تاثیر سالخوردگی بر مسیر مصنوعی ملاتونین پلاسما The influence of ageing on the extrapineal melatonin synthetic pathway

1. Introduction Ageing is unstoppable, complex biological process that affects various physiological and metabolic processes in a body, resulting in a decrease of their function (Barton et al., 2016). However, ageing is not a uniform process, since different organs, tissues and cell types may age at different rates (Hamezah et al., 2017; Bonomini et al., 2010). There are a few suggested mechanisms of ageing, and progressive accumulation of oxidative damage stands out as probably the most used explanation (Flores et al., 2012). Not all organs are equally exposed to the damaging factors, such as to the reactive oxygen species (ROS), since different organs have different functions. In that respect, liver and skin are, in general, more exposed to possible oxidative damaging factors than some other organs. A defense mechanism against ROS consists of antioxidant enzymes and various scavenging molecules. One of the most powerful scavenger of ROS in all organs, with more effective properties than classical antioxidant, is melatonin (Baydas et al., 2002). A majority of melatonin supplied to the body via blood originates from the pineal gland. However, we have here focused on a locally produced melatonin in various organs. A predominant melatonin synthesis in both animals and humans occurs via serotonin-N-acetylserotonin-melatonin pathway (Tan et al., 2016) and is regulated by the two key enzymes: arylalkyamine-Nacetyltransferease (AA-NAT) and acetylserotonin O-methyltransferase (ASMT) / hydroxyindole-O-methyltransferase (HIOMT). In addition to a dominant role of AA-NAT in acetylation of serotonin, alternative enzymes, arylamine-N-acetyltransfereases (NAT-1, NAT-2), were detected in rodent (C57BL/6 mouse) and human skin (Debiec-Rychter et al., 1996; Slominski et al., 2003; Kawakubo et al., 2000). An inactive AANAT enzyme, due to a specific gene insertion or deletion, is functionally replaced by NAT-1 enzyme during acetylation of serotonin (Slominski et al., 2005). Higher activity of these enzymes could suggest higher production of melatonin. It has been reported that melatonin levels were much higher in peripheral organs, especially in skin and liver, compared to the serum melatonin (Slominski et al., 2008; Bubenik, 2002). Apart from its important role in protection against ultraviolet and X-ray radiation-induced oxidative stress, melatonin and its metabolites in the skin may have other numerous functions, such as: induction of DNA repair and anticancer activity, blocking apoptosis, maintaining mitochondrial membrane potential and ATP synthesis, anti-inflammatory and immunostimulatory actions, regulation of melanin pigmentations, thermoregulations, and wound healing (Slominski et al., 2018; Slominski et al., 2017a). The melatonin activity in the skin is determined by a topography, health status of the skin, involved cell type, and the animal strain (Slominski et al., 2017a). Moreover, as it was first noticed in rat liver and later in other organs, melatonin can be metabolized by cytochrome 450 (CYP) into powerful antioxidant factors (AFMK and AMK), which have a role in attenuating of ROS and RNS (reactive nitrogen species) elements in mitochondria (Semak et al., 2008; Slominski et al., 2017b).