Aug. 18, 2004 ROCHESTER, Minn. -- Weight gain and bone thinning may seem to be natural complications of aging in humans and mice. Now, Mayo Clinic researchers have discovered a genetic basis for this physical decline -- and have suggested that “silencing,” or turning off a specific gene complex, may halt weight gain and control bone loss. The team found laboratory mice without this gene function have 70 percent less body fat and exhibit the dense bones and lean bodies of young mice.
The researchers dub the mice “Adonis,” after the youth in Greek mythology who had an ideal, youthful physique. Their report appears in the August issue of FASEB Journal published by The Federation of American Societies for Experimental Biology. The work connects the function of genes important in the immune response with processes of physical development and aging. This functional linkage between the immune system, and on body plan and aging, was first described in fruit flies through the study of a gene called Toll. The mouse and human version of Toll is TLR4, which stands for “Toll-like Receptor 4.”
“Normal mice as they age are like people. They get fatter and their bones get thinner,” says Jeffrey Platt, M.D., senior investigator of the study. “But in our investigation, the mice that have defects in TLR4 seemed to maintain the Adonis-like body as they got older. They didn’t become obese or experience loss of bone density.
“We undertook this research project to re-examine the idea of whether TLR4 shapes the body plan of the mouse. We wondered whether we might have missed a developmental function because we were looking at the immune system, not development.”
And that’s exactly what Mayo Clinic researchers found. “For me, the most exciting part is that the activity levels were the same in the two groups of mice. This means the mice that were lean with strong bones worked no harder than fat mice -- it was under genetic control,” Dr. Platt says. “It’s wishful thinking, I know, but that implied I could someday drop my membership in the athletic club and still have a young body type,” he quips, adding on a serious note, “What’s really exciting is that this finding raises the possibility that we could develop new treatments for obesity and osteoporosis because TLR4 can be targeted by drugs and inhibited.”
The group of mice under investigation was genetically the same as the healthy control mice except that they had mutations in TLR4 or in a signaling gene it needs called CD14. Bone density, bone mineral content, bone area, total body mass, fat body mass and fat-free body mass were tested and analyzed by computer with specialized software. Bone growth in the legs was evaluated. Physical activity was tracked with a computerized observational system. Food and water were provided throughout the experiment. Muscle mass was determined, but muscle strength was not checked. Eighteen tests were given to all mice to periodically check for bacteria, viruses and toxins.
Researchers found that the mutant mice whose TLR4 was silenced had:
· Greater bone mineral content at 20 weeks of age compared to normal mice -- and that this relationship increased as both groups aged.
· Larger bones at 20-24 weeks of age.
· 70 percent less body fat than the control group as they grew and aged.
Immunologists think that stimulation of TLR4 is a crucial first step in mounting an immune response in mice and in humans. TLR4 usually responds to endotoxins, which are carried by the bacteria that cause sepsis, a dangerous blood infection. Sepsis occurs in 400,000 people in the United States annually; as many as half may die. Because of its seriousness, Mayo Clinic immunology researchers were interested in understanding the mechanism of sepsis.
The Next Step
Further research is needed to determine whether the discovery can be used to treat osteoporosis, obesity or related conditions. “We and others are working on ways to block the function of TLR4 for modifying immune responses. These same agents may be useful for treating age-related osteoporosis or obesity,” says Dr. Platt. “However, as with all advances, we will first have to determine that the treatments are safe before we can determine whether they are effective, especially when given over a period of time.”
In addition to Dr. Platt, the Mayo Clinic research team included Geoffrey B. Johnson, a medical student at Mayo Clinic College of Medicine, and endocrinologist B. Lawrence Riggs Jr., M.D. Their work was supported by grants from the National Institutes of Health.
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