Disruptions in sleep-wake patterns have been linked to a variety of health problems, including an increase risk for obesity, type II diabetes, and hypertension. The link to increased risk of malignancy and premature aging is less clear, however. This manuscript reviews current epidemiological and experimental evidence linking alterations in sleep-wake patterns to malignancy and premature aging. Epidemiological evidence suggests that alterations in sleep-wake patterns (e.g.; night-shift or rotating-shift work) are associated with increases in leukemia, endometrial, breast, prostate, and colorectal cancers. Excessive long or short sleep duration is associated with increased mortality. These observations are further supported by experimental animal model systems: Sleep deprivation causes death in Drosophila cycle01 mutants. Manipulations of light-dark cycle in rodents or mutations that knock out certain genes in the circadian pathway accelerate aging and neoplastic growth. Melatonin, the pineal hormonal signal of darkness appears to have evolved in part to protect against mutagenesis by synchronizing cellular proliferation, differentiation, and apoptosis to the circadian peaks and troughs of genotoxic stress. A model based on circadian-gating of sleep-wake cycles, therefore, links the circadian pathway to the mutational theories of senescence and neoplasia.
circadian; sleep; wake; cancer; mutation; aging
Ahmad R, Bath PA: Identification of risk factors for 15-year mortality among community-dwelling older people using Cox regression and a genetic algorithm. J Gerontol A Biol Sci Med Sci 60:1052-1058, 2000.
Allgulander CL, Ljungberg, Fisher LD: Long-term prognosis in addiction on sedative and hypnotic drugs analyzed with the Cox regression model. Acta Psychiatr Scand 75:521-31, 1987.
Allgulander CL, Nowak J, Rice JP: Psychopathology and treatment of 30, 344 twins in Sweden. I. The appropriateness of psychoactive drug treatment. Acta Psychiatr. Scand. 82:420-426, 1990.
Alvarez GG, Ayas NT: The impact of daily sleep duration on health: a review of the literature. Prog Cardiovasc Nurs 19:56-59, 2004.
Anderson LE, Morris JE, Sasser LB, Stevens RG: Effect of constant light on DMBA mammary tumorigenesis in rats. Cancer Lett 148:121-126, 2000.
Ashok BT, Ali R: The aging paradox: free radical theory of aging. Exp Gerontol 34:293-303, 1999.
Bartsch C, Bartsch H: Significance of melatonin in malignant diseases (in German). Wien. Klin Wochenschr 109:7229, 1997.
Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE, Thomas TL, Zoran MJ: Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet 6:54456, 2005.
Bembenek J, Sehadova H, Ichihara N, Takeda M: Day/night fluctuations in melatonin content, arylalkylamine N-acetyltransferase activity and NAT mRNA expression in the CNS, peripheral tissues and hemolymph of the cockroach, Periplaneta americana. Comp Biochem Physiol B Biochem Mol Biol 140:27-36, 2005.
Blask DE, Sauer LA, Dauchy RT: Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2:113-132, 2002.
Bunger MK, Walisser JA, Sullivan R, Manley PA, Moran SM, Kalscheur VL, Colman RJ, Bradfield CA: Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis 41:122-132, 2005.
Cadenas S, Barja G: Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Free Radic Biol Med 26:1531-1537, 1999.
Carlberg C: Gene regulation by melatonin. Ann NY Acad Sci 917:387-396, 2000.
Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG: Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26:1241-1246, 2005.
Davis S, Mirick DK, Stevens RG: Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 93: 1557-62, 2001.
Dufour E, Larsson NG: Understanding aging: revealing order out of chaos. Biochim Biophys Acta 1658:122-32, 2004.
Filipski E, Delaunay F, King VM, Wu MW, Claustrat B, Grechez-Cassiau A, Guettier C, Hastings MH, Francis L: Effects of chronic jet lag on tumor progression in mice. Cancer Res 64:7879-7885, 2004.
Fornas O, Mato ME, Webb SM: Antiproliferative effect and cell cycle modulation by melatonin on GH(3) cells. Horm Res 53:251-255, 2000.
Ganguly S, Mummaneni P, Steinbach PJ, Klein DC, Coon SL: Characterization of the Saccharomyces cerevisiae homolog of the melatonin rhythm enzyme arylalkylamine N-acetyltransferase (EC 22.214.171.124). J. Biol. Chem. 276:47239-47247, 2001.
