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The last four decades, we assist to an increasing scientific interest on melatonin, a circadian hormone, a metabolic regulator which influences not only plants' metabolism and their defense against pathogens but mostly the animals and humans' metabolic pathways, their response to circadian disruption, stress and burnout syndrome. In humans, as a hormonal regulator, produced in the pineal grand as well in mitochondria, melatonin is involved in different, complex intracellular signaling pathways, with antioxidant and immune stimulating effects, proving to act as a circadian synchronizer, as a preventive and therapeutic agent in many degenerative diseases, and especially in hormone-dependent cancers. Preclinical or clinical studies showed recently the mechanisms involved in regulating the cellular activity, its role in aging and circadian disturbances and impact on degenerative diseases. Melatonin proved to have an anti-inflammatory, antiapoptotic and powerful antioxidant effect by subtle mechanisms in mitochondrial metabolic pathways. This overview includes recent and relevant literature data related to the impact of endogenous and exogeneous melatonin on the prevention of cancer progression and treatment of various degenerative diseases. Metabolomics, an emerging new omics' technology, based on high performance liquid chromatography coupled with mass spectrometry is presented as an encouraging technique to fingerprint and realize a precise evaluation and monitoring of the turnover of melatonin and its metabolites in different pathological circumstances.

Melatonin is probably produced in all cells but is only secreted by the pineal gland. The pineal secretion of melatonin is determined by the light-dark cycle, and it is only released at night. Melatonin regulates biological rhythms via its receptors located in the suprachiasmatic nuclei of the hypothalamus. Melatonin also has strong antioxidant activities to scavenge free radicals such as reactive oxygen species (ROS). The direct free radical scavenging actions are receptor independent. ROS play an important role in reproductive function including in the ovulatory process. However, excessive ROS can also have an adverse effect on oocytes because of oxidative stress, thereby causing infertility. It is becoming clear that melatonin is located in the ovarian follicular fluid and in the oocytes themselves, which protects these cells from oxidative damage as well as having other beneficial actions in oocyte maturation, fertilization, and embryo development. Trials on humans have investigated the improvement of outcomes of assisted reproductive technology (ART), such as in vitro fertilization and embryo transfer (IVF-ET), by way of administering melatonin to patients suffering from infertility. In addition, clinical research has examined melatonin as an anti-aging molecule via its antioxidative actions, and its relationship with the aging diseases, e.g., Alzheimer's and Parkinson's disease, is also underway. Melatonin may also reduce ovarian aging, which is a major issue in assisted reproductive technology. This review explains the relationship between melatonin and human reproductive function, as well as the clinical applications expected to improve the outcomes of assisted reproductive technology such as IVF, while also discussing possibilities for melatonin in preventing ovarian aging.

Circadian rhythms (CRs) are intrinsic clocks organizing the behavior and physiology of organisms. These clocks are thought to have coevolved with cellular redox regulation. Metabolism, redox homeostasis, circadian clock, and diet offer insights into aging. Mitochondria play a pivotal role in redox homeostasis, CR, and aging. Melatonin is synthesized in mitochondria, is the key regulator of CRs, and shows substantial antioxidative effects. Melatonin levels tend to decrease significantly with advancing age. Recent reports showed that disruptions of CRs may render aging populations even more susceptible to age-related disorders. Recent and high-quality articles investigating CR, redox homeostasis, aging, and their relationship during aging process were included. Putting special emphasis on the possible effects of melatonin on redox homeostasis and mitochondrial dynamics, recent clinical evidence highlighting the importance of circadian mechanisms was utilized. A deeper understanding of the role of altered mitochondrial redox homeostasis in the pathogenesis of age-related disorders and its relationship with CR could offer novel therapeutic interventions. Chronotherapy, a therapeutic approach considering CR of organisms and best therapeutic times, could potentially reduce side effects and improve therapeutic efficiency. Redox homeostasis, energy metabolism, and CR are all intertwined.

Testicular aging is linked to histological, morphological and functional alterations. In the present study, we investigated whether aging affects the inflammatory and oxidative status in the testis by comparing young adult, middle-aged adult and aged hamsters. The Syrian hamster, a thoroughly studied seasonal breeder, was chosen as the experimental model since it allows further investigations on the role of photoperiod and melatonin in testicular aging with a minimal impact of the experimental intervention on the animal well-being and the subsequent results achieved. In testes of aged hamsters, we found a decrease in melatonin concentration, a thickening of the wall of the seminiferous tubules as well as a significant increase in IL-1β, NLRP3 and cyclooxygenase 2 expression, PGD2 production, macrophages numbers, lipid peroxidation and anti-oxidant enzyme catalase levels. Interestingly, when aged hamsters were transferred from a long day (LD) to a short day (SD) photoperiod for 16 weeks, testicular melatonin concentration increased while local inflammatory processes and oxidative stress were clearly reduced. Overall, these results indicate that melatonin might display anti-inflammatory and anti-oxidant capacities in the aged testes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Biological ageing is generally accompanied by a gradual loss of cellular functions and physiological integrity of organ systems, the consequential enhancement of vulnerability, senescence and finally death. Mechanisms which underlie ageing are primarily attributed to an array of diverse but related factors including free radical-induced damage, dysfunction of mitochondria, disruption of circadian rhythms, inflammaging, genomic instability, telomere attrition, loss of proteostasis, deregulated sensing of nutrients, epigenetic alterations, altered intercellular communication, and decreased capacity for tissue repair. Melatonin, a prime regulator of human chronobiological and endocrine physiology, is highly reputed as an antioxidant, immunomodulatory, antiproliferative, oncostatic, and endocrine-modulatory molecule. Interestingly, several recent reports support melatonin as an anti-ageing agent whose multifaceted functions may lessen the consequences of ageing. This review depicts four categories of melatonin's protective effects on ageing-induced molecular and structural alterations. We also summarize recent findings related to the function of melatonin during ageing in various tissues and organs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Melatonin research has been experiencing hyper growth in the last two decades; this relates to its numerous physiological functions including anti-inflammation, oncostasis, circadian and endocrine rhythm regulation, and its potent antioxidant activity. Recently, a large number of studies have focused on the role of melatonin in the regeneration of cells or tissues after their partial loss. In this review, we discuss the recent findings on the molecular involvement of melatonin in the regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Thymus is an immunoendocrine organ, the hormones of which mainly influence its own lymphatic elements. It has a central role in the immune system, the neonatal removal causes the collapse of immune system and the whole organism. The thymic nurse cells select the bone marrow originated lymphocytes and destroy the autoreactive ones, while thymus originated Treg cells suppress the autoreactive cells in the periphery. The involution of the organ starts after birth, however, this truly happens in the end of puberty only, as before this it is overcompensated by developmental processes. From the end of adolescence the involution allows the life, proliferation and enhanced functioning of some autoreactive cells, which gradually wear down the cells and intercellular materials, causing the aging. The enhanced and mass function of autoreactive cells lead to the autoimmune diseases and natural death. This means that the involution of thymus is not a part of the organismic involution, but an originator of it, which is manifested in the lifespan-pacemaker function. Thus, aging can be conceptualized as a thymus-commanded slow autoimmune process. The neonatal removal of pineal gland leads to the complete destruction of the thymus and the crashing down of the immune system, as well as to wasting disease. The involution of the pineal and thymus runs parallel, because the two organs form a functional unit. It is probable that the pineal gland is responsible for the involution of thymus and also regulates its lifespan determining role. However, the data reviewed here do not prove the exclusive role of the pineal-thymus system in the regulation of aging and lifespan, but only call attention to such possibility.

