The results of studies on the effect of pineal indole hormone melatonin on the life span of mice, rats, fruit flies, and worms are critically reviewed. In mice, long-term administration of melatonin was followed by an increase in their life span in 12 experiments and had no effect in 8 of 20 different experiments. In D. melanogaster , the supplementation of melatonin to the nutrient medium during developmental stages gave contradictory results, but when melatonin was added to food throughout the life span, an increase in the longevity of fruit flies has been observed. Melatonin decreased the survival of C. elegans but increased the clonal life span of planaria Paramecium tertaurelia. Available data suggest antioxidant and atherogenic effects of melatonin. Melatonin alone turned out to be neither toxic nor mutagenic in the Ames test and revealed clastogenic activity in high concentration in the COMET assay. Melatonin inhibits mutagenesis induced by irradiation and by indirect chemical mutagens and inhibits the development of spontaneous and chemical-induced tumors in mice and rats. Further studies and clinical trials are needed to verify that melatonin is both safe and has geroprotector efficacy for humans.
Amherd R., Hintermann E., Walz D., Affolter M., Meyer UA (2000). Purification, cloning, and characterization of a second arylalkylamine N-acetyltransferase from Drosophila melanogaster. DNA Cell Biol19: 697—705.
2.
Anisimov SV, Boheler KR, Anisimov VN (2002). Microarray technology in studying the effect of melatonin on gene expression in the mouse heart. Dokl BiolSci383: 90—95.
3.
Anisimov VN (2001). Life span extension and cancer risk: myths and reality. Exp Geront36: 1101—1136.
4.
Anisimov VN (2001a). Melatonin and colon carcinogenesis. In: The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy , C Bartsch, H Bartsch, DE Blask, DP Cardinali, WJM Hrushesky , D Mecke (eds). Springer, Berlin, pp 240—258.
5.
Anisimov VN (2003). The relationship between aging and carcinogenesis . Crit Rev Oncol Hematol45: 277—304.
6.
Anisimov VN, Arutjunyan AV, Khavinson VKh (1996). Melatonin and epithalamin inhibit lipid peroxidation in rats. Dokl Russ Akad Nauk348: 765—767.
7.
Anisimov VN, Arutjunyan AV, Khavinson VKh (1997). Effects of melatonin and epithalamin on activity of antioxidant defense system in rats. Dokl Russ Akad Nauk352: 831—833.
8.
Anisimov VN, Mylnikov SV, Oparina TI, Khavinson VKh (1997a). Effect of melatonin and pineal peptide preparation epithalamin on life span and free radical oxidation in Drosophila melanogaster . Mech Ageing Dev97: 81—91.
9.
Anisimov VN, Popovich IG, Zabezhinski MA (1997b). Melatonin and colon carcinogenesis: I. Inhibitory effects of melatonin on development of intestinal tumors induced by 1,2-dimethylhydrazine in rats. Carcinogenesis18: 1549—1553.
10.
nisimov VN, Popovich IG, Shtylik AV, Zabezhinski MA, Ben-Huh H., Gurevich P., Berman V., Tendler Y., Zusman I. (2000). Melatonin and colon carcinogenesis. III. Effect of melatonin on proliferative activity and apoptosis in colon mucosa and colon tumors induced by 1,2-dimethylhydrazine in rats. Exp Toxicol Pathol52: 71—76.
11.
Anisimov VN , Zabezhinski MA, Popovich IG, Musatov SA, Andre V., Godard F. (2000a). Inhibitory effect of melatonin on 7,12-dimethylbenz[a]anthracene-induced carcinogenesis of the uterine cervix and vagina in mice and mutagenesis in vitro. Cancer Lett156: 199—205.
12.
Anisimov VN , Zavarzina NY, Zabezhinski MA, Popovich IG, Zimina OA, Shtylik AV, Arutjunyan AV, Oparina TI, Prokopenko VM, Mikhalski AI, Yashin AI (2001b). Melatonin increases both life span and tumor incidence in female CBA mice. J Gerontol BiolSci56A: B311—B323.
13.
Anisimov VN , Khavinson VKh , Provinciali M., Alimova IN, Baturin DA, Popovich IG, Zabezhinski MA, Imyanitov EN, Mancini R., Franceschi C. (2002). Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neutransgenic mice. Int J Cancer101: 7—10.
14.
Anisimov VN , Alimova IN, Baturin DA, Popovich IG, Zabezhinski MA, Manton KG, Semenchenko AV, Yashin AI (2003). The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu transgenic mice. Int J Cancer103: 300—305.
15.
Anisimov VN , Alimova IN, Baturin DA, Popovich IG, Zabezhinski MA, Rosenfeld SV, Manton KG, Semenchenko AV, Yashin AI (2003a). Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice . Exp Gerontol38: 449—461.
16.
Antolin I., Rodriguez C., Sainz RM, Mayo JC, Uria H., Kotler ML, Rodriguez-Colunga MJ, Tolivia D., Menendez-Pelaez A. (1996). Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J10: 882—890.
17.
