Evidence for Cellular Senescence to be Involved in Cardiac Hypertrophy

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.

Link: https://doi.org/10.1371/journal.pone.0182668

Comments

Just some speculation...As far as I'm aware, mice somatic cells don't have a hayflick limit, but they have been shown conclusively to become senescent. I expect this is down to high TOR signaling and Inflammation/ROS, etc. Although we are much longer lived than mice we keep our hearts for all that time without cell turnover, so it is likely senescence would eventually be a factor, and would be caused by similar pathways to those that effect non-hayflick limited mice cells.

Agree not much can be concluded from isoproterenol-induced hypertrophy.

Posted by: Mark at August 10th, 2017 6:17 AM

"As far as I'm aware, mice somatic cells don't have a hayflick limit, but they have been shown conclusively to become senescent."

Well, human cells in vivo usually don't enter senescence due to the Hayflick limit either, but due to DNA damage, oxidative stress, etc.

Posted by: Antonio at August 10th, 2017 7:47 AM

I am not sure we can say what the dominant cause of senescence is proliferating human cells because they are so interlinked. For example ROS can shorten telomeres but not cause senescence outright, which then decreases the time to the Hayflick Limit. Also very fast proliferating cells such as bone marrow might senesce more due to telomere limits than damage. It would be good to see a study to examine these causes and their contribution, but as I said it would be difficult because they feedback into each other.

Posted by: Mark at August 10th, 2017 9:50 AM

Mark: Some time ago I posted a link to a paper that states that the main cause of senescence in vivo in humans is not the Hayflick limit, but can't find it now (Google's search is not very useful). I will search for it again later.

Posted by: Antonio at August 10th, 2017 11:21 AM

I see heart hypertrophy as primarily a genetic problem. Take for instance the Fibroblast Growth Factor 21 rs838133 A/G. The A allele is protective and preventive of cardiac hypertrophy and oxidative stress, while the G allele functions less well which gives rise to hypertrophy and heart disease. If we could use CRISPR technology in the future to replace the bad SNP with an AA allelic SNP, we would greatly reduce the risk. There may be a few other genes involved in this too, which I am not aware of, but some cardiac researchers may know about.

Posted by: Biotechy at August 13th, 2017 9:52 AM

Thanks for that Antonio - problem is fibroplasts from a donor will have a telomere length only weakly correlated to the age of the donor, because they are constantly being replaced from the stem cell pool and you will only be capturing one moment in time (you'd need to take lots of samples from one person over a period of time to get a more accurate picture, or take sample from many different tissue types).

So we are left in the situation where we know that (a) short telomeres can cause aging on their own; but (b) even with long telomeres you can still age due to other factors. To separate out these factors would be very useful.

Posted by: Mark at August 14th, 2017 8:34 AM

"So we are left in the situation where we know that (a) short telomeres can cause aging on their own; but (b) even with long telomeres you can still age due to other factors."

That's not the situation that the data in the paper shows.

Posted by: Antonio at August 14th, 2017 12:09 PM

True, but the paper doesn't say very much at all.

Posted by: Mark at August 15th, 2017 2:51 AM

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