Background and Purpose: Advanced glycation endproducts (AGEs) produced by glycative stress are implicated in the risk of various age-related diseases. We hypothesized that DNA methylation is involved as a mechanism linking the two. This study analyzed the relationship between DNA methylation in skin samples and physical information, especially in terms of glycation stress. Methods: Male and female Caucasian patients aged 40 - 75 years at Riga Stradins University were included (296 patients), consisting of two groups: 149 patients in the metabolic syndrome (MS) group and 147 in the non-MS group. Methylation age (MethylAge) was calculated by measuring hydroxymethylated DNA by LC-MS and matching with cohort data from the Reunis Institute. Glycative stress indices were measured by skin AGE fluorescence (SAF) with an AGE Reader (DiagnOptics, The Netherland). In addition, physical measurements and blood sex chemistry tests were performed. Results: Items that showed significant correlations with MethylAge were chronological age (r = 0.594), waist circumference (r = 0.261), triglyceride (r = 0.317), and skin aging index (SAI, r = 0.318, p < 0.05 for each). The correlation between methylation age (y) and SAF (x) was particularly high (y = 131.9x² - 490.1x + 491.5, R² = 0.989, p < 0.001). The items that showed significant differences in MethylAge depending on the presence or absence of disease/lesions were MS, SAI, Sebhoroic keratosis and Lentigo type of hyperpigmentation (p < 0.05 for each). The glycation stress index SAF showed a significant correlation with the presence or absence of MS, oxidative stress index (glutathione, superoxide dismutase), and glycolipid metabolism index (fasting plasma glucose, total cholesterol, high-density lipoprotein-cholesterol). Conclusion: Assessment of MethylAge may be an important indicator for physiological aging affected by glycative and oxidative stress. The mechanism by which these stress affects methylation age requires further investigation.

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Objectives: Hassaku (Citrus hassaku) contains higher levels of auraptene in its rind compared to other citrus fruits. Auraptene has been reported to potentially have various health benefits in both in vitro and in vivo studies. We conducted an exploratory study of the effects of auraptene on humans at risk of metabolic syndrome using fractions of oil squeezed from Hassaku fruits, which contain high concentrations of auraptene. Methods: The participants were 14 adult men with an abdominal circumference of 85 cm or more and low-density lipoprotein-cholesterol (LDL-C) of 140 mg/dL or more. The participants were randomly divided into 2 groups of 7 each. The test food was Hassaku oil extract in the form of soft capsules, which was administered as auraptene (10 or 20 mg/day, respectively) for 12 consecutive weeks. The participants underwent clinical examinations, physical examinations, blood and urine tests before ingestion, and at 6 weeks and 12 weeks after ingestion. Results: In the 10 mg/day group (n = 7), a significant decrease from pre-ingestion to 12 weeks after ingestion was observed as follows: Total cholesterol: 233.7 ± 34.7 mg/dL → 218.3 ± 28.4 mg/dL (p = 0.038, t-test), Insulin: 13.17 ± 4.41 → 9.76 ± 3.71 μU/mL (p = 0.022, t-test). The 20 mg/day group (n = 7) also showed the same tendency of variation, but it was not significant. Conclusions: In the 10mg/day group, the ingestion of high-auraptene Hassaku oil extract improved lipid and glucose metabolism, which suggested the contribution to the effectiveness in prophylaxis and prevention of progression of metabolic syndrome and arteriosclerosis, and suppression of glycative stress.

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Over the past 80 years, we have been exposed to increased caloric intake associated with higher fat intake, concurrently with less physical activity. These lifestyle changes result in a marked increase in diseases associated with glycative stress, the condition characterized by excess aldehyde generation, such as obesity, type 2 diabetes, dyslipidemia, metabolic syndrome, and fatty liver/steatohepatitis. We describe our hypothesis as to how aldehydes are involved in the process of progression from fatty liver to steatohepatitis. Glycative stress is defined as an excess of aldehydes, and oxidative stress as an excess of free radicals and ROS (reactive oxygen species). In the body, carbohydrate- and fatty acid-derived aldehydes, which are produced in excess due to hyperglycemia and a high-fat diet, respectively, and modify proteins, lipids, and DNA by glycation. In our protection system, these aldehydes are, consuming NAD+ (nicotinamide adenine dinucleotide) and GSH (glutathione), catalyzed by GAPDH (glyceraldehyde-3-phosphate dehydrogenase), ALDH (aldehyde dehydrogenase), and GLO (glyoxalase). Concurrently, oxidative stress is intensified by a decrease in GSH, and fatty acid-derived aldehydes are mostly produced by the oxidation of fatty acids.Therefore, as fatty liver progresses, the production of fatty acid-derived aldehydes increases significantly. An increase in the NADH/NAD+ ratio in hepatocytes leads to a decrease in lipid β-oxidation and the progression of fat accumulation. DNA modification modifies the promoter region of the low-density lipoprotein receptor related protein 1 (LRP1) gene, and decreased expression of LRP1 leads to abnormalities in lipid metabolism in hepatocyte. Once AGEs, products of protein glycation, stimulate RAGE in macrophages and Kupffer cells to increase the secretion of inflammatory cytokines, inducing inflammation. Glycation of procollagen stimulates Ito cells (hepatic stellate cells), and decreased GSH stimulates fibroblasts to increase collagen production, thus inducing fibrosis. When NAD+ is insufficient, the TCA cycle malfunctions and fumaric acid increases, which results in GAPDH being modified by succinylation and converted to S-(2-succinyl) cysteine-GAPDH, reducing activity and increasing unprocessed aldehydes, creating a vicious cycle. From the above, we deduce that the turning point from fatty liver to steatohepatitis is NAD+ deficiency caused by excess aldehydes, which in turn causes damage to the TCA cycle. We believe that measures against glycative stress (excess aldehydes) are important for preventing steatohepatitis. The involvement of LRP1 remains to be determined.

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