Association Between Shortened Leukocyte Telomere Length and Cardio-Metabolic Outcomes

Abstract

In their meta-analysis of 27 published studies, D'Mello et al 1 show that shortened leukocyte telomere length (LTL) is associated with 3 primary end points: myocardial infarction, stroke, and type 2 diabetes mellitus. The meta-analysis and its findings raise several fundamental issues that are worth considering. After discussing the major findings and limitations, we focus on 3 central themes: the reliability of LTL measurements, the biological meaning of the association of LTL with cardio-metabolic outcomes, and future directions of telomere research with respect to cardiovascular disease (CVD) and longevity in humans. Article see p 82The underlying reason for meta-analysis is usually lack of consensus across studies. This clearly applies to the field of telomere epidemiology, which is awash with conflicting findings not only in the context of CVD but also cancer and longevity. The meta-analysis of D'Mello et al shows a significant association of LTL with each of the 3 primary end points, but the test for heterogeneity across the studies was significant for each disease. The authors suggest that ethnicity or perhaps demography, which is often associated with ethnicity, might explain some disagreements in findings across populations (and studies). Notably, however, 26 of the 27 studies analyzed across the 3 primary disease end points had odds ratios >1, indicating that the observed heterogeneity resulted from varying magnitudes of a positive association with disease and not from some studies showing inverse associations. The subgroup analysis in Figure 3 of the D'Mello paper suggests that the racial or ethnic group with the highest prevalence of the specific disease showed the smallest association with LTL (Asians for stroke, Hispanics and African Americans for diabetes mellitus). It is unclear why this would be so, unless the higher prevalence of disease in these groups was caused by influential ethnic-related determinants independent of the basic biological and heritable influences of telomere length. The authors were not able to get further data on race and ethnic group from the contributing studies to adequately address these important potentially confounding variables. The number of studies available in some of the racial and ethnic groups was simply too few to draw reliable conclusions as to their influence on the heterogeneity of the estimated disease risks. Also, the inverse association seen in the meta-analysis between sample size and odds ratios estimates (ie, the smaller the study, the more likely the odds ratios estimates were to be elevated) is consistent with the likely publication bias suggested by the authors. Smaller studies with null results are probably unpublished as demonstrated by both Haycock et al and D'Mello et al. Reliability of LTL MeasurementsThe reliability of LTL measurements and sample size are closely linked with respect to findings and conclusions because less reliable LTL measurements require larger samples to test associations and hypotheses. With an interassay coefficient of v...

Short Telomere Load, Telomere Length, and Subclinical Atherosclerosis

“…This might explain the significant association of total plaque burden with LTL in men, but not in women, in the unadjusted model. Indeed, the overall young age of the study population might help to explain the lack of association between LTL and plaque burden, especially for women, who generally have a lower atherosclerosis burden than men of the same age.Telomere dysfunction induces metabolic and mitochondrial compromise(35), and increased burden of oxidative stress can accelerate LTL attrition(12,29). Consistent with the results of multivariate regression analyses showing that femoral artery plaques are independently related to serum ox-LDL (36), we found significantly higher serum ox-LDL concentrations among participants with a higher plaque burden.…”

“…An association between short LTL and the occurrence of cardiovascular ischemic events has been described in several studies (13,14,29); however, information is still scarce on the relationship between LTL and subclinical atherosclerosis in subjects free from established CVD. The short telomere load correlates with the number of senescent cells (17), suggesting that an association between CVD and the number of short telomeres might be better than average LTL at predicting aging and associated atherosclerosis.…”

Leukocyte Telomere Length in Newborns: Implications for the Role of Telomeres in Human Disease

“…As we discussed in 2 recent communications, 29,30 the prevailing view is that LTL is a "telomeric clock" that captures the aging process, primarily in the form of accumulating burden of inflammation and oxidative stress. This view infers that individuals with short LTL might be biologically older because they experience a higher rate of aging, as displayed in a faster rate of LTL attrition.…”

“…By proposing that LTL is largely determined before adulthood, and to a large degree at birth, 29,30 we have moved away from the paradigm that has dominated the field of telomere epidemiology for more than a decade. We question neither the effects of inflammation and oxidative stress on LTL attrition nor their role in aging and its related diseases, including atherosclerosis.…”

No association between blood telomere length and longitudinally assessed diet or adiposity in a young adult Filipino population

“…Some researchers have recently suggested that TL is not the biomarker of cumulative inflammation and oxidative stress that it was previously thought to be and that, compared with biological factors, lifestyle factors play a relatively minor role in determining TL [16,55,101]. However, given the characteristics of our study sample and several methodological limitations, it remains unclear whether this is an explanation for the null results of the analyses presented here.…”