DOCTORS HAVE NOTICED THAT UNCONTROLLED DIABETICS SEEMED TO UNDERGO SOMETHING RESEMBLING ACCELERATED AGEING. MANY OF THE COMMON AILMENTS OF AGEING, SUCH AS CATARACTS, ATHEROSCLEROSIS, HEART ATTACKS, STROKES, LUNG AND JOINT STIFFENING – APPEARED EARLIER IN DIABETICS TOGETHER WITH WHAT IS KNOWN AS THE MAILLARD REACTION AND CONCLUDED THAT AGEING ITSELF MIGHT BE PARTIALLY DUE TO MAILLARD, (OR BROWNING) PRODUCTS ACCUMULATING AT A SLOW RATE IN THE BODY.
THE MAILLARD REACTION
The Maillard Reaction is the chemical attachment of glucose to proteins at places it does not normally belong, which makes a yellow-brown product. Glucose is sticky stuff, so it attaches spontaneously, given the appropriate temperature and amount of time and until recently, no one understood that this same process could occur at any body temperature. It was in the 1970’s it was noticed that people who have high levels of blood glucose due to poorly controlled diabetes also had glucose attached to some of their haemoglobin – a protein. As if by a Maillard Reaction, their haemoglobin has been modified.
Food browns and we brown because of glucose, the other major molecule of aerobic metabolism. My college housemate’s mother worked as a butcher at a local market. Hers was a wonderful job for us because she brought us home fine steaks night after night. The meat needed to be disposed of anyway, because it was too old to be legally sold – but it tasted fine just the same. I remember quite well, that this meat always had a rather peculiar appearance; before cooking, it was faintly brown on top as if had been lightly seared. Meat changes colour as it is cooked, of course, becoming golden then brown and I know that this old stored meat had very slowly undergone some of the same chemical reactions that meat goes rapidly during cooking. Moreover, as surprising as it may seem, we undergo some of these same chemical changes as we age, we brown.
Louis Maillard, a French chemist, who observed that a mixture of glucose to protein components, when heated, would turn from clear to yellow to a deep brown, discovered this peculiar phenomenon in 1912. Subsequently called the ‘Maillard Reaction’, this has process has been of great interest to food chemists concerned with making food tasty and tempting in appearance as possible ever since. What’s more, he noted that the result of this reaction was a series of unalterable new chemical structures in our tissues, which he called AGEs, a clever acronym from his more opaque chemical term, Advanced Glycosylation End-products.
But simply why would attaching glucose to proteins at places it doesn’t belong lead to the sort of deterioration we call ageing? The first reason is that some proteins form the structure and support of our bodies. Many of the most important structural proteins, such as my opossums’ collagen, live for decades in our bodies without their molecules turning over. Apparently, general characteristics of ageing take place in exactly those tissues that are stuffed with long-lived, non-renewing cells and molecules!
SO LET US THINK ABOUT COLLAGEN AGAIN…
Remember that it is a flexible protein, composed of three strands coiled around one another like a cable. Its flexibility is what makes it so useful for forming the foundation of arteries, veins, lungs and skin. Not to mention for making tendons and ligaments that twist and bend without breaking, and for forming cartilage, that cushions our joints with its resiliency. But as glucose attaches to collagen, it forms bridges or crosslink between strands of a single molecule and between molecules. As these bridges multiply over time, collagen’s flexibility gradually disappears and it turns yellow and stiff and no longer makes such wonderful lungs, tendons, ligaments or support for artery walls. Suddenly it’s stiff and brittle like browned toast. What’s more, collagen with attached glucose in the walls of the arteries acts like an opened jawed bear trap. It seizes and holds on to passing proteins and in this fashion, browning may play a part in trapping and accumulation of LDL cholesterol in the artery walls-an early stage of atherosclerosis!
Proteins do many things in the body besides provide its body structure; they turn genes on and off, direct cell replication, and chaperone other molecules to their appropriate site of action. As enzymes, they are essential for virtually all of the chemical activity of a cell. The fidelity that proteins carry out the functions they were designed for depends on their being chemically unaltered and when sugars attach to protein inappropriately, they can impair their function, and therefore disrupt the proper working of the cell. Attached sugars also make proteins less soluble in the body more likely to solidify and become non-functional, and less likely to be broken down by chemicals designed to destroy damaged molecules.