Background: Circadian disruptions can contribute to accelerated aging, and the circadian system regulates cognitive and physical functions; therefore, circadian markers (eg, melatonin) may be associated with key aspects of healthy aging and longevity., Objective: To evaluate urinary melatonin levels in relation to cognitive function, physical function, and mortality among 2,821 older men in the Osteoporotic Fractures in Men Study DESIGN: Cohort study., Measurements: In 2003-2005, participants provided first-morning spot urine samples, which were assayed for 6-sulfatoxymelatonin (the primary melatonin metabolite in urine); cognitive and physical function assessments were completed twice, at baseline and an average of 6.5 years later. Participant deaths were confirmed by central review of death certificates over a mean of 9.2 years of follow up., Results: In multivariable-adjusted regression models, we observed a significant trend of better Digit Vigilance Test scores (ie, decreased time to completion) at baseline across increasing melatonin quartiles (p-trend = 0.01); however, mean time-to-completion scores did not significantly differ comparing extreme quartiles (group means: 547.1 seconds (95% CI: 533.6, 560.6) versus 561.3 seconds (95% CI: 547.8, 574.9)), and there were no associations of urinary melatonin levels with other cognitive test scores, or any cognitive change scores over time. Furthermore, melatonin levels were not related to physical function scores (p-trends = 0.4 for walking speed, 0.7 for chair stands, and 0.6 for grip strength in fully-adjusted models) or mortality risk (p-trend = 0.3 in the fully-adjusted model)., Conclusion: We found little evidence of associations between urinary melatonin levels and key measures of healthy aging and mortality in this cohort of older men. Further research should explore the relation of melatonin, particularly if assessed earlier in life, and other circadian markers with healthy aging outcomes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Melatonin plays a major role in maintaining circadian rhythm. Previous studies showed that its secretion pattern and levels could be disturbed in persons with dementia, psychiatric disorders, sleep disorders or with cancer. Also ageing is a factor that could alter melatonin levels, although previous research provides contradicting results. As melatonin supplementation is increasingly applied in older persons as sleep medication, it is important to know if melatonin levels decrease in healthy ageing and/or secretion patterns change. The objective of this study is to determine physiological levels and secretion patterns of melatonin in healthy older people., Methods: We performed a systematic review and searched PubMed and Embase for studies published between January 1st 1980 and October 5th 2015 that measured melatonin in healthy persons aged ≥65years., Results: Nineteen studies were retrieved. The number of participants ranged from 5 to 60 per study. Melatonin was mostly measured by radioimmunoassay (RIA) and the number of measurements per 24hours varied from 1 to 96. Sixteen studies showed a secretion pattern with a clear peak concentration, mostly at 0200h or 0300h. Maximum concentrations varied greatly from 11.2 to 91.3pgml(-1). Maximum melatonin level in studies with participants mean aged 65-70years was 49.3pgml(-1) and in studies with participants mean aged ≥75years 27.8pgml(-1), p-value <0.001., Conclusion: Total melatonin production in 24hours seems not to change in healthy ageing, but the maximal nocturnal peak concentration of melatonin might decline. It is important to take this into account when prescribing melatonin supplementation to older people., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The protein family of sirtuins and FoXO1 transcription factor have been shown to play significant roles in the aging process. In this study we aimed to investigate the changes in the levels of SIRT2, NFκB and FoXO1 and oxidative parameters of colonic mucosa during aging, and the effects of exogenous melatonin (MLT). A total of twenty-four young (3-months-old) and aged (24 months old) male Wistar rats, divided into control [1% ethanol--phosphate-buffered saline (PBS), s.c. for 21 days] and melatonin (10 mg kg(-1) MLT 1% ethanol in PBS, s.c. for 21 days) were used in the study. The levels of malondialdehyde (MDA) as a parameter of lipid peroxidation, glutathione, NFkB pathway activation, SIRT2 expression, and FoXO1 transcription factor of colonic mucosa were assayed. The MDA levels and SIRT2 expression in the colonic mucosa were significantly increased in the aged group when compared to the younger group. However, the levels of FoXO1 transcription factor were significantly decreased in the aged group. Melatonin significantly decreased the MDA and SIRT2 expression levels of the colonic mucosa in the aged rats. In conclusion, our findings suggest a suppressive role of melatonin in the aging process of colonic tissue via decreasing SIRT2 expression.

