Genes Implicated in Delayed Aging and Longevity

Ron Zimmerman

March 12, 2014

SAN DIEGO — Why do some people live longer than others? And how can aging and death be delayed?

Nir Barzilai, MD, is on a genetic odyssey to answer these questions. In his work at the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx, New York, he is following the trail like a detective, hoping to find definitive answers.

First, he determined that only 1 in 10,000 people live to be 100 years of age. Next, he noticed that there is a remarkable history of exceptional longevity in the parents, siblings, and offspring of centenarians, which suggests a genetic source. He reasoned that if we survive one disease, then sooner or later we will die of another.

"If we can delay aging, we can delay the diseases associated with aging," Dr. Barzilai told Medscape Medical News here at the Future of Genomic Medicine VII.

"We understand intuitively that we all age at different rates," Dr. Barzilai explained. "We can look around and see that some people look younger than their peers."

Dr. Barzilai's team conducted the cross-sectional Longevity Genes Project of 600 Ashkenazi Jews older than 100 years to look for keys to the genomes that delay aging. Do they have perfect genes? Dr. Barzilai asked. His resounding conclusion was no.

There will be a big longevity dividend, worth billions of dollars to healthcare systems.

In addition to the centenarians, the researchers evaluated their offspring plus a control group. "We're looking at them to see what happens as they age in relation to the genes we're finding," he noted.

Among the study subjects, there were 227 autosomal and 7 x-chromosomal coding single nucleotide variants, which lead to Parkinson's disease, coronary heart disease, and other fatal ailments.

The centenarians tend to stay healthy and then die quickly. In fact, in the final 2 years of life, medical costs incurred by these patients was 60% less than patients who died several decades earlier, he reported.

According to Centers for Disease Control and Prevention data, medical costs in the final 2 years of life were $24,000 for those who died when they were 60 to 70 years, and $8000 for those who died when they were older than 100.

"Delaying aging delays age-related diseases," Dr. Barzilai pointed out, "so there will be a big longevity dividend, worth billions of dollars to healthcare systems," if we can understand how to do this.

The trail of questions continued. Is environment involved? Again, the answer was no.

In the Longevity Genes Project, 50% of the centenarians were obese, and 60% of the men and more than 40% of the women smoked cigarettes for more than 30 years. "One woman had been smoking for 95 years," he noted. In addition, exercise was very moderate in this group. "As an elderly population, they didn't interact with the environment in the way that we would want."

Dying Young at a Very Old Age

Could it be protective genes? "We're looking for genes that are associated with long lifespans," Dr. Barzilai explained. "We found several genotypes that have functional relevance. They actually change something in the body that is associated with longevity. We found through sequencing that these people had CEPT, the so-called longevity gene. It's over-represented in those 100 years old."

How does it work? "I don't quite know," he said. "It's doing a number of things: increasing the good cholesterol; increasing the size of lipoproteins, both high density and low density; protecting against diabetes, hypertension, and cardiovascular disease through independent intercellular effects. Dementia and Alzheimer's disease is reduced by 80% in this group. I don't know which of these is most important. That still needs to be resolved."

What led the researchers to look at the CEPT gene? "The families of these centenarians had very high levels of cholesterol, so we thought this gene was a good candidate to look for mutations," he said.

Another important observation is that, across species, small animals tend to live longer than large ones, Dr. Barzilai noted. "What happens in nature is that little dogs live longer than big dogs; ponies live longer than horses. If you mutate the growth pathway in many animal models, they live longer. Although I'm an endocrinologist, I didn't believe it initially. But we started looking and found at least 3 mechanisms by which you can suppress growth and get longevity."

"A lot of people think that human growth hormones are important for longevity, so they take them. But that's the opposite of what I'm finding. They're important when they're low, not when they're high," he explained.

The researchers found a direct relation between the insulin-like growth factor (IGF)-1 receptor and long life. Among the centenarians, "the lower the growth hormone, the lower the IGF, the longer they live," he said. "So if you're taking growth hormone because you want your skin to look young, that's okay, but if you're concerned with living long, then you don't take these drugs."

Life-Extending Drugs

There are several drugs that Dr. Barzilai does believe will extend lifespans. "We're looking at a drug that was developed by Merck for pancreatic cancer, although it failed there. It's an antibody against this growth-hormone receptor. It's a drug you give just once a week because it has a long half-life. We're giving it to mice, and we have results that show that the mice are living significantly longer. This is immediately adaptable to humans because it was developed and tested on humans."

Several geneticists at the conference cautioned against drawing conclusions from the data Dr. Barzilai presented. "It's a classic problem of studying the genetics of aging," said Mark Nunes, MD, a pediatrician at Kaiser Permanente in San Diego. "The downside of looking at a very specific population, such as the Ashkenazi Jewish population, is that there were obvious bottlenecks in the twentieth century. You can come up with a great hypothesis, but the limitation is that this population had some very unique dynamics.

"A centenarian today is someone who was 30 or 40 years old in Europe during World War II," Dr. Nunes noted. "To survive that, we don't know what the cofactors are, the multifactorial conditions. With the IGF-1 results, it's clear that different individuals over the course of their lives methylate their DNA at different rates and at different times. Stresses placed on people at different times of their lives influence gene expression. It's much more complicated that simply the DNA sequences."

We want to use the outcomes we've found to develop medications that will affect longevity.

Konrad Karczewski, PhD, who coauthored Exploring Personal Genomics with Joel Dudley, echoed that sentiment. "Dr. Barzilai's evidence is compelling because everyone wants to live longer and live well. It's interesting to see these people who don't have healthy lifestyles still live to 100, 110. I've seen these studies, but it may not be related to only 1 or 2 genes. It's extremely complex; arguably, more complex than finding the genetic trigger for a single a disease," he noted. "The absence of any 1 disease is complex; the absence of all those diseases is even more complex. It's likely the complex interactions of multiple factors, including environmental. There may be something else entirely that these people were doing that led to long lives."

Dr. Barzilai said he believes he's laid the groundwork in this field, but that the final answers still elude him. "There are 2 ways to move the field forward," he suggested. Up to now, the subjects his team has studied were preselected, but he wants to move to a population study.

"We want to use the outcomes we've found to develop medications that will affect longevity. We have several examples in the field, like resveratrol, which is a sirtuin-1 activator; that's mainstream medicine. Merck and Isis are also developing age-related drugs," Dr. Barzilai explained. "I founded a biotech to develop another set of peptides, coming from the mitochondria, that decline with aging. If we replace them, they have an effect on many age-related diseases."

Dr. Nunes had one final caution for Dr. Barzilai. "As far as drug development goes, that may be misguided. We need to look at other populations. Or is this an ethnic data issue? If you went to a nonspecific population and saw the same SNPs, you may have the same mutations. But overall, be careful of conclusions drawn from stratified populations."

Dr. Barzilai is founder and director of CohBar, Inc. Dr. Nunes and Dr. Karczewski have disclosed no relevant financial relationships.

Future of Genomic Medicine (FoGM) VII. Presented March 7, 2014.


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