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ANTI-AGING DRUGS AND SUPPLEMENTS
 
 5.2 DRUGS WITH CONTROVERSIAL OR UNPROVEN ANTI-AGING EFFECT (side-effects)  
   
 
  MELATONIN  
   


INTRODUCTION

Melatonin is a hormone produced by humans in the pineal gland - the "sleep" hormone. Its levels increase with darkness, reach their highest level in the middle of the night and fall until the morning. It has no side effects, even in individuals given doses 10000 times higher than normal. Melatonin is an effective scavenger of the extremely toxic hydroxyl radical and other free radicals. It may therefore provide protection to some micromolecules, especially DNA, but only in high doses. But high doses are not so sound, because it makes you feel sleepy and good for nothing on the next day. If you buy melatonin as a supplement, be careful where you buy it from because it may contain toxic impurities.
Below you find a list of scientific abstracts on Melatonin.

   
Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin.
Over-the-counter sleeping pills: a survey of use in Hong Kong and a review of their constituents.
Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation.
Melatonin: interesting, but not miraculous.
Melatonin: media hype or therapeutic breakthrough?
Daily melatonin supplementation in mice increases atherosclerosis in proximal aorta.
Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin.
Aging-dependent changes in the effect of daily melatonin supplementation on rat metabolic and behavioral responses.
Long-term supplementation with melatonin delays reproductive senescence in rats, without an effect on number of primordial follicles.
Long-term melatonin supplementation does not recover the impairment of natural killer cell activity and lymphocyte proliferation in aging mice.
Effect of melatonin and pineal peptide preparation epithalamin on life span and free radical oxidation in Drosophila melanogaster.
The effect of melatonin on the indices of biological age, on longevity and on the development of spontaneous tumors in mice.
Melatonin fails to modulate immune parameters influenced by calorie restriction in aging Fischer 344 rats.
Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels.
Effects of aging and melatonin administration on gonadotropin-releasing hormones (GnRH) gene expression in the male and female rat.
Melatonin treatment delays reproductive aging of female rat via the opiatergic system.
The use of melatonin for the treatment of insomnia.
The efficacy of vitamin E and melatonin as antioxidants against lipid peroxidation in rat retinal homogenates.
Melatonin and aging.
Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging.
The use of anti-aging hormones. Melatonin, growth hormone, testosterone, and dehydroepiandrosterone: consumer enthusiasm for unproven therapies.
Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis.
 
 
   
   
J Pineal Res. 2003 Aug;35(1):32-9
Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin.
Esparza JL, Gomez M, Romeu M, Mulero M, Sanchez DJ, Mallol J, Domingo JL.
Laboratory of Toxicology and Environmental Health and Pharmacology Unit, School of Medicine, "Rovira i Virgili" University, Reus, Spain.
In recent years, it has been suggested that oxidative stress is a feature of Alzheimer's disease in which aluminum (Al) could exacerbate oxidative events. The goal of the present study was to assess in rats the pro-oxidant effects induced by Al exposure, as well as the protective role of exogenous melatonin. Two groups of male rats were intraperitoneally injected with Al only or melatonin only, at doses of 5 and 10 mg/kg/day, respectively for 8 wk. During this period, a third group of animals received Al (5 mg/kg/day) and melatonin (10 mg/kg/day). At the end of the treatment period, rats were anesthesized and arterial blood was obtained. Thereafter, animals were killed and liver and brain (cortex, hippocampus and cerebellum) were removed. These tissues were processed to examine oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Samples of these tissues were also used to determine Al, Fe, Mn, Cu and Zn concentrations. The results show that Al exposure promotes oxidative stress in different neural areas, including those in which Al concentrations were not significantly increased. The biochemical changes observed in neural tissues show that Al acts as pro-oxidant, while melatonin exerts an antioxidant action in Al-treated animals. The protective effects of melatonin against cellular damage caused by Al-induced oxidative stress, together with its low toxicity, make melatonin worthy of investigation as a potential supplement to be included in the treatment of neurological disorders in which the oxidative effects must be minimized.

   
   
Gen Hosp Psychiatry. 2002 Nov-Dec;24(6):430-5
Over-the-counter sleeping pills: a survey of use in Hong Kong and a review of their constituents.
Chung KF, Lee CK.
Department of Psychiatry, University of Hong Kong, Hong Kong SAR, China.
This study examined the composition of over-the-counter (OTC) sleeping pills in Hong Kong and reviewed the current knowledge about the hypnotic efficacy and safety of their major herbal and dietary supplement constituents. We conducted a cross-sectional survey of OTC sleep aids at drug stores in a residential district of 0.3 million population and literature search using MEDLINE, EMBASE, PsycINFO, China Journal Net, China Biomedical Database and relevant English and Chinese literature. We identified 17 brands of OTC sleeping pill: eleven of them were composed of mixtures of Chinese and Western herbal agents and six brands contained 3 mg of melatonin. The Chinese herbal mixture suanzaorentang, comprising zizyphi spinosi semen, poria cocos, ligusticum wallichii, anemarrhenae rhizoma and glycyrrhizae radix in ratio of 7:5:2:1:1, was the most common OTC sleeping pill available in the survey. Our literature review showed that kava, valerian and melatonin were the better-researched herbs and dietary supplements, however, the data on hypnotic efficacy and safety was inadequate to support their clinical use. More rigorous investigations of the risk-benefit relationship of herbal agents and dietary supplements used for insomnia are needed.

