Crosstalk Between Aging, Circadian Rhythm, and Melatonin.

Circadian rhythms (CRs) are 24-hour periodic oscillations governed by an endogenous circadian pacemaker located in the suprachiasmatic nucleus (SCN), which organizes the physiology and behavior of organisms. Circadian rhythm disruption (CRD) is also indicative of the aging process. In mammals, melatonin is primarily synthesized in the pineal gland and participates in a variety of multifaceted intracellular signaling networks and has been shown to synchronize CRs. Endogenous melatonin synthesis and its release tend to decrease progressively with advancing age. Older individuals experience frequent CR disruption, which hastens the process of aging. A profound understanding of the relationship between CRs and aging has the potential to improve existing treatments and facilitate development of novel chronotherapies that target age-related disorders. This review article aims to examine the circadian regulatory mechanisms in which melatonin plays a key role in signaling. We describe the basic architecture of the molecular circadian clock and its functional decline with age in detail. Furthermore, we discuss the role of melatonin in regulation of the circadian pacemaker and redox homeostasis during aging. Moreover, we also discuss the protective effect of exogenous melatonin supplementation in age-dependent CR disruption, which sheds light on this pleiotropic molecule and how it can be used as an effective chronotherapeutic medicine.

Curcumin displays a potent caloric restriction mimetic effect in an accelerated senescent model of rat.

Curcumin, a strong natural compound with numerous health benefits, is extracted from the Curcuma longa. According to recent research findings, it also acts as a calorie restriction mimetic. We examined established aging biomarkers in erythrocytes and plasma and tested a persistent oral dietary dose of curcumin in young and D-galactose-induced accelerated rat aging models. For four weeks, D-gal (300 mg/kg b.w. subcutaneously) and curcumin (200 mg/kg b.w. oral) were administered simultaneously to test the protective effects of curcumin against D-galactose-induced accelerated aging and oxidative stress. In the accelerated senescent rat model, we discovered a significant rise in protein carbonyl, malonaldehyde (MDA), and advanced oxidation protein products. Increased levels of catalase, superoxide dismutase, ferric-reducing antioxidant potential, and reduced glutathione (GSH) were observed. Our findings reveal that curcumin has characteristics resembling a calorie restriction mimic and can successfully maintain redox equilibrium throughout the aging process in rat erythrocytes and plasma.

Aging, circadian disruption and neurodegeneration: Interesting interplay.

The circadian system is an intricate molecular network of coordinating circadian clocks that organize the internal synchrony of the organism in response to the environment. These rhythms are maintained by genetically programmed positive and negative auto-regulated transcriptional and translational feedback loops that sustain 24-hour oscillations in mRNA and protein components of the endogenous circadian clock. Since inter and intracellular activity of the central pacemaker appears to reduce with aging, the interaction between the circadian clock and aging continues to elude our understanding. In this review article, we discuss circadian clock components at the molecular level and how aging adversely affects circadian clock functioning in rodents and humans. The natural decline in melatonin levels with aging strongly contributes to circadian dysregulation resulting in the development of neurological anomalies. Additionally, inappropriate environmental conditions such as Artificial Light at Night (ALAN) can cause circadian disruption or chronodisruption (CD) which can result in a variety of pathological diseases, including premature aging. Furthermore, we summarize recent evidence suggesting that CD may also be a predisposing factor for the development of age-related neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), although more investigation is required to prove this link. Finally, certain chrono-enhancement approaches have been offered as intervention strategies to prevent, alleviate, or mitigate the impacts of CD. This review thus aims to bring together recent advancements in the chronobiology of the aging process, as well as its role in NDDs.

Therapeutic potential of melatonin and its derivatives in aging and neurodegenerative diseases.

Aging is associated with increasing impairments in brain homeostasis and represents the main risk factor across most neurodegenerative disorders. Melatonin, a neuroendocrine hormone that regulates mammalian chronobiology and endocrine functions is well known for its antioxidant potential, exhibiting both cytoprotective and chronobiotic abilities. Age-related decline of melatonin disrupting mitochondrial homeostasis and cytosolic DNA-mediated inflammatory reactions in neurons is a major contributory factor in the emergence of neurological abnormalities. There is scattered literature on the possible use of melatonin against neurodegenerative mechanisms in the aging process and its associated diseases. We have searched PUBMED with many combinations of key words for available literature spanning two decades. Based on the vast number of experimental papers, we hereby review recent advancements concerning the potential impact of melatonin on cellular redox balance and mitochondrial dynamics in the context of neurodegeneration. Next, we discuss a broader explanation of the involvement of disrupted redox homeostasis in the pathophysiology of age-related diseases and its connection to circadian mechanisms. Our effort may result in the discovery of novel therapeutic approaches. Finally, we summarize the current knowledge on molecular and circadian regulatory mechanisms of melatonin to overcome neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, however, these findings need to be confirmed by larger, well-designed clinical trials. This review is also expected to uncover the associated molecular alterations in the aging brain and explain how melatonin-mediated circadian restoration of neuronal homeodynamics may increase healthy lifespan in age-related NDDs.