Solidified proteins glued together into large masses, as it turns out, composed the characteristic brain lesions of Alzheimer’s disease, which will arguably become the most serious problem of ageing over the next several decades. Alzheimer’s disease and other mental debilitation increase dramatically with age, particularly after age 50. The risk of mental debilitation doubles about every five years in late life faster than the overall mortality-doubling rate, which is seven to ten years. By age 85, as many as half of us will be mentally impaired to some degree. Therefore, as populations around the world live longer over the next decade, the number of people who will be unable to take care of themselves, unable to recognise their spouses or children and unable to control their own bodily functions will increase at a depressing rate unless new medical treatments are developed.
The damaging brain lesions of Alzheimer’s disease-so called tangles and plaques-consist of proteins that are common and normal in the brain and that become damaging only when they solidify and aggregate into these gluey masses. Recently, browning products have found in both tangles and plaques, and it may be that browning products themselves are involved in development of the plaques and tangles. The impairment of proteins isn’t the only potential problem associated with glucose. Glucose can also bind directly to DNA, although it does so more slowly than it binds to proteins. Nevertheless, in non-dividing cells, such as those composing much of the brain and heart. DNA is a long-lived molecule on which AGEs can potentially accumulate. In principle, AGE attachment to DNA could disrupt the production of new cellular proteins, could interfere with DNA repair, and could even cause mutations.
AS OF NOW, HOWEVER, RELATIVELY LITTLE IS KNOWN ABOUT THESE PARTICULAR PROCESSES.
Chemical theorists tell us that the Maillard Reaction should proceed at a rate pretty much determined by the concentration of sugars and proteins, and the temperature at which these ingredients are kept. To the extent that browning is a central process of ageing, the anti ageing impact of caloric restriction might be partially explained by a reduced browning rate. If you feed laboratory rats, only 60 percent of the calories they would eat if given unlimited food supplies, their blood glucose level is reduced by about 25 percent, their body temperature declines by several degrees, and their ageing is retarded by about 20 to 25 percent.
But the larger picture is more complex. Most mammals maintain about the same concentration of sugars and proteins in their bodies and live near the same 37 degrees that humans do, and yet some mammals accumulate browning products rapidly and live only a year or two, while others brown slowly and live many decades.
HOW CAN THIS BE?
As was the case with oxidants, the production rate of browning products is apparently only part of the story. If they accumulate at different rates in different species, then there must be protective mechanisms and anti-ageing processes that are well developed in some species and poorly developed in others. Discovering the nature of these anti-ageing processes; then pharmaceutically being able to modify them – should hold great promise for understanding and modifying the age rate itself.
Currently, we know very little about these processes. We know that certain natural plant compounds, as well as synthetic drugs, can inhibit the formation of browning products in a test tube. So it seems likely that our bodies will also contain an array of anti-browning chemicals, although they are yet unknown. At least one of the body’s phagocytes, or scavenger cells, seems specialised too devour proteins or cells that have been ‘browned’.
IF OXIDATION AND BROWNING ARE TWO IMPORTANT GENERAL PROCESSES OF AGEING, IT MIGHT COME AS NO SURPRISE THAT THEY SEEM TO OPERATE COOPERATIVELY TO OUR DETRIMENT. THE DAMAGE CAUSED BY ONE AFFECTS THE OTHER.
So glucose and its derivative products can react with other chemicals to produce free radicals, and free radical can accelerate browning. Also, glucose can attach to cellular antioxidant enzymes and by doing so inactivate them leading to higher levels of free radicals and the damage they cause. These two processes are likely to be centrally involved in ageing, but there is no reason to expect that they completely explain it.
Evolutionary theory suggests that there will be many mechanisms of ageing. Browning and rusting may just be among the most general and easiest to identify. One other general process that has short-term benefits but long-term hazards is the continuing ability of cells to divide throughout life. The failure of proper regulation of this process leads, of course to cancer, which turns out to be perhaps the most general disease of ageing in the animal kingdom.