Quote

Abstract

Increased endogenous generation of advanced glycation endproducts (AGEs) contributes importantly to the vascular complications of diabetes, in part owing to activation of the pro-inflammatory RAGE receptor. However, AGE-altered oligopeptides with RAGE-activating potential can also be absorbed from the diet, and indeed make a significant contribution to the plasma and tissue pool of AGEs; this contribution is especially prominent when compromised renal function impairs renal clearance of AGEs. Perhaps surprisingly, foods rich in both protein and fat, and cooked at high heat, tend to be the richest dietary sources of AGEs, whereas low-fat carbohydrate-rich foods tend to be relatively low in AGEs. Conceivably, this reflects the fact that the so-called “AGEs” in the diet are generated primarily, not by glycation reactions, but by interactions between oxidized lipids and protein; such reactions are known to give rise to certain prominent AGEs, such as N-carboxymethyl-lysine and methylglyoxal. Although roasted nuts and fried or broiled tofu are relatively high in AGEs, low-fat plant-derived foods, including boiled or baked beans, typically are low in AGEs. Thus, a low-AGE content may contribute to the many benefits conferred to diabetics by a genuinely low-fat vegan diet. Nonetheless, the plasma AGE content of healthy vegetarians has been reported to be higher than that of omnivores – suggesting that something about vegetarian diets may promote endogenous AGE production. Some researchers have proposed that the relatively high-fructose content of vegetarian diets may explain this phenomenon, but there so far is no clinical evidence that normal intakes of fructose have an important impact on AGE production. An alternative or additional possibility is that the relatively poor taurine status of vegetarians up-regulates the physiological role of myeloperoxidase-derived oxidants in the generation of AGEs – in which case, taurine supplementation might be expected to suppress elevated AGE production in vegetarians. Thus, a taurine supplemented low-fat vegan diet may be recommended as a strategy for minimizing AGE-mediated complications in diabetics and in patients with renal failure.

Quote

Glutathione is not an essential nutrient, since it can be synthesized in the body from the amino acids L-cysteine, L-glutamic acid, and glycine. While all cells in the human body are capable of synthesizing glutathione, liver glutathione synthesis has been shown to be essential.

In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG). An increased GSSG-to-GSH ratio is considered indicative of oxidative stress.

Glutathione has multiple functions:

It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.[17]

Regulation of the nitric oxide cycle, which is critical for life but can be problematic if unregulated[18]

It is used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system and the lungs.[citation needed]

It has a vital function in iron metabolism. Yeast cells depleted of or
containing toxic levels of GSH show an intense iron starvation-like response and impairment of the activity of extra-mitochondrial ISC enzymes, followed by death.[19]

Calcitriol (1,25-dihydroxyvitamin D3), the active metabolite of vitamin D3, after being synthesized from calcifediol in the kidney, increases glutathione levels in the brain and appears to be a catalyst for glutathione production.[29

Low glutathione is commonly observed in wasting and negative nitrogen balance,[44] as seen in cancer, HIV/AIDS, sepsis, trauma, burns and athletic overtraining. Glutathione supplementation can oppose this process, and in AIDS, for example, result in improved survival rates.[45] However, studies in many of these conditions have not been able to differentiate between low glutathione as a result of acutely (as in septic patients) or chronically (as in HIV) increased oxidative stress and increased pathology as a result of preexisting deficiencies.

A limited series of case reports and small clinical trials suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder, major depressive disorder and schizophrenia.[undue weight? – discuss] Replenishment of glutathione using N-acetyl cysteine reduces symptoms of both disorders.[non-primary source needed][46] Glutathione (GSH) is the major free radical scavenger in the brain.[47]

Quote

Many important biological processes involve redox reactions.

Cellular respiration, for instance, is the oxidation of glucose (C6H12O6) to CO2 and the reduction of oxygen to water. The summary equation for cell respiration is:

C6H12O6 + 6 O2 ? 6 CO2 + 6 H2O

The process of cell respiration also depends heavily on the reduction of NAD+ to NADH and the reverse reaction (the oxidation of NADH to NAD+). Photosynthesis and cellular respiration are complementary, but photosynthesis is not the reverse of the redox reaction in cell respiration:

6 CO2 + 6 H2O + light energy ? C6H12O6 + 6 O2

Biological energy is frequently stored and released by means of redox reactions. Photosynthesis involves the reduction of carbon dioxide into sugars and the oxidation of water into molecular oxygen. The reverse reaction, respiration, oxidizes sugars to produce carbon dioxide and water. As intermediate steps, the reduced carbon compounds are used to reduce nicotinamide adenine dinucleotide (NAD+), which then contributes to the creation of a proton gradient, which drives the synthesis of adenosine triphosphate (ATP) and is maintained by the reduction of oxygen. In animal cells, mitochondria perform similar functions. See the Membrane potential article.

