Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies

Abstract

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span.

Objective: To examine whether LTL is associated with the life span of contemporary humans.

Design, setting, and participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019.

Main outcomes and measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees.

Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77).

Conclusions and relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

Figure 1.. Leukocyte Telomere Length (LTL) and Mortality

B, The bottom and top of each box indicate the first and third quartiles, respectively. The points outside the whiskers represent outlying observations beyond 1.5 times the interquartile range. With Bonferroni adjustment, P = .75 for alive vs cancer-related death, P < .001 for alive vs noncancer-related death, and P = 0.49 for cancer-related death vs noncancer-related death. Kb indicates kilobase.

Figure 2.. Hazard Ratios for All-Cause and Cause-Specific Mortality for Different Residual Leukocyte Telomere Lengths (LTLs)

Hazard ratios for individuals of different ages and with different residual LTLs were scaled to an individual aged 50 years with the mean LTL value for that age (ie, residual LTL of 0). Lines are truncated at the age corresponding to the 99th percentile of the distribution of ages at blood draw in the sample. When using flexible spline modeling, the SEs of the curves are largest in the tails of the distribution, which may explain why the curves for cancer mortality (D) turn downwards. The graphs in this figure are the point estimates and ignore uncertainty. However, a continued increase of the curves for high ages cannot be ruled out based on the model fit. Kb indicates kilobase.

Figure 3.. Hazard Ratios for All-Cause and Cause-Specific Mortality at Different Ages

Hazard ratios for individuals of different ages and with different values of residual leukocyte telomere length (LTL) were scaled to an individual aged 50 years with the expected mean LTL for that age (ie, residual LTL of 0). ALL indicates all-cause mortality; CAN, cancer mortality; CVD, cardiovascular disease mortality; kb, kilobase; and OC, other causes of death.

Figure 4.. Hazard Ratios (HRs) for Residual Leukocyte Telomere Length in Different Studies and Joint Analysis

The figure displays HRs for a 1-kilobase decrease in LTL, estimated in respective models, applied to separate studies and joint analyses. Squares indicate the effect sizes for each study, with lines representing the 95% CIs. Estimates for joint analyses and their 95% CIs are represented by diamonds. CHS indicates the Cardiovascular Health Study; CVD, cardiovascular disease; FHS, the Framingham Heart Study, OC, other cause; and WHI, the Women’s Health Initiative.