Arendt J. (1995). Melatonin and the Mammalian PinealGland. Chapman & Hall, London.
18.
Armstrong SM , Redman JR (1991). Melatonin: A chronobiotic with antiaging properties?Med Hypotheses34: 300—309.
19.
Bakaev VV, Efremov AV, Anisimov VN (1997). An attempt to slow aging in C. elegans. 8. Melatonin reduces life span of C. elegans. The Worm BreederGazette15(1): 36.
20.
Barlow-Walden LR, Reiter RJ, Abe M., Pablos M., Menendez-Pelaez A., Chen L-D., Poeggeler B. (1995). Melatonin stimulates brain glutathione peroxidase activity. Eurochem Int26: 497—502.
21.
Baturin DA, Alimova IA, Anisimov VN, Popovich IG, Zabezhinski MA, Provinciali M., Mancini R., Franceschi C. (2001). The effect of light regimen and melatonin on the development of spontaneous mammary tumors in HER-2/neu transgenic mice is related to a down regulationof HER-2/neu gene expression. Neuroendocrin Lett22: 439—445.
22.
Bellipanni G., Bianchi P., Pierpaoli W., Bulian D., Ilyia E. (2001). Effects of melatonin in perimenopausal and menopausal women: A randomized and placebo controlled study. Exp Gerontol36: 297—310.
23.
Bizot-Espiard JG, Double A., Cousin B., Lesieur D., Guardiola-Lemaitre B., Delagrange P., Ktorza A., Penicaud L. (1998). Lack of melatonin effects on insulin action in normal rats. Horm Metabol Res30: 711—716.
24.
Blask DE, Sauer LA, Dauchy RT (2002). Melatonin as a chronobiotic/anticancer agent: Cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem2: 113—132.
25.
Block JB, Dietrich MF, Tsunokai R. (1986). Inhibition of adriamycin and mitomycin C mutagenesis by menadione. Proc Am Assoc Cancer Res27: 307.
26.
Bodyak ND, Nekhaeva E., Wei JY, Khrapko K. (2001). Quantitation and sequencing of somatic deleted mtDNA in single cells: Evidence for partially duplicated mtDNA in aged human tissues. Human MolGenetics10: 17—24.
27.
Bonilla E., Medina-Leendertz S., Diaz S. ( 2002). Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin. Exp Gerontol37: 69—638.
28.
Bothorel B. , Barassin S., Saboureau M., Perreau S., Vivien-Roels B., Malan A., Pevet P. (2002). In the rat, exogenous melatonin increases the amplitude of pineal melatonin secretion by a direct action on the circadian clock. Eur J Neursci16: 1090—1098.
29.
Butler RN, Fossel M., Harman SM, Heward CB, Olshansky SJ, Perls TT, Rothman DJ, Rothman SM, Warner HR, West MD, Wright WE (2002). Is there an antiaging medicine? J Gerontol BiolSci57A: B333—B338.
30.
Cagnacci A., Arangino S., Renzi A., Paoletti AM, Melis GB, Cagnacci P., Volpe A. (2001). Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol54: 339—346.
31.
Cagnoli CM, Atabay C., Kharlamov E., Manev H. (1995). Melatonin protects neurons from singlet oxygen-induced apoptosis. J Pineal Res18: 222—226.
32.
Canpolat S., Sandal S., Yilmaz B., Yasar A., Kutlu S.Baydas G., Kelestimur H. (2001). Effects of pinealectomy and exogenous melatonin on serum leptin levels in male rat. Eur J Pharmacol428: 145—148.
33.
Capelli E., Campo I., Panelli S., Damiani G., Barbone MG, Lucchelli A., Cuccia M. (2002). Evaluation of gene expression in human lymphocytes activated in the presence of melatonin. Int Immunopharmacol2: 885—892.
34.
Clapp-Lilly KL , Smith MA, Perry G., Harris PL, Zhu X., Duffy LK (2001). Melatonin acts as antioxidant and pro-oxidant in an organotypic slice culture model of Alzheimer's disease . Neuroreport12: 1277—1280.
35.
Coller HA, Bodyak ND, Khrapko K. (2002). Frequent intracellular clonal expansions of somatic mtDNA mutations. Ann NY Acad Sci959: 434—447.
36.
Conti A., Maestroni G. (1996). Role of the pineal gland and melatonin in the development of autoimmune diabetes in non-obese diabetic mice. J Pineal Res20: 164—172.
37.
Conti A., Maestroni GJ (1998). Melatonin rhythms in mice: Role in autoimmune and lymphoproliferative diseases. Ann NY Acad Sci840: 395—410.
38.
Cos S., Sanchez-Barcelo EJ (2000). Melatonin and mammary pathological growth. Front Neuroendocrin17: 133—170.
39.
Cos S., Sanchez-Barcelo EJ (2001). Neuroimmunoendocrine Mechanisms in Malignancy . In: The Pineal Gland and Cancer, C Bartsch, H Bartsch, DE Blask, DP Cardinali , WJM Hrushesky, D Mecke (eds). Springer, Berlin , pp 219—239.
