August 18, 2004
Gene Knock-Outs Reduce Age-Related Bone Loss, Obesity In Mice

Weight gain and thinning of bones was partially prevented in mice by suppression of a gene.

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.”

Mutations in either of two genes prevented much of age-related bone loss and increase in fat.

The Experiment
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.

It would be interesting to know whether these mice will live any longer or shorter than wild type mice.

It might then seem logical for life extension advocates to advocate the development of drugs to silence TLR4 (perhaps based on DNA anti-sense technology or RNA interference technology). But keep in mind that TLR4 plays an important role in spurring the immune response to dangerous blood infections.

Background
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.

Perhaps this can be finessed somehow. If compounds that could act in place of TLR4 could be found then those compounds could be delivered to patients whose own TLR4 genes have been suppressed by a DNA anti-sense drug. Alternatively, perhaps a drug can be developed that will suppress TLR4's effects on fat cells or bone cells (aside: does TLR4 down-regulate osteoblasts or up-regulate osteoclasts?) without interfering with immune response.

Another possibility is to suppress whatever factors might be up-regulating TLR4 in aging bodies. But my guess is that the most likely factor for the cause of TLR4 expression in old folks is an accumulation of damage that causes an inflammation response. Generally speaking, as people age more of their inflammation and repair genes are activated. Possibly we can selectively suppress subsets of those genes to achieve some slowing of aging. But what we really need to do most of all is to be able to repair all the things that are breaking. Regular readers know that this means we need to develop therapies based on SENS (Strategies for Engineered Negligible Senescence).

Share |      Randall Parker, 2004 August 18 02:00 PM  Aging Studies


Comments
Billy Suarez said at July 24, 2007 10:43 AM:

If this proves to be helpful for so many people that face bone loss, than it is good news since there are a lot of drugs to prevent osteoporosis, bone loss in general, that have serious side effects on the bones themselves, like fosamax here, if not taken properly, especially on teeth. Genetics could be an answer, but let us wait.

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