We did a review of the literature data of main Russian publications and databases PubMed/Medline for the last 7 years. In the present article we examine the physiology of secretion of pineal hormone melatonin and its role in the vital processes of the body. The study was focused on the influence of melatonin on the female reproductive system, participation in the aging process and the formation of pathological menopause. The article presents research data on the effectiveness of the drug melatonin in the climacteric syndrome. It is revealed that up to the present time according to the literature data there is no information about the standards of secretion of melatonin for women of different age groups, and the lack of secretion of melatonin can be judged by clinical manifestations, and also when compared with groups of healthy women. Remain unclear issues in the application of drugs melatonin at various complications of pregnancy and gynecological diseases. Long-term use of melatonin is still open in climacteric syndrome.

Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.

Aging is associated with changes in several basic parameters of circadian rhythms in mammals leading to circadian dysfunction. The hypothalamic Suprachiasmatic nucleus (SCN) regulates neuronal, endocrine and behavioral rhythms through the expression of various clock genes and release of melatonin from pineal gland. In the present study, we investigated the effect of aging on daily rhythms of various clock genes such as rPer1, rPer2, rCry1, rCry2 and rBmal1 in the SCN of male Wistar rats. The m-RNA expression levels of these genes were studied by using quantitative Polymerase Chain Reaction (qPCR) in 3 age groups [3 (adult), 12 and 24 month (m)] at variable time points (Zeitgeber time (ZT)-0, 6, 12 and 18). The m-RNA expression for all genes studied was rhythmic in SCN of adult rats with maximum for rPer1 at ZT-6, rPer2, rCry1 and rCry2 at ZT-12 and rBmal1 at ZT-18. However in 12 and 24 m, the phases of expression of these genes were significantly altered with abolition of daily rhythms of rCry1, rCry2 and rBmal1 in 24 m. Melatonin, messenger of darkness, an endogenous synchronizer of rhythm, an antioxidant and an antiaging drug, declines with aging. We therefore studied the effects of melatonin administered subcutaneously at 1 h before the onset of darkness (ZT-11) for 11 days on age induced desynchronization in expression of these genes. We report here differential restoration of daily rhythm, phase, levels and stoichiometric interaction of m-RNA expression of these genes in various age groups in rat SCN with melatonin treatment.

The aging risk factor for Parkinson's disease is described in terms of specific disease markers including mitochondrial and gene dysfunctions relevant to energy metabolism. This review details evidence for the ability of nutritional agents to manage these aging risk factors. The combination of alpha lipoic acid, acetyl-l-carnitine, coenzyme Q10, and melatonin supports energy metabolism via carbohydrate and fatty acid utilization, assists electron transport and adenosine triphosphate synthesis, counters oxidative and nitrosative stress, and raises defenses against protein misfolding, inflammatory stimuli, iron, and other endogenous or xenobiotic toxins. These effects are supported by gene expression via the antioxidant response element (ARE; Keap/Nrf2 pathway), and by peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha), a transcription coactivator, which regulates gene expression for energy metabolism and mitochondrial biogenesis, and maintains the structural integrity of mitochondria. The effectiveness and synergies of the combination against disease risks are discussed in relation to gene action, dopamine cell loss, and the accumulation and spread of pathology via misfolded alpha-synuclein. In addition there are potential synergies to support a neurorestorative role via glial derived neurotrophic factor expression., (Copyright © 2014 The Author. Published by Elsevier Inc. All rights reserved.)

Neural aging as a progressive loss of function involves central and peripheral post-mitotic neurons and neural stem cells (NSCs). It promotes neurodegeneration, impairs neurogenesis, and can be considered a cause of cognitive impairment and sensory and motor deficits in the elderly. Age-related morphological atrophic changes and cellular alterations are addressed by neural aging mechanisms. Neurogenesis declines during aging through several mechanisms such as an increase in quiescence state, changes in lineage fate, telomerase dysfunction, the failure of the DNA repair system, increased apoptosis, and the impairment of self-renewal. The self-renewal transcriptional factor Sox2 has been correlated with retrotransposon L1 and certain cell-cycle- and epigenetic-related factors, which are sometimes considered age-related factors in NSC aging. As neurogenesis decreases, non-mitotic neurons undergo neurodegeneration by oxidative stress, sirtuin, insulin signaling and mTOR alteration, mitochondrial dysfunction, and protein misfolding and aggregation. As neurodegeneration and impaired neurogenesis promote the nervous system aging process, the identification of neuronal anti-aging is required to raise life expectancy. The role of melatonin in increasing neurogenesis and protecting against neurodegeneration has been investigated. Here, we review nervous system aging that is correlated with mechanisms of neurodegeneration and the impairment of neurogenesis and evaluate the effects of melatonin on these processes.

It has been suggested that the age-related decrease in the number of neurons in the hippocampus that leads to alterations in brain function, may be associated with an increase in apoptosis due to the reduced secretion of growth hormone (GH) and/or melatonin in old animals. In order to investigate this possibility, male Wistar rats of 22 months of age were divided into three groups. One group remained untreated and acted as the control group. The second was treated with growth hormone (hGH) for 10 weeks (2 mg/kg/d sc) and the third was subjected to melatonin treatment (1 mg/kg/d) in the drinking water for the same time. A group of 2-months-old male rats was used as young controls. All rats were killed by decapitation at more than 24 month of age and dentate gyri of the hippocampi were collected. Aging in the dentate gyrus was associated with an increase in apoptosis promoting markers (Bax, Bad and AIF) and with the reduction of some anti-apoptotic ones (XIAP, NIAP, Mcl-1). Expressions of sirtuin 1 and 2 (SIRT1 and 2) as well as levels of HSP 70 were decreased in the dentate gyrus of old rats. GH treatment was able to reduce the pro/anti-apoptotic ratio to levels observed in young animals and also to increase SIRT2. Melatonin reduced also expression of pro-apoptotic genes and proteins (Bax, Bad and AIF), and increased levels of myeloid cell leukemia-1 proteins and SIRT1. Both treatments were able to reduce apoptosis and to enhance survival markers in this part of the hippocampus.

