Centenarians - The Role of Genetics

Robert W. Griffith, MD
October 1, 2004

Professor Thomas Perls of Harvard Medical School is the founder of the New England Centenarian Study (NECS); this study reports on the heath of some of the United States' oldest citizens. He has distilled the most interesting results in his book "Living to 100". Here is the 6th in our series of extracts from the book. Robert Griffith, Editor.

Something was clearly working in favor of the centenarians, paving their way to extreme old age by protecting them from the environmental and internal damage that afflicts the rest of us. Our experience with centenarians had revealed some common threads, but lifestyle choices did not seem to tell the whole story. People who made similar choices still died at an average life expectancy. It seemed likely that genetic factors were also influencing the rate of aging.

Despite the popular belief that old age runs in families, many researchers have doubted there could be a specific set of genes that enable people to attain extreme old age. The argument goes like this: genes don't "care" about longevity because they're only concerned with procreation. Think of your genes as a convention of engineers who have all learned to build one airplane. Under ideal circumstances, they'd like the airplane to fly safely across the country, but their chief objective is to begin building copies as soon as their prototype demonstrates its ability to take off from one airport and land at another. The engineers build the airplane in Boston, board, and fly to Cleveland. Two engineers disembark and immediately begin building another airplane, more or less duplicating the craft they just left. They have no idea whether they airplane makes it to Pittsburgh, Chicago, St. Louis, Los Angeles, Hawaii, or Australia. They've reached the first stop, so they replicate the plane regardless of whether the design is sufficiently sound for a plane fit enough to fly across the country.

Evolution, the argument continues, isn't looking for airplanes that go to Australia. As long as the airplane successfully flies to Cleveland, the engineers can replicate it, and the same design will be used to fly to more cities and make additional planes. Similarly, as long as living organisms are sufficiently hardy to reach the point in life when they procreate, they and their genes will be duplicated.

According to this viewpoint, genes are not "interested" in what can transpire after reproduction. There's no reason for them to care whether a person lives to 40 or to 100. Genes, the body's construction engineers, are not influenced by whether or how long the structure they have created is built to last. Consequently, there is no pressure to select for genes that confer longevity, and thus genes for longevity should not exist.

As persuasive as the "airplane" argument is, we had to reject it, or at least modify it considerably, because of the study of centenarians' fertility history we did along with obstetrician/gynecologist Ruth Fretts. [As described in an earlier extract], that study demonstrated that there could be an evolutionary advantage to longevity: a slowly aging reproductive system would offer the opportunity to bear more children, while a long, healthy postmenopausal lifetime would allow mothers and grandmothers to successfully rear their descendents to adulthood.

This was a signal that, contrary to popular opinion, there probably are genes that contributes to longevity, particularly in women, and the reason they exist is that they add to the number of potential childbearing and child-rearing years. To return to our airplane analogy, it is as though the aircraft engineers do know that a plane that lasts longer is a better airplane: an airplane that can reach more cities is more likely to be duplicated.

The Hayflick phenomenon

The first suggestion of a genetic role in aging arose from the experiments of biologist Dr. Leonard Hayflick. In his laboratory Hayflick observed a batch of human cells as they divided in a nutrient broth. When they approached 50 cell divisions, they began to slow, until they stopped dividing completely. The cells' last divisions were followed by a period without activity that Hayflick called "cell senescence," which was then followed by cell death. [In additional experiments] he transplanted the nuclei of cells that had divided 50 times into younger cells, to see how many further divisions would take place. But when these older nuclei had been transplanted into them, younger cells would slowly divide only about 10 times before halting. When Hayflick performed the reverse experiment, younger nuclei that had only undergone a few divisions before transplantation would allow older cells to undergo 50 or more divisions. The maximum number of divisions a cell can undergo came to be known as the "Hayflick limit." Apparently, the cells lifespan was regulated by a "clock" in the nucleus that lasted for a precise number of ticks. Hayflick suspected that this clock was located in the cell's DNA, and that what he had seen in the laboratory was not only a duplicate of what happened in the human body, but that it might represent the process underlying aging.

