Aging is a multifactorial process that involves changes at the cellular, tissue, organ and the whole body levels resulting in decreased functioning, development of diseases, and ultimately death. Oxidative stress is believed to be a very important factor in causing aging and age-related diseases. Oxidative stress is caused by an imbalance between oxidants such as reactive oxygen species (ROS) and antioxidants. ROS are produced from the mitochondrial electron transport chain and many oxidative reactions. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. MG levels are elevated in hyperglycemia and other conditions. An excess of MG formation can increase ROS production and cause oxidative stress. MG reacts with proteins, DNA and other biomolecules, and is a major precursor of advanced glycation end products (AGEs). AGEs are also associated with the aging process and age-related diseases such as cardiovascular complications of diabetes, neurodegenerative diseases and connective tissue disorders. AGEs also increase oxidative stress. In this review we discuss the potential role of MG in the aging process through increasing oxidative stress besides causing AGEs formation. Specific and effective scavengers and crosslink breakers of MG and AGEs are being developed and can become potential treatments to slow the aging process and prevent many diseases.

Sulforaphane administration rectified pathological abnormalities in SHRSP kidneys and significantly improved blood pressure. This was associated with normalization of global kidney DNA methylation suggesting that DNA methylation could be associated with hypertension.

We used cultured endothelial cells as a model to examine whether up-regulation of aldolase B and enhanced methylglyoxal (MG) formation play an important role in high glucose-induced overproduction of advanced glycosylation endproducts (AGEs), oxidative stress and cellular dysfunction. High glucose (25 mM) incubation up-regulated mRNA levels of aldose reductase (an enzyme converting glucose to fructose) and aldolase B (a key enzyme that catalyzes MG formation from fructose) and enhanced MG formation in human umbilical vein endothelial cells (HUVECs) and HUVEC-derived EA. hy926 cells. High glucose-increased MG production in EA. hy926 cells was completely prevented by siRNA knockdown of aldolase B, but unaffected by siRNA knockdown of aldolase A, an enzyme responsible for MG formation during glycolysis. In addition, inhibition of cytochrome P450 2E1 or semicarbazide-sensitive amine oxidase which produces MG during the metabolism of lipid and proteins, respectively, did not alter MG production. Both high glucose (25 mM) and MG (30, 100 µM) increased the formation of N(ε)-carboxyethyl-lysine (CEL, a MG-induced AGE), oxidative stress (determined by the generation of oxidized DCF, H2O2, protein carbonyls and 8-oxo-dG), O-GlcNAc modification (product of the hexosamine pathway), membrane protein kinase C activity and nuclear translocation of NF-κB in EA. hy926 cells. However, the above metabolic and signaling alterations induced by high glucose were completely prevented by knockdown of aldolase B and partially by application of aminoguanidine (a MG scavenger) or alagebrium (an AGEs breaker). In conclusion, efficient inhibition of aldolase B can prevent high glucose-induced overproduction of MG and related cellular dysfunction in endothelial cells.

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Diabetes mellitus (DM) is believed to promote oxidative stress, which potentially provokes and accelerates complications in conditions such as atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular diseases. In this study, we evaluated the antioxidant therapeutic value of adding an angiotensin-converting enzyme (ACE) inhibitora low dose of captoprilas adjunct therapy to the treatment regimen of Type 2 diabetes mellitus (T2DM). Participants were distributed among two different groups: control and treated. T2DM patients in the treated group (group 2) were given a supplement of the ACE inhibitor capotopril, 12.5 mg/day, in addition to standard treatment. All subjects were interviewed for clinical examination. All patients in group 2 were re-examined monthly for 3 months to evaluate FBS, HbA1c, MDA, total GSH, reduced GSH, GSSG, and ox-LDL. All parameters were repeated for patients in group 2 after 1 and 3 months. The study showed improvements in the glycemic and oxidative stress status with the addition of a low dose of captoprilnot very prominent but statistically significant. Reduced GSH decreased by 73.6% (P = 0.016) and the TBARS level was decreased by 58.3% (P = 0.018) after 3 months of treatment, while ox-LDL was decreased by 26.4% (P = 0.036) at the end of treatment. In summary, the clinical improvements in the disease indices toward normal levels make the use of low doses of ACE inhibitors as adjunct therapy in T2DM worth pursuing. Thus, investigations directed at preventing or protecting against oxidative damage may open a new window for treatment of diabetes mellitus.