Longevity Tied to Genes That Preserve Telomere Length

A team led by researchers at Albert Einstein College of Medicine of Yeshiva University has found a clear link between living to 100 and inheriting a hyperactive version of an enzyme that rebuilds telomeres – the tip ends of chromosomes. The findings appear in the latest issue of the Proceedings of the National Academy of Sciences.

Telomeres play crucial roles in aging, cancer and other biological processes. Their importance was recognized last month, when three scientists were awarded the 2009 Nobel Prize in Physiology and Medicine for determining the structure of telomeres and discovering how they protect chromosomes from degrading.

Telomeres are relatively short sections of specialized DNA that sit at the ends of all chromosomes. One of the Nobel Prize winners, Elizabeth Blackburn, Ph.D., of the University of California at San Francisco, has compared telomeres to the plastic tips at the ends of shoelaces that prevent the laces from unraveling.

Each time a cell divides, its telomeres erode slightly and become progressively shorter with each cell division. Eventually, telomeres become so short that their host cells stop dividing and lapse into a condition called cell senescence. As a result, vital tissues and important organs begin to fail and the classical signs of aging ensue.

In investigating the role of telomeres in aging, the Einstein researchers studied Ashkenazi Jews because they are a homogeneous population that was already well studied genetically. Three groups were enrolled: 86 very old – but generally healthy – people (average age 97); 175 of their offspring; and 93 controls (offspring of parents who had lived a normal lifespan).

“Telomeres are one piece of the puzzle that accounts for why some people can live so long,” says Gil Atzmon, Ph.D., assistant professor of medicine and of genetics at Einstein, Genetic Core Leader for The LonGenity Project at Einstein’s Institute for Aging Research, and a lead author of the paper.

“Our research was meant to answer two questions: Do people who live long lives tend to have long telomeres? And if so, could variations in their genes that code for telomerase account for their long telomeres?”

The answer to both questions was “yes.”

“As we suspected, humans of exceptional longevity are better able to maintain the length of their telomeres,” said Yousin Suh, Ph.D., associate professor of medicine and of genetics at Einstein and senior author of the paper. “And we found that they owe their longevity, at least in part, to advantageous variants of genes involved in telomere maintenance.”

More specifically, the researchers found that participants who have lived to a very old age have inherited mutant genes that make their telomerase-making system extra active and able to maintain telomere length more effectively. For the most part, these people were spared age-related diseases such as cardiovascular disease and diabetes, which cause most deaths among elderly people.

“Our findings suggest that telomere length and variants of telomerase genes combine to help people live very long lives, perhaps by protecting them from the diseases of old age,” says Dr. Suh. “We’re now trying to understand the mechanism by which these genetic variants of telomerase maintain telomere length in centenarians. Ultimately, it may be possible to develop drugs that mimic the telomerase that our centenarians have been blessed with.”

The study, “Genetic Variation in Human Telomerase is Associated with Telomere Length in Ashkenazi Centenarians,” appears in the November 13 online issue of the Proceedings of the National Academy of Sciences. In addition to Drs. Atzmon and Suh, the study’s other Einstein researchers were co-lead author Miook Cho, M.S., Temuri Budagov, M.S., Micol Katz, M.D., Xiaoman Yang, M.D., Glenn Siegel, M.D., Aviv Bergman, Ph.D., Derek M. Huffman, Ph.D., Clyde B. Schechter, M.D., and Nir Barzilai, M.D.

About Albert Einstein College of Medicine of Yeshiva University
Albert Einstein College of Medicine of Yeshiva University is one of the nation’s premier centers for research, medical education and clinical investigation. It is home to 2,775 faculty members, 625 M.D. students, 225 Ph.D. students, 125 students in the combined M.D./Ph.D. program, and 380 postdoctoral research fellows. In 2008, Einstein received more than $130 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving eight hospitals and medical centers in the Bronx, Manhattan and Long Island – which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein – the College of Medicine runs one of the largest post-graduate medical training programs in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit www.einstein.yu.edu

Abstract

Telomere length in humans is emerging as a biomarker of aging because its shortening is associated with aging-related diseases and early mortality. However, genetic mechanisms responsible for these associations are not known. Here, in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls, we studied the inheritance and maintenance of telomere length and variations in two major genes associated with telomerase enzyme activity, hTERT and hTERC. We demonstrated that centenarians and their offspring maintain longer telomeres compared with controls with advancing age and that longer telomeres are associated with protection from age-related diseases, better cognitive function, and lipid profiles of healthy aging. Sequence analysis of hTERT and hTERC showed overrepresentation of synonymous and intronic mutations among centenarians relative to controls. Moreover, we identified a common hTERT haplotype that is associated with both exceptional longevity and longer telomere length. Thus, variations in human telomerase gene that are associated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans.

Source

Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, Siegel G, Bergman A, Huffman DM, Schechter CB, Wright WE, Shay JW, Barzilai N, Govindaraju DR, Suh Y. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1710-7. Epub 2009 Nov 13. PMID: 19915151

Albert Einstein College of Medicine of Yeshiva University Released: 11/11/2009

Key concepts: telomere length, dementia risk