   
   
Proc Soc Exp Biol Med. 2000 Oct;225(1):9-22
Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation.
Karbownik M, Reiter RJ.
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Ionizing radiation is classified as a potent carcinogen, and its injury to living cells is, to a large extent, due to oxidative stress. The molecule most often reported to be damaged by ionizing radiation is DNA. Hydroxyl radicals (*OH), considered the most damaging of all free radicals generated in organisms, are often responsible for DNA damage caused by ionizing radiation. Melatonin, N-acetyl-5-methoxytryptamine, is a well-known antioxidant that protects DNA, lipids, and proteins from free-radical damage. The indoleamine manifests its antioxidative properties by stimulating the activities of antioxidant enzymes and scavenging free radicals directly or indirectly. Among known antioxidants, melatonin is a highly effective scavenger of *OH. Melatonin is distributed ubiquitously in organisms and, as far as is known, in all cellular compartments, and it quickly passes through all biological membranes. The protective effects of melatonin against oxidative stress caused by ionizing radiation have been documented in in vitro and in vivo studies in different species and in in vitro experiments that used human tissues, as well as when melatonin was given to humans and then tissues collected and subjected to ionizing radiation. The radioprotective effects of melatonin against cellular damage caused by oxidative stress and its low toxicity make this molecule a potential supplement in the treatment or co-treatment in situations where the effects of ionizing radiation are to be minimized.

   
   
Prescrire Int. 1998 Dec;7(38):180-7
Melatonin: interesting, but not miraculous.
(1) In the United States melatonin is just a dietary supplement, but in Europe its status varies from country to country and also over time. It is illegal in some European member states but tolerated or authorised as a drug or dietary product elsewhere. Melatonin, a hormone secreted by the pineal gland, has been on the front cover of magazines throughout the world for its claimed effects on ageing, cancer and many other health problems, opening up a vast potential market. (2) Only its use in jet lag, sleep disorders and advanced cancer has been tested clinically (albeit scantily). (3) Melatonin seems to alleviate jet lag symptoms, but that could be linked to its moderate hypnotic effect. (4) The use of melatonin to treat major insomnia cannot be envisaged until its long-term safety has been proven. With this proviso, and if efficacy is confirmed in sufficiently large comparative trials, melatonin could prove useful for treating major sleep disorders in some patients, especially blind people and those with severe neurological disabilities. (5) According to open trials conducted by a single team, melatonin, alone or combined with interleukin-2, could slightly lengthen the survival of patients with some advanced cancers, but even partial tumour remissions are rare. (6) All other "indications" are based on simplistic hypotheses or purely commercial considerations.

   
   
Nurse Pract. 1997 Feb;22(2):66-7, 71-2, 77
Melatonin: media hype or therapeutic breakthrough?
Kendler BS.
Manhattan College, Riverdale, N.Y., USA.
Currently available as a dietary supplement, the pineal hormone melatonin is portrayed by the media as a formidable weapon against disease and aging. Accordingly, primary health care providers should be cognizant of which of its proposed uses are supported by biomedical research and which are, as yet, unproven. Melatonin entrains circadian rhythms and, thus, can treat jet lag, delayed sleep phase syndrome, and sleep disorders in the blind and in some neurologically impaired children. By virtue of its hypnotic effect, melatonin can mitigate insomnia in the elderly. Reductions in melatonin secretion have been associated with many disorders, including cardiovascular disease, Alzheimer's, diabetes, SIDS, and aging; however, melatonin's role in their etiology and/or pathophysiology is unproven. Preliminary studies suggest a possible adjuvant therapeutic role for melatonin in cancer therapy. Melatonin secretion is reduced by alcohol, caffeine, and some commonly prescribed drugs. Since tolerance, fatigue, and other side effects have been reported, melatonin use on consecutive nights should be avoided and only the lowest effective hypnotic dose should be taken.

   
   
Biochem Biophys Res Commun. 2002 May 10;293(3):1114-23
Daily melatonin supplementation in mice increases atherosclerosis in proximal aorta.
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.
Departement d'Atherosclerose, Inserm U545, Institut Pasteur, 1 rue du Pr Calmette, 59019 Lille, France.

Considerable evidence supports the hypothesis that LDL oxidation plays an important role in atherosclerosis. Even though high melatonin doses inhibit LDL oxidation in vitro, the effect of melatonin on atherosclerosis has never been studied. We have demonstrated that the feeding of hypercholesterolemic mice with an atherogenic diet supplemented with melatonin highly increases the surface of atherosclerotic lesions in the proximal aorta. These observations occur without detectable lipidic or glucidic phenotype alteration. Melatonin treatment increased highly the sensitivity of atherogenic lipoprotein to Cu(2+) and gamma-radiolysis generated oxyradical ex vivo oxidation during the fasting period. Moreover, these altered lipoproteins were less recognized by the LDL receptor metabolic pathway of murine fibroblasts while they transferred many more cholesteryl esters to murine macrophages. This study suggests that caution should be taken as regards high melatonin dosage in hypercholesterolemic patients.

