AGE Breakersby Carmia Borek, PhD
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For all the promise of youth-restoring remedies none has ever reversed the process of aging. Now, for the first time, researchers at Alteon Inc. (alteonpharma.com) have developed a drug that rejuvenates hearts and blood vessels, stiffened with age, by breaking up molecules that cause the trouble.
Glucose is the prime source of fuel for generating energy; but glucose has its dark side. Glucose can bind tightly to proteins and form abnormal (glycated) complexes that progressively damage tissue elasticity. An increased stiffness in the cardiovascular system, which leads to high blood pressure and an overworked heart, is one of the striking features of aging. By breaking these abnormal glucose-protein bonds, the drug ALT-711 can reverse the damage and restore elasticity to blood vessels and heart. Extensive animal studies and ongoing clinical trials show ALT-711 as a potential treatment for a wide range of aging-related disorders.
Since the early 1900s food chemists have known that glucose reacts with amino acids in proteins to form yellow-brown products with cross-linked structures. The Maillard reaction process—named after its discoverer—is the source of color, flavor and texture in cooking; it toughens and discolors food, for example, turning a roasting turkey golden brown or darkening a slice of toast. During the 1970s and 1980s, research done by Dr. A. Cerami and other investigators showed that the glucose-amino acid complexes, called advanced glycation endproducts (AGEs), also form slowly in vivo, on the surface of long-lived proteins such as collagen and elastin, in blood vessels and heart muscle, and crystallin in the lens. Once advanced glycation endproducts are formed they interact with neighboring proteins to produce pathological crosslinks that toughen tissues. The formation of advanced glycation endproducts and AGE-crosslinks are non-enzymatic processes and cannot be reversed by enzymes that disrupt protein bonds. It has been suggested that no other molecule has the versatility of structure and the potential toxic effects on proteins as advanced glycation endproducts. These molecules destroy normal protein structure, inhibit protein physiological function and cause damage that leads to irreversible disease conditions in vital organs.
AGEs effects on tissues
Since advanced glycation endproducts are by nature permanently bound to collagen and other long lived proteins, they accumulate continuously on vessel walls and other tissues, progressively crosslinking collagen and restricting its flexibility. The rate of advanced glycation endproducts’ accumulation and the degree of stiffness they produce are proportional to blood glucose levels and the length of time these levels persist. Evidence that advanced glycation endproducts are important contributors to a loss of elasticity is provided by observations that high blood sugar (hyperglycemia) in young diabetic rats accelerates the stiffening of the heart muscle (myocardium) and that chemicals that inhibit the formation of advanced glycation endproducts prevent the stiffening of the tissues. Additional supporting evidence comes from human observations. People with diabetes, whose high blood glucose is not readily restored to normal, show substantially larger amounts of advanced glycation endproducts in their tissues. They also show increased stiffness, compared to age matched non-diabetic individuals. Age-related cardiovascular disorders that are linked to advanced glycation endproducts—atherosclerosis, hypertension, stroke and heart failure—are frequent complications in diabetes. In fact it has been suggested that diabetes is an accelerated form of aging. Conversely, it is speculated that increased longevity associated with reduced caloric intake may be due to lower amounts of advanced glycation endproducts formed in the body.
AGEs and cardiovascular damage
Restricted movements due to advanced glycation endproduct crosslinking of collagen are especially damaging in blood vessels and the myocardium, whose normal functions depend on flexibility and distensibility. Loss of elasticity in the aorta, the major artery transporting blood from the heart, leads to high systolic blood pressure (systolic hypertension) and high pulse pressure (the gap between systolic and diastolic blood pressure). An increase in arterial stiffness intensifies the workload on the heart and is one of the causes of myocardial enlargement (hypertrophy) and heart failure.
Advanced glycation endproduct crosslinking and loss of elasticity in the myocardium gradually affect the left ventricle of the heart that pumps oxygen-rich blood into circulation. Increasing stiffness suppresses ventricular contractility, damages its ability to fill with blood (diastolic ventricular filling) and reduces blood delivery into the circulation (decreased output). Stiffness of the myocardium increases diastolic blood pressure, as arterial stiffness increases systolic blood pressure and pulse pressure. Epidemiological studies have shown that increased vessel stiffness is a reliable predictor of cardiovascular disease and mortality.
Other AGE induced damage
Considering that collagen is the most abundant protein in the body—a major protein in skin, bones, cartilage, tendons, teeth and the cardiovascular system—advanced glycation endproduct crosslinking of collagen can produce widespread damaging effects.
Advanced glycation endproduct formation also generates free radicals that can add to the damage inflicted by AGE crosslinking of proteins. For example, free radicals can react with components in blood vessels to form fatty plaques that further increase the risk of atherosclerosis, heart disease and stroke, in a cardiovascular system already compromised by loss of elasticity. Advanced glycation endproducts have been found in brain tissue and have been implicated in the pathology of Alzheimer’s disease, by inducing oxidative stress and causing structural modification of beta amyloid proteins that play a significant role in the disease.
Advanced glycation endproducts are also involved in other aging-related conditions, seen frequently in diabetes. AGEs damage the kidney, causing leakage in blood vessels, a thickening of the glomerulus walls and the filtering system, and renal failure. Progressive advanced glycation endproduct damage to blood vessels in the retina (retinopathy) results in blindness.