Modulatory effect of exogenous Coenzyme Q10 on redox and inflammatory biomarkers during aging in rats.

An impaired redox homeostasis is an important hallmark of biological aging. Coenzyme Q10 is an endogenous lipophilic antioxidant that decreases with age and has been linked to oxidative stress. The purpose of this study was to evaluate the effect of CoQ10 supplementation on redox homeostasis and levels of inflammatory cytokines in young and old rats. Male Wistar rats (young and old) were randomly divided into four groups (n = 6). Group I: young control, Group II: young rats treated with CoQ10, Group III: old control, Group IV: old rats treated with CoQ10. CoQ10 (20 mg/kg) was administered daily to Group II and IV via oral gavage. After 28 days of treatment, rats were sacrificed and biomarkers of oxidative stress and inflammatory cytokines were evaluated. Results demonstrated a significant (p ≤ 0.05) increase in malondialdehyde, protein carbonyl oxidation, advanced oxidation protein products, inflammatory cytokines: CRP, IL-6, TNF-α, and a decline in levels of superoxide dismutase, catalase, reduced glutathione, ferric reducing antioxidant potential in plasma and plasma membrane redox system in old rats when compared to young rats. After treatment with CoQ10 significant decrease in the level of MDA, PCO, AOPP, CRP, IL-6, and TNF-α was observed. Also, significant up-regulation of SOD, CAT, GSH, FRAP, and PMRS was observed. The results show that supplementing rats with CoQ10 aids in the maintenance of redox equilibrium with replenishment of antioxidant reserves and down-regulation of inflammatory biomarkers. Thus CoQ10 supplementation could be a potential anti-aging therapy.

Metformin ameliorates acetaminophen-induced sub-acute toxicity via antioxidant property.

Acetaminophen or N-acetyl-p-amino-phenol (APAP) is a drug which is available over-the-counter for fever and pain. Its overdosing causes oxidative stress and subsequent acute liver damage. In the present study, we scrutinized the protective effect of metformin co-treatment in APAP induced blood and liver sub-acute toxicity. This is a pre-clinical study in which male Wistar Rats (BW: 300 ± 20 g) were orally co-treated with APAP (1 g/kg/day) and metformin (300 mg/kg/day) for 28-days. Pro- and anti-oxidant markers viz reactive oxygen species, protein carbonyl, malondialdehyde (MDA), the ferric reducing ability of plasma (FRAP), plasma membrane redox system(PMRS) and reduced glutathione (GSH) were evaluated in blood. Additionally, in liver tissue, catalase (CAT), superoxide dismutase (SOD), MDA and GST level were also evaluated. Histological study and estimation of alanine aminotransferase (ALT), and aspartate aminotransferase (AST) level in serum were performed. APAP induces pro-oxidant markers as well as reduces anti-oxidant markers in blood and liver. Hepatic tissues degeneration and vacuolization of hepatocytes were evident after APAP treatment. Metformin treatment reduces pro-oxidant markers as well as increases anti-oxidant markers in both tissues. It also improves liver tissue architecture after treatment. The outcome of this study suggests that metformin has protective capability against APAP-induced blood and liver toxicity. Thus, metformin co-treatment with APAP attenuates oxidative stress and its consequences.

Melatonin exerts neuroprotection in a chronodisrupted rat model through reduction in oxidative stress and modulation of autophagy.

