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Human Gerontic Genes Found on Chromosome 4

August 27, 2001; Cambridge, MA ( WSJ and CNN) -- Prof. Tom Perls, M.D., Director of the New England Centenarian Study at Harvard University has just published in a recent issue of the Proc. of the National Academy of Sciences PNAS (August 28, 2001) with colleagues from Beth Israel Deaconess Medical Center and Children's Hospital a study of 137 paired siblings in their 90's or older who have lived more than 20 years longer than their expected average life expectancy. They have identified a segment of Chromosome 4 that is [100 - 500] genes long and contains at least one gerontic (longevity-controlling) gene. The function of these gene(s) remains unknown as of this time.

In one family, eight of ten siblings lived to be at least 90 years old. The odds of that happening due to chance would be 110 trillion! The spouses of all these sibs tended to die much younger at their expected times (according to actuarial tables) despite sharing a common life style with their more long-lived spouses. Thus, the "nurture vs. nature" argument swings the pendulum away from the environment and again toward the genome (recall that it had swung the other way following a 600-Danish-twin study published in 1993 that concluded that only 30 percent of human longevity could be attributable to genetics with the balance attributable to life style). Curiously, many of the sibs actually shared what would be considered poor longevity lifestyle choices by today's standards, like smoking, for example.

Editor's Note: What will it take to confirm this study? We need blood samples from the 30-odd worldwide living Supercentenarians (age >= 110 years) to locate their common genes, if they exist Then, we need to have a company like Human Genome Sciences of Rockville, MD provide us with the related proteins under a proper drug discovery program. This assumes that persons already born cannot have their genes modified by genetic engineering in the near-term future. Of course, engineering the human germ line is still a technically-distant and controversial goal, for whatever well-intentioned purposes.

Dr. Perls, Cofounder of Centagenetix, Inc. of Boston, MA, a closely-held new biotechnology company said that his new venture will be funded at $5 million by MPM Capital. This company was created to identify the genetic profiles of these and hundreds of other longevous individuals. See their website at

Scientists Find Genes for Long Life

August 29, 2001; Cambridge, MA (AP) Scientists say they've zeroed in on an area of your genetic code that might help explain the secret of some of Methuselah's 969 years. Their analysis of genetic material from sisters and brothers in their 90s and 100s shows that at least one gene, and possibly more, located on Chromosome 4 may hold the key to why some people live far longer than others.

Although the specific instruction or set of instructions is still a mystery, experts say the discovery should help guide more detailed experiments to uncover the mechanics of longevity. It may also help point to desirable versions of faulty genes that lead to age-related diseases like Alzheimer's, cancer, stroke and diabetes, they say. The findings are reported today in The Proceedings of the National Academy of Sciences.

Scientists Find Genetic Secrets of Longer Life
Lois Rogers, Medical Correspondent
The Times of London

August 26 2001; UK; Scientists have discovered a set of up to ten genes that they believe may carry the secret of longevity. The genes, nicknamed "genetic booster rockets," allow their carriers to fight off cancer, heart disease and dementia, as well as the fatal bone-thinning condition osteoporosis.

The genes have been discovered by researchers at Harvard Medical School, MA. They now want to identify the chemicals they produce in order to synthesize them into drugs that could protect elderly persons from debilitating diseases.

The project studied the genes of 137 100-year-olds, and those of their brothers and sisters aged between 91 and 109, to look for genes they had in common. The search identified a section of Chromosome 4 that appeared to be the same in all the old people. It is believed to contain up to ten crucial disease-fighting genes.

The results of the research, which was led by Dr. Thomas Perls, a geriatrician, and Lou Kunkel, a geneticist at the Howard Hughes Medical Institute, is being published by The National Academy of Sciences in America tomorrow. It derived from research on fruit flies which has shown that there are only a few genes that need to be altered to increase lifespan markedly. The team correctly assumed that a painstaking comparison of human gene profiles would lead to the discovery of similar factors in humans.

Perls is anxious to stress that the work is intended to improve quality of life and protect people from the diseases of aging, rather than to increase length of life for its own sake. "An average set of genes will allow you to live to your mid- to late-eighties; to get another 20 healthy years you have these disease-resistant genes," he said. "The people we studied did not have any particular pattern of diet or exercise, or social or economic circumstances. Maybe having this special set of genes somehow allows them to get away with things. We believe these people represent the ideal genome."

The first longevity gene was discovered seven years ago in a worm by Dr. Gordon Lithgow, a British scientist working in America. Since then arguments have raged about the number of efficient "repair" genes that might be involved in aging. The latest work provides evidence that the number may be quite small.

Abstract of the PNAS Paper

Annibale A. Puca [1][2], Mark J. Daly [3], Stephanie J. Brewster [4], Tara C. Matise [5], Jeffrey Barrett [3], Maureen Shea-Drinkwater [6], Sammy Kang [5], Erin Joyce [4], Julie Nicoli [1], Erica Benson [4], Louis M. Kunkel [1], and Thomas Perls [6], "A Genome-Wide Scan for Linkage to Human Exceptional Longevity Identifies a Locus on Chromosome 4. Proceedings of the National Academy of Sciences, USA, Vol. 98, Issue 18, pp. 10505-10508 (August 28, 2001).

1. Howard Hughes Medical Institute, Genetics Division, Children's Hospital, and Harvard Medical School, Boston, MA 02215;
3. Center for Genome Research at the Whitehead Institute for Biomedical Research, Cambridge, MA 02214;
5. Department of Genetics, Nelson Biological Laboratories, Rutgers University, Piscataway, NJ 08854;
4. Centagenetix, Inc.; Boston, MA 02119; and
6. Gerontology Division and Biometrics Center, Beth Israel Deaconess Medical Center and Division on Aging, Harvard Medical School, Boston, MA 02215

Contributed by Louis M. Kunkel, July 2, 2001


Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for Chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene, or genes, that exerts a substantial influence on the ability to achieve exceptional old age. Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.

2. To whom reprint requests should be addressed:
Howard Hughes Medical Institute,
Genetics Division,
Children's Hospital and Harvard Medical School,
300 Longwood Avenue,
Boston, MA 02115.
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