Cracking the Code of Longevity


Dec. 26, 2006— -- Living for 100 years is an unlikely prospect for most of us. But for those lucky few who make it to the century mark, a crucial gene variation relating to cholesterol levels may play an important part in their longevity.

Researchers now believe that this gene variation could also protect against age-related memory loss and senility -- keeping seniors sharp well into their 80s and 90s. The findings reported in this week's issue of the journal Neurology say future drugs may eventually help to provide others with this protection.

"We looked for reasons of longevity among the study group," said study author Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine. "We realized that maybe it's genetic because their habits varied widely."

The study looked at 158 people of Ashkenazi, or Eastern European Jewish descent, who were 95 years old or older.

Barzilai and his fellow researchers found that a quarter of those who lived to an average age of 100 had a certain genetic variation that increased the size of "good" HDL cholesterol particles in their blood.

This variation was present in only about one out of 12 subjects who were 30 years younger, suggesting that having the gene was associated with a better chance of a longer life.

"The idea that treating the standard cardiovascular risk factors (high cholesterol, low HDL, high blood pressure, diabetes) could forestall cognitive decline is provocative," said Dr. Dan Rader, director of preventive cardiology at the University of Pennsylvania School of Medicine. "Specifically, if HDL is really protective against dementia, it strongly supports the idea of developing treatments targeted toward HDL."

Researchers also found those who had the gene variant were twice as likely to score well on a brain function test as those without it. Similar results were found in a group of 124 Ashkenazi Jews between the ages of 75 and 85.

Experts not involved with the study say the findings are significant.

"Among long-lived individuals, this genetic variant also seems to preserve cognitive performance by a mechanism that seems independent of cardiovascular health," said Dr. David Beversdorf of the division of cognitive neurology at Ohio State University. "This is, to my knowledge -- and to the authors' knowledge -- the first gene identified with any of these effects."

But exactly how this change in HDL may preserve brain function in old age is less clear.

"It can work in a number of ways. It raises good cholesterol and increases lipoprotein particle size, which seems to prevent particle buildup in the arteries," Barzilai said. "Several things are possible."

Usually, discussions of the interplay between "good" HDL cholesterol and "bad" LDL cholesterol are limited to heart health and the artery-hardening disease atherosclerosis. However, these new findings suggest a link between senility and high cholesterol problems.

Dr. John Messmer, associate professor in the department of family and community medicine at the Pennylvania State College of Medicine, said he has thought for a "long time" that much of what is found in dementia is associated with atherosclerosis.

"Many researchers in the cardiovascular field suspect that much cognitive decline and even dementia may be due to atherosclerosis of cerebral vessels, and high HDL is one of the strongest protective factors against atherosclerosis known," Rader said.

But the fact that the study merely shows an association between the gene variation and lower rates of senility could temper the enthusiasm of those looking for a quick fix for age-related changes in the brain.

"This is an association; no causal link has been shown," said Dr. Myron Weiner, clinical professor of psychiatry and neurology at the University of Texas Southwestern Medical Center in Dallas. "It could be that this gene is associated with an as-yet undiscovered gene that is the real contributor to longevity and cognition."

And until a more definite link is drawn, the true impact of the findings remains unclear.

"This is pretty early in the research to know its full significance," said Dr. Norman Foster, director of the Center for Alzheimer's Care, Imaging and Research at the University of Utah in Salt Lake City. "LDL and HDL are known to affect vascular disease, and this may be the main effect on the brain."

Still, the treatment implications for the future have many looking forward to the possibility of new methods that could slow or halt some of the aging processes that lead to senility and other age-related changes.

If the findings can be extended to show that HDL levels play an important part in aging, targeting HDL could turn out to be the next strategy in the battle against senility.

"This may indeed be a highly significant finding if altering the gene product could combat [the] normal -- or even accelerated -- aging processes," said Dr. Wendy Wright, assistant professor of neurology and neurosurgery at the division of neurosciences critical care of Emory University Hospital in Atlanta.

Potentially, these treatments could take the form of drugs designed to raise levels of HDL, such as one that pharmaceutical giant Pfizer was working on, known as torcetrapib.

It was developed to help those with high cholesterol, but the drug trial was halted when it was found that it resulted in a higher risk of death for those taking it. But future drugs to raise HDL without this side effects may eventually be developed to stave off senility.

"The big picture is that drugs being developed to raise HDL or improve its function in order to reduce cardiovascular disease might eventually be able to be shown to also protect against cognitive decline and dementia," Rader said. "This would be huge, but it is a ways off."

Until researchers design drugs and trials to address the problem of senility, however, determining the true potential of such drugs is a guessing game.

"It is too soon for anyone other than researchers to get excited about it," Weiner said.

Though therapies remain speculative, many researchers remain optimistic that the finding could lead to a greater overall understanding of the factors behind senility.

"The point is that you don't have to get senile when you age, even if you are over 100," Messmer said. "If you don't have atherosclerosis, you are much more likely to have your mental faculties preserved."

And if you are not fortunate enough to have received this particular gene mutation from your parents?

"You have the option of not smoking, maintaining a normal weight, exercising regularly, treating high blood pressure and lowering cholesterol as far as possible," Messmer said. "Stop atherosclerosis, and keep your mind."

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