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Scientists Find New Clues to Aging

Mutant Protein Involved in Premature Aging Condition May Also Play Role in Normal Aging

By Kathleen Doheny
WebMD Health News

Reviewed by Louise Chang, MD

June 13, 2011 -- A mutant protein known to be involved in the rare premature aging condition known as progeria appears to play a role in normal aging, too, scientists report. The mechanism that triggers premature aging also seems to trigger normal cell aging.

The finding is expected to offer new clues about aging.

"We have learned something fundamental about the way your cells and mine are programmed to have a limited life span," says researcher Francis Collins, MD, PhD, director of the National Institutes of Health. "It looks like it is not just a passive process."

In the new research, Collins and his colleagues focused on the interaction between the mutant protein known as progerin and telomeres, the protective caps on the ends of chromosomes. Telomeres are often compared to the plastic tips on the ends of shoelaces.

As telomeres shorten, cells die.

Building on what they knew about the mutant protein in people with progeria, the scientists examined cells from healthy people. They found that the same mechanism or pathways may help explain both the rare condition and normal aging.

The new findings ''really do increase our confidence that progeria is an important model of the aging process," Collins tells WebMD.

The research is published online in The Journal of Clinical Investigation.

Progerin: What's Known

Collins and his team have long focused on progerin. It is a mutated version of a normal cellular protein called lamin A. Lamin A is encoded by a normal LMNA gene. Its job is to help maintain the nucleus of the cell, which holds genetic information.

In 2003, Collins' team found that a mutation in this LMNA gene leads to the rare premature aging condition progeria. It is also known as Hutchinson-Gilford progeria syndrome.

The condition occurs in one of every 4 million to 8 million people worldwide, says researcher and co-author Kan Cao, PhD, assistant professor of cellular biology and molecular genetics at the University of Maryland. Those affected have shortened life spans, typically living only about 13 years, Cao tells WebMD.

The children have hair loss, premature hardening of the arteries, and skeletal abnormalities. They usually die of cardiovascular complications, she says.

In 2007, the scientists found that cells in people without progeria also produce a small amount of progerin, even when they don't carry the mutation.

Focus on Progerin and Telomeres and Aging

In the current study, the scientists looked at millions of cells taken from seven healthy people, aged 10 to 92. They evaluated the cells in the lab for a year.

"We found the cells actually produce more and more mutant protein when they are getting old in vitro," Cao says. As the telomeres shorten, the end result is an accumulation of progerin, they found.

That of itself was not a huge surprise, she says.

The scientists knew that if progerin was being produced, the process of RNA splicing had to be in some way altered. RNA splicing refers to the way a cell processes genetic information when turning it into a protein.

''What we have shown here is that there is some way that short telomeres instruct the splicing apparatus to behave differently," Collins says. "It's an active process.''

The new research also indicates that these changes in the splicing occur when the gene is normal.

Once the telomeres become dysfunctional, they found, the splicing control is not working well.

The new research, Collins says, ''tells us the signal that comes from the shortened telomere that tells the cell to head for the exit [and die] is at least moderated by the turn on of the progerin."

Collins compares the effects of the shortening of telomeres and the production of progerin to different traffic signals that govern the life of a cell. ''If the [shortened] telomere is the yellow light, progerin turns it to red," he says.

Many questions are unanswered, he says. "We'd love to know what that signal is," he says. There may be other signals involved, he says.

Clues to Aging: Perspective

The new study ''gives us clues as to how we might study aging in everybody," says William Scott, PhD, professor of human genetics at the University of Miami's Hussman Institute for Human Genomics.

"They have shown that progerin plays a role in normal cellular aging," he says. What is yet to be found, he tells WebMD, is the importance of this protein in comparison to others involved in the process.

Scott says he would also like to know what role progerin levels play in different people as they age, he says. "Could this possibly explain the differences in how quickly people age?" he asks.

Telomeres, Progerin, and You

Beyond the traditional advice to maintain a healthy weight and not smoke, the new research doesn't spawn any practical advice for now, Collins says.

A clinical trial is under way to treat children with progeria with a drug that reduces levels of the protein, he says.

However, he says, for others, "I would be reluctant to have people jumping in with any pharmacological interventions."

SOURCES: Francis Collins, MD, PhD, director, National Institutes of Health, Bethesda, Md.Kan Cao, PhD, assistant professor of cell biology and molecular genetics, University of Maryland, College Park.William Scott, PhD, professor of human genetics.Cao, K. The Journal of Clinical Investigation, published online June 13, 2011. ©2011 WebMD, LLC. All Rights Reserved.





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