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Diabetes and ageing shares a common link in their biochemistry. Though there are numerous theories of ageing have been proposed in the past, none of them is universally acceptable. Among those theories the inflammatory theory and the glycation theory gained significant research interest in recent past. Both theories seem to have a common biochemical link in their initialization and progression.
The pivotal event in the ageing process seem to be the formation of Advanced Glycation End (AGE) products. Glycation is the non-enzymatic modification of various physiologic molecules such as protein, lipid and nucleic acid. In this chapter, we will discuss the ageing mechanism in details, the link with diabetes and its clinical implications in skin. We will also discuss some prevention strategies and future directions.
Diabetes is a pathogenic condition when Glucose level is abnormally elevated in blood. Many of the clinical complications of diabetes are thought to be a result of glycation and formation of advanced glycation end-products (AGE).
Glycation is biochemically a non-enzymatic (in contrast with glycosylation , which is enzymatic) process where a carbonyl group of glucose (or sometime fructose) binds with lipid, nucleic acid or amino acid(most commonly lysine or arginine) to form a schiff base. The schiff base is subsequently converted to a amadori product. The amadori product can still be reversed or may undergo further breakdown or protein cross linkings. The later processes create AGE that hampers with the function and anatomic integrity of the main molecule.
Apart from the direct damage, AGE also promote ageing through inflammatory pathway activation. There is a special class of cellular surface receptor known as RAGE (receptor for AGE). When AGE binds with such a receptor , the resulting secondary messenger activation leads to pro-inflammatory gene expressions , further RAGE formation and decreased Glutathione activity, which would potentially break down many AGE products. Thereby binding of AGE with RAGE is a crucial step which creates a vicious cycle of further damage.
Formation of AGE may be influenced by various factors such as genetics, age, presence of reactive oxygen species (ROS), hyperglycemia etc. Among various AGE products, in diabetes, perhaps the most studied is HBA1C or glycosylated hemoglobin, which is widely used as a clinical marker of long term diabetes control (Once the HBA1C is formed, it remains unaltered for the rest of it’s host RBC’s lifespan, which is 120 days.)
In skin, however the most commonly seen AGE is carboxy-methyl-lysine (others are pentosidine and di-carbonyl compounds). Collagen is the primary target due to its wide availability in skin and its slow turnover rate. Apart from collagen , other proteins such as elastin and vimentin (intermediate filament) are also damaged. This gradually leads to loss of elasticity and contractile capacity of skin as well as skin atrophy. While hyperglycemia in uncontrolled diabetes increases the overall AGE formation, sun-exposure (damage by UV ray and formation of ROS molecules) mainly causes damage to elastin, making the skin thick and non-elastic. Such photoageing is structurally different from general chronological ageing.
Cutaneous AGE formation can be both intra and extra-cellular. In the extracellular matrix, type I collagen is the primary target for glycation because of its abundance and low turnover rate. Attachment of AGE to it leads to reduced flexibility and mechanical support . Moreover, AGE also prevent collagen breakdown by MMP(Matrix metallo-protease) and thereby increases its turnover time further.
Apart from Type I collagen, type IV collagen (present in basal layer), fibronectin and elastin are also target of AGE (most commonly CML or carboxy-methyl-lysine). As mentioned previously, CML linked elastin is almost exclusively found in sun damaged skin presumably due to increased ROS formation due to ultraviolet ray. It is worth noting that ROS and AGE has a synergistic relationship and presence of one usually increases the formation of other through various mechanisms.
Extracellularly formed AGE not only bind to extra-cellular proteins, they also bind to cell surface receptors (as described previously). RAGE is present in both keratinocytes and fibroblasts. When AGE binds to its receptor over cellular surface(RAGE), it affects a wide range of physiological cellular function through various intracellular messenger system. Among them most important is nf-kb pathway. Direct intra-cellular AGE formation on the other hand, affects cytoskeletal proteins such as CK10 and vimentin, and therefore hampers their cellular functions. The formation of AGE in skin is increased with age, presence of diabetes and other factors such as smoking. Exogeneous AGE ingested through diet also have similar effect as endogenously produced AGE and described in the next section.
It is interesting to note that many of the AGEs have auto-fluorescence property which make them a potential candidate to be used as a biomarker in skin ageing or diabetic complications.
Various studies indicate that glycated product in diet may directly influence cellular functions similar to endogenously produced glycated products ( AGE are the advanced stage ). Around 10% of dietary glycated product is absorbed but it may be influenced by different factors such as molecular weight and genetics.
Restriction of sugars in diet may prevent endogenous AGE formation but paradoxically carbohydrates in diet usually have the lowest glycated content. On the contrary some factors in diet increases the chance of d-AGE (dietary AGE) formation and may cause adverse consequence in diabetic individuals. They are mentioned below.
High protein and fat content
High temperature during cooking such as deep frying
Low moisture environment cooking (boiling or water based Indian cooking practice is protective).
High or neutral PH (Acidic PH prevents glycation, such as cooking with lemon juice).
Any kind of food processing even pasteurization of milk.
Foods with low exogenous AGE are fruits and nuts. Minimally cooked or boiled vegetables, fish, skimmed milk, yoghurt, whole grains etc. Additionally beans and legumes might contain phenolic compounds which might help to prevent AGE formation, and an ideal item for diabetic individuals. Lifelong AGE restriction is diet proved to prevent aging and increase lifespan in animal models. In human, dietary AGE is seen to correlate with various inflammatory markers ( C-reactive protein, TNF- a, Vcam1). Apart from the above dietary changes, another widely studied method is calorie restriction which decreased AGE formation with skin collagen in mice model along with increased lifespan.
Considerable effort has been put to reverse the AGE formation or prevention considering its adverse consequence. Many naturally occurring compounds have been found to have anti-AGE effects but most of these observations are limited with animal models. The detail discussion of all of these compounds is beyond the scope of this text, so only the most important ones are described below.
Vitamin c (ascorbic acid) and vitamin E (tocopherol)
B complex vitamins such as thiamin, riboflavin, niacin and pyridoxin.
Minerals such as zinc, manganese, selenium etc
L-carnitine and alpha lipoic acid (thought to have a synergistic role).
Spices such as cinnamin, oregeno, ginger, garlic and different herbs
Anti-oxidants such as polyphenols and flavanoids (naturally seen in green tea, grape seed extracts.
Some other chemical compounds such as aminoguanidine, aspirin, penicillamine etc.
Apart from that, following a healthy diet with minimally processed item helps in reduce exogenous AGE load in the body (as described in the previous section). Certain human trials are worth mentioning in this context. Vitamin B6(pyridoxine) proved to delay diabetic nephropathy. Vitamin C proved to reduce serum glycation. L-carnitine reduced AGE production in skin. A new class of compounds ,called s-RAGE (small molecule inhibitor against RAGE) is currently under investigation and thought to antagonize AGE at receptor level.
In conclusion, diabetes and ageing share a common link of AGE formation. AGE is thought to be responsible for ageing and various diabetic complications through interfering with normal physiologic functions. AGE products exert their effect through intra and extracellular binding with various proteins and also by binding with cell surface receptors (RAGE). In skin, the primary target is extracellular collagen but intracellular proteins such as CK10 are also affected. Exogenous AGE ingested through diet is also have the same effect as endogenously produced AGE. However, it can be modified through different dietary modifications. Additionally different nutriceuticals are currently under investigations to prevent or break down AGE products.
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