   
   
Exp Gerontol. 2002 May;37(5):629-38
Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin.
Bonilla E, Medina-Leendertz S, Diaz S.
Instituto de Investigaciones Clinicas Dr Americo Negrette, Facultad de Medicina, Universidad del Zulia, Apartado Postal 1151 Maracaibo, Venezuela.

According to the free radical theory of aging, free radicals are involved in the production of changes in cellular metabolism that lead to a time-dependent functional decline in all living beings. Consequently, antioxidant and/or free radicals scavengers may retard the aging process. We explored the effect of melatonin on the life span of Drosophila melanogaster (Oregon wild strain). It was presumed that given the antioxidant and free radicals scavenger properties of melatonin, this hormone would prevent oxidative damage to the fly tissues and slow down the process of aging. Melatonin, added daily to the nutrition medium at a concentration of 100 microg/ml, increased significantly the life span of D. melanogaster. The maximum life span was 61.2 days in controls and 81.5 days in melatonin fed flies. Relative to the controls, the percentage increase in the melatonin fed flies was 33.2% in maximum life span, 19.3% in the onset of 90% mortality, and 13.5% in median life span. Furthermore, in a test of superoxide mediated toxicity it was shown that melatonin treatment increased the resistance of D. melanogaster to paraquat. Finally, the augmented resistance to an ambient temperature of 36 degrees C was also a demonstration of the antioxidative protection provided by the hormone.

   
   
J Pineal Res. 2001 Aug;31(1):89-94
Aging-dependent changes in the effect of daily melatonin supplementation on rat metabolic and behavioral responses.
Rasmussen DD, Mitton DR, Larsen SA, Yellon SM.
VA Puget Sound Health Care System, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle 98195, USA.

Pineal melatonin secretion has been reported to commonly decrease with aging, whereas intra-abdominal adiposity, plasma insulin and plasma leptin levels tend to increase. We recently demonstrated that daily melatonin administration starting at middle age suppressed male rat intra-abdominal fat, plasma leptin and plasma insulin to youthful levels, suggesting that aging-related changes in pineal melatonin secretion and in energy regulation may be functionally related. Accordingly, we have now investigated the effects of daily melatonin treatment on energy regulation in young versus middle-aged male Sprague Dawley rats. Addition of melatonin to the drinking water (0.2 microg/mL) produced nocturnal and diurnal plasma melatonin concentrations in middle-aged rats (12 months) equivalent to those of young adult (5 months) rats. Administration of this melatonin dosage every day for 10 wk starting at 10 months of age suppressed (P < 0.01) relative intra-abdominal fat, non-fasted plasma insulin and plasma leptin by 27, 39, and 51%, respectively (vs. vehicle-treated controls). In contrast, administration of melatonin for 10 wk starting at 3 months of age did not significantly alter (P> 0.10) any of these parameters. The melatonin administration stimulated (102%, P < 0.001) behavioral responsiveness of the middle-aged rats in a test of response to novelty, restoring youthful levels, but did not significantly alter behavioral responsiveness of the young rats. These results suggest that suppression of intra-abdominal adiposity and plasma leptin and insulin levels and stimulation of behavioral responsiveness in response to daily exogenous melatonin begins at middle age, coincident with and likely dependent upon the aging-associated decline in endogenous pineal melatonin secretion. These results further suggest that appropriate melatonin supplementation may potentially provide therapy or prophylaxis not only for the insulin resistance, increased intra-abdominal fat and resulting pathologies that occur with aging, but also for some aging-associated behavioral changes.

   
   
Exp Gerontol. 2000 May;35(3):343-52
Long-term supplementation with melatonin delays reproductive senescence in rats, without an effect on number of primordial follicles.
Meredith S, Jackson K, Dudenhoeffer G, Graham L, Epple J.
Cooperative Research, Lincoln University, Jefferson City, MO 65102-0029, USA.

The primary objective of the present experiment was to determine if lifelong supplementation with melatonin delayed reproductive senescence through decreased loss of ovarian primordial follicles. Holtzman rats were divided into three treatments on Day 10 after pupping (Day 0 = day of pupping). Treatment 1 pups had access to water, whereas Treatment 2 and 3 pups had access to water containing 10 microg/ml melatonin only at night (Treatment 2) or continuously (Treatment 3). Estrous cycles and weights of pups were monitored at selected times during the experiment; ovaries were removed for histology at 75 and 380 days of age. Vaginal opening in Treatment 2 was delayed (P <.01) compared with Treatments 1 and 3, but there was no difference (P > 0.05) among treatments in percentage of normal length estrous cycles from vaginal opening to 75 days of age. There were fewer (P < 0.001) abnormal-length estrous cycles from 180 to 380 days of age in Treatment 2 as compared with Treatments 1 or 3. There was no effect of treatment (P > 0.05) on number of primordial follicles. In conclusion, nighttime, but not continuous supplementation with melatonin, delayed puberty and reproductive senescence without any effect on number of primordial follicles.

