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Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered., Competing Interests: The authors declare no conflict of interest.

Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Herein we considered the role of oxidative stress on deficiencies of functional physical performance that could affect a future pre-frailty condition. Using principal component analyses (PCA), we created new variables to better describe the functionality regarding the physical performance of the upper and lower body limbs. Gait speed and the Short Physical Performance Battery (SPPB) score were classified by PCA to describe functional performance of the lower body limbs. Variables describing the general physical status, including weekly consumption of kilocalories and the musculoskeletal index, were classified together with grip strength of the dominant hand as indicators of functional performance of the upper body limbs. An intimate association between the functional physical performance of the upper body limbs and the total antioxidant capacity was observed in older subjects. Low levels of total antioxidant capacity were found in women 76 years or younger with deficiencies in the physical performance of both upper and lower body limbs. Similarly, we observed a close association between the functional physical performance of the lower body limbs and the levels of hemoglobin. In particular, low levels of hemoglobin were mostly found in men older than 76 years of age, showing impaired functional physical performance. In addition, the physical performance of the lower body limbs was shown to be more important than that of the upper body limbs in the statistical association with pre-frailty in the elderly. Therefore, specific low levels of hemoglobin and deficient oxidative defense in the elderly could significantly affect the functional physical performance and future outcomes of pre-frailty.

The objective of the present study was to investigate a large panel of oxidative stress biomarkers in long-term trained elderly men to analyse the effects of chronic training on an aged population. We collected blood samples from two groups of male volunteers older than 65 years who maintain a measure of functional independence: one group of sedentary subjects without a history of regular physical activity and the other of subjects who have sustained training, starting during middle age (mean training time=49 ± 8 years). We studied morbidity and polypharmacy, as well as haematological parameters including red cell count, haemoglobin concentration, haematocrit, mean corpuscular volume, red cell distribution width and several oxidative biomarkers including protein carbonyl content and lipid peroxidation in plasma and erythrocytes, red blood cell H2O2-induced haemolysis test, plasma total antioxidant activity and the main antioxidant enzymes of erythrocytes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. After adjusting for confounding factors, we observed an increase in all oxidative damage biomarkers in the plasma and erythrocytes of the long-term exercise group. However, we reported a decrease in the number of diseases per subject with statistical differences nearly significant (p=0.061), reduced intake of medications per subject and lower levels of red cell distribution width in the chronic exercise group. These results indicate that chronic exercise from middle age to old age increases oxidative damage; however, chronic exercise appears to be an effective strategy to attenuate the age-related decline in the elderly.

Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein., (Copyright © 2012 John Wiley & Sons, Ltd.)

The Syrian hamster Harderian gland exhibits sexually dimorphic porphyrin biosynthesis, wherein the female glands display an extraordinarily high concentration of porphyrins. Damage derived from this production of porphyrins, mediated by reactive oxygen species, causes the glands to develop autophagic processes, which culminate in detachment-derived cell death; these cells normally play a central role in the secretory activity of the gland. The main aim of this study was to analyze how a change in the redox state impacts autophagy. Female Syrian hamsters were treated daily with melatonin (25 μg, subcutaneously) at ZT 10 for 1-2 months (N-acetyl-5-methoxytryptamine), an endogenous antioxidant that ameliorates the deleterious effects of free radicals via a variety of mechanisms. The length of treatment affected the redox balance, the autophagy machinery, and the activation of p53 and NF-κB. One-month treatment displaces redox balance to the antioxidant side, promotes autophagy through a p53-mediated mechanism, and increases cell detachment. Meanwhile, 2-month treatment restores redox balance to the oxidant side, activates NF-κB reducing autophagy to basal levels, increases number of type II cells, and reduces number of detached cells. Our results conclude that the redox state can modulate autophagy through redox-sensitive transcriptions factors. Additionally, these findings support a hypothesis that ascribes differences in the autophagic-lysosomal pathway to epithelial cell types, thereby restricting detachment-induced autophagic cell death to epithelial cell type I., (© 2011 John Wiley & Sons A/S.)

