Beyond Sleep: 7 Ways Melatonin Attacks Aging Factors

Melatonin is known for helping some people achieve a better night's sleep, which is how it earned its nickname as "the sleep hormone."

While melatonin is involved in regulating our internal body clock, that's just the beginning of its health-promoting benefits. Based on extensive research, scientists have discovered that this hormone has beneficial effects on everything from heart disease and diabetes, to bone health and obesity. And best of all, emerging science now suggests that it may protect our genetic material and guard against age related disease and decline.1

Preclinical studies found that melatonin increased the life span of animals by up to 20%—prolonging their youthful character in the process.2-4 Scientific evidence now suggests that melatonin plays a crucial role in a variety of metabolic functions,5 including antioxidant and neuroprotection,6,7 anti-inflammatory defense,8 and immune system support.9

Because melatonin production reduces with age,10-14 experts believe that its decline contributes to both the aging process and a generalized deterioration of health.5,15-17 Years ago, scientists could only speculate at the underlying mechanisms behind melatonin's anti-aging properties. A growing body of evidence reveals how melatonin is able to play such a major role in the combating aging process.18-20

#1: Antioxidant Defense—Combat Free Radical Damage While You Sleep

Since its discovery over 50 years ago, melatonin has demonstrated itself as a functionally diverse molecule, with its antioxidant properties being amongst its most well-studied attributes.26,27 Since then, a vast amount of experimental research has revealed its vital role in the body's defense against numerous cell-damaging free radicals—and for good reason.27-30 Melatonin has been found to possess 200% more antioxidant power than vitamin E.31 Melatonin has been found to be superior to glutathione as well as vitamins C and E in reducing oxidative damage.6

As such a potent antioxidant, melatonin plays a powerful role in fighting free-radical-related diseases—from cardiovascular disease to cancer and practically everything in between.

In post-menopausal women, for example, melatonin has been found to inhibit lipid peroxidation (damage to your fat cells caused by free radicals), thus leading to decreased levels of low-density lipoprotein (LDL) cholesterol,31 one of the primary ingredients for the formation of atherosclerosis. A newer study on men confirmed these findings, suggesting that melatonin leads to overall lower levels of oxidative stress in humans.32 In individuals undergoing cardiopulmonary bypass surgery, melatonin exhibited a higher reduction in lipid peroxidation and improvements in red blood cell membrane stiffness.33

Other widely feared free radical diseases, such as age-related macular degeneration (AMD),34 acute respiratory distress syndrome (ARDS),35 glaucoma,36 and sepsis37 have also been responsive to increased melatonin levels.

#2: Melatonin Fights Back Against America's Major Killer

Since cardiovascular disease is the leading cause of death in the United States, melatonin's ability to protect against heart damage is especially noteworthy.38 In the past decade, melatonin has received considerable attention investigating its potential as a cardioprotective nutrient. Animal studies have provided ample evidence supporting melatonin's antioxidant protection against heart muscle injury,39,40 reducing the damage done by a heart attack,41,42 and improving the strength of the heart's pumping action following a heart attack.43-46

Other investigators reported that it decreases total cholesterol and LDL levels and increases HDL cholesterol levels.33,34 Scientists have discovered that individuals with metabolic syndrome have a lower melatonin production rate compared to healthier counterparts without metabolic syndrome and that individuals with metabolic disturbances in blood pressure, cholesterol, and blood sugar management (all classic features of metabolic syndrome) possess lower melatonin levels than those with normal metabolic function.47 Additional in-vivo studies have confirmed that melatonin can lower blood pressure levels.44-48

#3: Cancer Therapy Adjuvant and Immune Regulator

Emerging research suggests that melatonin has anticarcinogenic properties—that is, it has the ability to prevent cancer from occurring, or to induce the cancer cell death if it does occur. This has been attributed to melatonin's antioxidant, anti-inflammatory, anti-proliferative, and hormone-modulating properties.49,50

Melatonin's ability to interfere with cancer cell multiplication and growth ("proliferation"), as well as inducing cancer cell death ("apoptosis"), has been documented in cancer patients.51, 52

