How the Maillard Reaction is Linked to Disease
Scientists who study the chemistry of how food is cooked are exploring promising therapies to treat an array of diseases, from diabetes to Alzheimer’s.
Published January 20, 2006
By Jill Pope
Academy Contributor
It’s a chemical reaction central to daily life: the Maillard reaction browns our toast and makes roasted coffee smell wonderful. Oh yes, and it’s going on in our bodies all the time.
What happens when sugars and proteins are heated was first described in 1912, and it has intrigued food scientists for 50 years. Over the last 20 years, biomedical scientists have become fascinated as well. We now know that Maillard chemistry plays a role not just in normal aging, but also in a staggering array of age-related chronic conditions, among them atherosclerosis, diabetes, cardiovascular disease, and neurodegenerative diseases such as Alzheimer’s.
How are cooking and body processes related? Susan Thorpe, a prominent biochemist in the Maillard field who is based at the University of South Carolina, explains, “Much as we don’t like to think of our bodies this way, we are protein, sugar, and fat, and we are cooking at a low temperature.”
A Visionary’s Paper is Ignored
Louis Camille Maillard was a French physician and chemist who in 1912 wrote a paper, impressive in hindsight, describing a nonenzymatic browning reaction (that is, one not jump-started by enzymes) that occurred when he heated amino acids with sugars. His work suggested that the reaction might take place in the human body, and he even imagined the critical role we now know it plays in diabetes. At the time, the paper caused no stir.
It wasn’t until the late 1940s that food scientists became interested. For the next 25 years, they learned how the reaction improves the aroma, flavor, and texture of cooked foods. They also put some effort into finding ways to prevent this chemistry from causing undesirable changes in colors and flavors in foods that had to be stored a long time, such as powdered eggs and instant potatoes.
Then, in 1969, the reaction was recognized in the human body. Samuel Rahbar, now at the City of Hope National Medical Center and Beckman Research Institute, found while searching for a genetic marker for diabetes that his diabetic patients had glucose attached to their hemoglobin (the protein that carries oxygen). It had previously been assumed that the Maillard reaction required higher temperatures than those found in vivo.
Rahbar’s discovery of glycated hemoglobin had a major impact on diabetes management, giving doctors a better screening tool and patients a more reliable way to monitor blood sugar. It also opened dozens of research avenues. Once it was shown, in the late 1970s, that the reaction happened in all plasma proteins, biological research in this area took off.
Case in Point: A Lens Protein
The Maillard reaction is really a series of reactions. As an example, consider what happens when an eye protein encounters sugar. A long-lived protein, such as a lens protein, condenses with a sugar in a process called glycation. In subsequent reactions, the damaged lens protein is further abused by sugar as well as by oxidants (free radicals). When the chemistry is done, our lens protein has permanent glucose structures attached to it and appears brown under UV light. And it has a new name: advanced glycation endproduct (AGE).
AGEs accumulate with age and in age-related diseases. Many scientists believe they cause inflammation, loss of flexibility in tissues and organs, and ultimately, impaired function. In the case of our lens protein, the result could be cataracts.
Even the healthiest among us are accumulating AGEs in our tissues as we get older. But because of their elevated blood sugar, diabetic people accumulate AGEs much earlier in life than nondiabetic people. This buildup is seen in kidney disease, eye damage, and nerve damage—suggesting that AGEs are major contributors to diabetes complications. Tissues that depend on flexibility, such as the heart and blood vessels, are also affected.
Not everyone agrees with the theory that damaged protein accumulation causes aging and disease. It may turn out that AGEs simply correlate highly with life-threatening diseases in some other way. But debating that question is less important to many than stopping the damaging cycle.
Stop the Chemistry, I Want to Get Off
In light of the havoc Maillard chemistry can wreak in the body, there is considerable interest in finding ways to stop it, or at least slow it down.
