Pharma Seeks Genetic Clues to Healthy Ageing

Reuters

April 6, 2010

World

They may be a little wrinkly, and there may not be many of them, but centenarians are the fastest growing demographic in the developed world.

Scientists believe people who live to 100 years or more hold valuable secrets in their genes that can reveal targets for medicines to tackle a wide range of age-related diseases, as well as improving longevity itself.

"If you make it to 100, you must have had good health and a good life -- otherwise you wouldn't be at the tail end of the age distribution curve," Kaare Christensen of the Danish Aging Research Center told Reuters in an interview.
"So basically, we're trying to figure out how they do it."

Of course, genes are not the whole story: experts believe genetic factors account for a only fraction of longevity. Other factors like a healthy lifestyle, good diet and safe environment combine to play a role in determining when we die.

Yet so-called "longevity genes" certainly exist, and their importance grows the longer a person lives, so identifying them and finding out what they do to fight off killer diseases is a hot area of research.

With lifespans already increasing at a breathtaking rate -- an average of three months is being added to life expectancy every year at the moment -- scientists stress that a "magic pill" to help people live ever longer is not what anyone should be seeking.

Instead the aim is known as "compression of morbidity" -- improving the health of rapidly aging populations and squeezing to a minimum the amount of time at the end of their lives when they are sick, in pain, or dependent.

"None of us, probably, wants another five years in a nursing home," said Linda Partridge, director of University College London's Institute of Healthy Aging.
"But an additional five years without any particular health problems would be another matter."

Longevity Gene Pool

One thing is sure: the pool of people to work with is growing fast. There are around 450,000 centenarians in the world today and experts estimate that thanks to aging baby-boomers, there could be a million across the world by 2030.

Genetic science and technology is developing rapidly too, allowing scientists to scan the genes of the super-old in search of the secrets of long life -- and drugs to mimic them are starting to appear.

"The drug companies have got lots of patents out on some of these targets," said Partridge. "Nothing has actually emerged yet, but they are clearly working on them."

Until recently, only one candidate had shown any promise as a potential "longevity gene."

It is known as APOE. On the one hand, its variants have been linked with an increased risk of heart disease and of developing the brain-wasting disease, Alzheimer's. On the other, it is associated with a greater chance of a longer, healthier life.

Scientists have found that a particular variant known as APOE4, which gives carriers a higher risk of developing Alzheimer's and heart disease, is about 50 percent less common in centenarians than in younger people, suggesting that those without it are more likely to live longer.

Other "longevity gene" candidates are now starting to emerge, including one called FOXO3A and another called humanin, both of which have links to the body's insulin pathways.

With them comes more evidence that genes associated with long life are also linked to decreased risk of major killers like heart disease, Alzheimer's and diabetes.

Nir Barzilai of the Albert Einstein College of Medicine at Yeshiva University in New York has been conducting studies with a group of several hundred centenarians in the United States to see if he can find gene patterns that can be chemically copied.

"We are assuming that the 100 year-olds are enriched with longevity genes," he said in an interview. "And when you find genes, you discover the pathway, and then you can try to modulate the pathway with drugs."

As well as with the humanin gene, his team has been working with variations of a gene known as cholesteryl ester transfer protein, or CETP, which they have linked to long life, good heart health, a reduced risk of cognitive decline with age, and a smaller chance of developing Alzheimer's disease.

Drug companies are already targeting the CETP gene with an eye to helping prevent heart disease by upping so-called "good" or HDL cholesterol.

The U.S. drugmaker Merck & Co, for example, has a CETP drug in late-stage clinical trials to test its effectiveness in raising good cholesterol.

But Barzilai thinks it may turn out to do much more than that: "We believe that once this drug is out it could be the first drug to be used as an anti-aging drug," he said.

Swiss pharmaceutical company Roche also has a CETP drug, called dalcetrapib, in late-stage clinical trials in partnership with Japan Tobacco, in which it sees great potential.

Longer, Healthier Lives?

The emerging link between long life and disease resistance has already been seen in animal experiments.

Last week, British scientists found in experiments with laboratory worms that the DAF-16 gene, similar to FOXO genes in humans, is linked to aging and immunity.

And several studies have shown that when scientists successfully target the underlying aging process to make an animal live longer, they also protect them against aging-related diseases.

Resveratrol, a drug being developed by Britain's GlaxoSmithKline and based on a compound found in red wine, has been shown in studies on mice to give them longer and healthier lives.

And the antibiotic rapamycin, sold under the brand name Rapamune by Pfizer and designed to suppress the immune system in transplant patients, has also been shown to slow age-related disease and extend life-span in mice.

"These things are all very interwoven in each other," said Christensen.
Partridge also sees this as a sign that some medicines now on the horizon may be bigger hitters than previously thought.

"What it shows very clearly is there is an underlying aging process which acts as the major risk factor for aging-related diseases, and if you can somehow ameliorate its effects, then the animals become relatively disease-free," she said.
"They (the drugs) may be being developed specifically for dementia, or cancer, or some specific age-related disease, but the biological research is telling us that they're probably going to turn out to have surprisingly broad-spectrum effects."

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