August 31, 2006

NEW YORK TIMES

Live Long? Die Young? Answer Isn’t Just in Genes

By GINA KOLATA

Josephine Tesauro never thought she would live so long. At 92, she is straight backed, firm jawed and vibrantly healthy, living alone in an immaculate brick ranch house high on a hill near McKeesport, a Pittsburgh suburb. She works part time in a hospital gift shop and drives her 1995 white Oldsmobile Cutlass Ciera to meetings of her four bridge groups, to church and to the grocery store. She has outlived her husband, who died nine years ago, when he was 84. She has outlived her friends, and she has outlived three of her six brothers.

Mrs. Tesauro does, however, have a living sister, an identical twin. But she and her twin are not so identical anymore. Her sister is incontinent, she has had a hip replacement, and she has a degenerative disorder that destroyed most of her vision. She also has dementia. “She just does not comprehend,” Mrs. Tesauro says.

Even researchers who study aging are fascinated by such stories. How could it be that two people with the same genes, growing up in the same family, living all their lives in the same place, could age so differently?

The scientific view of what determines a life span or how a person ages has swung back and forth. First, a couple of decades ago, the emphasis was on environment, eating right, exercising, getting good medical care. Then the view switched to genes, the idea that you either inherit the right combination of genes that will let you eat fatty steaks and smoke cigars and live to be 100 or you do not. And the notion has stuck, so that these days, many people point to an ancestor or two who lived a long life and assume they have a genetic gift for longevity.

But recent studies find that genes may not be so important in determining how long someone will live and whether a person will get some diseases — except, perhaps, in some exceptionally long-lived families. That means it is generally impossible to predict how long a person will live based on how long the person’s relatives lived.

Life spans, says James W. Vaupel, who directs the Laboratory of Survival and Longevity at the Max Planck Institute for Demographic Research in Rostock, Germany, are nothing like a trait like height, which is strongly inherited.

“How tall your parents are compared to the average height explains 80 to 90 percent of how tall you are compared to the average person,” Dr. Vaupel said. But “only 3 percent of how long you live compared to the average person can be explained by how long your parents lived.”

“You really learn very little about your own life span from your parents’ life spans,” Dr. Vaupel said. “That’s what the evidence shows. Even twins, identical twins, die at different times.” On average, he said, more than 10 years apart.

The likely reason is that life span is determined by such a complex mix of events that there is no accurate predicting for individuals. The factors include genetic predispositions, disease, nutrition, a woman’s health during pregnancy, subtle injuries and accidents and simply chance events, like a randomly occurring mutation in a gene of a cell that ultimately leads to cancer.

The result is that old people can appear to be struck down for many reasons, or for what looks like almost no reason at all, just chance. Some may be more vulnerable than others, and over all, it is clear that the most fragile are likely to die first. But there are still those among the fragile who somehow live on and on. And there are seemingly healthy people who die suddenly.

Some diseases, like early onset Alzheimer’s and early onset heart disease, are more linked to family histories than others, like most cancers and Parkinson’s disease. But predisposition is not a guarantee that an individual will develop the disease. Most, in fact, do not get the disease they are predisposed to. And even getting the disease does not mean a person will die of it.

There are, of course, some valid generalizations. On average, for example, obese men who smoke will die sooner than women who are thin and active and never get near a cigarette. But for individuals, there is no telling who will get what when or who will succumb quickly and who will linger.

“We are pretty good at predicting on a group level,” said Dr. Kaare Christensen, a professor of epidemiology at the University of Southern Denmark. “But we are really bad on the individual level.”

Looking to Twins

James Lyons used to think his life would be short. Mr. Lyons, a retired executive with the Boy Scouts of America, thought of his father, who died at 55. “He had one heart attack. It was six hours from onset to death, and that was it.”

Then there were his first cousins on his father’s side. One died at 57 and another at 50. “He was in a barber chair and had a heart attack,” Mr. Lyons said of the 50-year-old. “He died on the spot.”

“He was a big strapping guy, 6-4, healthy and energetic. Then, boom. One day he was there, and the next day he was gone.”

“I approached my 50’s with trepidation,” said Mr. Lyons, who lives in Lansing, Mich.

But his 50’s came and went, and now he is 75. He is still healthy, and he has lived longer than most of his ancestors. He is baffled as to why.

It seems like common sense. Family members tend to look alike. And many characteristics are strongly inherited — height, weight, a tendency to develop early onset heart disease or to get diabetes. Even personalities run in families. Life span would seem to fit with the rest.

But scientists have been trying for decades to find out if there really is a strong genetic link to life spans and, if so, to what extent.

They turned to studies of families and of parents and children, but data analysis has been difficult and any definitive answer elusive. If a family’s members tend to live to ripe old ages, is that because they share some genes or because they share an environment?

“Is it good socioeconomic status, good health or good genes?” Dr. Christensen asked. “How can you disentangle it?”

His solution, a classic one in science, was to study twins. The idea was to compare identical twins, who share all their genes, with fraternal twins, who share some of them. To do this, Dr. Christensen and his colleagues took advantage of detailed registries that included all the twins in Denmark, Finland and Switzerland born from 1870 to 1910. That study followed the twins until 2004 to 2005, when nearly all had died.

Now, Dr. Christensen and his colleagues have analyzed the data. They restricted themselves to twins of the same sex, which obviated the problem that women tend to live longer than men. That left them with 10,251 pairs of same-sex twins, identical or fraternal. And that was enough for meaningful analyses even at the highest ages. “We were able to disentangle the genetic component,” Dr. Christensen said.

But the genetic influence was much smaller than most people, even most scientists, had assumed. The researchers reported their findings in a recent paper published in Human Genetics. Identical twins were slightly closer in age when they died than were fraternal twins.

But, Dr. Christensen said, even with identical twins, “the vast majority die years apart.”

The investigators also asked when the genetic factor kicked in. One hypothesis, favored by Dr. Christensen, was that the strongest genetic effect was on deaths early in life. He thought that deaths at young ages would reflect things like inherited predispositions to premature heart disease or to fatal cancers.

But there was almost no genetic influence on age of death before 60, suggesting that early death has a large random component — an auto accident, a fall. In fact, the studies of twins found almost no genetic influence on age of death even at older ages, except among people who live to be very old, the late 80’s, the 90’s or even 100. The average age at which people are dying today in the United States is 68.5 for men, and 76.1 for women, according to Arialdi M. Minio of the National Center for Health Statistics. This statistic differs from life expectancy, which estimates how long people born today are expected to live.

Finding Randomness

Even though there may be a tendency in some rare families to live extraordinarily long, the genetic influence that emerged from the studies of twins was significantly less than much of the public and many scientists think it is.

A woman whose sister lived to be 100 has a 4 percent chance of living that long, Dr. Christensen says. That is better than the 1 percent chance for women in general, but still not very great because the absolute numbers, 1 out of 100 or 4 out of 100, are still so small. For men, the odds are much lower. A man whose sister lived to be 100 has just a 0.4 percent chance of living that long. In comparison, men in general have a 0.1 percent chance of reaching 100.

Those data fit well with animal studies, says Caleb Finch, a researcher on aging at the University of Southern California. Genetically identical animals — from worms to flies to mice — living in the same environments die at different times.

The reason is not known, Dr. Finch said.

“It’s random,” he said. “Since we can’t find any regular pattern, that’s the hand wave explanation — randomness.”

And random can mean more than one thing.

“There are two phases of randomness,” Dr. Finch said. “There’s the randomness of life experiences. The unlucky ones, who get an infection, get hit on the head or get mutations that turn a cell into cancer. And there are random events in development.”

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