Sci. Aging Knowl. Environ., 8 February 2006
The Sour Side of Sweet
Sugar derivatives take a toll on cells
Sugars tantalize our taste buds and fuel our cells, but we pay a price for relying on the sweet, energy-rich molecules. Glucose and its breakdown products--especially one called methylglyoxal--can gum up vital cellular components. In the last 10 to 15 years, methylglyoxal and its chemical cousins have grabbed the attention of experts studying diabetes, cancer, and other diseases. One new paper suggests that methylglyoxal undermines health in an unexpected way: by altering the activity of a gene that controls blood vessel growth, possibly triggering one complication of diabetes. Scientists suspect that methylglyoxal disrupts the activity of other genes as well.
Chemists have long recognized sugar's dark side. Glucose can glom onto DNA and proteins and, through a series of transformations called the Maillard reaction, morph into permanent protuberances called advanced glycation end products, or AGEs (see Monnier and Obrenovich Perspective ). AGEs can disable proteins or cause them to stick together--for example, creating the abnormal links between collagen molecules that stiffen skin and joint cartilage as we grow older (see "Aging Research Grows Up"). The attachments cause other problems, too. For example, AGEs embedded in the extracellular matrix, the mesh that surrounds and supports cells, can spur cellular suicide (see Obrenovich and Monnier Perspective ). AGEs increase the stickiness of the brain proteins that accumulate in Alzheimer's disease, and they might also wear down our tissues as we age. Researchers also suspect that AGEs prompt symptoms of diabetes; patients suffering from the disease carry hefty amounts of the sugary nodules.
If sugars are bad, their breakdown products are worse. Cells process glucose in a biochemical pathway called glycolysis that releases ATP. The main output of glycolysis is pyruvate; cells squeeze this compound for more energy by shunting it into the Krebs cycle. But glycolysis can also emit unwanted methylglyoxal. The more glucose that enters glycolysis, the more methylglyoxal that emerges--explaining why diabetics, whose cells are awash in sugar, manufacture extra methylglyoxal. Sugar metabolism can also unleash methylglyoxal's destructive relatives glyoxal and 3-deoxyglucasone.
Methylglyoxal causes trouble because it's promiscuous. It is between 15,000 and 20,000 times more likely to combine with other molecules than is glucose, says endocrinologist Paul Beisswenger of Dartmouth Medical School in Lebanon, New Hampshire. These reactions can directly damage proteins and DNA. But like glucose, methylglyoxal can also indirectly cause problems by adhering to other molecules and transforming into AGEs. In fact, most of the AGEs in human tissues derive from methylglyoxal, says Beisswenger. Glyoxal and 3-deoxyglucasone can also instigate AGE generation. Methylglyoxal often settles on proteins, but it can also latch onto DNA, inciting mutations.
Recent work suggests that methylglyoxal underlies some complications of diabetes. In a study published last year, for instance, Beisswenger and colleagues found evidence that the compound promotes diabetes-related kidney damage. Amounts of the molecule climbed in patients as their kidney deterioration worsened. The result "further connects cellular toxicity with the levels of these highly reactive compounds," he says.
Fresh research links methylglyoxal to another complication of excess blood sugar: blindness. The work stems in part from the observation that a methylglyoxal-derived AGE amasses in the retinas of diabetic rats. Humans and rodents with the disease often lose their eyesight. The process starts when retinal capillaries dwindle, says molecular biologist Michael Brownlee of Albert Einstein College of Medicine in New York City. Then, as eye cells grow desperate for nutrients, the retina constructs replacement vessels. But they are fragile, and their leaks can cause blindness. Other work has shown that the gene angiopoietin-2 (Ang-2), which normally shuts down in most adult tissues but cranks up in the retinas of diabetic rodents, stimulates normal capillaries to shrink. So Brownlee and colleagues tested whether methylglyoxal spurs Ang-2 activity.
The researchers report in the 27 January issue of Cell that methylglyoxal fastens onto a protein called mSin3A, part of a conglomeration that normally crouches on Ang-2's promoter and shuts down the gene. However, methylglyoxal's attachment attracts another protein, inciting a chain reaction that eventually dislodges mSin3A and partners from the promoter and enables Ang-2 to fire up. Brownlee notes that his group's unpublished microarray work suggests that methylglyoxal adjusts the activity of other genes in addition to Ang-2. The paper is important, Beisswenger says, because the authors "show that methylglyoxal modifying a specific [gene-regulating] factor can lead to an adverse outcome" for the cell.
But cells don't just sit back and take the abuse. They fight back in two ways. First, they fashion an enzyme called glyoxalase that cleaves methylglyoxol into harmless molecules. Second, cells shove proteins damaged by methylglyoxal into the proteasome, a cellular trash disposer, says biochemist Daniel Cervantes of South Dakota State University in Brookings.
Whether methylglyoxal speeds aging is uncertain. Researchers haven't determined whether cells pump out more of the offender as we grow older, or whether glyoxalase activity falls with age. But some evidence hints that cells from older folks are more vulnerable to methylglyoxal. The proteasome falters over time, says Cervantes, and its stumbles might allow methylglyoxal-scarred proteins to build up. Also, glyoxalase requires a compound called reduced glutathione, whose quantities fall as we get older, says Brownlee--although researchers aren't sure whether that decline translates into increased methylglyoxal-induced damage.
The balance between methylglyoxal and glyoxalase plays a key role in one aging-related disease: cancer. Tumor cells pour out methylglyoxal, and the oversupply might be the price for making the large amount of DNA needed for rapid reproduction, Brownlee says. Cancer cells funnel sugars into glycolysis, the hypothesis goes, because molecules that enter this biochemical pathway can branch off to another pathway that builds an ingredient of DNA. However, most cancer cells also boost their production of glyoxalase, allowing them to shrug off the excess methylglyoxal.
To defuse cancer cells' defense, scientists have already designed chemotherapy compounds that hinder glyoxalase and leave tumor cells vulnerable to methylglyoxal. Diabetes researchers are searching for drugs with the opposite effect, and they've identified some molecules that squelch methylglyoxal, including the antidiabetes medicine metformin. But scientists need to find others with fewer side effects, says Cervantes. Those molecules might eliminate some of sugar's sour consequences.
February 8, 2006
Science of Aging Knowledge Environment. ISSN 1539-6150