Telomere shortening occurs with age and could contribute to some of the pathologies of ageing. The groups of Maria Blasco and Piero Anversa have joined efforts to study the consequences of telomere dysfunction on the cardiac phenotype, as heart failure is a frequent cause of death in the elderly, and their findings are described in The EMBO Journal.

Blasco and co-workers studied telomerase RNA knockout (Terc−/−) mice that lack telomerase activity at the second (G2) and fifth (G5) generation. Quantitative fluorescence in situ hybridization (Q-FISH) analysis confirmed that cardiac myocytes in G5 Terc−/− mice had significantly shorter telomeres than those from G2 Terc−/− mice, which, in turn, were shorter than in wild-type mice.

The tumour suppressor p53 — which modulates apoptosis and growth arrest — has been correlated with telomere dysfunction. Indeed, increased p53 expression was seen most clearly in myocyte nuclei from G5 Terc−/− mice, which had the shortest telomeres.

On examining heart function, Blasco and colleagues found that G5 Terc−/− mice had severe left ventricular (LV) failure, whereas LV function in G2 Terc−/− mice was normal. This led the authors to conclude that the cardiac phenotype in G5 Terc−/− mice is due to a critical shortening of telomeres rather than telomerase deficiency.

Next, the authors examined cardiac anatomy. Heart and LV weights were significantly decreased in G5 Terc−/− mice compared with wild-type and G2 Terc−/− mice. These findings corresponded to a significant increase in the volume (hypertrophy), and a significant decrease in the number, of myocytes in G5 Terc−/− mice versus wild-type and G2 Terc−/− mice. G2 Terc−/− hearts were also abnormal, but the changes were less pronounced than in G5 Terc−/− hearts.

But which mechanisms are responsible for hypertrophy and cell loss — increased cell death and/or impaired proliferation? Blasco and colleagues found that cell growth was impaired in G2 and G5 Terc−/− myocytes, and that the reduction was twofold higher in G5 than in G2 Terc−/− mice. In addition, cardiomyocyte death by apoptosis was 63% and 39% greater in G5 than in wild-type and G2 Terc−/− hearts, respectively.

So, the authors concluded that telomere shortening might be an important causal factor of heart failure in the elderly, and that telomerase-based therapies should be considered.