New Insight into Mechanism of Aging

The defective gene that causes Hutchinson-Gilford progeria syndrome leads to some cells that have two nuclei (blue) instead of one. Kan Cao, Collins laboratory, NHGRI

Researchers believe they've discovered how a rare genetic defect causes premature aging. The process they uncovered may play a role in the normal aging process as well.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease characterized by dramatic, premature aging. Newborns with the disease usually appear normal, but their growth rate slows within a year and they soon become much smaller than others their age. They begin to take on the appearance of older people and often suffer from symptoms, such as stiffness of joints, hip dislocations and cardiovascular disease, typically seen in people decades older. There's currently no treatment or cure. Children with the disease usually die from heart attack or stroke, living an average of only 13 years.

In 2003, researchers discovered that HGPS is caused by a single genetic change in a gene known as lamin A. Lamins are a part of the meshwork that provides support for the membrane around the nucleus, the compartment that holds the cell's DNA. The HGPS mutation results in a shortened protein called progerin/LAΔ50. Researchers knew that progerin/LAΔ50 creates unusual features in the nuclei of people with HGPS, but they didn't understand how these related to premature aging.

A team at NIH's National Human Genome Research Institute (NHGRI) led by the NHGRI director, Dr. Francis S. Collins, set out to further investigate the effect of the mutation. They first put the defective gene into normal cells and closely tracked its effects under the microscope. They reported in the March 20, 2007, issue of the Proceedings of the National Academy of Sciences that progerin/LAΔ50 has its most dramatic effect during mitosis, the period in a cell's life when it divides into two. The defective protein interferes with the division and distribution of the cell's DNA, resulting in a significant number of cells with two nuclei instead of one.

The researchers looked at cells taken from three people with HGPS and confirmed that they also had a higher percentage of cells with two nuclei. A recent study suggested that normal cells also contain small amounts of progerin/LAΔ50, so the team searched four different normal human cell lines for signs of the altered protein. They found a small number of cells producing progerin/LAΔ50, and a significant percentage of them had two nuclei.

In addition to giving us more insight into HGPS, these results suggest that the same molecular mechanisms responsible for HGPS may act at a low level in normal cells. Researchers hope that, by continuing to study premature aging diseases, they’ll gain further insight into the normal aging process.

— by Harrison Wein, Ph.D.