March 9, 2010
L’Chaim! Want to live to 100? Check your genes.
Last week, Louis Biderman turned 99. Yet he can recall, in perfect detail, the trip he took to Los Angeles in 1938, 72 years ago. “I drove 3,000 miles to the coast, 3,000 miles back — all that within six weeks,” he said by phone from his Yonkers, N.Y., home. He was riding in a 1937 Pontiac, which he bought for $1,002.
Biderman may see nothing special about himself — “I’m not interested in glorifying my past,” he said — but his crystal-clear memories serve as a reminder that he belongs to a small demographic that is holding the medical community rapt: individuals who are living to 100 with no trace of illnesses that plague the elderly, including Alzheimer’s, dementia, diabetes and heart disease.
At the forefront of the research on these winners of the genetic lottery is Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine of Yeshiva University in New York.
For much of his career, Barzilai researched diabetes. Eventually, witnessing the ways in which the disease affects some people and not others led him to ask the inevitable questions about nature vs. environment and the hereditary aspects of age-related illness.
“In the discipline of medicine, [we] organize ourselves in groups,” he said in an interview. “We research cancer, heart disease, Alzheimer’s.”
But Barzilai recognized a common risk factor in many of those diseases — age.
“If we could slow aging,” he said, “we could impact all of those diseases.”
Wanting to take a closer look at centenarians, their lifestyles and their genes, Barzilai initiated a long-term study in 1998 that would allow researchers to find out what may set this group apart and lead to their excessive longevity. Through media promotion and word of mouth, he assembled a cohort of Ashkenazi Jews, as their genetic makeup is in many ways homogeneous. The group included not just people who had lived to 100 or close to it, but their 70- to- 80-year-old children as well.
“The offspring are very important because they inherited some of the [longevity] genes,” said Barzilai. Normally, this type of long-term study would include an age-matched control group for both the centenarians and their offspring, but because of the unique circumstances of the study, only the younger group had a match.
As Pinchas Cohen, professor and chief of endocrinology at UCLA’s Mattel Children’s Hospital and a colleague of Barzilai’s who also studies age-related disease, said, “With centenarians, the control group died 30 years ago.”
After the test subjects were recruited, researchers met with each family at the family’s home and tested participants’ memory and cognitive functioning, took a sample of their blood and performed an overall physical. Since then, the participants have been retested annually, and the project has been named the Longevity Genes Project and has added a sister project called the LonGenity Project.
Over the last decade, the group has been the foundation for Barzilai and his colleagues to test longevity theories. They’ve identified a handful of genotypes that come up repeatedly in the centenarians and may account for up to 80 percent of the reason for their unprecedented lifespan. But whether researchers will ever be able to pinpoint the cause in 100 percent of cases remains to be seen.
The chance of living to 100 is slim; most estimates place the likelihood at around one in 10,000. And for the general population, 80 percent of the propensity for longevity and good health comes from lifestyle and environment, while only 20 percent comes from genes.
It would seem, though, that the centenarians are the exception to that rule.
“Over 90 percent of centenarians smoked for prolonged period[s],” Barzilai said in an e-mail, “and almost 30 percent for more than 40 years. None of them was exercising regularly.”
Excluding the possibility that their longevity was linked in any relevant way to lifestyle, Barzilai and his colleagues focused their efforts on the group’s DNA.
The first goal was to test the group’s lipid profiles to search for a common thread. The lipid profile looks at overall cholesterol, including so-called good and bad cholesterol, and triglycerides, the fats that circulate throughout the blood. The lipid profile is an indicator of a person’s risk for developing cardiovascular disease, hypertension and metabolic syndrome.
Barzilai and his colleagues tested blood samples from the centenarians, their children and the control group. In a study published in the October 2003 edition of the Journal of the American Medical Association (JAMA), they demonstrated that centenarians and their offspring were more likely to have a specific variation of the gene that regulates cholesteryl ester transfer protein (CETP), a protein that moves fat and cholesterol through the body, including high-density lipoproteins (HDL, or good cholesterol) and low-density lipoproteins (LDL, or bad cholesterol).
Because of this variation, the centenarians and their children had more HDL in their blood and larger lipoprotein particle sizes than the control group, indicating that this genetic mutation has a positive impact on longevity. About 8 percent of the general population has this variation, but it was present among 24 percent of the centenarians and their children.
The finding was exciting, but it didn’t address one of Barzilai’s primary concerns: quality of life.
“If I ask you if you want to be 100,” he said, “and [whether] you want to get there with just your body or also with your brain, you might choose to do it with cognitive function intact.”
And many of the centenarians were doing just that – in addition to good physical health, most, like Biderman, also retained their memory and wit.
The CETP gene, in which researchers had just identified a variation affecting longevity, happens to share some characteristics with a gene linked to Alzheimer’s— the apolipoprotein (APOE) allele. Based on this knowledge, the researchers initiated a new study that would ultimately follow 523 subjects of mixed ethnicities and religious backgrounds over the course of 4.3 years, to find out whether CETP also played a role in the development of age-related diseases that lead to cognitive decline.
Throughout the course of the study, the researchers tracked which participants developed dementia and Alzheimer’s. In a study published in January of this year in JAMA, they demonstrated that, indeed, the same genetic variation that causes higher levels of good cholesterol may also protect carriers from developing Alzheimer’s – a protection, said Barzilai, of up to 70 percent.
At UCLA, Cohen has been grappling with similar issues. His research, which touches on aging in a slightly more peripheral manner, has ranged from prostate cancer to cerebral palsy. It was primarily his work with diabetes, though, that led his path to continually cross with Barzilai’s over the years.