   
   
Life Sci. 1997;61(9):857-64
Long-term melatonin supplementation does not recover the impairment of natural killer cell activity and lymphocyte proliferation in aging mice.
Provinciali M, Di Stefano G, Bulian D, Stronati S, Fabris N.
Immunology Center, Gerontology Research Department, INRCA, Ancona, Italy.

In this study we evaluated the effect of long-term melatonin (MEL) treatment on the cytotoxic activity and number of natural killer (NK) cells and the proliferative response of spleen lymphocytes to phytohemagglutinin (PHA) or interleukin-2 (IL-2) in old mice. Seventeen-eighteen month-old Balb/c mice were supplemented with MEL (40-50 microg/day/mouse) and sacrificed after eight months. The MEL supplementation was unable to recover the low levels of both endogenous and IL-2-induced NK cell activity found in old untreated mice. Also the NK cell number was unaffected by MEL treatment. The spleen lymphocyte proliferative response to both PHA and IL-2 was not different in old MEL-treated compared to old untreated mice. These results indicate that long-term MEL supplementation does not recover the age-related deterioration of NK cell activity and lymphocyte proliferative capacity.

   
   
Mech Ageing Dev. 1997 Aug;97(2):81-91
Effect of melatonin and pineal peptide preparation epithalamin on life span and free radical oxidation in Drosophila melanogaster.
Anisimov VN, Mylnikov SV, Oparina TI, Khavinson VK.
Laboratory of Experimental Tumors, N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia.

It was shown previously that epithalamin delays age-related changes in reproductive and immune systems and increases the life span of mice and rats. These effects could be mediated by stimulating influences of epithalamin on synthesis and secretion of melatonin and on free radical processes. A comparative study on the effect of epithalamin and melatonin on both the life span of Drosophila melanogaster (strain HEM) and on the intensity of lipid peroxidation and activity of antioxidative enzymes in their tissues was the main aim of this work. Melatonin and epithalamin was added to the nutrition medium (100 micrograms/ml) during 2-3rd age of larvas. For survival analysis the flies were passed (five coupes per vessel) each 3-7 days. Lipid peroxidation was evaluated as the level of ketodienes (KD) and conjugated hydroperoxides (CHP) in fly tissues at the age of 11 days. Activity of Cu, Zn-superoxide dismuatse (SOD) and catalase was evaluated as well. The mean, median and maximum life span (MLS) were estimated. Mortality rate (MR) was calculated as alpha in the Gompertz equation (R = Ro (exp alpha t) and mortality rate doubling time (MRDT) as in 2/alpha. These parameters in groups of male and female flies exposed to melatonin and in male flies exposed to epithalamin were no different from the parameters for controls. However, exposure to epithalamin was followed in females by a significant increase in mean life span (by 17%, P < 0.02), of median (by 26%), of MLS by 14% and by a 2.12 times decrease of MR (P < 0.01) and MRDT (by 32%) compared with female controls. The level of CHP and KD in the tissues of male control flies was 40 and 49% less than that in females and indirectly correlates with male life span. Exposure to melatonin was followed by a decrease in the level of CHP and KD in females and the deletion of sex differences in them. Exposure to epithalamin significantly decreased the level of CHP and KD in female flies compared to controls (2.3 and 3.4 times, respectively, P < 0.001). Exposure to melatonin failed to influence the activity of catalase in males but increased it in females by 24% (P < 0.02) and failed to influence SOD activity both in males and females. Exposure to epithalamin was followed by a significant increase in activity of catalse, 20% in males and 7% in females and by an increase in SOD activity in males (41%). Thus, it was shown that exposure to epithalamin significantly increases the mean life span and MLS of female D.melanogaster and slowed down their aging rate by 2.12 times. This effect is in good agreement with the inhibiting effect of epithalamin in lipid peroxidation processes in fly tissues.

   
   
Vopr Onkol. 2000;46(3):311-9
The effect of melatonin on the indices of biological age, on longevity and on the development of spontaneous tumors in mice.
Anisimov VN, Zavarzina NIu, Zabezhinskii MA, Popovich IG, Anikin IV, Zimina OA, Solov'ev MV, Shtylik AV, Arutiunian AV, Oparina TI, Prokopenko VM, Khavinson VKh.
N. N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St. Petersburg.

Fifty female CBA mice were given melatonin with drinking water (20 mg/l) for 5 consecutive days monthly, beginning from the age of 6 months, until natural death. Another 50 intact mice were used as controls. Melatonin failed to significantly influence body weight or food consumption. Age-related switching-off of estrus function was delayed, body temperature decreased. Somewhat decreased motor activity did not affect physical one or endurance. Increase in life span led to higher spontaneous tumor incidence. Another experiment using 20 animals of the same line showed melatonin to inhibit free-radical processes. A conclusion was drawn that caution should be exercised before melatonin is recommended for long-term administration as a geroprotector.

   
   
Exp Biol Med (Maywood). 2002 Mar;227(3):201-7
Melatonin fails to modulate immune parameters influenced by calorie restriction in aging Fischer 344 rats.
Pahlavani MA, Vargas DA, Evans TR, Shu JH, Nelson JF.
Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78229, USA.