The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin's efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50-100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.

The pineal hormone melatonin (MLT) has potent anti-breast cancer activity, its actions are heavily mediated via the MT1 receptor and subsequent modulation of downstream signaling pathways including cAMP/PKA, Erk/MAPK, p38, and Ca2+/calmodulin. Also, via the MT1 pathway, MLT can repress the transcriptional activity of some mitogenic nuclear receptors including ERα, GR, and RORα, while potentiating the activity of other receptors (RARα and RXRα) involved in differentiation, anti-proliferation, and apoptosis. A review of the literature supports the view that MLT, via its MT1 receptor, can suppress all phases of breast cancer including initiation, promotion, and progression. During the fifth and sixth decades of life, the production of MLT diminishes, concurrently with an increase in the incidence of breast cancer. Inasmuch as MLT has been demonstrated to have anti-cancer activity, we hypothesized that there may be a causal link between the reduction in MLT production in the pineal gland and the incidence of breast cancer which increases with age. We designed this study to establish whether a truly inverse relationship exists between tissue-isolated mammary tumor growth in young (2 months), adult (12 months), and old (20 months) female Buffalo rats and the decrease in both MLT and the MT1 receptor with age, such that a causal link could be found. Serum MLT levels were measured in both the light and dark phases. A significant 29% decrease in serum MLT levels, measured at the nocturnal peak, was found in the adult and senescent rats (75% decrease) in comparison to that in young rats. In young rats, the nocturnal pineal gland MLT content exceeded daytime levels by 19-fold compared to a sevenfold increase in old mice. Also, the MT1 receptor was found to be significantly lower in the nighttime and early morning in the senescent rat uterus as compared to uteri from young and adult rats. Analysis of the rate of growth in transplanted, tissue-isolated, mammary tumors induced by N-nitroso-n-methyl-urea (NMU) showed a significant increase in the senescent rats, but not in the young or adult rats Additionally, diminished response to the inhibitory action on tumor growth of exogenous MLT was noted in senescent rats such that tumor growth was suppressed by only 33% compared to 48% and 66% in adult and young rats, respectively. The diminution of the response of tumors to exogenous MLT was found to correlate with reduced MT1 receptor expression in senescent compared to young and adult rats. These data suggest that the observed age-associated enhanced growth of tumors is related to the much reduced levels of MLT and its receptor in aged animals which reduce the sensitivity of tumors to inhibition by exogenous MLT.

The restoration of the thymic functions and the thymic re-growth may be achieved in old mice by some endocrinological (melatonin) or nutritional interventions (arginine or zinc), suggesting that the thymic involution in old age is a phenomenon secondary to age-related alterations occurring in neuroendocrine-thymus interactions. The targets for the thymic restoration may be hormone receptors and cytokines, strictly related to the presence of two nutritional factors, such as arginine and zinc, which are in turn essential for the efficiency of neuroendocrine-immune network both in ontogeny and ageing. The effect of melatonin is largely due to the presence of its specific receptors on cell membrane of thymocytes and Thymic Epithelial Cells (TECs). TECs synthesize thymulin peptide that is required for T-cell differentiation and maturation within the thymus gland. In this context, the role of zinc is pivotal because it is involved, through "zinc finger motifs", in the gene expression of melatonin receptors, in cell proliferation, apoptosis and thymulin reactivation. Zinc is also required for the biological action of arginine, via Nitric Oxide pathway. Therefore, the beneficial effect of melatonin or arginine on neuroendocrine-thymus interaction in ageing can also occur via a better zinc pool redistribution within the body where the capability of the zinc-binding proteins Metallothioneins (MT) in zinc release has a key role. These findings suggest that zinc, via MT buffering, can be a single mediator in modulating neuroendocrine-thymus interaction in ageing.

We have investigated the effect of melatonin administration on the cytometric and endocrine functions of the ovary during aging. Young cyclic (3 months old), middle-aged pre-acyclic (13 months old), and old acyclic (22 months old) female Wistar rats were used for two months, in both control and melatonin-treated groups. Cell cycle by flow cytometry: the percentage of ovarian cells in the G0-G1 phase was the highest in both control and melatonin-treated rats. However, melatonin treatment significantly reduced (P< 0.05) the percentage of cells in the G0-G1 phase compared to control rats. This reduction of cells in the G0-G1 phase is derived to the S phase in cyclic and acyclic rats. The possibility that a tumoral process leads to a proliferative effect observed in young and acyclic melatonin-treated rats was ruled out because no significant differences were found for p53 and Ki67 expression levels between control and melatonin groups. Density of oocytes: the oocyte number per ovary unit volume was not affected by melatonin treatment in the three age ranges studied. Melatonin treatment in middle-aged (pre-acyclic) rats resulted in significantly higher (P< 0.05) ovarian volume; higher oocyte volume, without significant differences, and oocytes in circular form were significantly (P< 0.05) higher than in control rats. Melatonin treatment during pre-acyclic age range could resynchronize the estrous cycle periodicity. Melatonin treatment was able to maintain the same levels of estradiol in the pre-acyclic age groups studied as those observed in the young cyclic rats. The present results indicate that melatonin administration to middle-aged female rats produces beneficial effects that extend the reproductive function of the ovary.