It has been successfully used in individuals with advanced stage cancers undergoing conventional anticancer therapy, by either slowing disease progression and/or decreasing treatment side effects.53-60 In a review of 8 randomized, controlled clinical trials evaluating the benefits of melatonin as an adjuvant therapy for cancer patients with solid tumors undergoing chemotherapy or radiation therapy, researchers found that concurrent use of 20 mg of melatonin once daily versus conventional treatment alone, improved the rate of complete or partial remission by nearly 50%, increased the one-year survival rate by 45%, and decreased the devastating side effects of conventional therapy such as low platelet count, neuropathy, and fatigue by 89%, 83%, and 65% respectively.59 What's more, these effects were consistent across different types of cancer and there were no adverse events reported.59

Melatonin's anticarcinogenic properties can also be attributed to its effect on your immune system. Laboratory studies revealed that melatonin can activate T-helper cells, which triggers other immune cells in order to help kill off foreign invaders or pathogens.61,62 Additionally, melatonin stimulates natural killer cell, monocyte, and macrophage synthesis, and has been found to facilitate healthy cell-to-cell communication, which enhances the body's appropriate immune system response to foreign invaders.63,64 Based on available evidence, leading experts suggest that patients with cancers and particularly metastatic solid tumors, might benefit from melatonin use, potentially leading to improved therapeutic outcomes.62-70 Certainly, more research is warranted.

#4: Protect Against Diabetic Complications

Diabetes—as with cardiovascular disease and cancer—belongs to the family of "free radical diseases."71 Research has found that people with type 2 diabetes and retinopathy experience alterations of their melatonin secretion.72 Considering the large body of evidence identifying melatonin as a major free-radical scavenger, it is not surprising that preclinical research repeatedly and consistently documents its beneficial antioxidative effects in diabetics and those with high blood sugar (hyperglycemia).73,74

Melatonin has also been shown to protect pancreatic beta-cells and several diabetes-affected organs (including kidney, retina, brain, and vasculature) from free radical damage.75 In studies, melatonin treatment has produced reductions in blood glucose, hemoglobin A1c, and cholesterol.75

Scientists see great promise for melatonin's potential to improve quality of life by alleviating many of the complications associated with diabetes, such as retinopathy, nephropathy, and cardiovascular disease.49,74,75

#5: Help Delay Alzheimer's Disease

Another unique and powerful property of melatonin is its ability to cross the blood-brain barrier. Oral intake of melatonin has been shown to increase levels of melatonin in the brain.76 Melatonin also protects the blood brain barrier particularly in cases of hypoxic injury that may cause increased permeability of the blood brain barrier and lead to more damage to the delicate brain tissue as compounds that normally would be kept out by a functioning blood brain barrier gain entrance to the brain.77 Intensive research over the past decade has indicated melatonin's beneficial effects in experimental models of neurodegenerative disorders, specifically those linked to oxidative damage.78 In fact, melatonin's broad spectrum antioxidant activity in many central nervous system neurodegenerative diseases has been well-documented and reviewed.78,79

Specifically, melatonin can help delay the onset of Alzheimer's disease (AD) and help protect vital cellular structures, such as mitochondria, from oxidative damage and decay.80 Declines in mitochondrial function are a hallmark feature of many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease.81 Melatonin may also promote improved sleep patterns and prevent cognitive impairment and improve the confusion and restlessness that often occurs in the evening (called sundowning) in AD patients.80,82,83 Preclinical studies revealed that melatonin exerts pronounced neuroprotective effects against beta amyloid plaque, one of the specific underlying causes of Alzheimer's disease.84-86

More recent investigations show that melatonin may prevent brain cell death while maintaining energy and oxygen metabolism in highly stressed neuronal mitochondria.87,88 Interestingly, decreased night time melatonin levels have been associated with the severity of mental impairment in dementia patients, and disturbed circadian rhythms seem to be correlated with cognitive performance in elderly and Alzheimer's patients.81,89,90 It is important to note that while melatonin may prove beneficial in earlier stages of Alzheimer's disease, it is much less effective in late stage Alzheimer's and may fail to improve sleep or agitation.92,93