The aim of this study was to determine if long-term treatment with melatonin (MEL), a purported anti-aging agent, was as effective as calorie restriction (CR) in modulating immune parameters in aging Fischer 344 male rats. Splenic lymphocytes were isolated from 17-month-old rats that, beginning at 6 weeks of age, were treated with MEL (4 or 16 microg/ml in drinking water) and from 17-month-old rats fed ad libitum (AL) or rats fed a CR diet (55% of AL intake). The number of splenic T cell populations and T cell subsets was measured by flow cytometry, the proliferative response of splenocytes to Concanavalin A (Con A) and lipopolysaccharide (LPS) was measured by [(3)H]thymidine incorporation, and the induction of cytokine production (IL-2 and IFN-gamma) was measured by ELISA assay. In addition, the level of the natural killer (NK) cell activity was assessed by fluorimetric assay. CR rats had a higher number of lymphocytes expressing the naive T cell marker (CD3 OX22) than AL rats (P < 0.05). CR rats also showed greater induction of proliferative response, IL-2 and IFN-gamma levels following Con A simulation, and NK cell activity than AL rats (P < 0.05). MEL-treated rats did not differ from AL rats in any of these parameters or in any other measurement. These results indicate that MEL treatment is unable to modulate immune function in a manner comparable with that of CR.

   
   
Endocrinology. 1999 Feb;140(2):1009-12
Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels.
Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM.
VA Puget Sound Health Care System, and Department of Medicine, University of Washington, Seattle 98195, USA.

Human and rat pineal melatonin secretion decline with aging, whereas visceral fat and plasma insulin levels increase. Melatonin modulates fat metabolism in some mammalian species, so these aging-associated melatonin, fat and insulin changes could be functionally related. Accordingly, we investigated the effects of daily melatonin supplementation to male Sprague-Dawley rats, starting at middle age (10 months) and continuing into old age (22 months). Melatonin was added to the drinking water (92% of which was consumed at night) at a dosage (4 microg/ml) previously reported to attenuate the aging-associated decrease in survival rate in male rats, as well as at a 10-fold lower dosage. The higher dosage produced nocturnal plasma melatonin levels in middle-aged rats which were 15-fold higher than in young (4 months) rats; nocturnal plasma melatonin levels in middle-aged rats receiving the lower dosage were not significantly different from young or middle-aged controls. Relative (% of body wt) retroperitoneal and epididymal fat, as well as plasma insulin and leptin levels, were all significantly increased at middle age when compared to young rats. All were restored within 10 weeks to youthful (4 month) levels in response to both dosages of melatonin. Continued treatment until old age maintained suppression of visceral (retroperitoneal + epididymal) fat levels. Plasma corticosterone and total thyroxine (T4) levels were not significantly altered by aging or melatonin treatment. Plasma testosterone, insulin-like growth factor I (IGF-I) and total triiodothyronine (T3) decreased by middle age; these aging-associated decreases were not significantly altered by melatonin treatment. Thus, visceral fat, insulin and leptin responses to melatonin administration may be independent of marked changes in gonadal, thyroid, adrenal or somatotropin regulation. Since increased visceral fat is associated with increased insulin resistance, diabetes, and cardiovascular disease, these results suggest that appropriate melatonin supplementation may potentially provide prophylaxis or therapy for some prominent pathologies associated with aging.

   
   
Peptides. 1997;18(7):1023-8
Effects of aging and melatonin administration on gonadotropin-releasing hormones (GnRH) gene expression in the male and female rat.
Li S, Givalois L, Pelletier G.
Laboratory of Molecular Endocrinology, CHUL Research Center, Quebec, Canada.

It is well documented that in the rat of both sexes aging is associated with a decline in reproductive functions. We have recently shown that melatonin exerts a positive influence on GnRH gene expression in the adult male rats. In order to evaluate the effect of aging as well as melatonin on GnRH mRNA levels, we have studied the effect of 2.5-day administration of melatonin to young (50-55 day of age) and aged (18 month of age) rats of both sexes. In the young males melatonin induced a 11% increase in the hybridization signal. In the aged males, the GnRH mRNA levels were 13% lower than those observed in the young animals. Melatonin administration to aged animals completely restored GnRH mRNA levels when compared to those observed in the young untreated male rats. In contrast, melatonin did not modify the hybridization signal in young female rats, while aging induced a 20% decrease in mRNA levels. Melatonin administration to aged female induced a 18% increase in GnRH mRNA levels, thus completely reversing the influence of aging. These results indicate that the decrease in GnRH gene expression which is likely involved in the decline of reproductive functions in aging can be totally reversed by a short term administration of melatonin, then suggesting that the pineal hormone may be involved in the decrease of GnRH neuronal activity during aging.

   
   
Neuroendocrinology. 1992 Sep;56(3):364-70
Melatonin treatment delays reproductive aging of female rat via the opiatergic system.
Trentini GP, Genazzani AR, Criscuolo M, Petraglia F, De Gaetani C, Ficarra G, Bidzinska B, Migaldi M, Genazzani AD.
Institute of Pathological Anatomy, University of Modena, Italy.