Gensler HL, Bernstein H: DNA damage as the primary cause of aging. Q Rev Biol 56:279-303, 1981.
Hajak G: A comparative assessment of the risks and benefits of zopiclone: a review of 15 years' clinical experience. Drug Saf 21:457-469, 1999.
Hannibal J, Fahrenkrug J: Neuronal input pathways to the brain's biological clock and their functional significance. Adv Anat Embryol Cell Biol 182:1-71, 2006.
Hansen J: Increased breast cancer risk among women who work predominantly at night. Epidemiology 12:74-77, 2001.
Hardeland R, Balzer I, Poeggeler B, Fuhrberg B, Uria H, Behrmann G, Wolf R, Meyer TJ, Reiter RJ: On the primary functions of melatonin in evolution: mediation of photoperiodic signals in a unicell, photooxidation, and scavenging of free radicals. J Pineal Res 18:104-111, 1995.
Hardeland R, Behrmann G, Fuhrberg B, Poeggeler B, Burkhardt S, Uria H, Obst B: Evolutionary aspects of indoleamines as radical scavengers. Presence and photocatalytic turnover of indoleamines in a unicell, Gonyaulax polyedra. Adv. Exp. Med. Biol. 398:279-284, 1996.
Hardeland R, Burkhardt S, Antolin I, Fuhrberg B, Coto-Montes A: Melatonin and 5-methoxytryptamine in the bioluminescent dinoflagellate Gonyaulax polyedra. Restoration of the circadian glow peak after suppression of indoleamine biosynthesis or oxidative stress. Adv Exp Med Biol 460:387-390, 1999.
Harlow BL, Cramer DW: Self-reported use of antidepressants or benzodiazepine tranquilizers and risk of epithelial ovarian cancer: evidence from two combined case-control studies (Massachusetts, United States). Cancer Causes Control 6:130-134, 1995.
Harlow BL: Psychotropic medication use and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 7:697-702, 1998.
Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ: Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int 35:627-634, 1995.
Hays JC, Blazer DG, Foley DJ: Risk of napping: excessive daytime sleepiness and mortality in an older community population. J Am Geriatr Soc 44:693-698, 1996.
Hintermann E, Jeno P, Meyer UA: Isolation and characterization of an arylalkylamine N-acetyltransferase from Drosophila melanogaster. FEBS Lett 375:148-150, 1995.
Holstein TW, Hobmayer E, David CN: Pattern of epithelial cell cycling in hydra. Dev Biol 148:602-611.
Hunt CR, Dix DJ, Sharma GG, Pandita RK, Gupta A, Funk M, Pandita TK: Genomic instability and enhanced radiosensitivity in Hsp70.1- and Hsp70.3-deficient mice. Mol Cell Biol 24:899-911, 2004.
Ijiri K: Cell death (apoptosis) in mouse intestine after continuous irradiation with gamma rays and with beta rays from tritiated water. Radiat Res 118:180-191, 1989.
Karbownik M: Potential anticarcinogenic action of melatonin and other antioxidants mediated by antioxidative mechanisms. Neuro Endocrinol Lett 23 (Suppl. 1):39-44, 2002.
Kiefer TL, Lai L, Yuan L, Dong C, Burrow ME, Hill SM: Differential regulation of estrogen receptor alpha, glucocorticoid receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins. J Pineal Res 38:231-239, 2005.
Kojima M, Wakai K, Kawamura T, Tamakoshi A, Aoki R, Lin Y, Nakayama T, Horibe H, Aoki N, Ohno Y: Sleep patterns and total mortality: a 12-year follow-up study in Japan. J Epidemiol 10:87-93, 2000.
Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP: Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev 20:1868-1873, 2006.
Kripke DF: Why we need a tax on sleeping pills. South Med J 76:632-636, 1983.
Kripke DF, Simons RN, Garfinkel L, Hammond EC: Short and long sleep and sleeping pills. Is increased mortality associated? Arch Gen Psychiatry 36:103-116, 1979.
Kripke DF, Garfinkel, Wingard DL, Klauber MR, Marler MR: Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry 59:131-136, 2002.