#6: Combat Obesity with Melatonin

In recent years, dietitians and medical experts have recognized that obesity is often associated with stress, emotional eating, sleep-deprivation, and hormonal changes later in life. A recent study in women with night eating syndrome (an eating disorder characterized by late-night binge eating) added further confirmation to this. It found that women suffering from this disorder had pronounced circadian melatonin rhythm disturbances, which also affected levels of cortisol (a stress hormone that can be a factor in weight problems) and ghrelin (a hormone that stimulates hunger). It also affected a variety of other behavioral and physiological circadian markers involved in appetite and neuroendocrine regulation.94

While no human weight-management trials using melatonin have been published thus far,95 preclinical trials are encouraging. In middle-aged rodents, daily melatonin administration was found to suppress abdominal fat, plasma leptin levels, and insulin levels, while also reducing body weight and food intake.96,97 Other researchers reported that melatonin was associated with decreased intra-abdominal fat, decreased plasma insulin and leptin levels, and the absence of age-related weight gain.95,98

Furthermore, laboratory investigations discovered melatonin's ability to activate brown adipose tissue, which encourages your body to burn fat instead of storing it.99-101In recent years, brown fat has increasingly become a target for halting the global obesity epidemic.102 In a rat model of pre-diabetic, diet-induced obesity, supplementing obese rats with 4mg/kg/day of melatonin resulted in reductions in body weight, belly fat, serum insulin levels, and triglycerides.103 In humans, the equivalent dose is 48 mg for a 165 lb adult, which is a very high dose that could produce next day drowsiness. Typical human doses for melatonin range from 300 micrograms to 10 milligrams at bedtime.

#7: Help Prevent Osteoporosis

Data derived from animal research suggests that melatonin has beneficial effects on bone repair and remodeling, and bone mineral density,104 which would make it an ideal candidate for the prevention of osteoporosis or as adjuvant after bone fractures.

A very small, yet compelling recently published double-blind, placebo-controlled pilot study investigated the effects of melatonin on bone health and quality of life in 18 perimenopausal women (ages 45-54) for 6 months. It found that melatonin improved physical symptom scores (e.g., feeling and sleeping better), increased osteocalcin (a marker for bone formation), and decreased levels of Type-I collagen cross-linked N-telopeptide (a marker for bone resorption), indicating that melatonin may restore imbalances in bone remodeling and prevent bone loss.105 However, while the results from this small study appear clinically relevant, further investigation is warranted.

Summary

Aging is a multi-factorial process, involving a heavy load of free radicals, metabolic, hormonal, and changes in immunity. Although there is currently no direct clinical evidence demonstrating that melatonin may prolong the human life span, there are several reasons to postulate its role in the aging cascade:

• Melatonin participates in many vital life processes, and its secretion falls gradually over time.
• Diminished melatonin levels appear to correlate with the deterioration of many metabolic functions and decreasing hormone levels, thus possibly contributing to the acceleration of aging processes.
• Melatonin exhibits immunomodulatory properties; suppressed immunity has been implicated in the acceleration of aging processes.
• Melatonin has remarkable low toxicity and is without significant side effects if used at <10 mg/day (provided as 'regular' or 'fast-release');106

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References

1. Zawilska JB, Skene DJ, Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep. 2009 May-Jun;61(3):383-410.

2. Maestroni GJ, Conti A, Pierpaoli W. Pineal melatonin, its fundamental immunoregulatory role in aging and cancer. Ann N Y Acad Sci. 1988;521:140-8.

3. Lesnikov VA, Pierpaoli W. Pineal cross-transplantation (old-to-young and vice versa) as evidence for an endogenous "aging clock." Ann N Y Acad Sci. 1994 May 31;719:456-60.

4. Pierpaoli W, Regelson W. Pineal control of aging: effect of melatonin and pineal grafting on aging mice. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):787-91.

5. Korkmaz A, Topal T, Tan DX, Reiter RJ. Role of melatonin in metabolic regulation. Reviews in Endocrine & Metabolic Disorders 2009 Dec; 10(4): 261-70.

6. Reiter RJ, Paredes SD, Korkmaz A, Jou MJ, Tan DX. Melatonin combats molecular terrorism at the mitochondrial level. Interdiscip Toxicol. 2008 Sep;1(2):137-49.

