Prof Juan Carlos Kaski, St George's, University of London, UK

A study by Samani et al. (1) over 15 years ago triggered interest in the hypothesis that reduced telomere length predisposed to early cardiovascular disease. Interestingly, a recent meta-analysis by D’Mello et al confirmed Samani’s findings (2) and two other studies have suggested causality between telomere length and cardiovascular disease (3,4) These studies have reinforced the notion that people with inherited shorter telomeres are more likely to develop cardiovascular disease as a result of earlier vascular senescence. A recent study published in JACC (5), however, contradicts this notion. Indeed, the PESA study did not show any association between telomere length and the early development of atherosclerosis (5).

The reasons for the discrepancy among studies have been discussed by in an editorial article by Rietzschel et al. (6). They summarized the different hypotheses exiting at this time point regarding the possible association/causality between telomere length and premature cardiovascular disease postulated by Samani et al (2). Some investigators attribute the association to the effects of cardiovascular risk factors on telomere length; hence risk factors would affect both the development of atherosclerosis and size of the telomeres. Others think that shorter telomeres can per se have a causal effect at a later stage in the process of atherogenesis. The possibility also exists of a false association between these two factors. Finally, some researchers, believe that short telomeres could induce hematopoietic stem cell senescence and thus impair the function of circulating endothelial progenitor cells, which can lead to less effective endothelial repair and atherosclerotic plaque instability (7). The latter appears to be favored by Rietzschel et al. (6).  Several questions have been raised by the well conducted PESA study (5), as follow: a) Is there a true association between telomere length and premature atherosclerosis; b) Should the older investigations be now questioned and new studies carried out using more stringent methodologies; c) Does PESA study represent the end of the hypothesis linking shorter telomere length and premature cardiovascular disease; d) will telomere research suffer as a consequence of these latest findings?

Cardio Debate has asked expert molecular biologist Professor J Erusalimsky, from the University of Cardiff, to help us understand the magnitude of the problem and the effects that the PESA study can potentially have on this research area.

References

  1. Samani N.J., Boultby R., Butler  R., et al; Telomere shortening in atherosclerosis. Lancet. 2001;358:472-473.
  2. D’Mello M.J.J., Ross S.A., Briel  M., et al; Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis. Circ Cardiovasc Genet. 2015;8:82-90.
  3. Brouilette S.W., Moore  J.S., McMahon  A.D., et al;for the West of Scotland Coronary Prevention Study Group Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet. 2007;369:107-114.
  4. Codd V., Nelson  C.P., Albrecht  E., et al; Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013;45:422-427.
  5. Fernández-Alvira J.M., Fuster V., Dorado  B., et al; Short telomere load, telomere length, and subclinical atherosclerosis: the PESA study. J Am Coll Cardiol. 2016;67:2467-2476.
  6. Telomeres and Atherosclerosis – The attrition of an attractive hypothesis. Rietzschel ER, Bekaert S, De MeyerT. J Am Coll Cardiol. 2016;67:2477-2479. doi:10.1016/j.jacc.2016.03.541
  7. Minamino T., Miyauchi  H., Yoshida  T., et al; Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002;105:1541-1544.
Cardio Debate Expert Comments

Telomeres are the physical ends of chromosomes. They are made of a repeated DNA sequence (TTAGGG), several thousand base pairs long, to which specialized binding protein are anchored, together forming a capping structure that protects the tips of the chromosome. Synthesis of telomeric DNA requires telomerase, an enzyme that adds TTAGGG repeats to the 3’ ends of the DNA chain. The majority of human adult somatic cells either lack, or have very low levels of telomerase. Under these conditions, and due to the way conventional DNA polymerases work (they are unable to replicate the 5’ end of the lagging strand), DNA synthesis during cell division results in a gradual shortening of the telomere. In addition, telomeric DNA is very susceptible to oxidative damage and therefore, the rate of telomere erosion is also affected by the oxidative burden of the cell.  Telomeric DNA shortening eventually compromises the functional integrity of the whole telomere cap, triggering an intracellular stress response which results in the onset of cellular senescence.

Telomere length is generally homogeneous across tissues within the same individual. Hence, the widely used measure of average leukocyte telomere length reflects the length of telomeres in other parts of the body. Telomere length is largely determined by inheritance. In addition, environmental, lifestyle and psycho-social factors, including smoking, obesity, lack of physical activity, low educational attainment and chronic psychological stress, have all been found to be associated with shorter average telomere length.1 Leukocyte telomere shortening is observed in vivo in association with normal aging, with age-related diseases including diabetes, cancer and dementia, and with increased risk of all-cause mortality.1 Similarly, experimental and epidemiological evidence accumulated over the last 20 years support a role for shorter telomeres and cell senescence in cardiovascular disease (CVD),2 with strong associations seen with advanced vessel pathology and acute vascular syndromes (stroke and MI).3  However, whether short telomeres constitute a causal factor in atherogenesis has remained unclear. Indeed, two previous cross-sectional population-based surveys (Asklepios4 and Brunnek5) showed that in fact, average leukocyte telomere length was not associated with subclinical atherosclerosis. In a refinement of these surveys the PESA study6 confirms those early conclusions.

The PESA study6 represents an important addition to the understanding of telomere biology in the context of CVD, mainly on two accounts; first, it carried out a more a precise evaluation of the atherosclerotic burden than previous studies, and second, in addition to measuring the average telomere length, it examined the association between subclinical atherosclerosis and the abundance of the shortest telomeres. The importance of the latter rests in the notion that it is the presence of a few critically short telomeres the trigger for senescence, though these and average telomere length generally correlate. Thus, while the PESA study provides very strong additional evidence that telomere length is not causally related to the initial stages of atherosclerosis, future longitudinal studies will need to assess whether telomere length is associated with the progression of CVD disease. Furthermore, work is still required to evaluate whether the long standing association between established CVD and telomere length is the result of an epiphenomenon or alternatively, whether indeed short telomeres and senescence contribute to plaque rupture and its clinical sequelae.

References

  1. Blackburn EH, Epel ES, Lin J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 2015;350:1193-1198.
  2. Erusalimsky JD, Kurz DJ. Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp.Gerontol. 2005;40:634-642.
  3. D’Mello MJ, Ross SA, Briel M et al. Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis. Circ.Cardiovasc.Genet. 2015;8:82-90.
  4. De MT, Rietzschel ER, De Buyzere ML et al. Systemic telomere length and preclinical atherosclerosis: the Asklepios Study. Eur.Heart J 2009;30:3074-3081.
  5. Willeit P, Willeit J, Brandstatter A et al. Cellular aging reflected by leukocyte telomere length predicts advanced atherosclerosis and cardiovascular disease risk. Arterioscler.Thromb.Vasc.Biol. 2010;30:1649-1656.
  6. Fernandez-Alvira JM, Fuster V, Dorado B et al. Short Telomere Load, Telomere Length, and Subclinical Atherosclerosis: The PESA Study. J.Am.Coll.Cardiol. 2016;67:2467-2476.