Several Maillard inhibitors have been developed. One is Biostratum’s Pyridorin (pyridoxamine), a member of the vitamin B6 family that blocks AGE formation. Pyridorin is being tested in clinical trials for the treatment of diabetic kidney disease. Three Phase II clinical trials have been completed, and Phase III trials are planned. In the studies, scientists measured patients’ levels of serum creatinine, a widely accepted indicator of impaired kidney function. Treatment with Pyridorin significantly decreased the rate at which creatinine levels rose.
Another inhibitor now in preclinical (animal) trials at Biostratum, BST-4997, works by intervening at a different point, but appears to be even more effective. These drugs offer the potential to slow the progress of kidney disease, giving people more dialysis-free years.
Crosslinks: Reversing the Irreversible?
AGEs are notorious for forming protein crosslinks—becoming closely networked and resistant to being broken. Pimagedine (aminoguanadine, developed by Alteon), is a third kind of Maillard inhibitor for diabetic kidney disease that works by blocking the formation of protein crosslinks. The drug has been shown effective in clinical trials thus far, significantly reducing the amount of protein patients excreted in their urine.
Another substance moving through clinical trials may cause scientists to rethink AGEs entirely. Alagebrium (also by Alteon), the first AGE breaker, appears to work by cutting these protein crosslinks, and is being tested in patients with heart disease. Studies presented at the American Heart Association Scientific Session in November 2005 reported that it caused significant reduction in the mass of the left heart ventricle, a decrease in stiffening of the arteries, and improved function of the lining of the blood vessels. Alagebrium, and other crosslink breakers that may follow it, hold out a previously unimagined possibility—restoring function and flexibility to tissues and organs that have already sustained damage.
Treating Alzheimer’s by Blocking a Receptor
Alzheimer’s sufferers have been found to have three times the amount of AGEs in their brains as do healthy counterparts of the same age. But there is hope: a number of animal studies are looking at ways to treat Alzheimer’s by blocking the receptor for AGE (RAGE). Research suggests that the receptors that bind AGEs may also bind the proteins that accumulate in Alzheimer’s.
If the AGE receptor can be blocked, the accumulation of “senile plaques” in animal brains can also be limited. In one clever ploy, Yasuhiko Yamamoto of Kanazawa University, Japan and coworkers created a decoy receptor, called sRAGE, which they found trapped AGEs and competed with destructive RAGE-AGE communication.
A Role for Diet
What impact do browned foods have on our health? Maillard reaction products are mainly absorbed in the small intestine, and about 10% of dietary AGEs are absorbed in the bloodstream. According to Jennifer Ames, professor of human nutrition and health at the School of Biological and Food Sciences, Queen’s University, Belfast, Northern Ireland, most of the work on AGEs in diet has looked at how they affect atherosclerosis. Results suggest that a low-AGE diet is better for health—”especially for people who have, or who are at risk of developing, diseases related to inflammatory processes,” she says.
In light of these and other findings, Helen Vlassara of the Mount Sinai School of Medicine suggests that people reconsider the AGE content of common foods. Foods higher in fat and protein, such as meat and cheese, will give higher AGE levels. And in general, cooking at a higher temperature creates higher levels of AGEs. Sautéing, steaming, and poaching create fewer Maillard products than frying, grilling, and broiling.
Because oxidants contribute to Maillard chemistry, a diet rich in antioxidants may protect against disease. Toshihiko Osawa of Nagoya University and Yoji Kato of the University of Hyogo have found that antioxidative foods, such as turmeric, can prevent diabetic complications in rats. They also examined the role of glutathione (GSH), an antioxidant found in broccoli and pork, and found that it prevented diabetic kidney and nerve disease.
Eat Less, Live More
Like aging, Maillard chemistry seems inevitable. Drugs may soon help counter the damage. And, to the extent that we can fight it, eating more antioxidant-rich foods, and fewer char-broiled steaks, may help. But, at least in animal studies, only one thing has been shown to extend life—eating less. Most of us in America are eating too much, and an epidemic of type II diabetes is part of the price we pay. The best advice may sound familiar: eat a balanced diet, with lots of fresh fruits and vegetables, and don’t overeat.
Learn more about the Academy’s Nutrition Science program.
