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You are here: Biology of Aging >

Mechanisms of Aging: Glycation and Cross-linking

Some substances contributing to the aging process, such as tobacco tar, can be avoided. Yet others are an essential part of metabolism we cannot be without. The most important of the latter is glucose.

Glucose is the most common carbohydrate in food; it is the main structural unit of starch and a part of sucrose (table sugar). Most of the energy we get from bread, cereals, pasta and many other foods comes from glucose. The level of glucose in the bloodstream is one of the most important physiological parameters because glucose is the primary fuel for the central nervous system. If the blood level of glucose drops below a certain point for a long enough time, a person will lose consciousness, fall into coma and die. High blood glucose seen in diabetes is also harmful, albeit less dramatically. To avoid dangerous swings in glucose level, the body has a sophisticated system for maintaining blood glucose within an appropriate range. Some reserve glucose is always stored in the liver in the form of glycogen (a polymer similar to starch). On top of that, the liver can synthesize glucose from protein if needed. During starvation, the body would gradually break down its muscle protein for the sake of providing the central nervous system with glucose.

Thus whether we have glucose in our food or not, we always have it in our bloodstream. Unfortunately, in addition to being a vital cellular fuel, glucose is also a substance that can cause damage by randomly reacting with proteins and DNA. This process is called glycation or Maillard reaction. A common example of Maillard reaction is the browning and hardening of a piecrust. A similar process occurs in the body at a lower rate with numerous negative consequences. In particular, glycated enzymes often fail to work as well as they should; other glycated proteins may lose their shape and become insoluble or unstable. For instance, protein glycation is believed to be one of the primary causes of cataracts. Glycation reduces the solubility of lens proteins making them precipitate, which leads to the loss of transparency.

Probably the worst consequence of glycation is cross-linking, which is the formation of chemical bridges between proteins or other large molecules. A material that undergoes cross-linking usually becomes harder, less elastic and has a tendency to tear or crack. Cross-linking is responsible for hardening of a rubber mat or a garden hose left in the sun. In the aging body, cross-linking contributes to hardening of arteries, wrinkling of the skin and stiffening of joints.

An extreme example of damage done by glycation and cross-linking are some of the complications of diabetes which, incidentally, are in many ways similar to the aging process. The principal clinical feature of diabetes is a high level of glucose in the blood. Since the rate of chemical reactions is proportionate to the concentration of the reagents, the higher the glucose level, the greater the rate of glycation and cross-linking. When cross-linked, arterial walls become hard, brittle and less able to pulsate, and capillaries become less permeable to nutrients and oxygen. The net result is the loss of proper blood supply to the tissues, which leads to poor wound healing, nerve damage, and ulcer formation. Most tissues, such as muscle or lungs, require insulin to be able to absorb glucose from the blood. In some tissues, however, namely the nerves, kidneys and retina, glucose can penetrate without insulin and cause particularly extensive damage. These tissues suffer most from high blood glucose, which explains why peripheral neuropathy (nerve damage), kidney failure and blindness are some of the common complications of diabetes.

Research indicates that the most common type of glucose-based cross-links in aging tissues is glucosepane, a chemical bridge formed when glycated proteins react with certain amino acids of other proteins. Diabetics have about twice as many glucosepane cross-links as nondiabetics of the same age. Also, the levels of glucosepane correlate with age-related diseases.

Glucose is not the only possible cause of cross-linking. Cigarette smoke, UV-radiation, heavy metals, peroxides, acetaldehyde (a product of alcohol metabolism) are all potent cross-linkers. Free radicals promote and accelerate many types of cross-linking and may also be cross-linkers themselves.

What can be done minimize or reverse cross-linking? The easiest step is to eliminate cross-linking caused be avoidable environmental factors. Minimize your sun exposure and/or use effective UVA+UVB sunscreen (this will reduce cross-linking in the skin). Reduce consumption of alcohol and avoid smoking (alcohol metabolite acetaldehyde and smoke tar are potent cross-linkers). Keep your antioxidant defenses in shape, especially during the time of stress (see our article on free radicals).

Arguably, the most important step in minimizing glycation and cross-linking is to maintain good carbohydrate tolerance. Interestingly, good carbohydrate tolerance is one of the most common metabolic features of centenarians and may be partly responsible for their unusual longevity. You can find out how your body handles carbohydrates by asking your doctor to perform the so-called glycated hemoglobin test (a.k.a. HbA1c test). An over-the-counter do-it-yourself version of HbA1c test is also available, albeit it may be less accurate. HbA1c test shows how much of your hemoglobin has reacted with glucose and is a good measure of the overall level of glycation and cross-linking in the body. HbA1c also correlates with your average blood sugar level over the 3 month preceding the test. The normal HbA1c range for healthy individuals is 4% to 5.9%. Some experts believe that the values in the lower half of the range are optimal for health and longevity. (See HbA1c test article for more details.) If your HbA1c result is above normal, you need to be under the supervision of a physician. If it is close to the upper limit of the range, you would be wise to adjust your lifestyle towards better carbodydrate metabolism. This may include more exercise, weight reduction, a diet based on low-glycemic foods, blood-sugar lowering supplements (such as cinnamon extract) and so forth.

Are there any targeted treatments to specifically block or reverse glycation and cross-linking? In animal studies, a nutrient carnosine has been shown to inhibit cross-linking. In particular, carnosine inhibits the protein-protein and DNA-protein cross-linking induced by various aldehydes, including glucose. Whether long-term carnosine supplementation has longevity benefits in humans remains to be determined. A number of vitamin derivatives, particularly benfothiamine (a fat-soluble form of vitamin B1) and pyridoxamine (a form of vitamin B6) show promise as inhibitors of certain pathways of glycation and cross-linking. Again, their long-term benefits in humans are unclear. Some researchers are also studying protease supplements, such as serrapeptidase or bromelain, as a possible means to break up exsiting protein-protein cross-links. Others are looking for the holy grail of anti-cross-linking: a targeted agent capable of prevent or reverse the all-important glucosepane cross-links.


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