Melatonin modulates adult hippocampal neurogenesis in adult mice. Also, plasma melatonin levels and new neuron formation decline during aging probably causing cognitive alterations. In this study, we analyzed the impact of exogenous supplementation with melatonin in three key events of hippocampal neurogenesis during normal aging of mice. The analysis was performed in rodents treated with melatonin during 3, 6, 9 or 12 months. We found an increase in cell proliferation in the dentate gyrus of the hippocampus after 3, 6 and 9 months of treatment (>90%). Additionally, exogenous melatonin promoted survival of new cells in the dentate gyrus (>50%). Moreover, melatonin increased the number of doublecortin-labeled cells after 6 and 9 months of treatment (>150%). In contrast, melatonin administered during 12 months did not induce changes in hippocampal neurogenesis. Our results indicate that melatonin also modulates the neurogenic process in the hippocampus during normal aging of mice. Together, the data support melatonin as one of the positive endogenous regulators of neurogenesis during aging., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The senescence accelerated mouse (SAMP8) is a spontaneous animal model of overproduction of amyloid precursor protein (APP) and oxidative damage. It develops early memory disturbances and changes in the blood-brain barrier resulting in decreased efflux of amyloid-β protein from the brain. It has a marked increase in oxidative stress in the brain. Pharmacological treatments that reduce oxidative stress improve memory. Treatments that reduce amyloid-β (antisense to APP and antibodies to amyloid-β) not only improve memory but reduce oxidative stress. Early changes in lipid peroxidative damage favor mitochondrial dysfunction as being a trigger for amyloid-β overproduction in this genetically susceptible mouse strain. This sets in motion a cycle where the increased amyloid-beta further damages mitochondria. We suggest that this should be termed the Inflammatory-Amyloid Cycle and may well be similar to the mechanisms responsible for the pathophysiology of Alzheimer's disease. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The review analyzed morphology, molecular and functional aspects of pineal gland aging and methods of it correction. The pineal gland is central organ, which regulates activity of neuroimmunoendocrine, antioxidant and other organisms systems. Functional activity of pineal gland is discreased at aging, which is the reason of melatonin level changing. The molecular and morphology research demonstrated, that pineal gland hadn't strongly pronounced atrophy at aging. Long-term experience showed, that peptides extract of pineal gland epithalamin and synthetic tetrapeptide on it base epithalon restored melatonin secretion in pineal gland and had strong regulatory activity at neuroimmunoendocrine and antioxidant organism systems.

The influence of melatonin on age dynamics of neutrophils and lymphocytes in blood of laboratory rats kept under different light conditions and predatory mammals--farmer silver fox, raccoon dog kept under natural light (NL) was investigated. The decrease of lymphocyte level, increase neutrophils content and alteration of neutrophils/lymphocytes ratio of aged rats (24 months) kept under natural light (NL) and standard light (LD) and adult silver foxes (2-5 years) kept under natural light in comparison with juvenile animals were detected. The reduced lymphocytes level and increased neutrophil level in rats under constant light (LL) were revealed in younger ages. The melatonin effect was detected in aged rats and adult silver foxes and not observed in juvenile animals.

Human life span, with or without modern medicine is around 85-95 years. All living creatures have their inner clock that measures their daily (circadian) and their seasonal (circannual) time. These time changes are mediated by the alteration of levels of melatonin, an evolutionary ancient hormone, which is produced in many body tissues, including the pineal gland, retina and the gastrointestinal tract (GIT). Light is blocking the production of melatonin in the pineal gland, darkness is stimulating it. So, the diurnal changes of light intensity of melatonin, provide a "daily clock" and the seasonal changes provide a "seasonal clock". Finally, the reduction of melatonin observed with aging, may indicate the presence of an "age clock". Melatonin is a strong antioxidant (often it is called scavenger of free radicals), which protects the body from the effects of noxious compounds. Therefore it was hypothesized that the reduction of melatonin levels with age contributes to the aging process. So far, the only remedy to extend the life span was a 40% reduction in caloric intake, which prolonged the life in mice, rats, dogs and monkeys by 30-50%. A large group of people imitate these experiments performed on animals, but the results of these experiments will not be known for several decades. How is being hungry prolonging the life span? There is a connection between caloric reduction and melatonin levels in GIT. Several experiments indicate that fasting in animals substantially increased their production of GIT melatonin. Therefore, instead of being permanently hungry, a prolongation of human life could be achieved by a replacement melatonin therapy. A daily intake of melatonin before bed time might achieve the same effect as fasting e.g. an increase of body melatonin levels, which will protect the individual from the ravages of old age. That includes Parkinson's disease and Alzheimer's disease. There is a large group of people taking melatonin daily who believe that melatonin is the "fountain of youth". Those are the subjects which will one day provide an experimental evidence of the efficacy of melatonin.

The role of the thymus in the influence of pineal gland on the number of stromal precursor cells to colonies of fibroblasts (CFU-F), progenitor cells to granulocyte-macrophage colonies (CFU-GM), CD3+, CD4+ and CD8+ cells in the bone marrow of adult and old mice CBA/Ca was investigated. False-operated and thymusectomized mice were injected Melatonin in the evening (spring season) or Epithalamin in the morning (summer and autumn). After the injection of Melatonin into adult mice the number of CFU-F and the value of the ratio CFU-F/CFU-GM decreased in false-operated animals, whereas the same indicators increased in thymusectomized animals. Under the influence of Melatonin, the ratio of CD4+/CD8+ cells increased in mice with an intact thymus and reduced in mice with a removed gland by increasing the number of CD8+ cells. The injection of Epithalamin led to the increasing in the number of CFU-F in summer, but did not lead to that in the autumn; the effect diminished in mice with a removed thymus. The orientation of changes of the indices under the influence of the pineal gland's factor in adult mice with an intact thymus corresponds to their seasonal fluctuations. After the injection of Melatonin into old mice CFU-F/CFU-GM ratio slightly reduced in false-operated animals and did not change in thymusectomized ones. Under the influence of melatonin the CD4+/CD8+ ratio of cells slightly increased in old mice with and without the thymus. Thus, the influence of the pineal gland' factors (Melatonin, Epithalamin) on the cellular structure of bone marrow, first of all on the cells of the microenvironment, in adult mice has an adaptive character and is realized with the participation of the thymus. In old mice, the thymus is also involved in the action of Melatonin on bone marrow, but the effect is less pronounced and is manifested mainly through changes in amount of CFU-GM.