Aging is commonly defined as a physiological phenomenon associated with morphological and functional deleterious changes in which oxidative stress has a fundamental impact; therefore, readjusting the oxidative balance should have beneficial effects. In our study, we tested the antioxidant melatonin in old mouse brains and showed positive effects at the cellular and mitochondrial levels. Melatonin attenuated β-amyloid protein expression and α-synuclein deposits in the brain compared to aged group. Furthermore, oxidative stress was increased by aging and induced the nuclear translocation of nuclear factor-kappa B (NF-κB), which was suppressed by melatonin treatment. The antioxidant mitochondrial expression, superoxide dismutase 2 (SOD2), was increased in both control and melatonin-treated old mice, despite the different activation states of the NF-κB pathway. The NF-κB pathway was activated in the old mice, which may be explained by this group's response to the increased oxidative insult; this insult was inhibited in melatonin-treated animals, showing this group an increase in active mitochondria population that was not observed in old group. We also report that melatonin is capable of restoring the mitochondrial potential of age-damaged neurons. In conclusion, melatonin's beneficial effects on brain aging are linked to the increase in mitochondrial membrane potential and SOD2 expression, which probably reduces the mitochondrial contribution to the oxidative stress imbalance., (© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S.)

Novel functions of melatonin continue to be uncovered. Those summarized in this report include actions at the level of the peripheral reproductive organs and include functions as an antioxidant to protect the maturing oocyte in the vesicular follicle and during ovulation, melatonin actions on the developing fetus particularly in relation to organizing the circadian system, its potential utility in combating the consequences of pre-eclampsia, reducing intrauterine growth restriction, suppressing endometriotic growths and improving the outcomes of in vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many cancer types have been known for decades. Until recently, however, melatonin had not been tested as a protective agent against exocrine pancreatic tumors. This cancer type is highly aggressive and 5 year survival rate in individuals with pancreatic cancer is very low. Recent studies with melatonin indicate it may have utility in the treatment of these otherwise almost untreatable pancreatic cancers. The discovery of melatonin in plants has also opened a vast new field of research which is rapidly being exploited although the specific functions(s) of melatonin in plant organs remains enigmatic. Finally, the described application of melatonin's use as a chemical reductant in industry could well serve as a stimulus to further define the utility of this versatile molecule in new industrial applications.

Senescence-accelerated mice (SAMP8) and senescence-accelerated resistant mice (SAMR1) were studied at 5 and 10 months of age, respectively. In the animals, neurodegenerative processes and how they were influenced by melatonin were examined. Melatonin (10 mg/kg) or vehicle (ethanol at 0.066%) treatments were administrated from the age of 1 to 9 months in the drinking water. Differences in the neurodegenerative markers examined were found between the two strains with a more damaged protein, phosphorylated Tau at Ser392, increased neurofibrillary tangles (NT) and higher alpha-synuclein expression in SAMP8 versus SAMR1 mice overall, when the mice were 10 months of age. Changes in density of receptors and oxidative stress-related signaling with age were found in the brains of SAM strains at 10 months as shown by a marked decrease in the level of MT-1 melatonin receptor and retinoic acid receptor-related orphan receptor (ROR)-alpha1. This diminution was earlier and more pronounced in SAMP8 mice. Likewise, the levels of nuclear factor-kappa B (NF-kB) transcriptional factor were higher in SAMP8 mice compared with SAMR1 mice regardless of age confirming the direct role of oxidative stress in the aging process. Treatment with melatonin in SAMP8 and SAMR1 mice reduced the neurodegenerative changes with an increase of ROR-alpha1 levels without an apparent influence in the levels of MT-1 receptor. However, different melatonin effects on NF-kB signaling were observed suggesting that NF-kB could trigger inflammatory processes in a different way, being SAM strain-dependent and associated with age-related oxidative stress levels. The effectiveness of melatonin in improving age-related neural impairments is corroborated.

The blind subterranean mole rat Spalax ehrenbergi superspecies has evolved adaptive strategies to cope with underground stress. Hypoxia is known to stimulate reactive oxygen species generation; however, mechanisms by which Spalax counteracts oxidative damage have not been investigated before. We studied in Spalax the oxidative status of the Harderian gland (HG), an organ which is particularly vulnerable to oxidative stress in many rodents. With regard to the sexual dimorphism found in this gland, differences between males and females were determined and compared to the surface-dwelling Syrian hamster. Our results show, for the first time, that Spalax exhibits remarkably low biomolecular damage, which implies the existence of physiological strategies to avoid oxidative damage under fluctuating O(2) and CO(2) levels existing in the mole rat's subterranean niche. Correspondingly, main antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione reductase (GR), exhibited high activities in both genders; in particular, remarkably high levels were measured in SOD. SOD and GR activities showed statistically significant differences between sexes. Melatonin, an important circadian agent is also a very important antioxidant molecule and is synthesized in the Harderian glands (HGs) of Spalax. Therefore, the possible interaction between antioxidant enzymes and melatonin is suggested.

