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Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians
Gil Atzmonab12, Miook Choa1, Richard M. Cawthonc, Temuri Budagovb, Micol Katzb, Xiaoman Yangb, Glenn Siegelb, Aviv Bergmand, Derek M. Huffmanab, Clyde B. Schechtere, Woodring E. Wrightf, Jerry W. Shayf, Nir Barzilaiab, Diddahally R. Govindarajug and Yousin Suhab2
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
gDepartment of Neurology, Boston University School of Medicine, Boston, MA 02118
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.