“We’ve been collaborating for 25 to 30 years,” said Cohen, adding that their association began when they attended the Israel Institute of Technology together in the 1980s. “[But] the work that led to the most current and exciting discovery is something we started doing about five or six years ago.”
At that time, Barzilai had already assembled his cohort of centenarians, and Cohen had been studying a naturally occurring protein in the body called humanin.
Humanin had previously been shown to slow the death of brain cells associated with Alzheimer’s disease. Like Type 2 diabetes, Alzheimer’s is associated with poor insulin function. Taking into consideration the link between the two age-related diseases, Cohen and Barzilai set out to discover whether humanin also plays a role in the development of Type 2 diabetes.
In a study published in the journal PLoS One in July 2009, researchers tested the effects of humanin on lab rats. They were able to demonstrate that the protein works in part to help the liver metabolize glucose, a process linked to insulin action that is impaired with the onset of Type 2 diabetes. Humanin, they concluded, likely has a role in preventing both diseases as people age.
And sure enough, while humanin in the general population decreases with age, the centenarians and their offspring had notably higher levels and significantly fewer instances of Type 2 diabetes.
A genetic predisposition for either the CETP variation or higher levels of humanin are part of what researchers call “longevity genes” — a series of variations that likely will lead its lucky carrier to live an unprecedented long and healthy life. But the findings, while exciting, don’t necessarily mean that the key to long life has been definitively identified.
And, in fact, said Cohen, researchers may never know exactly why some people live for so long and others don’t.
“It’s impossible to say what the contribution of each genetic observation is, in terms of the years it adds. I don’t think we have the tools to put it that way,” he said. “From, say, 75 to 100, you probably need cumulative effects of 10 to 20 genes that each add a few years.”
But that won’t stop them from trying. One gene that currently shows promise is a growth hormone, called insulin-like growth factor 1 (IGF-1).
“We identified that, in female centenarians and their daughters, there seems to be a very subtle mutation in the IGF-1 receptor, which controls growth,” said Cohen. Shorter women have a very subtle variation, he said, leading to lower levels of IGF-1 in the bloodstream.
“Everything else being equal, 5-foot-7 or 5-foot-3, the woman who is 5-foot-3 is more likely to live longer.” The same did not hold true for males, although researchers don’t yet know why.
This finding happens to fly in the face, though, of a current trend in which people who are beginning to show the physical signs of aging are injected with growth hormone for cosmetic purposes.
“When middle-age people take growth hormone,” said Cohen, “there are some improvements, they look a little younger — there’s no question that there’s an effect. However, these effects are superficial and don’t contribute to actual increased longevity.” This trend points to a division in the field of anti-aging — those who search for ways to live longer, healthier lives, and those who seek to retrieve the skin, strength and figure they boasted 20 years ago.
What has become abundantly clear over the course of the last decade is that longevity, as well as good cognitive functioning, is hereditary. And since we can’t control our genes, said Barzilai, the steady stream of information from the medical community about treating our bodies well to ensure that they work for as long as possible still holds true: Eat right, exercise regularly, don’t smoke, and keep drinking to a minimum, to name a few.
“Those are all things that are important,” said Barzilai. “They are likely to bring you from dying before age 78 to [dying] after the age of 78.”
In the meantime, Barzilai hopes that drug companies will soon find a way to turn his research into medicine, and the effort has already begun. Merck, a major pharmaceutical company, is developing a CETP inhibitor that will help increase levels of HDL, according to Barzilai. The drug is in Phase 2 studies, and may be ready as soon as 2012.
At UCLA, Cohen is looking into the possibility of daily injections of humanin-like peptides that could affect cellular growth. “We can deal with diabetes with this peptide,” he said. “It basically goes away, without having the side effects of insulin.” While this may take more time than the CETP inhibitor, Cohen added that if all goes well, it could be approved by the FDA in five or six years.
While these drugs may have the side effect of an extra few years of life due to improved health, Barzilai is adamant about the fact that he’s not out to push longevity for the sole purpose of allowing people to see another year go by.
“The goal of my study is to prevent the chronic, debilitating disease of aging,” he said. “The goal is quality of life, not longevity. If, at the end, people will live 85 years and die one day healthy, I’m fine with it. I wish that for myself.”
Since its inception 10 years ago, the study has grown to include another group of 70-year-olds with parents who lived to be older than 95; it now counts more than 500 centenarians, 700 of their offspring and approximately 600 individuals in the control group, composed of people whose parents both died before the age of 95.
And Barzilai sees no end in sight.
“It’s an aging study, so things are going to happen slowly,” he said. “[The offspring] are 70 years old, and I am 54 years old. [It will end] when I die.”
After 30 minutes on the phone, Biderman’s wife is calling in the background for him to wrap things up. But he has a few points to add. First, he believes that his lifestyle may have had an effect on his longevity. “I lived a real outdoor life,” he said of the years he spent in New Jersey as a young man. “Chopped trees, developed my good health.”
As far as his participation in Barzilai’s study, his attachment to it is that of someone who has seen many things come and go over the course of a lifetime.
“To see what, in a person’s lifetime, makes you last long, it’s a very good thought,” he said. “[If] it’s knowledge about what goes on in my cerebellum, what gets blown away like wisps in the wind and what stays ... if they can ever figure out what makes the difference, it will be worthwhile.”
Nevertheless, Biderman adds his vote of encouragement. “I hope you have some luck and find out what makes people live to 99,” he said before hanging up the phone.
“And,” he added, “stay Jewish.”