40.
Coto-Montes A., Hardeland R. (1999). Antioxidative effects of melatonin in Drosphila melanogaster: Antagonization of damage induced by the inhibition of catalase. J Pineal Res27: 154—158.
41.
Cummings J. , Spanswick VJ, Smyth JF (1995). Re-evaluation of the molecular pharmacology of mitomycin. CEur J Cancer31A: 1928—1933.
42.
Cuzzocrea S. , Tan DX, Costantino G., Mazzon E., Caputi AP, Reiter RJ (1999). The protective role of endogenous melatonin in carageenaninduced pleurisy in the rat. FASEB J13: 1930—1938.
43.
Deerberg F. , Bartsch C., Pohlmeyer G., Bartsch H. (1997). Effect of melatonin and physiological epiphysectomy on the developmet of spontaneous endometrial carcinoma in BDII/HAN rats. Cancer Biother. Radiopharmacol12: 420.
44.
de Grey AD (2000). The reductive hotspot hypothesis: An update. Arch Biochem Biophys373: 295—301.
45.
de Grey Adnj , Baynes JW, Berd D., Heward CB, Pawelec GP, Stock G. (2002). Is human aging still mysterious enough to be left only to scientists?BioEssays24: 667—676.
46.
de Grey Adnj , Gavrilov L., Olshansky SJ, Coles LS, Cutler RG, Fossel M., Harman SM (2002a). Antiaging technology and pesudoscience. Science296: 656.
47.
Deshaies RJ (1999). SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol15: 435—467.
48.
Dillin A., Crawford DK, Kenyon C. (2002). Timing requirements for insulin/IGF-1 signaling in C. elegans. Science298: 830—834.
49.
Duel PB, Wheaton DL, Shultz A., Nguyen H. (1998). Inhibition of LDL oxidation by melatonin requires supraphysiologic concentrations. Clin Chem44: 1931—1936.
50.
Fabis M., Pruszynska E., Mackowiak P. (2002). In vivo and in situ action of melatonin on insulin secretion and some metabolic implications in the rat. Pancreas25: 166—169.
51.
Finnochiaro L., Calleber J., Launay JM, Jallon JM (1988). Melatonin miosynthesis in Drosophila: Its nature and its effect. J Neurochem50: 382—387.
52.
Freedman DA , Zeizel H. (1988). From mouse—to man: The quantitative assessment of cancer risks. StatistSci3: 3—56.
53.
Gart JJ, Krewski D., Lee PN, Tarone S., Wahrendorf J. (1986). Statistical Methods in Cancer Research. Vol. III—The Design and Analysis of Long-Term Animal Experiments. IARC Scientific Publication 79, IARC, Lyon.
54.
Gilad E., Cuzzocrea S., Zingarelli B., Salzman AL, Szabo C. (1997). Melatonin is a scavenger of peroxynitrite. Life Sci60: PL169—PL174.
55.
Giusti P., Gusella M., Lipartiti M., Milani D., Zhu W., Vicini S., Manev H. (1995). Melatonin protects primary cutures of cerebellar granuleneurons from kainate but not from N-methyl-D-aspartat excitotoxicity . Exp Neurol131: 39—46.
56.
Goto M., Oshima I., Tomita T., Ebihara S. (1989). Melatonin content of the pineal gland in different mouse strains. J Pineal Res7: 195—204.
57.
Gozzo A., Lesieur D., Duriez P., Fruchart JC, Teissier E. (1999). Structure-activity relationshipes in a series of melatonin analogues with the low-density lipoprotein oxidation model. Free Radic. Biol Med26: 1538—1543.
58.
Guerrero JM , Reiter RJ (2002). Melatonin-immune system relationships. Curr Top Med Chem2: 167—179.
59.
Hamilton ML , Van Remmen H., Drake JA, Yang H., Guo ZM, Kewitt K., Walter CA, Richardson A. (2001). Does oxidative damage to DNA increase with age?Proc Natl Acad Sci USA98: 10469—10474.
60.
Harman DH (1994). Free-radical theory of aging: Increasing the functional life span. Ann NY Acad Sci717: 257—266.
61.
Harms C., Lautenschlager M., Bergk A., Freyer D., Weih M., Dirnagl U., Weber JR, Hortnagl H. (2000). Melatonin is protective in necrotic but not in caspase-dependent, free radical-independent apoptotic neuronal cell death in primary neuronal cultures. FASEB J14: 1814— 1824.
62.
Hemminki A. (1999). The molecular basis and clinical aspects of Peutz-Jeghers syndrome. Cell Mol Life Sci55: 735—750.
63.
Hintermann E., Jeno P., Meyer UA (1995). Isolation of an arylalkylamine N-acetyltransferase from Drosophila melanogaster . FEBS Lett375: 148— 150.
64.
Iacovitti L. , Stull ND, Hohnston K. (1997). Melatonin rescues dopamine neurones from cell death in tissue culture models of oxidative stress. Brain Res768: 317—326.
65.
