Progeria Research Foundation

Old for her age.
Scientists are learning more about the molecular mechanisms behind progeria.

Too Old, Too Fast

Researchers have unearthed new clues behind a disease that effectively turns young children into senior citizens. A protein called progerin prods stem cells to go astray, causing them to mature into the wrong cell types. The findings may have implications for understanding normal aging as well.

Children with Hutchinson-Gilford progeria syndrome (HGPS) develop late-life ailments such as osteoporosis and atherosclerosis, and they usually die from heart disease in their early teens. In 2003, scientists identified the wrongdoer as progerin, a faulty version of the protein lamin A. Normally, lamin A helps strengthen the cell nucleus, but progerin leads to misshapen nuclei and higher-than-normal amounts of DNA damage. Beyond that, researchers didn't know much about how progerin results in illness.

To learn more, cell biologists Paola Scaffidi and Tom Misteli of the U.S. National Cancer Institute in Bethesda, Maryland, engineered cultured skin cells to manufacture progerin and then measured changes in gene activity. Of the more than 1000 genes whose activity levels changed in response to progerin, several belonged to a biochemical circuit known as the Notch pathway, which helps coax stem cells to specialize into a variety of cell types. That was an interesting clue because many progeria symptoms involve tissues derived from mesenchymal stem cells, which give rise to bone, muscle, and fat cells.

So Scaffidi and Misteli tested whether progerin disrupted development of cultured mesenchymal stem cells. As the researchers report online this week in Nature Cell Biology, the mutant protein prodded some stem cells to take an alternative path and become blood vessel cells. Stem cells that did transform into bonemakers were hyperactive, a result that gibes with recent clinical findings that HGPS patients build up and break down bone more rapidly than normal, says Misteli.

The researchers also found that progerin-producing stem cells were loath to mature into fat cells, which could explain why HGPS patients typically lose the fat layer beneath the skin, leading to thin skin. Cells that carried an overactive form of Notch showed similar developmental disruptions, suggesting that progerin makes trouble by turning up the Notch pathway. The work "links the cellular and molecular defects with symptoms in these patients," says Misteli.

The results might also provide insight into aging itself. Scaffidi and Misteli previously demonstrated that even normal cells fashion some progerin (Science, 19 May 2006, p. 1059), and the new data suggest that this small quantity might promote aging by undermining stem cells' capacity to replace damaged or dead cells.

"The results make a lot of sense," says developmental biologist Thomas Gridley of the Jackson Laboratory in Bar Harbor, Maine. The first trials of drugs to alleviate HGPS symptoms have just begun. However, notes developmental biologist Colin Stewart of the Institute of Medical Biology in Singapore, these medicines target progerin, and the findings suggest that compounds that intervene in the Notch pathway are also worth investigating.

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