If genes were involved in aging, especially in achieving extreme old age, we suspected that they would perform at least two crucial functions. First they would allow people to age very slowly. Second, genes that allowed people to live to 100 would have to reduce the risk of contracting the common diseases of aging, such as diabetes, heart disease, cancer, and Alzheimer's disease. [But] finding genes that protect people from disease, as we theorized longevity genes would do, would be extraordinarily difficult. Most researchers assume that healthy aging would involve as many as 8,000 genes. So we still held little hope for identifying genes that facilitate longevity.

Long-living families?

However, as centenarians began to enter the study, another unexpected pattern appeared. Now and then we would enroll centenarians who had a centenarian brother or sister. Slightly more frequently, a centenarian would enter the study and tell us about a brother, sister, or custom who was 90 or older, and still healthy. Family clustering of centenarians such as this was extremely a surprising. Although we had been discouraged from looking for genetic factors for longevity, it was hard to deny what we were seeing.

One of our frustrations was the more frequent case of nonagenarian siblings who were in excellent health and appeared well on their way to 100, but were too young to enroll. As it turned out it was precisely those healthy 90-year-olds who made us realize that our study could work. As we had learned, people who live to that age in good health are excellent candidates to become centenarians, and they have a similar genetic complement to that of their centenarian siblings. We had spoken with many centenarians who had healthy siblings aged in their early, middle, or late nineties. These younger brothers and sisters would be credible proxy centenarians.

This discovery marked the beginning of the Centenarian Sibling Pair Study, which was launched in 1997. At this point we have enrolled more than 50 sibling pairs, the largest such group in the world.

[Then] our research took a dramatic turn that all but convinced us we were on the right track. Our close monitoring of local newspapers in the eight towns where we recruited centenarians for the NECS yielded a fortunate find. There, on the front page of the Quincy Patriot Ledger was a photo of a 108-year-old man blowing out the candles on his birthday cake. And right beside him, looking on, was his 103-year-old sister. To most readers, it was just a cute photo -- to us it was a gold mine. We rushed off to recruit the two healthy centenarians for the Sibling Pair Study. An even greater surprise awaited us in the family of Mr. R., as this very healthy centenarian turned out to be named. As we arranged to meet with him and his sister, he asked whether we might want to meet his other sister, who was 97. We were astonished. The chances of identifying a family in which there were two living centenarians and a 97-year-old sister who appeared healthy enough to make it to 100 were just too small to be calculated. Imagine our reaction when they told us it was too bad we hadn't arrived two years earlier when their 101- and 102-year-old sisters were still alive.

Soon, two more spectacular finds came to light: the P. and F families. Both these families had relatively high numbers of centenarians, as well as other long-lived individuals. According to current thinking about longevity, it would have been all but impossible to find three such centenarian-rich families.

[After gathering information on the pedigree of these families and discussing our findings with geneticists] we realized that we had even more evidence of a limited number of aging genes: there was a strong likelihood of family intermarriage by cousins in two of these three families. Intermarriage has often been associated with the development of harmful inherited diseases. For instance, Tay-Sachs disease, a debilitating neuromuscular disorder, probably resulted from continued intermarriage among Eastern European Ashkenazi Jews. We may have found a mirror-image case in which a positive trait, that of extreme longevity, has emerged as a result of intermarriage. This discovery reinforced our belief that a small number of genes -- perhaps fewer than 10 -- might be responsible for extreme longevity in the R. family.

Does this mean that individual efforts to extend life span are worthless? That, until gene therapy can be provided, there is no point in adopting healthy lifestyles? We were left to ponder the significance of this for human health.

In the next extracts from his book, Professor Perls tries to answer the question raised in the last paragraph, above. You can buy his book "Living to 100" at Amazon; click here

Source

• Living to 100: Lessons in Living To Your Maximum Potential at Any Age. TT. Perls, MH. Silver, 1st edition, Basic Books, New York, NY, 1999

Related Links
The Centenarians Study
Lifestyles of Centenarians
Genetics, Environment, and Obesity
Genetics of Alzheimer Disease - Updated

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