Imaida K., Hagiwara A., Yoshino H., Tamano S., Sano M., Futakuchi M., Ogawa K., Asamoto M., Shirai T. (2000). Inhibitory effects of low doses of melatonin on induction of preneoplastic liver lesions in a medium-term liver bioassay in F344 rats: Relation to the influence of electromagnetic near field exposure . Cancer Lett155: 105—114.
66.
Itoh MT, Shinozawa T., Sumi Y. ( 1999). Circadian rhythms of melatonin-synthesizing enzyme activities and melatonin levels in planarians. Brain Res830: 165—173.
67.
Izmaylov DM , Obukhova LK (1999). Geroprotector effectiveness of melatonin: Investigation of life span of Drosophila melanogaster . Mech Ageing Dev106: 233—240.
68.
Karasek M., Reiter RJ (2002). Melatonin and aging. Neuroendocrinol Lett23(Suppl. 1): 14—16.
69.
Karbownik M. , Garcia JJ, Lewinski A., Reiter RJ (2001). Carcinogen-induced, free radical-mediated reduction in microsomal membrane fluidity: Reversal by indole-3-propionic acid. J Bioenerg Biomembr33: 73—78.
70.
Kawanishi S. , Hiraki Y., Oikawa S. (2001). Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging. Mutat Res488: 65—76.
71.
Kenyon C. (2001). A conserved regulatory system for aging. Cell105: 165—168.
72.
Koratkar R. , Vasudha A., Ramesh G., Padma M., Das UN (1992). Effect of melatonin on cisplatinum induced genetic damage to the bone marrow cells of mice. Med Sci Res20: 179—180.
73.
Korkushko OV , Khavinson VKh , Butenko GM, Shatilo VB (2002). Thymic and Pineal Peptide Bioregulators in Accelerated Aging Prevention. Nauka, St. Petersburg .
74.
Kotler M., Rodriguez C., Sainz RM, Antolin I., Menendez-Pelaez A. (1998). Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res24: 83—89.
75.
Krek W. (1998). Proteolysis and the G1-S transition: The SCF connection . Curr Opin Genet Dev8: 36—42.
76.
Lenz SP, Izui S., Benediktsson H., Hart DA ( 1995). Lithium chloride enhances survival of NZB/W lupus mice: Influence of melatonin and timing of treatment. Int J Immunopharmacol17: 581—592.
77.
Lesnikov VA, Pierpaoli W. (1994). Pineal cross-transplantation (old-to-young and vice versa) as evidence for an endogenous “aging clock.” Ann NY Acad Sci719: 461—473.
78.
Liang SB, Ohtsuki Y., Furihata M., Takeuchi T., Iwata J., Chen B., Sonobe H. (1999). Sun-expoure- and aging-dependent p53 protein accumulation results in growth advantage for tumour cells in carcinogenesis of nonmelanocytic skin cancer. Virchows Arch434: 193—199.
79.
Liebermann PM, Wolfler A., Schauenstain K. (2000). Melatonin and immune function. In: The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy , C Bartsch, H Bartsch, DE Blask, DP Cardinali, WJM Hrushesky , D Mecke (eds). Springer, Berlin, pp 372— 383.
80.
Lipman RD, Bronson RT, Wu D., Smith DE, Prior R., Cao G., Han SN, Martinn KR, Meydani SN, Meydani M. (1998). Disease incidence and longevity are unaltered by dietary antioxidant supplementation initiated during middle age in C57BL/6 mice. Mech Ageing Dev103: 269— 284.
81.
Lissoni P. (2002). Is there a role for melatonin in supportive care?Support Care Cancer10: 110—116.
82.
Liu F., Ng TB, Fung MC ( 2001). Pineal indoles stimulate the gene expression of immunomodulating cytokines. J Neural Transm108: 397— 405.
83.
Lund J., Tedesco P., Duke K., Wang J., Kim SK, Johnson TE (2002). Transcriptional profile of aging in C. elegans . Curr Biol12: 1566—1573.
84.
Maestroni GJM (1998). Is hematopoiesis under the influence of neural and neuroendocrine mechanisms?Histol Histopathol13: 271—274.
85.
Maestroni GJM (2001). Melatonin and the immune system: Therapeutic potential in cancer, viral diseases, and immunodeficiency states. In: The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy, C Bartsch, H Bartsch, DE Blask, DP Cardinali, WJM Hrushesky , D Mecke (eds). Springer, Berlin, pp 384—394.
86.
Mahmutoglu I., Kappus H. (1987). Redox cycling of bleomycin-Fe(III) by an NADP-dependent enzyme, and DNA damage in isolated rat liver nuclei. Biochem Pharmacol36: 3667—3671.
87.
Malm OJ, Skaug OE, Lingjaerde P. (1959). The effect of pinealectomy on bodily growth. Acta Endocrinol30: 22—28.
88.
Malpaux B., Migaud M., Tricoire H., Chemineau P. (2001). Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin. J Biol Rhythms16: 336—347.
89.