Histone deacetylases (HDAC) have been under intense scientific investigation for a number of years. However, only recently the unique class III HDAC, sirtuins, have gained increasing investigational momentum. Originally linked to longevity in yeast, sirtuins and more specifically, SIRT1 have been implicated in numerous biological processes having both protective and/or detrimental effects. SIRT1 appears to play a critical role in the process of carcinogenesis, especially in age-related neoplasms. Similarly, alterations in circadian rhythms as well as production of the pineal hormone melatonin have been linked to aging and cancer risk. Melatonin has been found act as a differentiating agent in some cancer cells and to lower their invasive and metastatic status. In addition, melatonin synthesis and release occurs in a circadian rhythm fashion and it has been linked to the core circadian machinery genes (Clock, Bmal1, Periods, and Cryptochromes). Melatonin has also been associated with chronotherapy, the timely administration of chemotherapy agents to optimize trends in biological cycles. Interestingly, a recent set of studies have linked SIRT1 to the circadian rhythm machinery through direct deacetylation activity as well as through the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway. In this review, we provide evidence for a possible connection between sirtuins, melatonin, and the circadian rhythm circuitry and their implications in aging, chronomodulation, and cancer.

That free radicals and the damage they inflict are related to deteriorative cellular and organismal changes associated with aging and also with the development of a variety of age-related diseases is widely debated. There seems to be little doubt that free radical mutilation of essential molecules contributes to these conditions. Numerous investigators, on the basis of their experimental results, have drawn this conclusion. If the free radical theory of aging and disease development has validity, antioxidants could presumably be successfully used to delay the molecular destruction, cellular loss, and organismal death. In the current review we summarize the experimental data related to the utility of melatonin in protecting against reactive oxygen and reactive nitrogen species-induced cellular damage. While the data supporting a role for melatonin in forestalling aging and prolonging life span per se is not compelling, the findings related to melatonin's ability to reduce the severity of a variety of age-related diseases that have as their basis free radical damage is convincing. To date, the bulk of these investigations have been performed in experimental models of diseases in animals. It is now imperative that similar studies be conducted using humans whose quality of life may benefit from treatment with melatonin.

Aging is associated with a decline in immune function (immunosenescence), a condition known to correlate with increased incidence of cancer as well as infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. Circulating melatonin decreases with age, and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes and macrophages. It also stimulates the production of natural killer cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from natural killer cells and T helper lymphocytes are enhanced by melatonin. Melatonin has the potential therapeutic value to enhance immune function in aged individuals., (Copyright 2008 S. Karger AG, Basel.)

All organisms present circadian rhythm in most of their physiological functions, and among them there stand out sleep, motor activity, immune function, the secretion of melatonin, and the production and release of numerous neurotransmitters, in particular of serotonin because of its relationship with the aforementioned factors. Aging changes these rhythms, altering sleep quality and contributing to immunosenescence. Treatment with exogenously administered melatonin or tryptophan may restore these impaired functions due to aging. In our animal model (Streptopelia risoria), both the hormone and the amino acid acted on the activity-rest rhythms, modulating the circulating levels of melatonin and serotonin, and increased the cell viability and resistance to induced oxidative stress of blood heterophils, at the same time as enhancing the phagocytic function and neutralizing the superoxide anions deriving from this immune function. Also, in the old individuals, the treatments with melatonin and tryptophan at the concentrations and times of administration considered suitable improved nocturnal rest besides reverting the immunosuppressory and oxidative effects accompanying phagocytosis at these advanced ages.

Increasing number of people in advanced age is one of the most distinctive demographic events of the 21(st) century which raise many social and medical issues. Therefore, there is a search for any therapeutic agent improving the quality of life of the elderly. Melatonin, the hormone of the pineal gland, received recently a great deal of attention because of its suggested role in aging processes and availability as over-the-counter drug or food supplement in some countries, including Poland. In this survey the basic data on the possible role of melatonin in human aging as well as its possible therapeutic significance are reviewed and discussed.

Specific endocrine changes occur with the ageing process. The last decade has witnessed significant progress in the basic and clinical science of ageing, thereby rejuvenating the interest in anti-ageing medicine, especially that of hormone replacement, by medical professionals and the lay public. However, endocrine manipulation as a therapeutic strategy for ageing is still evolving as continuing research attempts to answer the many questions of what it can achieve at the risk of incurring unknown long-term adverse effects. The current day doctor is confronted with a host of options, and will benefit from a synopsis of the latest evidence before making the most appropriate decision for aged patients seeking hormonal replacement therapy as a means to counter the effects of ageing. This review aims to give a rapid overview of the endocrine profile of geriatric population and the studies on the more controversial hormonal replacement therapies for the aged.

Circadian rhythms of behaviour and gene expression are coupled to endogenous neuronal oscillators located in the hypothalamic suprachiasmatic nuclei (SCN), which are synchronised by the environmental light cycle. Besides light, other factors such as the pineal hormone melatonin, temperature and feeding have entraining properties. During senescence, the circadian system becomes weaker and susceptible to desynchronisation. It is unknown to what extent age-related changes are the result of the deterioration of the hypothalamic master clock. Supplementing ageing mice with melatonin as well as maintaining them on a hypocaloric diet extends the life span and delays age-related diseases. By means of DNA microarrays and the quantitative polymerase chain reaction, we have conducted an exploratory study to compare the effect of long-term melatonin substitution (MEL) and caloric restriction (CR) on circadian gene expression in hypothalamic samples, which contained the SCN as well as other important nuclei involved in nutrient balance, reproduction, and so on. Over 4% of the hypothalamic transcripts showed an overt circadian rhythm in expression, and many of these contain E boxes in their promoter regions, suggesting a direct regulation by circadian clock genes. MEL and CR significantly influenced some of these rhythmically expressed transcripts, but often in opposite ways. Importantly, our studies emphasise that the apparent direction of treatment effects (i.e. up-regulation versus down-regulation) depends on the time of day at which the samples are compared.

