Advanced glycation end products (AGEs) are formed by the Maillard reaction, a non-enzymatic reaction that occurs during the browning of food. AGE formation is promoted by heating and oxidation by metal ions. However, there are no reports comparing the form of AGE contents from each reducing sugar depending on the type of metal ion. Therefore, we used an immunochemical method to evaluate the effects of Cu and Fe on the formation of N^ε-(carboxymethyl)lysine (CML), an oxidation-dependent AGEs formed from glucose, fructose, and ribose, which are representative reducing sugars in the body. Consequently, the CML increased with Fe in glucose, Cu in fructose, and Fe in ribose. The Amadori rearrangement products, prepared by reacting each of the above three types of reducing sugars with bovine serum albumin under anaerobic conditions, were subjected to the Fenton reaction with hydrogen peroxide and various metal ions. The amount of CML produced was significantly increased in glucose with Fe and Cu, and in ribose with Cu compared to the control, however in fructose, no change was observed for any of the metal ions. This indicates that the metal ions that affect CML formation differ depending on the reducing sugar used. In conclusion, the amount of CML formed by metal ions is greater from the reaction of reducing sugars with proteins than from the Amadori rearrangement products; therefore, it is thought that CML is mainly produced via dicarbonyl compounds produced by the oxidation of reducing sugars.

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Aging, the natural, complex and inevitable process in the life cycle of living beings, therefore also of man, according to today's knowledge, most likely takes place on the basis of a program located in the genome. This does not reduce the importance of dividing this process into normal or physiological aging and accelerated or pathological aging related to diseases. A whole set of current theories try to explain the essence of this process. In addition to different variations of the programmed aging theory, the following theories are also relevant: the theory of reactive oxygen species (ROS), cross-linking theory of long protein molecules, mutation theory, autoimmune theory, free radical Harman's theory, microglial aging theory, and the non-enzymatic glycation theory that is the result of the effects of advanced glycation end products (AGE compounds). According to the authors of this study, today's understanding of this inevitable, complex, one-way and irreversible event connected to living nature, with the crucial role of the five proteins mentioned in the title of this paper, is primarily based on the strong involvement of epigenetics in this complex process. Two basic processes related to epigenetics and essential for explaining the aging process, are deoxyribonucleic acids (DNA) methylation and DNA demethylation of CpG (cytosine/phosphate/guanine) sequences in the promoters of the LRP1 and RAGE genes. The first process, determined by deoxyribonucleic acid methyltransferases proteins (DNMTs), involves the insertion of methyl groups (-CH₃) at the C5 position of cytosine in the template strand of DNA, where these genes are located (formation of 5mC). The second process is the oxidative demethylation of 5mC via TET (ten-eleven translocates), TDG (thymine DNA glycosylase) and BER enzymes (base excision repair enzymes). The transcription processes of the five genes involved (LRP1, RAGE, DNMT1, DNMT3A, DNMT3B) have been taking place since the very beginning of life. In addition to their role in controlling growth and development, the crucial function of these processes is to repair the damage caused by a set of adverse events in complex macromolecular structures, mostly caused by the action of oxidation and glycation stress. In essence, this means the creation of new “healthy” receptors as mentioned. Here it is important to emphasize that genomic damage is otherwise subject to the effects of other reparation systems, but their analysis is not the subject of this study. The aforementioned “restorative” transcriptions, under the strong influence of transcription factors (TFs: Sp1, specificity protein 1; Sp3, specificity protein 3), take place under the control of their programs located in the genome. In order to maintain life in the harsh selection struggle typical for each species, there is a precisely determined maximum possible lifespan for its individuals. Here, the processes of DNA methylation and demethylation play an important role. They also have their own precisely defined programs, and the aim of this study is to try to provide answers to the question of the aforementioned interactions. An additional goal of this study is to present the latest findings on the specific blockade of, in old age, the increased expression of the RAGE receptor, and on targeted gene therapy aimed at the muted expression of the LRP1 receptor in old age.

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Microglia phagocytotic activity is vital for homeostasis of the brain by clearing waste, debris, and insoluble aggregates of amyloid β (Aβ) and other proteins. Genetic predisposition is an important factor in the etiology of Alzheimer’s disease (AD), with mutations in genes regulating microglia function and phagocytosis strongly associated with AD risk. However, factors such as lifestyle (e.g., smoking), systemic processes (e.g., glycative and oxidative stresses), and dysbiosis of the intestinal and oral microbiomes have also been implicated in the pathogenesis of neurodegenerative diseases. Mesenchymal stem cell secretome has shown promise as a treatment to improve microglia phagocytosis and cognitive function, while conversely pathogenic bacterial molecular patterns (putatively transmitted by extracellular vesicles [EVs]) are suspected to promote neurodegeneration. In this study, we used our recently developed Aβ phagocytosis model to examine the effects of EVs from probiotic microorganisms on phagocytotic capacity of BV2 microglia. Among the bacterial and yeast strains tested, EVs from Bacillus coagulans lilac-01 and Escherichia coli DH5α both induced a substantial increase in Aβ uptake in a dose dependent manner. As EVs are capable of crossing the blood brain barrier and directly interact with microglia, probiotic EVs have great potential as a treatment for improving microglia functioning in AD and other neurodegenerative diseases.

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Objective: Firmness and elasticity of skin and sagging skin are great concerns for middle- and advanced-aged women. We conducted an exploratory study on the effectiveness of amino acid mixtures for these issues. Method: The research participants, 24 women with low levels of skin elasticity measurements (R7) and high levels of a glycative stress marker, skin autofluorescence (SAF), were chosen from 77 potential female participants who were aware of skin deterioration, e.g., loss of elasticity and sagging. The 24 participants were classified into two groups, the His-Thr group and Orn-Thr group (each group: 12 women). Oral ingestions of amino acid mixtures were administrated for 8 weeks, with each group receiving: 1.65 g of His (histidine), 0.8 g of Orn (ornithine) and 1.65 g of Thr (threonine). Effects of skin elasticity, SAF, moisture retention (skin moisture and trans epidermal water loss [TEWL]) and skin color difference were examined after the 8-week oral administration. Both groups, the His-Thr group and Orn-Thr group, showed significant improvements in skin-related subjective symptoms, and indicators of skin elasticity, SAF and TEWL. Results: The His-Thr group significantly improved lightness assessments (L*) in color difference tests and assessments of dry skin levels by doctors in comparison with the Orn-Thr group. It was judged that there were no safety issues as no adverse events were reported. Furthermore, both groups showed increases in plasma pentosidine concentration. Pentosidine is a product formed in the blood by the reaction of aldehydes with amino acids, peptides, or sugars. During this process, aldehyde modification of proteins can be prevented inside and outside vascular endothelial cells, and therefore it can thought that exogenous amino acids exert a bioprotection effect. Conclusion: The present study suggested possibilities that amino acid supplementation had favorable effects on the firmness, elasticity, and anti-sagging of skin for middle- and advanced-aged women. His is an amino acid required to maintain homeostasis of filaggrin, which is known for wound healing and moisturizing. We will aspire to conduct and develop further research on the administrations of His and Orn mixtures.

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