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Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms
Author(s) -
Hardeland Rüdiger
Publication year - 2013
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12090
Subject(s) - melatonin , senescence , biology , proinflammatory cytokine , context (archaeology) , telomere , microbiology and biotechnology , dna damage , immune system , oxidative stress , free radical theory of aging , phenotype , longevity , pineal gland , mitochondrion , neuroscience , genetics , endocrinology , immunology , inflammation , gene , dna , paleontology
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 aging‐suppressor SIRT 1, 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.