To assess whether oxidative damage in some tissues was related to their melatonin concentration, endogenous melatonin levels and the age-linked protein and lipid damage in spleen, thymus and liver in 5-month-old SAM P8 mice were examined. The results show that high levels of melatonin in spleen and thymus correlate with lower protein and lipid damage. The liver, which had much lower melatonin concentrations than the other two tissues, had much higher levels of oxidatively damaged protein, as measured by carbonyl values. These results add new evidence concerning the protective role of endogenous melatonin as an antioxidant agent, and suggest that a treatment with this molecule might help to reduce age-associated functional deficits in many organs, including those of the immune system.

Melatonin, the main secretory product of the pineal gland, is known to collaborate against oxidative stress within cells, but its mechanism of action in terms of stimulating antioxidant enzymes remains unclear. Herein, we propose that melatonin modulates antioxidant enzyme activities via its interaction with calmodulin, which in turn inhibits downstream processes that lead to the inactivation of nuclear RORalpha melatonin receptor. Eventually, this nuclear transcription factor downregulates NF-kappaB-induced antioxidant enzyme expression. Therefore, the increment in antioxidant enzyme activities induced by melatonin involves the inhibition of the RORalpha pathway. Thus, in addition to its direct free radical scavenging activities, melatonin has important actions in oxidative defense by stimulating enzymes which metabolize free radicals and radical products to innocuous metabolites.

Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and of low molecular weight antioxidants (LMWAs) are described in various phylogenetically distant organisms. Substantial amplitudes are detected in several cases, suggesting the significance of rhythmicity in avoiding excessive oxidative stress. Mammalian and/or avian glutathione peroxidase and, as a consequence, glutathione reductase activities follow the rhythm of melatonin. Another hint for an involvement of melatonin in the control of redox processes is seen in its high-affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor. Although antioxidative protection by pharmacological doses of melatonin is repeatedly reported, explanations of these findings are still insufficient and their physiological and chronobiological relevance is not yet settled. Recent data indicate a role of melatonin in the avoidance of mitochondrial radical formation, a function which may prevail over direct scavenging. Rhythmic changes in oxidative damage of protein and lipid molecules are also reported. Enhanced oxidative protein modification accompanied by a marked increase in the circadian amplitude of this parameter is detected in the Drosophila mutant rosy, which is deficient in the LMWA urate. Preliminary evidence for the significance of circadian rhythmicity in diminishing oxidative stress comes from clock mutants. In Drosophila, moderately enhanced protein damage is described for the arrhythmic and melatonin null mutant per0, but even more elevated, periodic damage is found in the short-period mutant per(s), synchronized to LD 12:12. Remarkably large increases in oxidative protein damage, along with impairment of tissue integrity and--obviously insufficient--compensatory elevations in protective enzymes are observed in a particularly vulnerable organ, the Harderian gland, of another short-period mutant tau, in the Syrian hamster. Mice deficient in the per2 gene homolog are reported to be cancer-prone, a finding which might also relate to oxidative stress. In the dinoflagellate Lingulodinium polyedrum [Gonyaulax polyedra], various treatments that cause oxidative stress result in strong suppressions of melatonin and its metabolite 5-methoxytryptamine (5-MT) and to secondary effects on overt rhythmicity. The glow maximum, depending on the presence of elevated 5-MT at the end of subjective night, decreases in a dose-dependent manner already under moderate, non-lethal oxidative stress, but is restored by replenishing melatonin. Therefore, a general effect of oxidative stress may consist in declines of easily oxidizable signaling molecules such as melatonin, and this can have consequences on the circadian intraorganismal organization and expression of overt rhythms. Recent findings on a redox-sensitive input into the core oscillator via modulation of NPAS2/BMAL1 or CLK/BMAL1 heterodimer binding to DNA indicate a direct influence of cellular redox balance, including oxidative stress, on the circadian clock.

Effects of delta-aminolevulinic acid (ALA) and melatonin were investigated in the female Syrian hamster Harderian gland. This is an organ physiologically exposed to strong oxidative stress due to the highest porphyrinogenic rates known in nature. Enzyme activities of porphyrin biosynthesis and of antioxidative protection, oxidative protein modification, and histological integrity were studied. In the porphyrin biosynthetic pathway, ALA and melatonin acted synergistically by downregulating ALA synthase (ALA-S) and stimulating product formation from ALA; the combination of ALA and melatonin suppressed ALA-S activity, down to about 1% of that in controls. While ALA effects on porphyrinogenesis can be interpreted in terms of homeostasis, melatonin's actions may be seen in relation to seasonality and/or reduction of oxidative stress. Among antioxidant enzymes, superoxide dismutase (SOD) and glutathione reductase (GR) activities were diminished by ALA, presumably due to the vulnerability of their active centers to free radicals, whereas melatonin moderately increased SOD. Both ALA and melatonin strongly stimulated catalase (CAT), thereby counteracting the oxidative stress induced by ALA and its metabolites. Nevertheless, exogenous ALA caused a strong net rise in protein carbonyl and considerable damage of tissue. When given together with ALA, melatonin antagonized these effects and largely protected the integrity of glandular structures.