In female rat age-related reproductive decline is accompanied by progressive impairment of the neuroendocrine mechanisms that regulate LH secretion. The biosynthetic activity of the pineal gland is markedly depressed and the nocturnal secretion of melatonin decreases significantly. The aim of the present study was to evaluate whether the nocturnal administration of melatonin via the drinking water (0.4 micrograms/ml) throughout the course of aging from 14 to 24 months of age could (1) influence the age-related changes that occur in basal serum levels of LH and in the LH response to GnRH or to naloxone stimulation at 16, 18 and 20 months of age, and (2) delay the onset of the postreproductive constant estrous-anovulatory state as evaluated by the daily recording of vaginal smears and by occurrence of polyfollicular ovaries at 24 months of age. Our results demonstrate that melatonin replacement delays the increase in LH serum levels and the decrease in LH response to GnRH that occur in 18-month-old control animals. Furthermore, they show that melatonin treatment prevents the loss of LH response to naloxone manifested in control rats between 16 and 20 months of age. Melatonin also appears to prevent the progressive increase in the monthly occurrence of estrus phases as well as to decrease the number of rats with polyfollicular ovaries at 24 months of age in comparison to control animals. These results suggest that the age-related decrease in circulating melatonin during the night may contribute to the reproductive decline of aging, and that this effect may involve the central opioid system.

   
   
Biol Signals Recept. 1999 Jan-Apr;8(1-2):84-9
The use of melatonin for the treatment of insomnia.
Zisapel N.
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

The pineal product melatonin is involved in the regulation of the sleep/wake cycle in humans. In blind individuals and in people travelling through time zones, melatonin rhythms are sometimes unsynchronized with the diel cycle, and nocturnal sleep may be disturbed. Low or distorted melatonin rhythms have repeatedly been reported in middle aged and elderly insomniacs. Melatonin administration effectively synchronized the sleep wake cycle in blind individuals and in subjects suffering from jet lag and advanced sleep onset in subjects suffering from delayed sleep phase syndrome. In elderly insomniacs, melatonin replacement therapy significantly decreased sleep latency, and/or increased sleep efficiency and decreased wake time after sleep onset. In addition, melatonin substitution facilitated benzodiazepine discontinuation in chronic users. These data show an association between melatonin rhythm disturbances and difficulties to promote or maintain sleep at night. Specific melatonin formulations may be useful to treat circadian-rhythm-related sleep disorders and age-related insomnia.

   
   
J Pineal Res. 1998 May;24(4):239-44
The efficacy of vitamin E and melatonin as antioxidants against lipid peroxidation in rat retinal homogenates.
Siu AW, Reiter RJ, To CH.
Department of Optometry and Radiography, The Hong Kong Polytechnic University, Hung Hom, Kowloon.

Free radical-induced oxidation can cause severe cell damage in biological systems. Melatonin, a pineal secretory product, is a recently identified antioxidant that protects cells from the damaging effects of free radicals. We compared the effect of melatonin and vitamin E, another antioxidant, against lipid peroxidation (LPO) in rat retinal homogenates. The aim was to characterize the antioxidative efficacy of melatonin in retina, a tissue highly susceptible to oxidative damage. The LPO product, malondialdehyde (MDA), was determined to provide an index of cell damage in vitro. After the incubation with iron(II) ions, the free radical scavenging effectiveness of four different concentrations (i.e., 0.5, 1.0, 2.0, and 4.0 mM) of vitamin E and melatonin were determined by comparing the final levels of MDA. Lipid peroxidation product levels were significantly reduced in a dose-response manner by all concentrations of vitamin E. Melatonin, in concentrations of either 2.0 or 4.0 mM, also significantly reduced LPO. Statistical analysis of the data showed that vitamin E treatment always yielded a lower level of LPO products than did the same concentration of melatonin. The concentrations of each agent required to inhibit 50% of the lipid damage (IC50) were 0.69 mM and 4.98 mM for vitamin E and melatonin, respectively. Both vitamin E and melatonin protect the retina against LPO in a dose-dependent manner. Although the IC50 value for melatonin is about 7.2 times higher than that of vitamin E, melatonin's pharmacological and physiological role in the treatment and/or prevention of certain retinal diseases in vivo should be further investigated.

   
   
Neuroendocrinol Lett. 2002 Apr;23 Suppl 1:14-6
Melatonin and aging.
Karasek M, Reiter RJ.
Laboratory of Electron Microscopy, Chair of Pathomorphology, Medical University of Lodz, 92-216 Lodz, Czechoslowacka 8/10, Poland.

Although many theories relating the pineal secretory product melatonin to aging have been put forward, the role of this agent in the aging process is not clear. However, there are several reasons to postulate a role for melatonin in this process. Melatonin levels fall gradually over the life-span. Melatonin is a potent free radical scavenger. Melatonin deficiency is related to suppressed immunocompetence. In at least one animal model melatonin supplementation increased life-span although several other studies have failed. The aging process is multifactorial, and no single element seems to be of basic importance. It seems, however, that although melatonin can not be univocally recognized as a substance delaying aging, some of its actions may be beneficial for the process of aging. However, the precise role of melatonin in the aging process remains to be determined.

