δ-aminolevulinic acid and decreased pineal melatonin production: A common event in acute porphyria studies in the rat. J. Clin. Invest. 1996;53:104–111. doi: 10.1172/JCI118376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Pappolla, M.A., Omar, R.A., Kim, K.S., Robakis, N.K.: Immunohistochemical evidence of oxidative stress in Alzheimer’s disease. Am. J. Pathol. 140:621–628. [PMC free article] [PubMed]
  • 113.Harris M.E., Hensley K., Butterfield D.A., Leedle R.A., Carney J.M. Direct evidence of oxidative injury produced by the Alzheimer’s beta-amyloid (1–40) peptide in cultured hippocampus neurons. Exp. Neurol. 1995;131:193–202. doi: 10.1016/0014-4886(95)90041-1. [DOI] [PubMed] [Google Scholar]
  • 114.Adams J.D., Odunze I.N. Oxygen free radicals and Parkinson’s disease. Free Rad. Biol. Med. 1991;10:161–169. doi: 10.1016/0891-5849(91)90009-R. [DOI] [PubMed] [Google Scholar]
  • 115.Olanow C.W. An introduction to the free radical hypothesis in Parkinson’s disease. Ann. Neurol. 1992;32:S2–S9. doi: 10.1002/ana.410320703. [DOI] [PubMed] [Google Scholar]
  • 116.Pappolla M., Sos M., Bick R.J., Omar R.A., Hickson-Bick D.L.M., Reiter R.J., Efthimiopoulos S., Sambamurrti K., Robakis N.K. Oxidative damage and cell death induced by amyloid peptide fragment is completely prevented by melatonin. In: Igbal K., Winkblad B., Nishimura T., Takeda M., Wisniewski H.M., editors. Alzheimer’s Disease: Biology, Diagnosis and Therapeutics. New York: John Wiley; 1997. pp. 741–749. [Google Scholar]
  • 117.Sainz R.M., Mayo J.C., Aria H., Kotler M., Antolin I., Rodriquez C., Menendez-Pelaez A. The pineal neurohormone melatonin prevents in vivo and in vitro apoptosis in thymocytes. J. Pineal Res. 1995;19:178–188. doi: 10.1111/j.1600-079X.1995.tb00187.x. [DOI] [PubMed] [Google Scholar]
  • 118.Skene D.J., Vivien-Roels B., Sparks D.L., Hunsaker J.C., Pevet P., Ravid D., Swaab D.F. Daily variation in the concentration of melatonin and 5-methoxytryplophol in the human pineal gland: Effect of age and Alzheimer’s disease. Brain Res. 1990;528:170–174. doi: 10.1016/0006-8993(90)90214-V. [DOI] [PubMed] [Google Scholar]
  • 119.Miller J.W., Selhub J., Joseph J.A. Oxidative damage caused by free radicals produced during catecholamine autooxidation: Protective effect of 0-methylation and melatonin. Free Radical Biol. Med. 1996;21:241–249. doi: 10.1016/0891-5849(96)00033-0. [DOI] [PubMed] [Google Scholar]
  • 120.Sundstrom E., Stromberg I., Tsutsumi T., Olson L., Jonsson G. Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57BI/6 mice: Comparison with three other strains of mice. Brain Res. 1987;805:26–38. doi: 10.1016/0006-8993(87)90986-3. [DOI] [PubMed] [Google Scholar]
  • 121.Rojas P., Rios C. Increased striatal lipid peroxidation after intracerebroventricular MPP+ administration to mice. Pharmacol. Toxicol. 1993;72:364–368. doi: 10.1111/j.1600-0773.1993.tb01345.x. [DOI] [PubMed] [Google Scholar]
  • 122.Armstrong S.M., Redman J.R. Melatonin and circadian rhythmicity. In: Yu H.S., Reiter R.J., editors. Melatonin. Boca Raton: CRC Press; 1993. pp. 187–224. [Google Scholar]
  • 123.Dawson P., Encel N. Melatonin and sleep in humans. J. Pineal Res. 1993;15:1–12. doi: 10.1111/j.1600-079X.1993.tb00503.x. [DOI] [PubMed] [Google Scholar]
  • 124.Acuña-Castroviejo D., Escames G., Macias M., Muñoz-Hoyos A., Molina Carbello A., Arauzo M., Montes R., Vines F. Cell protective role of melatonin in the brain. J. Pineal Res. 1995;19:56–63. doi: 10.1111/j.1600-079x.1995.tb00171.x. [DOI] [PubMed] [Google Scholar]
  • 125.Ben-Nathan D., Maestroni G.J.M., Lustig S., Conti A. Protective effects of melatonin in mice infected with encychalitis viruses. Arch. Virol. 1995;140:223–230. doi: 10.1007/BF01309858. [DOI] [PubMed] [Google Scholar]
  • 126.Ellis L.C. Melatonin reduces mortality from Aleutian disease in mink (Mustela vison) J. Pineal Res. 1996;21:214–217. doi: 10.1111/j.1600-079X.1996.tb00288.x. [DOI] [PubMed] [Google Scholar]

Articles from Age are provided here courtesy of American Aging Association

RESOURCES