Kripke DF, Klauber MR, Wingard DL, Fell RL, Assmus JD, Garfinkel L: Mortality hazard associated with prescription hypnotics. Biol Psychiatry 43:687-693, 1998.
Kubo T, Ozasa K, Mikami K, Wakai K, FujinoY, WatanabeY, Miki T, Nakao M, Hayashi K, Suzuki K, Mori M, Washio M, et al.: Prospective cohort study of the risk of prostate cancer among rotating-shift workers: findings from the Japan collaborative cohort study. Am J Epidemiol 164:549-555, 2006.
Kumar CA, Das UN: Effect of melatonin on two stage skin carcinogenesis in Swiss mice. Med Sci Monit 6:471-475, 2000.
Lee PP, Pang SF: Melatonin and its receptors in the gastrointestinal tract. Biol Signals 2:181-193, 1993.
Mallon L, Broman JE, Hetta J: Sleep complaints predict coronary artery disease mortality in males: a 12-year follow-up study of a middle-aged Swedish population. J Intern Med 251:207-216, 2002.
Mediavilla, MD, Cos S, Sanchez-Barcelo EJ: Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 65:415-420, 1999.
Mediavilla MD, Guezmez A, Ramos S, Kothari L, Garijo F, Sanchez Barcelo EJ: Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-ras proto-oncogene. J Pineal Res 22: 86-94, 1997.
Merlo J, Hedblad B, Ogren M, Ranstam J, Ostergren PO, Ekedahl A, Hanson BS, Isacsson SO, Liedholm H, Melander A: Increased risk of ischaemic heart disease mortality in elderly men using anxiolytics-hypnotics and analgesics. Results of the 10-year follow-up of the prospective population study "Men born in 1914", Malmo, Sweden. Eur J Clin Pharmacol 49:261-265, 1996.
Moretti RM, Marelli MM, Maggi R, Dondi D, Motta M, Limonta P: Antiproliferative action of melatonin on human prostate cancer LNCaP cells. Oncol Rep 7:347-351, 2000.
Mormont MC, F. Levi: Circadian-system alterations during cancer processes: a review. Int J Cancer 70: 241-247, 1997.
Nickel A, Wohlrab W: Melatonin protects human keratinocytes from UVB irradiation by light absorption. Arch Dermatol Res 292:366-368, 2000.
Pandita TK, Higashikubo R, Hunt CR: HSP70 and genomic stability. Cell Cycle 3:591-592, 2004.
Patel SR, Malhotra A, Gottlieb DJ, White DP, Hu FB: Correlates of long sleep duration. Sleep 29:881-889, 2006.
Pawlikowski M, Winczyk K Karasek M: Oncostatic action of melatonin: facts and question marks. Neuro Endocrinol Lett 23 (Suppl 1): 24-29, 2002.
Penas EM, Cools J, Algenstaedt P, Hinz K, Seeger D, Schafhausen P, Schilling G, Marynen P, Hossfeld DK, Dierlamm J: A novel cryptic translocation t(12;17)(p13;p12-p13) in a secondary acute myeloid leukemia results in a fusion of the ETV6 gene and the antisense strand of the PER1 gene. Genes Chromosomes Cancer 37:79-83, 2003.
Phillips B, Mannino DM: Does insomnia kill? Sleep 28:965-971, 2005.
Pinheiro SP, Schernhammer ES, Tworoger SS, Michels KB: A prospective study on habitual duration of sleep and incidence of breast cancer in a large cohort of women. Cancer Res 66:5521-5525, 2006.
Qin L, Wang X, Duan Q, Chen B, He S: Inhibitory effect of melatonin on the growth of H22 hepatocarcinoma cells by inducing apoptosis. J Huazhong Univ Sci Technol Med Sci 24:19-21, 31, 2004.
Rechtschaffen A, Bergmann BM, Everson CA, Kushida CA, Gilliland MA: Sleep deprivation in the rat: X. Integration and discussion of the findings. Sleep 12:68-87, 1989.
Rechtschaffen A, Gilliland MA, Bergmann BM, Winter JB: Physiological correlates of prolonged sleep deprivation in rats. Science 221:182-184, 1983.
Ruifrok AC, Weil MM, Thames HD, Mason KA: Diurnal variations in the expression of radiation-induced apoptosis. Radiat Res 149:360-365, 1998.
