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* Correspondence: marko.miler@ibiss.bg.ac.rs To the Editor, Keeping in mind our recent breakthrough in the field of biomedical effects of citrus flavanones, achieved by using an insufficiently exploited rat experimental model of old age (1,2), we consider it important to highlight the status of the antioxidative defense system in this animal model, as it is a crucial physiological definer. In general, aging represents a complex process characterized by the deterioration of overall health, slowing of the metabolism, and accumulation of numerous mutations (3). The United Nations World Population Aging Report in 2015 suggested that 12.5% of the entire human population is older than 60 years, while some demographic assessments of the World Bank predict it to reach 17% older than 65 years by 2050. Aging is associated with elevated incidences of chronic diseases, such as diabetes, hypertension, dyslipidemia, liver function disturbances, endocrine issues, osteoporosis, sarcopenia, and cancer (3,4). Changes in the antioxidant defense system (ADS), detoxification mechanisms, and cell reparation underlie the majority of the mentioned diseases (5). Namely, as a consequence of the decrease in ADS and cell reparation capacities during aging, the rate of oxidative damage increases. If reactive oxygen species (ROS) are not efficiently removed from the milieu, accumulation of oxidized and glycoxidized products can subsequently cause cellular senescence (6). It is well known that antioxidant enzymes such as superoxide dismutase (SOD) 1 and 2, catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), as well as nonenzymatic glutathione (GSH), eliminate ROS such as superoxide anion (O2−) or hydrogen peroxide (H2O2). As a consequence of the lack of their efficient removal, this can lead to damage of cellular proteins, lipids, and organelles. Oxidative metabolism in the liver causes the production of highly reactive ROS, whereby 90% of these molecules are generated in the mitochondria during the process of aerobic metabolism, but also during the detoxification of drugs and other xenobiotics (5). Additionally, thyroid hormones directly elevate mitochondrial respiration and produce large amounts of ROS in the liver (7). Impairment of the liver’s ADS may also cause lipid accumulation, as well as nonalcoholic fatty liver disease or other liver pathologies, or can even lead to cancer (6). In support of this thesis, in advanced age the liver is subjected to a progressive decrease in the intensity of blood flow, while sinusoidal capillaries become thicker, less porous, and defenestrated, thus affecting chylomicron uptake, drug elimination, and the accumulation of harmful macromolecules (8). In our experiments, 24-month-old male Wistar rats were used, and in order to define the animal model, we compared properties of their antioxidant defense system in the liver (given its importance as mentioned above) to the adequate systems of 4-month-old (adult) rats. All the procedures related to the care and use of our experimental rats were in accordance with the ethical standards, as already described in detail (1,2). It was reported that the concentration of free testosterone decreases in males with advanced age, while this change directly correlated to a lower detoxification capacity and pharmacokinetics of xenobiotics in the liver (9,10). Presumably, our experimental animals were unable to eliminate various deleterious products of metabolism and damaged macromolecules in an adequate manner. Although the liver has a highly performing ADS in comparison with the modest defense in other organs (e.g., in the brain), oldaged liver is also susceptible to oxidative damage. Namely, in the livers of old rats we observed decreased activity of SOD1, CAT, and GR by 53%, 47%, and 39% respectively, compared to the same parameters in young rats’ livers (Figure 1A). Additionally, gene expression of SOD1 and GR were decreased by 33% and 28%, respectively (Figure 1B). Protein expression analysis showed a significant decrease Received: 11.12.2018 Accepted/Published Online: 04.05.2019 Final Version: 11.06.2019 Letter to the Editor

Old age-associated impairment of the rat liver antioxidant defense system: the basis for affirmation of the experimental model