Despite efforts to curb the incidence of obesity and its comorbidities, this condition remains the fifth leading cause of death worldwide. To identify ways to reduce this global effect, we investigated the actions of daily melatonin administration on oxidative stress parameters and autophagic processes as a possible treatment of obesity in ob/ob mice. The involvement of melatonin in many physiological functions, such as the regulation of seasonal body weight variation, glucose uptake, or adiposity, and the role of this indoleamine as an essential antioxidant, has become the focus of numerous anti-obesity studies. Here, we examined the oxidative status in the livers of obese melatonin-treated and untreated mice, observing a decrease in the oxidative stress levels through elevated catalase activity. ROS-mediated autophagy was downregulated in the liver of melatonin-treated animals and was accompanied by significant accumulation of p62. Autophagy is closely associated with adipogenesis; in this study, we report that melatonin-treated obese mice also showed reduced adiposity, as demonstrated by diminished body weight and reduced peroxisome proliferator-activated receptor gamma expression. Based on these factors, it is reasonable to assume that oxidative stress and autophagy play important roles in obesity, and therefore, melatonin could be an interesting target molecule for the development of a potential therapeutic agent to curb body weight. [ABSTRACT FROM AUTHOR]

The quinalphos metabolite 2-hydroxyquinoxaline (HQO), previously shown to photocatalytically destroy antioxidant vitamins and biogenic amines in vitro, was tested for toxicity in several small aquatic organisms and for mutagenicity in Salmonella typhimurium. In the rotifer Philodina acuticornis. HQO caused the disappearance of large individuals and increased hydroperoxide concentration. The latter effect was not only observed in animals kept in a light/dark cycle, but also in constant darkness, indicating that HQO can assume a reactive state and/or form reactive intermediates under the influence of either light or redox-active metabolites, in particular, free radicals. Cell proliferation was inhibited in the ciliate Paramecium bursaria. In the dinoflagellate Lingulodinium polyedrum, which allows early detection of cellular stress on the basis of bioluminescence measurements, strong rises in light emission became apparent on the 2nd day of exposure to HQO and continued until cells died between 12 and 18 days of treatment. Oxidative damage of protein by HQO was demonstrated by measuring protein carbonyl in L. polyedrum in vivo as well as in light-exposed bovine serum albumin in vitro. In an Ames test of mutagenicity, HQO proved to be genotoxic in both light- and dark-exposed bacteria. HQO appears as a source of secondary quinalphos toxicity, which deserves further attention. [ABSTRACT FROM AUTHOR]

Presents information on a study which investigated the effects of continuos light on antioxidant enzymes, porphyric enzymes, and cellular damage in the Harderian gland of the Syrian hamster. Information on the Harderian glands; Methodology of the study; Results and discussion.

Melatonin was considered to be the sole member of this natural family. The emergence of naturally occurring melatonin isomers (MIs) has opened an exciting new research area. Currently, several MIs have been identified in wine, and these molecules are believed to be synthesized by either yeasts or bacteria. A tentative nomenclature for the MIs is proposed in this article. It will be important to explore whether all organisms have the capacity to synthesize MIs, especially under the conditions of environmental stress. These isomers probably share many of the biological functions of melatonin, but their activities seem to exceed those of melatonin. On basis of the limited available information, it seems that MIs differ in their biosynthetic pathways from melatonin. Especially in those compounds in which the aliphatic side chain is not attached to ring atom 3, the starting material may not be tryptophan. Also, the metabolic pathways of MIs remain unknown. This, therefore, is another promising area of research to explore. It is our hypothesis that MIs would increase the performance of yeasts and probiotic bacteria during the processes of fermentation. Therefore, yeasts producing elevated levels of these isomers might have a superior alcohol tolerance and be able to produce higher levels of alcohol. This can be tested by comparing existing yeast strains differing in alcohol tolerance. Selection for MIs may become a strategy for isolating more resistant yeast and Lactobacillus strains, which can be of interest for industrial alcohol production and quality improvements in bacterially fermented foods such as kimchi. [ABSTRACT FROM AUTHOR]