Circadian disruption due to artificial light affects cellular redox homeostasis and may lead to neurodegenerative diseases. The aim of the present study was to investigate the effect of continuous light exposure (CLE) and continuous dark exposure (CDE) along with melatonin supplementation on neuronal redox status, mitochondrial complexes, membrane bound transporters, inflammation, autophagy and neurodegeneration in chronodisrupted model of rat. In the study artificial light of white LED bulb with 500 lux intensity was used. Melatonin (10 mg/kg b.w., orally) was supplemented to control and CLE groups for 10 days. Standard protocols were employed to measure pro-oxidants, non-enzymatic antioxidants, and mitochondrial complexes in brain tissues. Membrane-bound ion transporter activities were evaluated in the crude synaptosomes. Gene expression analysis was performed to assess the expression of inflammatory, autophagy and neuronal marker genes. Histopathological changes in cerebral cortex and different hippocampus regions of the brain were studied. Melatonin exerted a significant normalization of redox status biomarkers in brain tissue. Further melatonin restored the activities of mitochondrial complexes and synaptosomal membrane bound ion transporters. RT-PCR data revealed that melatonin downregulated the expression of inflammatory (TNF-α, IL-6) autophagy (Atg-3, Beclin-1) and neurodegenerative genes (Ngb and NSE) in CLE group. Melatonin also preserved the histology architecture in cerebral cortex and hippocampus. Our results indicate that melatonin exerts a potent neuroprotective effect through reduction of oxidative stress, inflammation and autophagy. Melatonin supplementation might be a promising neurotherapeutic in the treatment neurodegenerative disorders caused by circadian disturbances.

Age-dependent effect of continuous 'artificial light at night' on circadian rhythm in male rats: neuroprotective role of melatonin.

Circadian disruption due to artificial light at night (ALAN) is an alarming threat to modern society. In the present study we evaluated the protective effect of melatonin on age dependent redox insults and neurochemical deficits induced by ALAN in the brain of chronodisrupted rat model. Young (3 months) and old (22 months) male Wistar rats were exposed to ALAN along with melatonin supplementation (10 mg Kg-1, oral) for 10 days. Results demonstrated significant increment in the pro-oxidant biomarkers: reactive oxygen species, lipid hydroperoxidation, protein carbonyl, nitric oxide while suppression in the total thiol, ferric reducing antioxidant potential level, superoxide dismutase and catalase activities in the brain of ALAN exposed groups with higher amplitude in aged rats. Further these oxidative modifications were protected by subsequent administration of melatonin. Mitochondrial complexes (C-I to C-IV) activity was significantly altered in young and old ALAN exposed groups with melatonin showing protective effect. Histopathological analysis show dense cytosolic staining and neuronal degeneration in cerebral cortex and different hippocampus regions with greater extent in old ALAN rats effectively moderated by melatonin supplementation. RT-PCR data analysis revealed melatonin effectively downregulated neuroinflammatory (IL-6, TNF α) and neurodegenerative marker (Ngb) while upregulating the aging (Sirt 1) gene expression in both young and old melatonin supplemented ALAN exposed groups. Our results may help in understanding the degree of ALAN induced photo-oxidative damage in neuronal redox homeostasis during aging. We also show that melatonin supplementation might provide a basis for amelioration of oxidative disturbances to improve circadian entrainment in aged populations.

Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and D-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging.

Spermidine (SPD) is a natural polyamine present in all living organisms and is involved in the maintenance of cellular homeostasis by inducing autophagy in different model organisms. Its role as a caloric restriction mimetic (CRM) is still being investigated. We have undertaken this study to investigate whether SPD, acting as a CRM, can confer neuroprotection in D-galactose induced accelerated senescence model rat and naturally aged rats through modulation of autophagy and inflammation. Young male rats (4 months), D-gal induced (500 mg/kg b.w., subcutaneously) aging and naturally aged (22 months) male rats were supplemented with SPD (10 mg/kg b.w., orally) for 6 weeks. Standard protocols were employed to measure prooxidants, antioxidants, apoptotic cell death and electron transport chain complexes in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy and inflammatory marker genes. Our data demonstrate that SPD significantly (p ≤ 0.05) decreased the level of pro-oxidants and increased the level of antioxidants. SPD supplementation also augmented the activities of electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. RT-PCR data revealed that SPD up-regulated the expression of autophagy genes (ATG-3, Beclin-1, ULK-1 and LC3B) and down-regulated the expression of the inflammatory gene (IL-6) in aging brain. Our results provide first line of evidence that SPD provides neuroprotection against aging-induced oxidative stress by regulating autophagy, antioxidants level and also reduces neuroinflammation. These results suggest that SPD may be beneficial for neuroprotection during aging and age-related disorders.

Age-dependent altered redox homeostasis in the chronodisrupted rat model and moderation by melatonin administration.

