Monday, February 27, 2006

Of Mice and Men

An interesting study was published in the Proceedings of the National Academy of Sciences from researchers at Oregon Health & Science University who discovered that removing a gene involved in repairing damaged DNA causes mice to develop the metabolic syndrome.

The findings were the subject of the article, Removing DNA Repair Gene Causes Metabolic Syndrome, published in Genomics and Proteomics last week.

Those of you who are frequent readers of my column know I am cautious about trying to extrapolate findings from animal models to make a case for why things happen in humans. This finding however, is fascinating. Indeed, it may open the door to truly understanding what is happening in the metabolism of a person developing and eventually presenting with metabolic syndrome - characterized by the following features: obesity, hypertension, dislipidemia (high LDL and triglycerides with low HDL), insulin resistance and high blood sugars.

This study is the first to link DNA repair with the metabolic syndrome, and the findings suggest an important role for what is the "NEIL1 gene product" in the prevention of the diseases associated with the disorder, including obesity, hypertension, high cholesterol, insulin resistance and kidney disease. R. Stephen Lloyd, PhD, senior scientist at OHSU's Center for Research on Occupational and Environmental Toxicology (CROET) and co-author of the study said that "...if there are catalytically compromised forms of NEIL1 within the U.S. population, these people will be predicted to be at increased risk for developing the metabolic syndrome," a disease believed to affect more than 40 million Americans. Lloyd and his colleagues originally discovered the NEIL1-deficient mouse's propensity for developing the metabolic disorder about two years ago.

Where this gets really interesting is in the explanation of what happens when this piece of DNA is lacking or damaged.

"If you have oxidative stress inside the cell, then the bases in the DNA can become damaged, and the responsibility of this whole group of enzymes is essentially to monitor the entire genome, looking for genomic bases that have been oxidatively damaged," Lloyd explained. "They have the responsibility of then removing the damaged bases, which initiates a process by which the cell puts in a normal piece of DNA where the damaged DNA was. This happens every second of your life."

Llyod and his colleague, the study's lead author, Vladimir Vartanian, PhD, created "knock-out" mice - animals bred to lack the NEIL1 gene. Hold on to your hat - here is where the rubber meets the road of this finding - the researchers found that "the mice lacking the enzyme reached weights of between 45 and 52 grams at age 7 months, while normal mice weighed in at only 28 grams. They also were extremely lethargic, their hair was turning gray, and some were even going bald. And there were gender differences." The male mice had more severe presentation of the features of Metabolic Syndrome, at an earlier age, than the female mice did.

"This means mutations in the NEIL1 gene, or the gene's absence altogether, could have a catastrophic effect on the body's ability to restore DNA to its undamaged state."

"Our analysis is that the inability to repair damage to the genetic material, whether it is in the nucleus or whether it's in the mitochondria, is what's leading to a destabilization of a normal metabolic process," Lloyd said. "That then begins to cascade and ultimately results in the symptoms that are consistent with the metabolic syndrome."

Those last two quotes from the article are critical to our understanding of just how devastating damage to our DNA is. And, while the researchers are eager to continue with research into this particular gene to figure out how to develop a screening test for humans, I think there is enough solid understanding about what potentially damages our DNA and how to try to prevent or reverse such damage.

We must eat foods rich in nutrients - those that provide us with a full range of antioxidants - and ensure we're eating adequate protein for our essential amino acids, along with quality fats and oils for our essential fatty acid requirements and requirement for fat soluable vitamins. While the above study was indeed only mice - the finding that a piece of the DNA missing or damaged has such a profound effect metabolically, that is it causes Metabolic Syndrome, should be setting off alarms bells in the research community!

Later today, I'm even going to show you that researchers have had warning bells going off for years in their data but have ignored it as they continue to desperately prove a low-fat diet is optimal for health. This while more and more people are presenting with Metabolic Syndrome, Insulin Resistance and Diabetes!

1 comment:

  1. Hmmm...I'd suggest that the first research project should be one to determine whether you need to *breed* mice without the gene or whether putting normal mice on a long cycle of yo-yo dieting can cause gene mutation!