Inflammaging, Metabolic Syndrome and Melatonin: A Call for Treatment Studies

Abstract

The metabolic syndrome (MS) is a collection of risk factors for cardiovascular disease, including obesity, hypertension, hyperinsulinemia, glucose intolerance and dyslipidemia. MS is associated with low-grade inflammation of the white adipose tissue, which can subsequently lead to insulin resistance, impaired glucose tolerance and diabetes. Adipocytes secrete proinflammatory cytokines as well as leptin and trigger a vicious circle which leads to additional weight gain largely as fat. The imbalance between inflammatory and anti-inflammatory signals is crucial to aging. Healthy aging can benefit from melatonin, a compound known to possess direct and indirect antioxidant properties, to have a significant protective effect on mitochondrial function, to enhance circadian rhythm amplitudes, to modulate the immune system and to exhibit neuroprotective actions. Melatonin levels decrease in the course of senescence and are more strongly reduced in diseases related to insulin resistance. This short review article analyzes the multiple protective actions of melatonin that are relevant to the attenuation of inflammatory responses and progression of inflammaging and how melatonin is effective to curtail MS in animal models of hyperadiposity. The clinical data supporting the possible therapeutic use of melatonin in human MS are also reviewed. Since attention has been focused on the development of potent melatonin analogs with prolonged effects (ramelteon, agomelatine, tasimelteon, piromelatine) and in clinical trials these analogs were administered in doses considerably higher than those usually employed for melatonin, clinical trials on melatonin in the range of 50-100 mg/day are needed to further assess its therapeutic value in MS.

Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer’s Disease and Melatonin

“…Reversal of inflammation by melatonin occurs at different levels. Melatonin is effective in suppressing IR, a hallmark of the metabolic syndrome, by reversing the blockade of a key step in transduction of insulin signals, that is, reduced phosphorylation of IRS-1 [67]. Another important aspect of anti-inflammaging activity of melatonin is its role as an immunological buffer, comprising both proinflammatory and anti-inflammatory effects.…”

“…If we expect melatonin to be effective in improving health, especially in elderly people, it is likely that the low doses of melatonin commonly administered up to the present (under 10 mg/day) are not beneficial. Published reports indicate that melatonin is a safe drug with low toxicity (for references see [67]). In 2 dose-escalation studies of melatonin in healthy volunteers, tolerability and pharmacokinetics of up to 100 mg oral doses of melatonin were assessed with no adverse effects detected [100, 101].…”

Melatonin: A Silent Regulator of the Glucose Homeostasis

“…Melatonin also acts on bone metabolism, activating its MT1 and MT2 specific receptors in an autocrine or paracrine fashion, near the target tissues. Melatonin may exert vasodilatatory (MT2) or vasoconstriction (MT1) effects, depending on the receptor type or the target cell, and it can also down-regulate the cortisol secretion [9].…”

“…Melatonin also exerts different effects on the carbohydrates metabolism, considering various targets: it stimulates glucose uptake in muscle cells by phosphorylation of insulin receptor substrate-1 through MT2 signaling, MT2 receptors are expressed in hepatocytes, and melatonin therapy elevates glucose release from the liver [9].…”

“…Suppression of melatonin secretion by nocturnal light exposure could be a trigger for type 2 diabetes development (Figure 4) [9].…”