Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms

Abstract

The classic theories of aging such as the free radical theory, including its mitochondria-related versions, have largely focused on a few specific processes of senescence. Meanwhile, numerous interconnections have become apparent between age-dependent changes previously thought to proceed more or less independently. Increased damage by free radicals is not only linked to impairments of mitochondrial function, but also to inflammaging as it occurs during immune remodeling and by release of proinflammatory cytokines from mitotically arrested, DNA-damaged cells that exhibit the senescence-associated secretory phenotype (SASP). Among other effects, SASP can cause mutations in stem cells that reduce the capacity for tissue regeneration or, in worst case, lead to cancer stem cells. Oxidative stress has also been shown to promote telomere attrition. Moreover, damage by free radicals is connected to impaired circadian rhythmicity. Another nexus exists between cellular oscillators and metabolic sensing, in particular to the agingsuppressor SIRT1, which acts as an accessory clock protein. Melatonin, being a highly pleiotropic regulator molecule, interacts directly or indirectly with all the processes mentioned. These influences are critically reviewed, with emphasis on data from aged organisms and senescence-accelerated animals. The sometimes-controversial findings obtained either in a nongerontological context or in comparisons of tumor with nontumor cells are discussed in light of evidence obtained in senescent organisms. Although, in mammals, lifetime extension by melatonin has been rarely documented in a fully conclusive way, a support of healthy aging has been observed in rodents and is highly likely in humans. R€ udiger Hardeland

Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes

“…Disruption of the circadian rhythms has been linked to metabolic disorders such as type 2 diabetes (reviewed by [38]). Furthermore, melatonin has been shown to be an immune stimulator (reviewed by [39]) and seems to be directly involved in the modulation of insulin secretion. However the effect of melatonin on insulin secretion is debatable, as melatonin has been shown to inhibit insulin secretion in vivo and in vitro in rodent models, whereas in one study it enhanced insulin secretion in human islets [40,41].…”

“…This hypothesis is supported by the observed age-related reduction in endogenous melatonin levels. Reduced melatonin levels have been linked to immunosenescence, a process that is thought to contribute to autoimmune diseases in elderly people (reviewed by [39]). …”

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

“…14,31 Melatonin, the main secretory product of the pineal gland, can easily cross the blood-brain barrier and has plentiful neuroprotective properties such as regulating circadian rhythms and providing anti-inflammatory and neuronal protection. [32][33][34] As a naturally occurring compound, melatonin has potential effects on inhibiting autophagy through a redox-mediated scavenge of free radicals and lipid peroxidation, 35 as well as its well-known antioxidant properties. 36 Emerging evidence suggests that melatonin can be used as a neuroprotective agent in the rodent models of PD 32,37,38 by ameliorating the dysfunction of mitochondria, [39][40][41][42] blocking CASP3 (caspase 3, apoptosis-related cysteine peptidase) activation and cellular apoptosis, 43 and protecting TH (tyrosine hydroxylase)-positive nerve terminals.…”

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

“…Moreover, both melatonin and SIRT1 display antiinflammatory properties, 28,29,[64][65][66] and have been shown to be neuroprotective 29,51,67 . Many details are known on antioxidative/antinitrosative actions of melatonin 30,[68][69][70] . Notably, antioxidative protection is strongly related to the circadian system, which includes but also exceeds the rhythmicity of melatonin 45,71 .…”

“…Low-grade oxidative stress and neuroinflammation typically precede clinical symptoms of neurodegeneration 27 . Details concerning the relationship between oxidative/nitrosative stress, inflammation and neurodegeneration have been outlined and reviewed elsewhere [28][29][30] . Numerous other findings that have been repeatedly reviewed, meta-analyzed or studied on a broad scale have shown that sleep loss can be associated with depressive disorders 18,19,[31][32][33][34][35] and neurodegeneration 4,[36][37][38] .…”