Maron DM, Ames BN ( 1984). Revised methods for the Salmonella mutagenicity test . In: Handbook of Mutagenicity Test Procedures, BJ Kilbey, MS Legator , W Nochols, C Ramel (eds). Elsevier, Amsterdam , pp 93— 140.
90.
Mediavilla MD, Cos S., Sanchez Barcelo EJ (1999). Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci65: 415—420.
91.
Meki AR, Abdel-Ghaffar SK, El-Gibaly I. (2001). Aflatoxin B1 induces apoptosis in rat liver: Protective effect of melatonin. Neuroendocrinol Lett22: 417—426.
92.
Menendez-Pelaez A., Rodriguez C., Dominguez D. (1991). 5-Aminolevulinate synthase mRNA levels in the Harderian gland of Syrian hamsters: Correlation with porphyrin concentrations and regulation by androgens and melatonin. Mol Cell Endocrinol80: 177—182.
93.
Meredith S. , Jackson K., Dudenhoeffer G., Graham L., Epple J. (2000). Long-term supplementation with melatonin delays reproductive senescence in female rats, without an effect on number of primordial follicles. Exp Gerontol35: 343—352.
94.
Michel JJ, Xiong Y. (1998). Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A. Cell Growth Differ9: 435—449.
95.
Mocchegiani E., Santarelli L., Tibaldi A., Muzzioli M., Bulian D., Cipriano K., Olivieri F., Fabris N. (1998). Presence of links between zinc and melatonin during the circadian cycle in old mice: Effects on thymic endocrine activity and on survival. J Neuroimmunology86: 111—122.
96.
Mockova K., Mnichova M., Kubatka P., Bojkova B., Ahlers I., Ahlersova E. (2000). Mammary carcinogenesis induced in Wistar: Han rats by thecombination of ionizing radiation and dimethylbenz(a)anthracene: Prevention with melatonin. Neoplasma247: 227—229.
97.
Musatov SA, Rosenfeld SV, Togo EF, Mikheev VS, Anisimov VN (1997). The influence of melatonin on mutagenicity and antitumor action of cytostatic drugs in mice. Vopr Onkol43: 623—627.
98.
Musatov SA, Anisimov VN, Andre V., Godard F., Sichel F. (1998). Modulatory effects of melatonin on genotoxic response of reference mutagens in the Ames test and the COMET assay. Mutat Res417: 75—84.
99.
Mustonen AM , Nieminen P., Hyvarinen H. (2002). Effects of continuous light and melatonin treatment on energy metabolism of the rat. J Endocrinol Invest25: 716—723.
100.
Mylnikov SV , Lyubimova NE (2000). Effect of pineal peptides on mortality rate and ntioxidant capacity in Drosophila melanogaster. AdvGerontol4: 84—87.
101.
Nakae J., Biggs WH, Kitamura T., Cavenee WK, Wright CV, Arden KC, Accili D. (2002). Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nature Genet32: 45—253.
102.
Nishida S. , Segawa T., Murai I., Nakagawa S. (2002). Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Delta-5 desaturase activity . J Pineal Res32: 26—33.
103.
Oakin-Bendahan S., Anis Y., Nir I., Zisappel N.K.(1995). Effects of long-term administration of melatonin and a putative antagonist on the ageing rat. Neuro Report6: 785—788.
104.
Osseni RA, Rat P., Bogdan A., Warnet JM, Touitou Y. (2000). Evidence of prooxidant and antioxidant action of melatonin on human liver cell line HepG2. Life Sci68: 387—399.
105.
Ouhtit A., Ueda M., Nakazawa H., Ichihashi M., Dumaz N., Sarasin A., Yamasaki H. (1997). Quantitative detection of ultraviolet-specific p53 mutations in normal skin from Japanese patients. Cancer Epidemiol. Biomarkers Prev6: 433—438.
106.
Oxenkrug G. , Requintina P., Bachurin S. (2001). Antioxidant and antiaging activity of N-acetylserotonin and melatonin in the in vivo models. Ann NY Acad Sci939: 190—199.
107.
Pablos MI, Reiter RJ, Ortiz GG, Guerrero JM, Agapito MT, Chuang JI, Sewerynek E. (1998). Rhythms of glutathione peroxidase and glutathione reductase in brain of chick and their inhibition by light. Neurochem Int32: 69—75.
108.
Pappolla MA , Sos M., Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S., Robakis NK (1997). Melatonin prevents death of neuroblastoma cels exposed to the Alzheimer amiloid peptide. J Neurosci17: 1683—1690.
109.
Payao SL, de Carvalho CV, da Silva ER, Lopes C., Markus RP, Winter LM, Smith MA (2001). Pinealectomy-associated decrease in ribosomal gene activity. Biogerontology2: 105—108.
110.
Pevet P., Bothorel B., Slotten H., Saboureau M. (2002). The chronobiotic properties of melatonin. Cell Tissue Res309: 183—191.
111.
Picinato MC , Haber EP, Cipolla-Neto J., Curi R., de Oliveira Carvalho CR, Carpinelli AR (2002). Melatonin inhibits insulin secretion and decreases PKA levels without interfering with glucose metabolism in rat pancreatic islets . J Pineal Res33: 156—160.