Objectives: To provide an overview of the trajectory of select biomarkers and their potential usefulness in symptom management in the older individual with cancer., Data Sources: Empirical data and literature review., Conclusion: Biomarkers offer significant opportunities to understand the biological impact of cancer and its treatment on older adults whose response is likely different from their younger counterparts. Large well-designed multi-site clinical trials with adequate numbers and power are necessary to create evidenced-based practice changes., Implications for Nursing Practice: Nurses need to understand the science and implications of biomarkers to develop interventions in response to the mechanisms of symptoms experienced by older adults with cancer.

The neurohormone melatonin is released from the pineal gland in close association with the light-dark cycle. There is a temporal relationship between the nocturnal rise in melatonin secretion and the 'opening of the sleep gate' at night. This association, as well as the sleep promoting effect of exogenous melatonin, implicates the pineal product in the physiological regulation of sleep. Aging is associated with a significant reduction in sleep continuity and quality. A decreased production of melatonin with age is documented in a majority of studies. Diminished nocturnal melatonin secretion with severe disturbances in sleep/wake rhythm has been consistently reported in Alzheimer's disease (AD). A recent survey on the effects of melatonin in sleep disturbances, including all age groups, failed to document significant and clinically meaningful effects of exogenous melatonin on sleep quality, efficiency and latency. However, in clinical trials involving elderly insomniacs and AD patients suffering from sleep disturbances exogenous melatonin has repeatedly been found to be effective in improving sleep. The results indicate that exogenous melatonin is more effective to promote sleep in the presence of a diminished production of endogenous melatonin. A MT1/MT2 receptor analog of melatonin (ramelteon) has recently been introduced as a new type of hypnotics with no evidence of abuse or dependence.

The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.

The high incidence of age-related diseases in the increasing population of elderly people has stimulated interest in the search for protective agents that have the capability of preventing premature aging and delaying the onset of degenerative disorders. To preserve health in old age becomes a primary goal for biomedicine, because the increasing longevity in our societies is associated with a rise in morbidity. The difficulties in finding new approaches and safe strategies for prevention, intervention, and treatment are related to the lack of theoretical background as well as to insufficient models to test the efficacy of anti-aging agents. Melatonin is a prime candidate for slowing the aging process and targeting its underlying pathology. Melatonin has profound gerontoprotective and antioxidant activities. Because enhanced oxidative stress plays a crucial role in the aging process and chronic diseases associated with senescence, the adminstration of a potent amphiphilic antioxidant agent with high bioavailability such as melatonin may become a promising, safe, and effective intervention strategy to slow aging and the initiation and progression of age-related disorders. Investigations on melatonin and its anti-aging activity may be of great benefit in increasing life quality of the elderly.

The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e. melatonin, are synchronized to the 24-hr day by environmental light, received by the retina and transmitted to the SCN via the retinohypothalamic tract. Melatonin not only plays an important role in the regulation of circadian rhythms, but also acts as antioxidant and neuroprotector that may be of importance in aging and Alzheimer's disease (AD). Circadian disorders, such as sleep-wake cycle disturbances, are associated with aging, and even more pronounced in AD. Many studies have reported disrupted melatonin production and rhythms in aging and in AD that, as we showed, are taking place as early as in the very first preclinical AD stages (neuropathological Braak stage I-II). Degeneration of the retina-SCN-pineal axis may underlie these changes. Our recent studies indicate that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the SCN is responsible for melatonin changes during the early AD stages. Reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation, to restore the circadian rhythm and to relieve the clinical circadian disturbances, has shown promising positive results.

The worldwide prolongation of the mean life expectancy has resulted in a rapid increase of the size of the elderly population (over the age of 60), both in numbers and as a proportion of the whole. As a consequence, increasing the number of potential beneficiaries of health and pension funds, mainly those aged 65 and over raises many social and economic problems since they are supported by a relatively smaller number of potential contributors, i.e. those in the economically active ages between 18 and 64. Therefore, there is a search for any therapeutic agent improving quality of life in the elderly. A role for melatonin as such a compound was recently suggested. In this survey, data on the possible role of melatonin in human aging and age-related diseases are briefly presented. Undoubtedly the aging process is multi-factorial, and no single factor has been identified which satisfactorily explains the phenomenon. Although many theories relating the pineal gland and its secretory product melatonin to aging have been proposed, the role of this agent in the aging process is still unclear. However, for several reasons it seems reasonable to postulate a role for melatonin in this process. Melatonin levels decline gradually over the life-span and may be related to lowered sleep efficacy, very often associated with advancing age, as well as to deterioration of many circadian rhythms. Melatonin exhibits immunomodulatory properties, and a remodeling of immune system function is an integral part of aging. Finally, because melatonin is a potent free radical scavenger, its deficiency may result in reduced antioxidant protection in the elderly which may have significance not only for aging per se but also may contribute to the incidence or severity of some age-related diseases. Presently available data do not allow us to conclude that melatonin may have a role in extending normal longevity. However, although melatonin cannot be recognized as 'rejuvenating' agent, some of its actions may be beneficial for the aging process. Administration of melatonin may improve temporal organization in advanced age. Moreover, it has beneficial effects on sleep as well as age-related diseases. Although recommendations of melatonin supplementation in elderly should be considered, there is a need for extensive studies on the use of melatonin in order to improve the quality of life in advanced age.

