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.

Departments of Medicine and Genetics at the Albert Einstein College of Medicine in Bronx NY 10461 collaborated to study the inheritance and maintenance of telomere length and variations in two major genes associated with telomerase enzyme activity (hTERT and hTERC) in a cohort of Ashkenazi Jewish centenarians and their offspring. The results indicate that centenarians and their offspring maintain longer telomeres compared to controls with advancing age. Longer telomeres are associated with protection from age-related diseases, better cognitive function, and lipid profiles of healthy aging. Thus, variations in human telomerase gene associated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans.

Telomeres consist of TTAGGG tandem repeats at the ends of chromosomes and protect these regions from degradation and DNA repair activities. Telomeres progressively shorten with each cell division until a critically shortened length is achieved upon which the cells enter replicative senescence. Telomere shortening may be associated with organismal aging with concomitant metabolic decline and increased risk for disease and death. Shorter telomere length has been shown to be associated with age-related diseases including coronary heart disease, hypertension and dementia as well as general risk factors for disease such as insulin resistance and obesity. Furthermore, oxidative stress and inflammation, two major postulated causal factors of aging, are known to accelerate telomere shortening. Telomere length may be an important biomarker of aging because it reflects the cumulative burden of oxidative stress and inflammation.

Phenotypes of centenarians, their offspring (approximate age of 70 years), offspring-matched controls without a family history of longevity, all of Ashkenazi Jewish descent, were studied. The results indicate that centenarians and their offspring maintain longer telomeres compared to controls with advancing age. High heritability (86%) for telomere length between centenarians and their offspring was observed, suggesting that telomere length has a strong genetic component in families with exceptional longevity.When controls and centenarians are combined to represent cross-sectional age groups of unrelated individuals from middle age to oldest old (range: 43-105 years), telomere length declines with age until the age of 85 years (Fig. 1). However, individuals older than 86 years of age as well as the centenarians show longer telomere lengths compared with unrelated individuals younger than 85 years of age, with a mean difference of 0.17 (±0.04) in the linear regression model adjusting for age and gender. The telomere length of offspring exceeds that of controls in a hierarchical linear model, on average by 0.082 [95% confidence interval (CI): 0.017-0.148; P = 0.014]. Because centenarians and their offspring are appreciable singleton families, we used the regression approach for non-independencies of the observed subjects. To account for parametric model bias as well as for unknown sequence variants in the gene, among which 5 were previously unknown unique variants that were not reported in various SNP databases (Table 3). The locations of these variants are shown in Fig. 4. Nine variants in the hTERT gene are in the coding region, including two nonsynonymous variants, 893 G > A (Ala-279 Thr) and 3242 G > A (Ala-1062 Thr), which are rare and found only in controls (Table 3). In silico analysis using SIFT (sorts intolerant from tolerant substitutions) (30) and PolyPhen (31), which predict the effects of amino acid changes on protein function, indicates that these changes are likely to be benign. Interestingly, rare synonymous or intronic variants in hTERT are enriched in centenarians (n = 19) compared with controls (n = 3) (Table 2; P = 0.041). In addition, three previously un-described intronic variants in hTERC were also found, two of which were rare and found only in centenarians (Table 3).

Telomere Length, Age-Associated Diseases, and Lipid Profiles of Healthy Aging. Association analysis between telomere and major age-related diseases among centenarians, their offspring, and controls indicated that significantly shorter telomere lengths (adjusted for age, gender, and group) are present in subjects with hypertension (P = 0.006), the metabolic syndrome (P = 0.03), or diabetes (P = 0.03) compared with those without these disorders (Fig. 2). Moreover, when we tested the relation between telomere length and cognitive function in centenarians, those with impaired cognitive [Mini-Mental State Examination (MMSE) score <25] had significantly shorter telomeres compared with those with normal cognitive function after adjustment for age and gender (Fig. 2; P = 0.02). We then tested whether telomere length correlated with the lipid profiles, which are known predictors of aging-related diseases such as coronary artery and metabolic syndromes (29). These analyses revealed that telomere length is associated with the lipid profiles of aging, showing a positive association with increased sizes of LDL (P = 0.0001) and HDL (P = 0.03), percentage large particle sizes of LDL (P = 0.0002) and HDL (P = 0.01), and levels of Apo-A1 (P = 0.005) and HDL (P = 0.04) (Table), whereas there is a negative association with very LDL (P = 0.008). Total cholesterol, triglycerides, LDL, and VLDL levels show no significant correlation (Table 2). These suggest that longer telomeres are positively correlated with lipid profiles of healthy aging.