112.
Pieri C., Marra M., Moroni F., Decchioni R., Marcheselli F. (1994). Melatonin: A peroxyl radical scavenger more effective than vitamin E. Life Sci55: 271—276.
113.
Pieri C., Recchioni R., Moroni F., Marcheselli F., Marra M., Marinoni S., Di Primio R. (1998). Melatonin regulates the respiratory burst of humanneutrophils and their depolarization. J Pineal Res24: 43—49.
114.
Pierpaoli W. (1998). Neuroimmunomodulation of aging. A program in the pineal gland. Ann NY Acad Sci840: 491—497.
115.
Pierpaoli W., Maestroni GJ (1987). Melatonin: A principal neuroimmunoregulatory and anti-stress hormone: Its anti-aging effect. Immunol Lett16: 355—361.
116.
Pierpaoli W. , Regelson W. (1994). Pineal control of aging: Effect of melatonin and pineal grafting on aging mice. Proc Natl Acad Sci USA91: 787—791.
117.
Pierpaoli W. , Dall'Ara A., Pedrinis E., Regelson W. (1991). The pineal control of aging: The effects of melatonin and pineal grafting on survival of older mice . Ann NY Acad Sci621: 291—313.
118.
Pierpaoli W. , Bulian D., Dall'Ara A., Marchetti B., Gallo F., Morale MC, Tirolo C., Testa N. (1997). Circadian melatonin and young-to-old pineal grafting postpone aging and maintain juvenile conditions of reproductive functions in mice and rats. Exp Gerontol32: 587—602.
119.
Pierrefiche G. , Laborit H. (1995). Oxygen free radicals, melatonin, and aging. Exp Gerontol30: 213—227.
120.
Pierrefiche G. , Topall G., Courboin G., Henriet I., Laborit H. (1993). Antioxidant activity of melatonin in mice. Res Commun Chem Pathol Pharmacol80: 211—223.
121.
Pletscher SD , Macdonald SJ, Marguerie R., Certa U., Stearns SC, Goldstein DB, Patridge L. (2002). Genome-wide transcript profiles in aging and calorically restricted Drosophila melanogaster. Curr Biol12: 712—723.
122.
Pozo D., Reiter RJ, Calvo JR, Guerrero JM (1994). Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. Life Sci55: PL455—PL460.
123.
Provinciali M., Di Stefano G., Bulian D., Tibaldi A., Fabris N. (1996). Effect of melatonin and pineal grafting on thymocyte apoptosis in aging mice . Mech Ageing Dev90: 1—19.
124.
Prunet-Marcassus B., Ambid K., Viguerie-Bascands N., Penicaud L., Castella L. (2001). Evidence for a direct effect of melatonin on mitochondrial genome expression of Siberian hamster brown adipocytes. J Pineal Res30: 108—115.
125.
Qi W., Reiter RJ, Tan DX, Manchester LC, Siu AW, Garcia JJ (2001). Increased level of oxidatively damaged DNA induced by chromium (III) and H2O2: Protection by melatonin and related molecules . J Pineal Res29: 54—61.
126.
Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM (1999). Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology140: 1009—1012.
127.
Recchioni R., Marcheselli F., Moroni F., Gaspar R., Damjanovich S., Pieri C. (1998). Melatonin increases the intensity of repsiratory burst and prevents L-selectin shedding in human neutrophils in vitro. Biochim Biophys Res Communic252: 20—24.
128.
Reiter RJ (1995). The pineal gland and melatonin in relation to aging: A summary of the theories and of the data. Exp Gerontol30: 199—212.
129.
Reiter RJ (2001). Reactive oxygen species, DNA damage, and carcinogenesis: Intervention with melatonin. In: The Pineal Gland and Cancer. Neuroimmunoendocrine Mechanisms in Malignancy, C Bartsch, H Bartsch, DE Blask, DP Cardinali , WJM Hrushesky, D Mecke (eds). Springer, Berlin , pp 442—455.
130.
Reiter RJ, Tan DX, Kim SJ, Manchester LC, Qi W., Garcia JJ, Cabrera JC, El-Sokkary G., Rouvier-Garay V. (1999). Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mech Ageing Dev110: 157—173.
131.
Reiter RJ, Tan DX, Manchester LC, Qi W. (2001). Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: A review of the evidence. Cell Biochem Biophys34: 237—256.
132.
Reiter RJ, Tan DX, Allegra M. (2002). Melatonin; reducing molecular pathology and dysfunction due to free radicals and associated reactants. Neuroendocrinol Lett23(Suppl. 1): 3—8.
133.
Reppert SM , Weaver DR (1995). Melatonin madness. Cell83: 1059—1062.
134.
Romanenko VI (1983). Melatonin as a possible endogenous leukemogenic (blastomogenic) agent. Hematol Transfuz (Moscow)2: 47—50.
135.
Romanenko VI (1985). Comparative Evaluation of the Blastomogenic Activity of Methoxy Derivatives of Serotonin. Dissertation . All-Union Cancer Research Center, Moscow.
