In this open access paper, evidence is presented for senescent cells to be involved in the development of age-related cardiac hypertrophy, detrimental changes in the structure of the heart. The results here are somewhat more speculative than much of the recent evidence for cellular senescence to contribute to specific age-related conditions, most of which is direct and robust. Firstly the authors are arguing for senescence to be a relevant mechanism in a cell population that largely doesn't replicate, and therefore will not be generating large numbers of transient senescent cells as somatic cells hit the Hayflick limit. Fewer transient senescent cells means fewer senescent cells that fail to self-destruct and linger to cause issues. Another objection is the animal model used, which did not involve aged individuals, and so there is always the possibility that the type of damage and change in heart tissue caused here is not all that relevant to aging. Nonetheless, the results seem interesting, and there is always the point that fibrosis - a major feature of heart aging - is now well connected to cellular senescence in other tissues.
Pathological cardiac hypertrophy is the cellular response to biomechanical or neurohumoral stimuli. The defining features of hypertrophy are increased cardiomyocyte size, enhanced protein synthesis and reinduction of the so-called fetal gene program. Although hypertrophy has traditionally been considered as an adaptive response required to sustain cardiac output, in the long term, hypertrophy predisposes individuals to heart failure, arrhythmia and sudden death. Despite the recent advances in understanding the molecular and cellular processes that contribute to cardiac hypertrophy, there remains the need for further investigation.
Cellular senescence describes the permanent form of cellular proliferative arrest. Senescent cells are characterized by phenotypic changes; for example, increased cell size, enhanced senescence-associated β-galactosidase (SA-β-gal) activity and high levels of cyclin-dependent kinase inhibitors (CDKIs) which block the cell cycle. The mammalian heart has long been considered a quiescent organ. Although there are a few studies suggesting that cardiomyocytes can divide at a low rate under certain conditions, it is widely believed that the majority of cardiomyocytes, if not all of them, are out of cell cycle shortly after birth. Therefore, the question that has been raised is whether cardiomyocytes can undergo senescence. Previous studies have revealed that cardiomyocytes from old mice show certain senescence-associated properties, including high SA-β-gal activity, increased CDKIs expression, accumulated lipofuscin and decreased telomerase activity. Based on the fact that cardiac senescence and hypertrophy share defining features and signaling pathways, the aim of our study is to find out whether cardiac senescence is involved in the process of pathological cardiac hypertrophy and what could be the specific biomarkers for evaluating cardiac aging.
Our present results show for the first time that a cardiac senescence phenotype occurs in isoproterenol-induced pathological cardiac hypertrophy by analysis of a wide range of senescence markers. Similar results were also reported in an angiotensin II-induced cardiac hypertrophy model, and dilated cardiomyopathy caused by cardiac-specific Bmi1 deletion manifested by the increased ratio of SA-β-gal positive cells. It suggested that not only does cardiac senescence exist in the heart but also that it is involved in multiple hypertrophy models.