7. Daglioglu E, Serdar Dike M, Kilinc K, et al. Neuroprotective effect of melatonin on experimental peripheral nerve injury: an electron microscopic and biochemical study. Cent Europ Neurosurg. 2009 Aug; 70(3): 109-14.

8. Esposito E, Cuzzocrea S. Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol. 2010 Sep;8(3):228-42.

9. Srinivasan V, Pandi-Perumal SR, Brzezinski A, Bhatnagar KP, Cardinali DP. Melatonin, immune function and cancer. Recent Pat Endocr Metab Immune Drug Discov. 2011 May;5(2):109-23.

10. Iguchi H, Kato K-I, Ibayashi H. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinolo Metab. 1982;55:27-29.

11. Magri F, Sarra S, Cinchetti W, Guazzoni V, Fioravanti M, Cravello L, Ferrari E. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. J Pineal Res. 2004 May;36(4):256-61.

12. Zhao ZY, Xie Y, Fu YR, Bogdan A, Touitou Y. Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age. Chronobiol Int. 2002 Nov;19(6):1171-82.

13. Thomas DR, Miles A. Melatonin secretion and age. Biol Psychiatry. 1989;25:365-7.

14. Touitou F, Fevre M, Bogdan A, et al. Patterns of plasma melatonin with ageing and mental condition: stability of nyctohemeral rhythms and differences in seasonal variations. Acta Endocrinol. 1984; 106:145-51.

15. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Lopez-Burillo S . Melatonin, longevity and health in the aged: an assessment. Free Radic Res. 2002 Dec;36(12):1323-9.

16. Paredes SD, Reiter RJ. Melatonin: Helping cells cope with oxidative disaster. Cell Membr Free Radic Res. 2010 Dec; 2(3): 99-111.

17. Rodella LF, Favero G, Rossini C, et al. Aging and vascular dysfunction: beneficial melatonin effects. Age. 2011 Nov 23. Epub ahead of print.

18. Reiter R, Tang L, Garcia JJ, Muñoz-Hoyos A. Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci. 1997;60(25):2255-71.

19. Gruber J, Schaffer S, Halliwell B. The mitochondrial free radical theory of ageing—where do we stand? Front Biosci. 2008 May 1;13:6554-79.

20. Hekimi S, Lapointe J, Wen Y. Taking a "good" look at free radicals in the aging process. Trends Cell Biol. 2011 Oct;21(10):569-76.

21. Illnerova H, Buresova M, Presl J. Melatonin rhythm in human milk. J Clin Endocrinol Metab. 1993 Sep;77(3): 838-41.

22. Dubbels R, Reiter RJ, Goebel A, et al. Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res. 1995 Jan;18(1):28-31.

23. Tan DX, Hardeland R, Manchester LC, et al. Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. J Exp Botany. 2012 Jan; 63(2): 577-97.

24. Baba K, Pozdeyev N, Mazzoni F, et al. Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):15043-8.

25. Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol. 2011 Sep 14;17(34):3888-98.

26. Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res. 2010;181:127-51.

27. Stetinová V, Smetanová L, Grossmann V, Anzenbacher P. In vitro and in vivo assessment of the antioxidant activity of melatonin and related indole derivatives. Gen Physiol Biophys. 2002 Jun;21(2):153-62.

28. Reiter RJ, Tan D, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress: a review. J Biomed Sci. 2000;7:444-58.

29. Cuzzocrea S, Reiter RJ. Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol. 2001;426:1-10.

30. Cardinali DP, Furio AM, Reyes MP. Clinical perspectives for the use of melatonin as a chronobiotic and cytoprotective agent. Ann N Y Acad Sci. 2005;1057:327-36.

31. Sofic E, Rimpapa Z, Kundurovic Z, et al. Antioxidant capacity of the neurohormone melatonin. J Neural Transm. 2005;112:349-58.

32. Reiter RJ, Tan DX, Mayo JC, et al. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol. 2003;50:1129-46.

33. Wakatsuki A, Okatani Y, Ikenoue N, et al. Melatonin inhibits oxidative modification of low-density lipoprotein particles in normolipidemic post-menopausal women. J Pineal Res. 2000;28:136-42.