Rumble R, Morgan K: Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 40:787-791, 1992.
Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ: Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60:1407-1426, 2003.
Sainz RM, Mayo JC, Tan DX, Leon J, Manchester L, Reiter RJ: Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate 63:29-43, 2005.
Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD: Melatonin and mammary cancer: a short review. Endocr Relat Cancer 10:153-159, 2003.
Seidman MD, Quirk WS, Shirwany NA: Reactive oxygen metabolites, antioxidants and head and neck cancer. Head Neck 21:467-79, 1999.
Shadan FF: A circadian model for viral persistence. Med Hypotheses 68:546-553, 2007.
Shadan FF: Circadian Tempo: A Paradigm for genome stability? Med Hypotheses 68:883-891, 2007.
Shaw PJ, Tononi G, Greenspan RJ, Robinson DF: Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 417:287-291, 2002.
Slominski A, Pisarchik A, Semak I, Sweatman T, Wortsman J, Szczesniewski A, Slugocki G, McNulty J, Kauser S, Tobin DJ, Jing C, Johansson O: Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB J 16:896-898, 2002.
Slominski A, Wortsman J, Tobin DJ: The cutaneous serotoninergic/melatoninergic system: securing a place under the sun. FASEB J 19:176-194, 2005.
Soto-Vega E, Meza I, Ramirez-Rodriguez G, Benitez-King G: Melatonin stimulates calmodulin phosphorylation by protein kinase C. J Pineal Res 37:98-106, 2004.
Sundquist J, Ekedahl A, Johansson SE: Sales of tranquillizers, hypnotics/sedatives and antidepressants and their relationship with underprivileged area score and mortality and suicide rates. Eur J Clin Pharmacol 51:105-109, 1996.
Tamakoshi A, Ohno Y: Self-reported sleep duration as a predictor of all-cause mortality: results from the JACC study, Japan Sleep 27:51-54, 2004.
Thorogood M, Cowen P, Mann J, Murphy M, Vessey M: Fatal myocardial infarction and use of psychotropic drugs in young women. Lancet 340:1067-1068, 1992.
Tilden AR, Becker MA, Amma LL, Arciniega J, McGaw AK: Melatonin production in an aerobic photosynthetic bacterium: an evolutionarily early association with darkness. J Pineal Res 22:102-106, 1997.
van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D, Buijs R, Bootsma D et al.: Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398:627-630, 1999.
Vieira R, Miguez JM, Aldegunde M: GABA modulates day-night variation in melatonin levels in the cerebral ganglia of the damselfly Ischnura graellsii and the grasshopper Oedipoda caerulescens. Neurosci Lett 376:111-115, 2005.
Vijg J: Somatic mutations and aging: a re-evaluation. Mutat Res 447:117-135, 2000.
Wynford-Thomas D, Jones CJ, Wyllie FS: The tumour suppressor gene p53 as a regulator of proliferative life-span and tumour progression. Biol. Signals 5:139-153, 1996.
Yamamoto H, Mohanan PV: Effects of melatonin on paraquat or ultraviolet light exposure-induced DNA damage. J Pineal Res 31:308-313, 2001.
Yeh KT, Yang MY, Liu TC, Chen JC, Chan WL, Lin SF, Chang JG: Abnormal expression of period 1 (PER1) in endometrial carcinoma. J Pathol 206:111-120, 2005.
Youngstedt SD, Kripke DF: Long sleep and mortality: rationale for sleep restriction. Sleep Med Rev 8:159-174, 2004.
Yu HS, Hernandez V, Haywood M, Wong CG: Melatonin inhibits the proliferation of retinal pigment epithelial (RPE) cells in vitro. In Vitro Cell Dev Biol Anim 29A:415-418, 1993.
Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T: Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol. Biomarkers Prev. 14:268-270, 2005.
Zhu Y, Zheng T, Stevens RG, Zhang Y, Boyle P: Does "clock" matter in prostate cancer? Cancer Epidemiol Biomarkers Prev 15:3-5, 2006.
Giannetto C, Fazio F, Casella S, Assenza A, Marafioti S, Piccione G. Comparison of daily rhythms of oxygen metabolites and serum barrier to oxidation in domestic animals. Cent Eur J Biol. 6: 91-98, 2011.