Circadian disruption or chronodisruption (CD) occurs when day-night cycles and other internal rhythms are not adjusted to environmental light-dark regimens and are unable to synchronize among each other. Artificial light-induced oxidative stress is a major concern as the circadian physiology of the cell is chronically altered due to suppression of the time-keeping hormone, melatonin. The relationship between age-related impaired redox status and disrupted circadian rhythms is still not fully understood. The present study evaluated the effect of artificial light at night (ALAN) with respect to aging and role of melatonin supplementation. This study was conducted on young (3 months) and old (24 months) male Wistar rats subdivided into four groups control (C), melatonin treated (MLT), artificial light at night (ALAN), and ALAN+MLT group. Pronounced changes were observed in the old compared to the young rats. Reactive oxygen species (ROS), malondialdehyde (MDA), plasma membrane redox system (PMRS), protein carbonyl (PCO), and sialic acid (SA) were significantly (p ≤ 0.05) increased, while ferric reducing ability of plasma (FRAP) and reduced glutathione (GSH) were significantly (p ≤ 0.05) suppressed in light-exposed young and old animals compared to their age-matched controls. Advanced oxidation protein products (AOPP) increased non-significantly in young rats of the ALAN group; however, significant (p ≤ 0.05) changes were observed in the old rats of the ALAN group compared to their respective controls. Advanced glycation end products (AGEs) increased and acetylcholinesterase (AChE) activity decreased, significantly (p ≤ 0.05) in young animals of the ALAN group, while nonsignificant changes of both parameters were recorded in the old animals of the ALAN groups compared with their age-matched controls. Melatonin supplementation resulted in maintenance of the normal redox homeostasis in both young and old animal groups. Our study suggests that aged rats are more susceptible to altered photoperiod as their circadian redox homeostasis is under stress subsequent to ALAN. Melatonin supplementation could be a promising means of alleviating age-related circadian disturbances, especially in light-polluted areas.

Whey protein concentrate protects against age-dependent alteration in redox biomarkers.

Aging is associated with decreased cellular cysteine uptake, which acts as a precursor for glutathione biosynthesis. Whey protein, a liquid aspect of milk, is an effective cysteine delivery system. The study was undertaken to evaluate the potential role of whey protein concentrate (WPC) on the redox biomarkers during aging. Male Wistar rats were divided into following four groups: young control (4 months old); young treated with WPC (300 mg/kg b.w./day orally); old (24 months old) control; old treated with WPC for 28 days. After treatment, changes in body weight, lipid profile and levels of redox biomarkers were determined. A marked decrease in prooxidants such as reactive oxygen species, lipid peroxidation and protein carbonyl and significant (p ≤ 0.05) increase in antioxidants such as reduced glutathione and GST levels were observed after WPC supplementation in old age rats. We also found marked decrease in the level of sialic acid and AGEs after WPC supplementation. In conclusion, WPC provides protection against age-dependent redox imbalance which might be attributed to its antioxidant activity.

Redox homeostasis in a rodent model of circadian disruption: Effect of melatonin supplementation.

Continuous light or dark photoperiods are the leading cause of disruption in the circadian rhythm of day-night cycle. The purpose of this study was to understand the cellular redox balance in a model of circadian disrupted rat model and determine the effect of melatonin supplementation. Young male Wistar rats were randomly divided into five groups (n = 4). Group (I): normal day-night (12 h:12 h) cycle, Group (II): normal rats treated with melatonin, Group (III): rats subjected to continuous light exposure (CLE), Group (IV): CLE rats treated with melatonin, and Group (V) Rats subjected to continuous dark. Melatonin (10 mg/kg) was administered orally at dusk to the Group (II) & (IV). Rats were sacrificed after 10 days of treatment and biomarkers of oxidative stress were evaluated. Results demonstrated significant (p < 0.05) increase of malondialdehyde (MDA), plasma membrane redox system (PMRS), protein carbonyl oxidation (PCO), advanced oxidation protein products (AOPPs), and advanced glycation end products (AGEs) during CLE. A significantly (p < 0.05) decreased level of reduced glutathione (GSH) and ferric reducing antioxidant potential in plasma (FRAP) was also observed during CLE. Treatment with melatonin in CLE rats showed reduced level of MDA, PMRS, PCO, AOPPs and AGEs while GSH and FRAP activity were increased. During continuous dark exposure (CDE) the biomarkers of oxidative stress were attenuated compared to control. Supplementation of melatonin could be a promising strategy to maintain redox homeostasis during prolonged condition of light exposure and other conditions of redox imbalance.