34. Chakravarty S, Rizvi SI. Day and night GSH and MDA levels in healthy adults and effects of different doses of melatonin on these parameters. Int J Cell Biol. 2011;2011:404591. Epub 2011 Apr 28.

35. Ochoa JJ, Vilchez MJ, Palacios MA, et al. Melatonin protects against lipid peroxidation and membrane rigidity in erythrocytes from patients undergoing cardiopulmonary bypass surgery. J Pineal Res. 2003; 35:104-8.

36. Yi C, Pan X, Yan H, Guo M, Pierpaoli W. Effects of melatonin in age-related macular degeneration. Ann N Y Acad Sci. 2005 Dec;1057:384-92.

37. Gitto E, Reiter RJ, Amodio A, et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res. 2004 May;36(4):250-5.

39. Srinivasan V, Mohamed M, Kato H. Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent Pat Endocr Metab Immune Drug Discov. 2012 Jan;6(1):30-9.

40. Reiter RJ, Tan DX, Paredes SD, Fuentes-Broto L. Beneficial effects of melatonin in cardiovascular disease. Ann Med. 2010 May 6;42(4):276-85.

41. Baykan A, Narin N, Narin F, Akgün H, Yavaşcan S, Saraymen R. The protective effect of melatonin on nicotine-induced myocardial injury in newborn rats whose mothers received nicotine. Anadolu Kardiyol Derg. 2008 Aug;8(4):243-8.

42. Mukherjee D, Roy SG, Bandyopadhyay A, et al. Melatonin protects against isoproterenol-induced myocardial injury in the rat: antioxidative mechanisms. J Pineal Res. 2010 Apr;48(3):251-62.

43. Chen Z, Chua CC, Gao J, Hamdy RC, Chua BH. Protective effect of melatonin on myocardial infarction. Am J Physiol Heart Circ Physiol. 2003 May;284(5):H1618-24.

44. Sahna E, Parlakpinar H, Turkoz Y, Acet A. Protective effects of melatonin on myocardial ischemia/reperfusion induced infarct size and oxidative changes. Physiol Res. 2005;54(5):491-5.

45. Sallinen P, Manttari S, Leskinen H, et al. Long-term postinfarction melatonin administration alters the expression of DHPR, RyR(2), SERCA2, and MT(2) and elevates the ANP level in the rat left ventricle. J Pineal Res. 2008 Feb 13.

46. Dominguez-Rodriguez A, breu-Gonzalez P, Garcia-Gonzalez MJ, et al. A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocaRdial Infarction undergoing primary Angioplasty The Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty (MARIA) trial: study design and rationale. Contemp Clin Trials. 2007 Jul;28(4):532-9.

47. Corbalán-Tutau MD, Madrid JA, Nicolás F, Garaulet M. Daily profile in two circadian markers "melatonin and cortisol" and associations with metabolic syndrome components. Physiol Behav. 2012 Jun 15. [Epub ahead of print]

48. Cagnacci A, Arangino S, Angiolucci M, et al. Potentially beneficial cardiovascular effects of melatonin administration in women. J Pineal Res. 1997;22:16-9.

49. Cavallo A, Daniels SR, Dolan LM, et al. Blood pressure-lowering effect of melatonin in type 1 diabetes. J Pineal Res. 2004;36:262-6.

50. Cagnacci A, Cannoletta M, Renzi A, et al. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens. 2005;18:1614-8.

51. Grossman E, Laudon M, Yalcin R, et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med. 2006 Oct;119(10):898-902.

52. Rechciński T, Trzos E, Wierzbowska-Drabik K, Krzemińska-Pakuła M, Kurpesa M. Melatonin for nondippers with coronary artery disease: assessment of blood pressure profile and heart rate variability. Hypertens Res. 2010 Jan;33(1):56-61.

53. Pawlikowski M, Winczyk K, Karasek M. Oncostatic action of melatonin: facts and question marks. Neuro Endocrinol Lett. 2002;23:S24-9.

54. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. 2008 Sep;7(3):189-203.

55. Lissoni P, Rovelli F, Malugani F, et al. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuroendocrinol Lett. 2001;22:45-47.

56. Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ. Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs. 2012 Jun;21(6):819-31.

57. Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Rueda N. Breast cancer therapy based on melatonin. Recent Pat Endocr Metab Immune Drug Discov. 2012 May 1;6(2):108-16.

58. Song N, Kim AJ, Kim HJ,et al. Melatonin suppresses doxorubicin-induced premature senescence of A549 lung cancer cells by ameliorating mitochondrial dysfunction. J Pineal Res. 2012 Apr 4. doi: 10.1111/j.1600-079X.2012.01003.x. Epub ahead of print.

59. Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20. Epub 2012 Jan 24.

60. Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as adjuvant cancer care with and without chemotherapy: A systematic review and meta-analysis of randomized trials. Hepatobiliary Pancreat Dis Int. 2002 May;1(2):183-6.

61. Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in untreatable advanced hematologic malignancies. Eur J Cancer. 1999;35:1688-92.

62. Lissoni P, Bucovec R, Bonfanti A, et al. Thrombopoietic properties of 5-methoxytyrptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia. J Pineal Res. 2001;30:123-6.

63. Cerea G, Vaghi M, Ardizzoia A, et al. Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Res. 2003 Mar-Apr;23(2C):1951-4.

64. Berk L, Berkey B, Rich T, et al. Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119). Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):852-7.

65. Lissoni P, Brivio F, Fumagalli L, et al. Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res. 2008 Mar-Apr;28(2B):1377-81

66. Lissoni P, Fumagalli L, Paolorossi F, Rovelli F, Roselli MG, Maestroni GJ. Anticancer neuroimmunomodulation by pineal hormones other than melatonin: preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin. J Biol Regul Homeost Agents. 1997 Jul-Sep;11(3):119-22.

67. Bubenik G, Blask D, Brown G. Prospects of the clinical utilization of melatonin. Biol Signals Recept. 1998;7:195-219.

68. Zhang Z, Insena PF, Liang B, et al. Melatonin immune modulation and aging. Autoimmunity. 1997;26:43-53.

69. Srinivasan V, Maestroni G, Cardinali D, et al. Melatonin, immune function and aging. Immun Ageing. 2005;2:17.

70. Radogna F, Diederich M, Ghibelli L. Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol. 2010 Dec 15;80(12):1844-52.

71. Preiser JC. Oxidative stress. JPEN J Parenter Enteral Nutr. 2012 Mar;36(2):147-54. Epub 2012 Feb 1.

72. Hikichi T, Tateda N, Miura T. Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy. Clin Ophthalmol. 2011;5:655-60.

73. Baydas G, Canatan H, Turkoglu A. Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin-induced diabetes mellitus. J Pineal Res. 2002 May;32(4):225-30.

74. Korkmaz A, Ma S, Topal T, Rosales-Corral S, Tan DX, Reiter RJ. Glucose: a vital toxin and potential utility of melatonin in protecting against the diabetic state. Mol Cell Endocrinol. 2012 Feb 26;349(2):128-37.

75. Gumustekin M, Tekmen I, Guneli E, et al. Short-term melatonin treatment improved diabetic nephropathy but did not affect hemorheological changes in diabetic rats. Pharmazie. 2007 Sep;62(9):693-8.

76. Aygün D, Kaplan S, Odaci E, Onger ME, Altunkaynak ME. Toxicity of non-steroidal anti-inflammatory drugs: a review of melatonin and diclofenac sodium association. Histol Histopathol. 2012 Apr;27(4):417-36.

77. Kaur C, Ling EA. Antioxidants and neuroprotection in the adult and developing central nervous system. Curr Med Chem. 2008;15(29):3068-80.

78. Bonnefont-Rousselot D, Collin F. Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology. 2010 Nov 28;278(1):55-67.

79. Hardeland R. Melatonin metabolism in the central nervous system. Curr Neuropharmacol. 2010 Sep;8(3):168-81.

80. Srinivasan V, Pandi-Perumal SR, Cardinali DP, et al. Melatonin in Alzheimer's disease and other neurodegenerative disorders. Behavioral and Brain Functions 2006;2:15.

