Longitudinal versus Cross-sectional Evaluations of Leukocyte Telomere Length Dynamics: Age-Dependent Telomere Shortening is the Rule

BACKGROUND Leukocyte telomere length (LTL) is considered a biomarker of human aging and based on cross-sectional studies it shortens with age. However, longitudinal studies reported that many adults display LTL lengthening. METHODS Using Southern blots, we compared cross-sectional rates of age-related LTL change across a ∼20 year age range with those based on longitudinal evaluations in three surveys (S1, S2, and S3) with three time intervals: S1-S2 (5.8 years), S2-S3 (6.6 years), and S1-S3 (12.4 years). Hierarchical linear modeling was used to explore LTL dynamics using LTL data from S1, S2, and S3. RESULTS Cross-sectionally, mean LTL shortenings were 24.6, 25.4, and 23.6 bp/y at S1, S2, and S3, respectively. Longitudinally, more variation was observed in the rate of LTL change during the shorter than longer follow-up periods. Furthermore, using simple differences in LTL, 14.4% and 10.7% of individuals displayed LTL lengthening during S1-S2 and S2-S3, respectively, but only 1.5% during S1-S3 (p < 0.001). The estimated mean rate of LTL shortening based on averaging empirical Bayes' estimates of LTL from a parsimonious hierarchical linear modeling model was 31 bp/y with a range from 23 to 47 bp/y with none of the participants showing LTL lengthening over the average 12.4 years of follow-up. CONCLUSIONS As aging displays a unidirectional progression, it is unlikely that LTL elongates with age. LTL elongation in longitudinal studies primarily reflects measurement errors of LTL in relation to the duration of follow-up periods.