136.
Rosenfeld SV (2002). Effect of Melatonin and Epitalon on Mutagenesis, Tumor Development and Life Span in SAM Mice with Accelerated Senescence. Dissertation. St. Petersburg I.P. Pavlov State Medical University , St. Petersburg.
137.
Rosenfeld SV, Togo EF, Mikheev VS, Popovich IG, Zabezhinski MA, Anisimov VN (2001). Dynamics of chromosomal aberrations in male mice of various strains during aging. Bull Exp Biol Med131: 482—483.
138.
Roy D. , Belsham DD (2002). Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GNRH neurons. Signal transduction mechanisms. J Biol Chem277: 251—258.
139.
Roy D. , Angelini NI, Fujieda H., Brown GM, Belsham DD (2001). Cyclical regulation of GnRH gene expression in GT1-7 GnRH secreting neurons by melatonin. Endocrinology142: 4711—4720.
140.
Sainz RM, Mayo JC, Uria H., Kotler M., Antolin I., Rodriguez C., Menendez-Pelaez A. (1995). The pineal neurohormone melatonin prevents in vivo and in vitro apoptosis in thymocytes. J Pineal Res19: 178—188.
141.
Sainz RM, Mayo JC, Kotler M., Uria H., Antolin I., Rodriguez C. (1998). Melatonin decreases mRNA for histone H4 in thymus of young rats. Life Sci63: 1109—1117.
142.
Sainz RM, Mayo JC, Reiter RJ, Antolin I., Esteban MM, Rodriguez C. (1999). Melatonin regulates glucocorticoid receptor: An answer to its antiapoptotic action in thymus. FASEB J13: 1547—1556.
143.
Sharman KG , Sharman EH, Yang E., Bondy SC (2002). Dietary melatonin selectively reverses age-related changes in cortical cytokine mRNA levels, and their responses to an inflammatory stimulus. Neurobiol Aging23: 633— 638.
144.
Shen YX, Xu SY, Wei W., Wang XL, Wang H., Sun X. (2002). Melatonin blocks rat hippocampal neuronal apoptosis induced by amyliod beta-peptide 25—35. J Pineal Res32: 163—167.
145.
Simpson AJG (1997). A natural somatic mutation frequency and human carcinogenesis. Adv Cancer Res71: 209—240.
146.
Skaper SD, Floreani M., Negro A., Facci L., Giusti P. (1998). Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: Selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway. J Neurochem70: 1859—1868.
147.
Skulachev VP (2001). The programmed death phenomena, aging, and the Samurai law of biology. Exp Gerontol36: 995—1024.
148.
Staats J. (1985). Standardized nomenclature for inbred strains of mice: Eight listing. Cancer Res45: 945—977.
149.
Stehle JH, von Gall C., Korf HW ( 2002). Organization of the circadian system in melatonin-proficient C3H and melatonin-deficient C57BL mice: A comparative investigation. Cell Tissue Res309: 173—182.
150.
Subramanian A., Kothari L. (1991). Melatonin, a supresor of spontaneous murine mammary tumors. J Pineal Res10: 136—140.
151.
Sun FY , Lin X., Mao LZ, Ge WH, Zhang LM, Huang YL, Gu J. (2002). Neuroprotection by melatonin against ischemic neuronal injury associated with modulation of DNA damage and repair in the rat following a transient cerebral ischemia. J Pineal Res33: 48—56.
152.
Susa N., Ueno S., Furukawa Y., Ueda J., Sugiyama M. (1997). Potent protective effect of melatonin on chromium (VI)-induced DNA strand breaks, cytotoxicity and lipid peroxidation in primary cultures of rat hepatocytes. Toxicol Appl Pharmacol144: 377—384.
153.
Tailleux A. , Torpier G., Bonnefont-Rousselot D., Lestavel S., Lemdani M., Caudeville B., Furman C., Foricher R., Gardes-Albert M., Lesieur D., Rolando C., Teissier E., Fruchart JC, Clavey V., Fievet C., Duriez P. (2002). Daily melatonin supplementation in mice increases atherosclerosis in proximal aorta. Biochem Biophys Res Commun293: 1114—1123.
154.
Tan DX , Chen LD, Poeggeler B., Manchester LC, Reiter RJ (1993). Melatonin: A potent, endogenous hydroxyl radical scavanger. Endocrine J1: 57—60.
155.
Tan DX , Reiter RJ, Chen LD, Poeggeler B., Manchester LC, Barlow-Walden RL (1994). Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole, Carcinogenesis15: 215—218.
156.
Tan DX , Reiter RJ, Manchester LC, Yan MT, El-Sawi M., Sainz RM, Mayo JC, Kohen R., Allegra M., Hardeland R. (2002). Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem2: 181— 197.
157.
Tang L., Reiter RJ, Li ZR, Ortiz GG, Yu BP, Garcia JJ (1998). Melatonin reduces the increase in 8-hydroxy-deoxyguanosine levels in the brain and liver of kainic acid-treated rats. Mol Cell Biochem178: 299— 303.