81. Cardinali DP, Pagano ES, Scacchi Bernasconi PA, Reynoso R, Scacchi P. Melatonin and mitochondrial dysfunction in the central nervous system. Horm Behav. 2012 Feb 25. [Epub ahead of print]

82. Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer's disease. Neuro Endocrinol Lett 2002;23:20-3.

83. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 2003;70:334-41.

84. Pappolla MA, Chyan YJ, Poeggeler B, et al. Alzheimer beta protein mediated oxidative damage of mitochondrial DNA: prevention by melatonin. J Pineal Res. 1999;27:226-9.

85. Pappolla M, Bozner P, Soto C, et al. Inhibition of Alzheimer B-fibrillogenesis by melatonin. J Biol Chem. 1998;273:7185-8.

86. Pappolla MA, Soss M, Omar RA, et al. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neuro Sci. 1997;17:1683-90.

87. Bachurin S, Oxenkrug G, Lermontova N, et al. N-acetylserotonin, melatonin and their derivatives improve cognition and protect against beta-amyloid-induced neurotoxicity. Ann N Y Acad Sci. 1999;890:155-66.

88. Wang X. The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther. 2009 Winter;15(4):345-57. Review.

89. Van Someren EJ, Mirmiran M, Swaab DF. Non-pharmacological treatment of sleep and wake disturbances in aging and Alzheimer's disease: chronobiological perspectives. Behav Brain Res. 1993;57:235-53.

90. Dowling GA, Burr RL, Van Someren EJ, et al. Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease. J Am Geriatr Soc. 2008 Feb;56(2):239-46. Epub 2007 Dec 7.

91. Cardinali DP, Furio AM, Brusco LI. Clinical aspects of melatonin intervention in Alzheimer's disease progression. Curr Neuropharmacol. 2010 Sep;8(3):218-27.

92. Singer C, Tractenberg RE, Kaye J, et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep. 2003;26:893–901.

93. Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry. 2009;17:166-9.

94. Goel N, Stunkard AJ, Rogers NL, et al. Circadian rhythm profiles in women with night eating syndrome. J Biol Rhythms. 2009 Feb;24(1):85-94.

95. Rastmanesh R, de Bruin PF. Potential of melatonin for the treatment or prevention of obesity: An urgent need to include weight reduction as a secondary outcome in clinical trials of melatonin in obese patients with sleep disorders. Contemp Clin Trials. 2012 Jul;33(4):574-5. Epub 2012 Apr 5.

96. Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, et al. 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. Endocrinology. 2000;141:487-97.

97. Prunet-Marcassus B, Desbazeille M, Bros A, et al. Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity. Endocrinology. 2003;144:5347-52.

98. Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology. 1999 Feb;140(2):1009-12. Erratum in: Endocrinology 2002 Apr;143(4):1269.

99. Puig-Domingo M, Guerrero JM, Reiter RJ, et al. Thyroxine 5'-deiodination in brown adipose tissue and pineal gland: implications for thermogenic regulation and role of melatonin. Endocrinology. 1988 Aug;123(2):677-80.

100. Torres-Farfan C, Valenzuela FJ, Mondaca M, et al. Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland. J Physiol. 2008 Aug 15;586(16):4017-27.

101. Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev. 2011 Mar;12(3):167-88.

102. Ginter E, Simko V. Brown fat tissue - a potential target to combat obesity. Bratisl Lek Listy. 2012;113(1):52-6.

103. Nduhirabandi F, Du Toit EF, Blackhurst D, Marais D, Lochner A. Chronic melatonin consumption prevents obesity-related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet-induced obesity. J Pineal Res. 2011 Mar;50(2):171-82. doi: 10.1111/j.1600-079X.2010.00826.x. Epub 2010 Nov 15.

104. Ramírez-Fernández MP, Calvo-Guirado JL, de-Val JE, et al. Melatonin promotes angiogenesis during repair of bone defects: a radiological and histomorphometric study in rabbit tibiae. Clin Oral Investig. 2012 Feb 11. Epub ahead of print.

105. Kotlarczyk MP, Lassila HC, O'Neil CK, et al. Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res. 2012 May;52(4):414-26.

106. Seabra MLV, Bignotto M, Pinto LR Jr, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29:193–200.