Free radical reactions are redox reactions that occur as a part of homeostasis and killing microorganisms, where an electron detaches from a molecule and then reattaches almost instantaneously. Free radicals are a part of redox molecules and can become harmful to the human body if they do not reattach to the redox molecule or an antioxidant. Unsatisfied free radicals can spur the mutation of cells they encounter and are, thus, causes of cancer.

Quote

Glucose can bind with proteins in a process called glycation, making cells stiffer, less pliable and more subject to damage and premature aging. This process is involved in the aging of the skin.[2]

Replacing dietary carbohydrate with fats such as butter, coconut oil, and olive oil necessarily reduces the intake of glycation's substrate, glucose. The fewer sugar molecules are available for glycation, the less glycation end products there will be. Ketosis, therefore, provides an obvious path to the reduction of AGEs. [OUTDATED: fats contain high exogenous AGEs]

These harmful compounds can affect nearly every type of cell and molecule in the body and are thought to be one factor in aging and in some age-related chronic diseases. They are also believed to play a causative role in the blood-vessel complications of diabetes mellitus.

It is proportional to the dietary intake of exogenous (preformed) AGEs and the consumption of sugars with a propensity towards glycation such as fructose[7] and galactose.[8]

Compounds that have been found to inhibit AGE formation in the laboratory include Vitamin C,[32] benfotiamine, pyridoxamine, alpha-lipoic acid,[33] taurine,[34] pimagedine,[35] aspirin,[36][37] carnosine,[38] metformin,[39] pioglitazone,[39] and pentoxifylline.[39]

Studies in rats have found that resveratrol can prevent the negative effects of the AGEs.[40]

Quote

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis.[1] However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically.[1] This may result in significant damage to cell structures. Cumulatively, this is known as oxidative stress. ROS are also generated by exogenous sources such as ionizing radiation.

Normally, cells defend themselves against ROS damage with enzymes such as alpha-1-microglobulin, superoxide dismutases, catalases, lactoperoxidases, glutathione peroxidases and peroxiredoxins. Small molecule antioxidants such as ascorbic acid (vitamin C), tocopherol (vitamin E), uric acid, and glutathione also play important roles as cellular antioxidants. In a similar manner, polyphenol antioxidants assist in preventing ROS damage by scavenging free radicals. In contrast, the antioxidant ability of the extracellular space is less - e.g., the most important plasma antioxidant in humans is uric acid.

In general, harmful effects of reactive oxygen species on the cell are most often:[4]

damage of DNA
oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation)
oxidations of amino acids in proteins
oxidatively inactivate specific enzymes by oxidation of co-factors


Current studies demonstrate that the accumulation of ROS can decrease an organism's fitness because oxidative damage is a contributor to senescence. In particular, the accumulation of oxidative damage may lead to cognitive dysfunction, as demonstrated in a study in which old rats were given mitochondrial metabolites and then given cognitive tests. Results showed that the rats performed better after receiving the metabolites, suggesting that the metabolites reduced oxidative damage and improved mitochondrial function.[8] Accumulating oxidative damage can then affect the efficiency of mitochondria and further increase the rate of ROS production.[9] The accumulation of oxidative damage and its implications for aging depends on the particular tissue type where the damage is occurring. Additional experimental results suggest that oxidative damage is responsible for age-related decline in brain functioning.

Superoxide dismutases (SOD) are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen.

According to the Free-radical theory, oxidative damage initiated by reactive oxygen species is a major contributor to the functional decline that is characteristic of aging. While studies in invertebrate models indicate that animals genetically engineered to lack specific antioxidant enzymes (such as SOD), in general, show a shortened lifespan (as one would expect from the theory), the converse manipulation, increasing the levels of antioxidant enzymes, has yielded inconsistent effects on lifespan (though some studies in Drosophila do show that lifespan can be increased by the overexpression of MnSOD or glutathione biosynthesizing enzymes). Also contrary to this theory, deletion of mitochondrial SOD2 can extend lifespan in Caenorhabditis elegans.[14]