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Cellular Senescence Contributes to Impaired Heart Regeneration

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Posted 05 December 2018 - 11:02 AM

This paper is a preprint, meaning it hasn't gone through peer review yet, so apply the appropriate multiple to its chances of containing significant errors. The authors outline evidence for the age-related accumulation of senescent cells to impair heart regeneration. I'd have to say that this is an expected outcome of cellular senescence, given what is presently known of senescent cells, and in particular the ways in which their potent mix of inflammatory signaling disrupts normal tissue function. Of course the scientific community still has to provide satisfactory proof for that to be the case for the heart specifically, and join the dots between the underlying mechanisms.

Since a number of senolytic therapies exist, treatments capable of selectively removing 25-50% of senescent cells from various tissues, it is the case that the best way to proceed in linking aspects of aging to cellular senescence is to destroy senescent cells and see what happens as a result. That is considerably faster and more efficient than purely investigative methods. The challenge here is that senolytic therapies clear senescent cells from most tissues, all tissues are affected in their own particular ways, and there are only so many researchers with the funding to carry out assessments. So while we'd all like to know how senolytics affect lymph nodes, or the stomach lining, or pick your favorite tissue type here, it will probably be a while before the research community works its way down the list to reach these line items.

Ageing is the greatest risk factor for many life-threatening disorders. Although long-term exposure to known cardiovascular risk factors strongly drives the development of cardiovascular pathologies, intrinsic cardiac aging is considered to highly influence the pathogenesis of heart disease. However, the fields of the biology of aging and cardiovascular disease have been studied separately, and only recently their intersection has begun to receive the appropriate attention.

Aging leads to increased cellular senescence in a number of tissues and work suggests senescent cell burden can be dramatically increased in various tissues and organs with chronological ageing or in models of progeria. Cellular senescence is associated with increased expression of the senescence biomarker, p16Ink4a (also known as Cdkn2a), impaired proliferation, and resistance to apoptosis. Senescent cells disrupt tissue structure and function because of the components they secrete, which act on adjacent as well as distant cells, causing fibrosis, inflammation, and a possible carcinogenic response. Indeed, senescent cells possess a senescence-associated secretory phenotype (SASP), consisting of pro-inflammatory cytokines, chemokines, and extracellular-matrix-degrading proteins, which have deleterious paracrine and systemic effects. Remarkably, even a relatively low abundance of senescent cells (10-15% in aged primates) is sufficient to cause tissue dysfunction.

Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease aged 32-86 years. In aged subjects (older than 74 years) over half of CPCs are senescent, unable to replicate, differentiate, regenerate, or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs senescent. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (using the INK-ATTAC model or wild-type mice treated with dasatinib and quercetin senolytics) in vivo activates resident CPCs and increased the number of small, proliferating cardiomyocytes. Thus therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

Link: https://doi.org/10.1101/397216

View the full article at FightAging

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