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The Genetic Secrets of Longevity

A study of long-lived families will help isolate the genetic mysteries that allow some people to live disease-free into their nineties and beyond.
July 24, 2006

Thomas Perls has definitive proof that both mind and body can escape the decay of time. He’s seen firsthand the brain of a deceased 100-year-old woman that showed no signs of the neurological wear-and-tear that usually accumulates in the aging brain. Not a hint, for example, of the plaques and tangles that accompany normal aging and are a hallmark of Alzheimer’s disease. What’s more, before her death, the donor had the cognitive abilities of a 60-year-old.

In 2005, Maria Esther Capovilla of Ecuador was confirmed as the oldest living person by Guinness World Records. At 116, she was still reading and walking without a cane. Researchers hope to understand how people like Capovilla live so long and remain so healthy. (Credit: Reuters)

As director of the New England Centenarian Study at Boston Medical Center, Perls has spent the last decade hunting for genetic and environmental clues to these ageless wonders. He hopes studies of very long-lived people will explain why some individuals succumb to diabetes, heart disease, or Alzheimer’s at a relatively young age, while others live two decades beyond the average life expectancy and show remarkably few signs of the passage of time. (The extraordinary brain described above was donated by a participant in the study.)

Perls’ study, made up of 800 centenarians, is the largest ever conducted of people who have lived to the age of 100 and beyond. Not only do these people live long, but many of them seem to escape the disability associated with diseases of aging or to compress that disability period into a short time span very late in life.

While researchers haven’t yet found the source of centenarians’ enviable passage into old age, they have published numerous studies showing that longevity runs in families.

Perls’ team is now starting a new, larger study of long-lived families, which he hopes will bring better insight into the specific genetic and environmental factors that underlie longevity. His center will conduct one arm of the Long Life Family Study, funded by the National Institute on Aging, in which scientists at four different sites will recruit 1,000 families that show exceptional longevity. Eventually he hopes to be able to translate the findings from these families into broadly usable treatments for the diseases of aging.

Here Perls tells Technology Review what he’s learned so far about aging – and what he hopes to uncover.

Technology Review: What makes centenarians so interesting from a medical perspective?

Thomas Perls: These individuals have a remarkable potential for resilience. Forty percent of centenarians have diseases they’ve been living with 20 years, but they don’t show disability from these diseases until their early-to-mid-nineties. What is this resilience that allows people to live with these diseases and not have problems until the relative end of their extremely long lives?

In addition, 13 percent of centenarians seem to escape the diseases of aging altogether. Some even do this despite some horrendous health habits. We want to figure out how to translate that into strategies for other people. Our goal is to get people to markedly delay or escape disability associated with aging. If we could do that, it would be a huge boon to the health system and our society.

TR: Has conducting these studies changed your own view on aging?

TP: Most people think, ‘the older you get, the sicker you get.’ But the reality is, the older you get, the healthier you’ve been. Living to 100 is an important marker of aging well and good health.

TR: What are the most important factors that influence aging?

TP: The keys to achieving extreme old age probably vary a great deal for different people. But we know from other studies what’s needed to reach your eighties in good health. The best example is the Seventh-Day Adventist Health study. Seventh-Day Adventists have an average life expectancy of 88 years, the oldest life expectancy for any group in the United States – ten years longer than the rest of the country. Because of their religious beliefs, they don’t eat meat, smoke, or drink alcohol (though perhaps some alcohol is good for you). They set aside weekends for religious practice and family time, which may help them effectively manage stress. These habits are likely what it takes to get where most of us should be able to get to – into our late eighties in good health.

TR: What about getting beyond that?

TP: We hope that our participation as a study center for the NIH’s Long Life Family Study will help shed light on that. We will study families with at least several very old living siblings and look for factors that they have in common which might explain their abilities to achieve extreme old age. We go to the subjects’ homes and collect some basic physical data – height, weight, blood pressure, lung function and strength, as well as measures of cognitive function. We’ll also draw blood for genetic and other tests.

TR: How does focusing the study on long-lived families help the search for genetic factors?

TP: With family members, we have a better chance of figuring out what these people have in common. It’s more than just genetics; it’s environmental factors like smoking, religion, obesity, the ability to handle stress.

We hope that collecting these environmental, medical, and behavioral data will ultimately help guide us in our choices of genes for further study. If you find everyone doesn’t have diabetes, you might look at genes related to insulin signaling and fat metabolism.

Extremely old individuals will also probably lack certain genetic variations, such as those that increase the risk for early heart disease or cancer. And maybe they’ll have genes that help them age slowly, have increased resilience, and escape or markedly delay age-related disease.

TR: What genes do you think will be most crucial for longevity?

TP: I think genes that modulate risk for heart disease will be very important. That’s still the number-one killer, even among the very old. In addition, more and more scientific studies show that fat metabolism will play a big role.

These people must certainly lack genetic variations that lead to high cholesterol or early cancer. But there might also be something protective, so-called longevity-enabling genes, especially in very old people who show no signs of disease or who have terrible health habits and yet still survive to 100 years and older. This is a very controversial idea in the field, but they may have genes that play a role in the rate of aging. If you could translate that into drugs, it would be huge. [For an in-depth look at how scientists are using longevity studies in animals to develop drugs to treat the diseases of aging, see “The Fountain of Health,” March/April 2006.]

TR: Have you identified any candidate genes?

TP: We previously found that centenarians were more likely to have a certain variant of the gene for microsomal transfer protein, which plays a role in packaging cholesterol. However, subsequent studies have had different results. One study confirmed the findings, while a few others did not. That shows how important it is to confirm results in different populations and suggests that the importance of various genetic longevity factors varies from one population to another.

TR: Previous studies in animals suggest that caloric restriction is one of the most effective ways to extend life. Is this a factor in your studies?

TP: Male centenarians are almost always lean. But there is no evidence that they had low calorie intakes compared to the average for their birth cohort, certainly not to the degree that would be analogous to calorie-restriction diets in primates and mice. Interestingly, many of the centenarian women can be stocky. Women may be able to get away with having more fat because they are much better able to deal with age- and fat-related diseases.

TR: What excites you most about starting the Long Life Family Study?

TP: It’s been a while since I had the chance to go out and visit centenarians. They are historical treasures and tend to be very gregarious. They’ve been around for 100 years, so they have a lot to say and are terrific fun to be with.

For more information on the study, visit, or call 1.888.333.6327.

To calculate your own life expectancy, try Perls’ life expectancy calculator.

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