Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians

Gil Atzmona,b,1,2, Miook Choa,1, Richard M. Cawthonc, Temuri Budagovb, Micol Katzb, Xiaoman Yangb, Glenn Siegelb, Aviv Bergmand, Derek M. Huffmana,b, Clyde B. Schechtere, Woodring E. Wrightf, Jerry W. Shayf, Nir Barzilaia,b, Diddahally R. Govindarajug, and Yousin Suha,b,2

aDepartments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461; bInstitute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461; cDepartment of Human Genetics, University of Utah, Salt Lake City, UT 84112; dDepartment of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461; eDepartment of Family and Social Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; fDepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and gDepartment of Neurology, Boston University School of Medicine, Boston, MA 02118

quantitative traits (16). Heritability estimates for telomere length vary from 35 to 80% (9, 13, 17). Although several candidate fi genes have been identi ed as potential modulators of telomere length in humans (17, 18), none of these genes seem to play a direct role in maintenance of telomere length (19). Recently, one of the most obvious candidate genes of telomere maintenance, telomerase, has been shown to play a direct role in the main- tenance of telomere length in humans (20). Telomerase is a specialized ribonucleoprotein enzyme complex that adds telo- mere repeats to the ends of chromosomes and has two essential components: a catalytic component encoded by the human te- lomerase reverse transcriptase (hTERT) and a human telome- rase RNA component (hTERC). The latter component provides the template for nucleotide addition by hTERT. Heterozygote mutations in the hTERT and hTERC genes lead to short telo- meres and are the major risk factors for rare hematopoietic disorders of bone marrow failure, including aplastic anemia and dyskeratosis congenital. These results indicate that the levels of functional telomerase are critical for telomere maintenance (21). fi Telomerase is expressed at high levels in speci c germline cells, proliferating stem-like cells, and many cancers, whereas in nor- mal adult cell types, it is either not expressed or is expressed at very low levels that are not suffi cient to maintain telomere length. However, telomerase can be unregulated in these cells under certain conditions to maintain telomere length (22). This suggests that effi cient regulation of telomerase gene expression in response to stresses that are known to reduce telomere length such as oxidative damage or infl ammation would lead to better telomere maintenance.

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 con- trols, we studied the inheritance and maintenance of telomere length and variations in two major genes associated with telo- merase enzyme activity, hTERT and hTERC. We demonstrated that centenarians and their offspring maintain longer telomeres com- pared 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 syn- onymous 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 asso- ciated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans.

longevity heritability aging biomarker

Telomeres consist of the TTAGGG tandem repeats at the ends of chromosomes and are known to protect these regions from degradation and DNA repair activities (1). Telomeres progressively shorten with each cell division in cultured primary human cells (2) until a critically shortened length is achieved, upon which the cells enter replicative senescence (3). Although the relevance of replicative senescence to in vivo aging remains poorly understood, numerous reports suggest that telomere shortening may be associated with organismal aging, with con- comitant metabolic decline and increased risk for disease and death (4, 5). For example, several cross-sectional studies in hu- mans have shown that telomere length in white blood cells is – inversely related to the age of the cell donor (6 9). Likewise, shorter telomere length has been shown to be associated with age-related disease including coronary heart disease, hyper- tension, and dementia, as well as general risk factors for disease such as insulin resistance and obesity (10). Furthermore, oxida- tive stress and infl ammation, two major postulated causal factors of aging, are known to accelerate telomere shortening, suggest- ing that telomere length may be an important biomarker of aging fl because it re ects the cumulative burden of oxidative stress and fl in ammation (4, 11). In addition, most (5, 12, 13) but not all studies (14, 15) have shown a positive association between te- lomere length and overall survival in humans. These results in- dicate that telomere shortening could be used as a biomarker of disease risk and progression as well as early mortality. However, biological mechanisms responsible for these associations are not known.