   
   
Ann N Y Acad Sci. 2002 Apr;959:238-50
Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging.
Reiter RJ, Tan DX, Manchester LC, El-Sawi MR.
Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.

Melatonin has a number of properties as a consequence of which it could be beneficial to animals as they age. Of particular interest are its ubiquitous actions as a direct and indirect antioxidant and free radical scavenger. Besides directly detoxifying a variety of reactive oxygen and reactive nitrogen species, at least one product that is formed as a result of these interactions is also a potent free radical scavenger. Thus, the product that is formed when melatonin detoxifies hydrogen peroxide, that is, N1-acetyl-N2-formyl-5-methoxykynuramine is an efficient scavenger, at least equivalent to melatonin itself. This antioxidant cascade increases the ability of melatonin to resist oxidative damage. Other actions of melatonin, such as stimulation of antioxidative enzymes also improves its status as an antioxidant. Finally, recent observations documenting melatonin's ability to stimulate electron transport and ATP production in the inner-mitochondrial membrane also has relevance for melatonin as an agent that could alter processes of aging. These findings, coupled with diminished melatonin production in advanced age, has prompted scientists to consider melatonin in the context of aging. As of this writing there is no definitive evidence to prove that melatonin alters the rate of aging, although data relating to melatonin deferring some age-related degenerative conditions is accumulating rapidly.

   
   
Md Med J. 1997 Apr;46(4):181-6
The use of anti-aging hormones. Melatonin, growth hormone, testosterone, and dehydroepiandrosterone: consumer enthusiasm for unproven therapies.
Shomali ME.
Department of Medicine, University of Maryland, USA.

Since ancient times, humans have been concerned with developing and preserving youthful vigor. Today, there is enough understanding of the aging process to attempt to delay it. This review considers four popular and easily obtainable anti-aging hormones: melatonin, growth hormone, testosterone, and dehydroepiandrosterone (DHEA). Many of the benefits of using these hormones, which are promoted in the lay literature, are based on animal studies and weak associations. This review critically examines the scientific literature. At this time, there is insufficient evidence to recommend these hormones as therapies for aging, and there are potential risks from their use. The information provided here will help physicians discuss the use of these hormones with inquiring patients.

   
   
J Pineal Res. 1993 May;14(4):151-68
Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis.
Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC.
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio 78284-7762.

Melatonin is a very potent and efficient endogenous radical scavenger. The pineal indolamine reacts with the highly toxic hydroxyl radical and provides on-site protection against oxidative damage to biomolecules within every cellular compartment. Melatonin acts as a primary non-enzymatic antioxidative defense against the devastating actions of the extremely reactive hydroxyl radical. Melatonin and structurally related tryptophan metabolites are evolutionary conservative molecules principally involved in the prevention of oxidative stress in organisms as different as algae and rats. The rate of aging and the time of onset of age-related diseases in rodents can be retarded by the administration of melatonin or treatments that preserve the endogenous rhythm of melatonin formation. The release of excitatory amino acids such as glutamate enhances endogenous hydroxyl radical formation. The activation of central excitatory amino acid receptors suppress melatonin synthesis and is therefore accompanied by a reduced detoxification rate of hydroxyl radicals. Aged animals and humans are melatonin-deficient and more sensitive to oxidative stress. Experiments investigating the effects of endogenous excitatory amino acid antagonists and stimulants of melatonin biosynthesis such as magnesium may finally lead to novel therapeutic approaches for the prevention of degeneration and dysdifferentiation associated with diseases related to premature aging.

 
 
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FASTING / LOW CALORIE PROGRAMS
on the Adriatic Coast
The Anti-Aging Fasting Program consists of a 7-28 days program (including 3 - 14 fasting days). 7-28-day low-calorie diet program is also available .
More information
    The anti-aging story (summary)
Introduction. Statistical review. Your personal aging curve
  Aging and Anti-aging. Why do we age?
    2.1  Aging forces (forces that cause aging
     
Internal (free radicals, glycosylation, chelation etc.) 
External (Unhealthy diet, lifestyle, wrong habits, environmental pollution, stress, poverty-change "poverty zones", or take it easy. etc.) 
    2.2 Anti-aging forces
     
Internal (apoptosis, boosting your immune system, DNA repair, longevity genes) 
External (wellness, changing your environment; achieving comfortable social atmosphere in your life, regular intake of anti-aging drugs, use of replacement organs, high-tech medicine, exercise)
    2.3 Aging versus anti-aging: how to tip the balance in your favour!
 
