Leukocyte Telomere Length Is Associated With Noninvasively Measured Age-Related Disease: The Cardiovascular Health Study

Although biologic age may be impossible to define completely, it will be better understood by uncovering biomarkers of aging. In the future, these biomarkers might guide preventive or therapeutic interventions before clinical onset of age-related disease. Leukocyte telomere length (LTL) might be such a biomarker because it ostensibly records the accruing burden of inflammation and oxidative stress, processes thought to contribute to aging and disease pathogenesis (1–3). LTL undergoes progressive shortening with age, and in the general population, it is comparatively short in individuals with atherosclerosis or those at risk for this aging-related disease (4). The evidence for LTL as an overall biomarker of aging remains unclear, though, due to variation in the strength of detected associations, differences in results based on measurement method and selected outcome, lack of data coupling longitudinal measurements of LTL and aging phenotypes, and theoretical considerations of whether a single marker can accurately and strongly record aging across the life span (5–7). Most studies of LTL concern only clinically diagnosed disease, but in cohort studies of older individuals without clinically diagnosed disease, the prevalence and severity range of subclinical disease can be substantial when assessed using several noninvasive methods (8–11). Furthermore, undiagnosed disease can powerfully predict incident adverse events independent of diagnosed disease (8–14). Defining disease in categorical (yes/no) terms is imprecise, whereas using quantitative biomarkers might provide a more realistic picture of age-related disease load. Therefore, previous studies relying on disease categorization may have missed associations between LTL and age-related disease. Most studies exploring the links between LTL and age-related disease have focused on a single organ or biologic system rather than “disease burden” across systems. Here, we define “disease burden” as the sum of noninvasively measured markers of age-related dysfunctions in structure or physiology of different organ systems. This distinction is relevant because LTL apparently records systemic burden of inflammation and oxidative stress. Thus, a study of LTL and disease burden is warranted to clarify the validity of LTL as a biomarker of aging or age-related disease. Recently, Newman and colleagues (15) developed a physiologic index of comorbidity (index), a 10-point scale that tabulates the severity of age-related chronic disease using noninvasive tests of the vasculature, lungs, kidneys, brain, and glucose metabolism. This estimates an individual’s disease burden regardless of whether disease is clinically recognized. Given its more continuous range, it demonstrated the spectrum of chronic disease in a general population of community-dwelling older adults. The index explained 40% of the age effect on mortality risk and illustrated that high disease burden, even when clinically unrecognized, was significantly associated with mobility limitation and failure to complete activities of daily living. The index appears to be a valid measure of disease burden and stratifies individuals into a wide range of risk. Using data on LTL and age-related disease burden from the Cardiovascular Health Study (CHS), we conducted this analysis to test two hypotheses: (a) Shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).