Telomere shortening: a diagnostic tool and therapeutic target for cardiovascular disease?

Extract

This editorial refers to ‘Rate of telomere shortening and cardiovascular damage: a longitudinal study in the British birth cohort’^†, by S. Masiet al., on page 3296.

The high prevalence of cardiovascular disease and related mortality and functional decline resulting from increasing life expectancy highlights the need to understand how ageing influences vascular and cardiac function. Currently, ageing is viewed as a consequence of prolonged exposure to environmental and cardiovascular risk factors, during which accumulation of damage increases the risk of cardiovascular dysfunction and disease. However, the striking variability in the age of onset of manifestation of cardiovascular diseases and the large variability of cardiovascular phenotypes with ageing is inadequately explained by the traditional cardiovascular risk factors, but may be explained by variation in biological age.

Leucocyte telomere length (LTL) and telomerase activity are possible reliable markers of biological age, with shorter telomeres and reduced telomerase activity reflecting more advanced age. Telomeres are the TTAGGG nucleotide repeats at the ends of the DNA helix, protecting the end segment of the chromosome between cell divisions, and play an essential role in stabilizing the ends of chromosomes. With ageing and with every cell division, the telomere shortens in length. If the telomere becomes very short and when the telomere maintenance system is failing, the cell stops dividing, leading to cellular senescence and cellular death.¹ The initial LTL of a person is mainly determined by genetic factors. This is confirmed by a genome-wide meta-analysis identifying several loci associated with telomere length.² Also, paternal age at birth is strongly related to LTL, independent of early life socio-economic status.³ A recent study has shown that the main determinant of age-related LTL shortening is LTL at birth.⁴ However, because of the sensitivity of the G triplets of the TTAGGG telomere repeats to the superoxide radical, it is plausible that oxidative stress is also an important factor involved in the age-related telomere shortening.⁵ Accordingly, oxidative stress has been postulated to cause endothelial and cardiovascular dysfunction through its effect on telomere length in the vessel wall. Telomere shortening in circulating leucocytes has been put forward as a biomarker of this process on the assumption that telomere shortening in circulating leucocytes reflects telomere shortening of the haematopoietic compartment. This is relevant since circulating progenitor cells and myeloid cells that are derived from this compartment are key for maintenance and remodelling of the vasculature.⁶