    3.1 Caloric restriction and fasting extend lifespan and decrease all-cause mortality (Evidence)
      Human studies
Monkey studies
Mouse and rat studies
Other animal studies
    3.2 Fasting and caloric restriction prevent and cure diseases (Evidence)
        Obesity
Diabetes
Hypertension and Stroke
Skin disorders
Mental disorders
Neurogical disorders
Asthmatic bronchitis, Bronchial asthma
Bones (osteoporosis) and fasting
Arteriosclerosis and Heart Disease
Cancer and caloric restriction
Cancer and fasting - a matter of controversy
Eye diseases
Chronic fatigue syndrome
Sleeping disorders
Allergies
Rheumatoid arthritis
Gastrointestinal diseases
Infertility
Presbyacusis
    3.3 Fasting and caloric restriction produce various
      biological effects. Effects on:
        Energy metabolism
Lipids metabolism
Protein metabolism and protein quality
Neuroendocrine and hormonal system
Immune system
Physiological functions
Reproductive function
Radio-sensitivity
Apoptosis
Cognitive and behavioral functions
Biomarkers of aging
    3.4 Mechanisms: how does calorie restriction retard aging and boost health?
        Diminishing of aging forces
  Lowering of the rate of gene damage
  Reduction of free-radical production
  Reduction of metabolic rate (i.e. rate of aging)
  Lowering of body temperature
  Lowering of protein glycation
Increase of anti-aging forces
  Enhancement of gene reparation
  Enhancement of free radical neutralisation
  Enhancement of protein turnover (protein regeneration)
  Enhancement of immune response
  Activation of mono-oxygenase systems
  Enhance elimination of damaged cells
  Optimisation of neuroendocrine functions
    3.5 Practical implementation: your anti-aging dieting
        Fasting period.
Re-feeding period.
Safety of fasting and low-calorie dieting. Precautions.
      3.6 What can help you make the transition to the low-calorie life style?
        Social, psychological and religious support - crucial factors for a successful transition.
Drugs to ease the transition to caloric restriction and to overcome food cravings (use of adaptogenic herbs)
Food composition
Finding the right physician
    3.7Fasting centers and fasting programs.
  Food to eat. Dishes and menus.
    What to eat on non-fasting days. Dishes and menus. Healthy nutrition. Relation between foodstuffs and diseases. Functional foods. Glycemic index. Diet plan: practical summary. "Dr. Atkins", "Hollywood" and other fad diets versus medical science
     

Vegetables
Fruits
Bread, cereals, pasta, fiber
Glycemic index
Fish
Meat and poultry
Sugar and sweet
Legumes
Fats and oils
Dairy and eggs
Mushrooms
Nuts and seeds
Alcohol
Coffee
Water
Food composition

  Anti-aging drugs and supplements
    5.1 Drugs that are highly recommended
      (for inclusion in your supplementation anti-aging program)
        Vitamin E
Vitamin C
Co-enzyme Q10
Lipoic acid
Folic acid
Selenium
Flavonoids, carotenes
DHEA
Vitamin B
Carnitin
SAM
Vinpocetine (Cavinton)
Deprenyl (Eldepryl)
    5.2 Drugs with controversial or unproven anti-aging effect, or awaiting other evaluation (side-effects)
        Phyto-medicines, Herbs
HGH
Gerovital
Melatonin
      5.3 Drugs for treatment and prevention of specific diseases of aging. High-tech modern pharmacology.
        Alzheimer's disease and Dementia
Arthritis
Cancer
Depression
Diabetes
Hyperlipidemia
Hypertension
Immune decline
Infections, bacterial
Infections, fungal
Memory loss
Menopause
Muscle weakness
Osteoporosis
Parkinson's disease
Prostate hyperplasia
Sexual disorders
Stroke risk
Weight gaining
    5.4 The place of anti-aging drugs in the whole
      program - a realistic evaluation
 
    6.1 Early diagnosis of disease - key factor to successful treatment.
      Alzheimer's disease and Dementia
Arthritis
Cancer
Depression
Diabetes
Cataracts and Glaucoma
Genetic disorders
Heart attacks
Hyperlipidemia
Hypertension
Immune decline
Infectious diseases
Memory loss
Muscle weakness
Osteoporosis
Parkinson's disease
Prostate hyperplasia
Stroke risk
Weight gaining
    6.2 Biomarkers of aging and specific diseases
    6.3 Stem cell therapy and therapeutic cloning
    6.4 Gene manipulation
    6.5 Prosthetic body-parts, artificial organs
        Blood
Bones, limbs, joints etc.
Brain
Heart & heart devices
Kidney
Liver
Lung
Pancreas
Spleen
    6.6 Obesity reduction by ultrasonic treatment
  Physical activity and aging. Experimental and clinical data.
        Aerobic exercises
Stretching
Weight-lifting - body-building
Professional sport: negative aspects
 
  Conclusion: the whole anti-aging program
    9.1 Modifying your personal aging curve
      Average life span increment. Expert evaluation.
     
Periodic fasting and caloric restriction can add 40 - 50 years to your lifespan
Regular intake of anti-aging drugs can add 20-30 years to your lifespan
Good nutrition (well balanced, healthy food, individually tailord diet) can add 15-25 years to your lifespan
High-tech bio-medicine service can add 15-25 years to your lifespan
Quality of life (prosperity, relaxation, regular vocations) can add 15-25 years to your lifespan
Regular exercise and moderate physical activity can add 10-20 years to your lifespan
These approaches taken together can add 60-80 years to your lifespan, if you start young (say at age 20). But even if you only start later (say at 45-50), you can still gain 30-40 years


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    9.2 The whole anti-aging life style - brief summary 
    References eXTReMe Tracker
        The whole anti-aging program: overview
         
       

       
     
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