Caloric restriction and hormone treatment delay reproductive senescence in female mammals, but a natural model of decelerated reproductive aging does not presently exist. In addition to describing such a model, this study shows that an abiotic signal (photoperiod) can induce physiological changes that slow senescence. Relative to animals born in April, rodents born in September delay their first reproductive effort by up to 7 mo, at which age reduced fertility is expected. We tested the hypothesis that the shorter day lengths experienced by late-born Siberian hamsters ameliorate the reproductive decline associated with advancing age. Short-day females (10L:14D) achieved puberty at a much later age than long-day animals (14L:10D) and had twice as many ovarian primordial follicles. At 10 mo of age, 86% of females previously maintained in short day lengths produced litters, compared with 58% of their long day counterparts. Changes in pineal gland production of melatonin appear to mediate the effects of day length on reproductive aging; only 30% of pinealectomized females housed in short days produced litters. Exposure to short days induces substantial decreases in voluntary food intake and body mass, reduced ovarian estradiol secretion, and enhanced production of melatonin. One or more of these changes may account for the protective effect of short day lengths on female reproduction. In delaying reproductive senescence, the decrease in day length after the summer solstice is of presumed adaptive significance for offspring born late in the breeding season that first breed at an advanced chronological age.

Aging is associated with a decline in immunity described as immunosenescence. This is paralleled by a decline in the production of several hormones, as typically illustrated by the menopausal loss of ovarian oestrogen production. However, other hormonal changes that occur with aging and that potentially impact on immune function include the release of the pineal gland hormone melatonin and pituitary growth hormone, adrenal production of dehydroepiandrosterone and tissue-specific availability of active vitamin D. It remains to be established whether hormonal changes with aging actually contribute to immunosenescence and this area is at the interface of fact and fiction, clearly inviting systematic research efforts. As a step in this direction, the present review summarizes established facts on the physiology of secretion and function of hormones that, in most cases, decline with aging and that are likely to affect the immune system.

Recently it has been suggested that a previously undetected, rhodopsin-based, visual pigment, located in some retinal ganglion cells and having a peak sensitivity around 460 nm, may be responsible for light-induced melatonin suppression and, perhaps, maintenance of the circadian rhythm. Using data from the literature, it is shown that, as absorption in the crystalline lens for shorter visible wavelengths increases substantially with age, while the pupil diameter tends to decrease, the effective retinal exposure received under the same ambient lighting conditions by the pigment is almost 10 times lower in an old, as compared with a young, eye. Interestingly, replacement of the old crystalline lens by an intraocular implant restores the exposure to youthful levels. The possible effects of these changes with age on circadian rhythms are discussed.

This brief review considers the potential role of melatonin in the processes of aging, the prolongation of life span and health in the aged. Studies completed to date generally suggest that exogenously administered melatonin may serve to extend life span in invertebrates, but evidence supporting this conclusion in mammals is less compelling. Thus, any conclusion regarding a role for melatonin in extending normal longevity, particularly in mammals, would be premature. With regard to deferring the signs of chemically-induced neurodegenerative conditions in experimental animals, the data are remarkably strong and there is a modicum of evidence that in humans with debilitating diseases melatonin may have some beneficial actions. Indeed, this should be one focus of future research since as the number of elderly increases in the population, the frequency of costly age-related diseases will become increasingly burdensome to both the patient and to society as a whole.

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.

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.

From the age of 6 months until their natural deaths, female CBA mice were given melatonin with their drinking water (20 mg/l) for 5 consecutive days every month. Intact mice served as controls. The results of this study show that the consumption of melatonin did not significantly influence food consumption, but it did increase the body weight of older mice; it did not influence physical strength or the presence of fatigue; it decreased locomotor activity and body temperature; it inhibited free radical processes in serum, brain, and liver; it slowed down the age-related switching-off of estrous function; and it increased life span. However, we also found that treatment with the used dose of melatonin increased spontaneous tumor incidence in mice. For this reason, we concluded that it would be premature to recommend melatonin as a geroprotector for long-term use.

The present study tested the hypothesis that responsiveness to melatonin, the presence of the melatonin rhythm in circulation, and parameters of the GnRH neuron system are sustained across the aging continuum in Siberian hamsters. Afternoon melatonin injections induced testicular atrophy in 42% of aged males compared with 100% of adult males. The proportion of aged males failing to respond to the melatonin injections was similar to the proportion that failed to undergo testicular regression upon exposure to short days. Exposure to short days induced testicular atrophy in juvenile and adult hamsters; however, regression was incomplete or absent in 43% of aged males. The nocturnal rise in melatonin was similar with regard to duration and peak amplitude, and appropriate with respect to photoperiod in 25-day-old juveniles, adult (5 months), and aged (17 months) hamsters. Neither advanced age nor timed melatonin treatments affected GnRH neuron numbers or distribution. Fertility was maintained in aged and adult males to a comparable extent with respect to latency to first litter and number of pups per litter; reproductive success was dramatically reduced in aged compared with adult females. Because melatonin rhythms accurately reflect day length information throughout the continuum from puberty to advanced age, the present evidence suggests that limitations in testis regression in response to short days or exogenous melatonin in a subset of aged males result from a reduced ability to respond to melatonin. In the wild, failure to undergo testicular regression in the presence of shortening day lengths may extend the breeding season of aged males.

Age-related changes in the mammalian circadian system may be associated with a decline in circulating melatonin levels. Using 'jet lag' paradigms involving abrupt shifts in the light-dark cycle, we showed that a melatonin agonist, S-20098, accelerated by approximately 25% resynchronization of the circadian activity rhythm in old hamsters to the new light-dark cycle. It suggests the usefulness of melatonin-related compounds to treat circadian disorders associated with aging.

Organisms living on the earth may undergo inevitable toxification by biological 'garbage', a variety of bio-metabolites. Such garbage includes a particularly large number of toxic carbonyls, such as alpha,beta-unsaturated carbonyls created by free radicals, glycation, and other post-translational side-reactions during various stresses and diseases. The accumulation of these toxic substances and their crosslinking products leads to the formation of different age pigments, such as lipofuscin, lens cataracts, and crosslinked collagen. The diurnal fluctuation in the concentration of the pineal gland hormone, melatonin, may be responsible for the 'cleaning activities' that reverse the covalently-bound semi-toxified proteins and nucleic acids. This toxification-cleaning cycle may explain the biochemical necessity for sleep of human and animals during aging., (Copyright 2000 Harcourt Publishers Ltd.)