Date Published: October 26, 2016
Publisher: Public Library of Science
Author(s): Sarah E. Goglin, Ramin Farzaneh-Far, Elissa S. Epel, Jue Lin, Elizabeth H. Blackburn, Mary A. Whooley, Raymund J. Wellinger.
Short telomere length independently predicts mortality in patients with coronary heart disease. Whether 5-year change in telomere length predicts subsequent mortality in patients with coronary heart disease has not been evaluated.
In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline and after five years of follow-up. We divided the sample into tertiles of telomere change: shortened, maintained or lengthened. We used Cox survival models to evaluate 5-year change in telomere length as a predictor of mortality.
During an average of 4.2 years follow-up, there were 149 deaths. Change in telomere length was inversely predictive of all-cause mortality. Using the continuous variable of telomere length change, each standard deviation (325 base pair) greater increase in telomere length was associated with a 24% reduction in mortality (HR 0.76, 95% CI 0.61–0.94; p = 0.01), adjusted for age, sex, waist to hip ratio, exercise capacity, LV ejection fraction, serum creatinine, and year 5 telomere length. Mortality occurred in 39% (79/203) of patients who experienced telomere shortening, 22% (45/203) of patients whose telomere length was maintained, and 12% (25/202) of patients who experienced telomere lengthening (p<0.001). As compared with patients whose telomere length was maintained, those who experienced telomere lengthening were 56% less likely to die (HR 0.44, 95% CI, 0.23–0.87). In patients with coronary heart disease, an increase in leukocyte telomere length over 5 years is associated with decreased mortality.
Leukocyte telomere length may serve as a marker of biological aging and predictor of mortality. Whether 5-year change in telomere length predicts subsequent mortality has not been evaluated. In a longitudinal study of 608 patients who were followed for 9.2 years, we found that leukocyte telomere shortening during the first five years was an independent predictor of mortality during the subsequent 4.2 years. Every 325 base pair increase in telomere length during the first 5 years was associated with 24% lower mortality during follow-up. This is the first study to show that 5-year change in telomere length predicts subsequent mortality.
Telomeres are tandem DNA repeat sequences at the ends of eukaryotic chromosomes that protect genomic information during mitosis. During cell division, DNA polymerase cannot fully replicate the 3’ end of linear DNA, resulting in a progressive loss of telomere repeats. After a critical degree of telomere shortening, cells can undergo transcriptional profile alterations, lose the ability to replicate and cease dividing (cellular senescence), and may undergo apoptosis. Human telomere length is influenced by both genetic and environmental factors. These observations have led to an increasing interest in telomere maintenance as the possible basis for a “biological clock,” as initially proposed on theoretical grounds by Olonikov in 1973, which integrates the cumulative lifetime burden of genetic factors and environmental stressors independently of chronological age.
The characteristics of the study population categorized by 5-year change in telomere length are shown in Table 1. After dividing the sample into tertiles, there were a total of 203 participants who experienced telomere shortening, 203 who maintained their telomere length and 202 who experienced telomere lengthening. As compared with participants who experienced telomere lengthening, those with telomere shortening were older and more likely to be male. Participants with telomere shortening also had higher waist to hip ratio, lower treadmill exercise capacity, higher LV ejection fraction, and worse kidney function. Baseline telomere length did not differ across the 3 categories, but those who experienced 5-year telomere shortening had shorter 5-year telomere length than those who experienced 5-year telomere lengthening. There were no differences in ethnicity, education, income, body mass index, or comorbidities across categories of telomere trajectory.
Telomere maintenance has a significant impact on the ability of cells to continue dividing. However, previous studies evaluating a single measurement of leukocyte telomere length as a predictor of mortality have yielded mixed results[17, 18]. We hypothesized that change in telomere length, when examined several years apart, may be a more robust indicator of telomere health (and a stronger predictor of mortality) than a one-time measurement. In this longitudinal study of 608 patients with stable coronary artery disease who were followed for 9.2 years, we found that change in leukocyte telomere length during the first five years was an independent predictor of mortality during the subsequent 4.2 years. Each 325 base pair increase in telomere length during the first 5 years was associated with 24% lower mortality during the subsequent 4.2 years. This observation raises the possibility that change in telomere length may influence mortality and/or serve as a biomarker of cellular aging.