158.
Thomas JN, Smith-Sonneborn J. (1997). Supplemental melatonin increases clonal lifespan in the protozoan Paramecium tetraurelia. J Pineal Res23: 123—130.
159.
Tian YM, Li PP, Jiang XF, Zhang GY, Dai YR (2001). Rejuvenation of degenerative thymus by oral melatonin administration and the antagonistic action of melatonin against hdroxyl radical-induced apoptosis of cultured thymocytes in mice. J Pineal Res31: 214—221.
160.
Touitou Y. (2001). Human aging and melatonin. Clinical relevance . Exp Gerontol36: 1083—1100.
161.
Touitou Y., Bogdan A., Haus E., Touitou C. (1997). Modifications of circadian and circannual rhythms with age. Exp Gerontol32: 603—614.
162.
Tu MP, Epstein D., Tatar M. (2002). The demography of slow aging in male and female Drosophila mutant for the insulin-receptor substrate homologue chico. Aging Cell1: 75—80.
163.
Tuker MS (1998). Estimation of mutation frequencies in normal mammalian cells and the development of cancer. Semin Cancer Biol8: 407— 419.
164.
Turek VP (1996). Melatonin hype hard to swallow. Nature379: 295—296.
165.
Turek FW, Zee P., Van Reeth O. (1999). Melatonin and aging. Adv Exp Med Biol460: 435—440.
166.
Turusov VS , Lanko NS, Krutovskikh VA, Parfenov YD (1982). Strain differences in suceptibility of female mice to 1,2-dimethylhydrazine . Carcinogenesis3: 603—608.
167.
Urata Y., Honma S., Goto S., Todoroki S., Iida T., Cho S., Honma K., Kondo T. (1999). Melatonin induces gamma-glutamylcysteine synthetase mediated by activator protein-1 in human vascularendothelial cells. Free Radic Biol Med27: 838—847.
168.
U.S. General Accounting Office, Anti-aging products pose potential for physical and economic harm , Special Committee on Aging, GAO-01-1129, September 2001 (http://aging.senate.gov/hr73gao.pdf ).
169.
Vainio H, Magee P, McGregor D, McMichael AJ (eds) (1992). Mechanisms of Carcinogenesis in Risk Identification. IARC Sci Publ. No 116, IARC, Lyon.
170.
Vanecek J. (1998). Cellular mechanism of melatonin action. Physiol Rev78: 687—721.
171.
Vijayalaxmi, Reiter RJ, Meltz ML (1995). Melatonin protects human blood lymphocytes from radiation-induced chromosome damage. MutatRes346: 23—31.
172.
Vijayalaxmi, Reiter RJ, Meltz ML (1998). Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes . Mutat Res397: 203—208.
173.
Vijalaxmi, Meltz ML, Reiter RJ, Herman TS (1999). Melatonin and protection from genetic damage in blood and bone marrow: Whole-body irradiation studies in mice. J Pineal Res27: 221—225.
174.
Vijg J. (2000). Somatic mutations and aging: A re-evaluation. Mutat Res447: 117—135.
175.
Wakatsuki A., Okatani Y., Ikenoue N., Izumiya C., Kaneda C. (2000). Melatonin inhibits oxidative medification of low-density lipoprotein particles in normolopidemic post-menopausal women. J Pineal Res28: 136— 142.
176.
Waldhauzer F., Kovacs J., Reiter E. (1998). Age-related changes in melatonin levels in humans and its potential consequences for sleep disorders . Exp Gerontol33: 759—772.
177.
Warner HR, Ingram D., Miller RA, Nadon NL, Richardson AG (2000). Program for testing biological interventions to promote healthy aging. Mech Ageing Dev155: 199—208.
178.
Weindruch R., Kayo T., Lee CK, Prolla TA (2000). Gene expression profiling of aging using DNA microarrays. Mech Ageing Dev123: 177— 193.
179.
Welle S. (2002). Gene transcript profiling in aging research. Exp .Gerontol.37: 583—590.
180.
Wolfler A. , Caluba HC, Abuja PM, Dohr G., Schauenstain K., Liebmann PM (2001). Proxoidant activity of melatonin promotes fas-induced cell death in human leukemic Jurkat cells. FEBS Lett502: 127—131.
181.
Wolden-Hanson T., Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, Rasmussen DD (2000). Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat . Endocrinology141: 487—497.
182.
Yasuo S., Yoshimura T., Bartell PA, Iigo M., Makino E., Okabayashi N., Ebihara S. (2002). Effect of melatonin administration on qPer2, qPer3, and qClock gene expression in the suprahiasmatic nucleus of Japanese quail . Eur J Neurosci16: 1541—1546.
183.
Yoo YM , Yim SV, Kim SS, Jang HY, Lea HZ, Hwang GC, Kim JE, Kim SA, Lee HJ, Kim CJ, Chung JH, Leem KH (2002). Melatonin suppresses NO-induced apoptosis via induction of Bcl-2 expression in PGT-beta immortalized pineal cells. J Pineal Res33: 146— 150.
