Atrial Fibrillation Progression Correlates with Senescent Cell Burden

Researchers here provide evidence to support a role for cellular senescence in the progression of atrial fibrillation. You might recall a recent study showing that this heart condition is driven by fibrosis, which is a good reason to suspect that the presence of senescent cells may be a causative mechanism. There is a good amount of data from recent years to show that the inflammatory signaling produced by lingering senescent cells in aged tissues causes fibrosis, and that targeted removal of these errant cells can reverse fibrosis. Given that age-related fibrosis is a feature of many degenerative conditions of the lungs, heart, kidneys and other organs, and that there is presently little that that existing clinical medicine can do to turn back fibrosis, it is good news indeed that senolytic therapies to clear senescent cells may step up to fill this gap.

Atrial fibrillation (AF) is associated with increased mortality due mainly to heart failure and embolic complications. AF is well known to occur more frequently with increasing age and is linked to vascular aging. During AF, inflammation, apoptosis, endothelial dysfunction, and platelet activation contribute to creating a prothrombotic state and promoting atrial remodeling. While the link between aging and thrombogenicity is well established, the cellular and molecular mechanisms are still under consideration.

Premature cellular senescence is an irreversible form of cell cycle arrest that can be triggered by various cellular stresses, including DNA damage, oxidative stress, and oncogene activation. It is characterized by the acquisition of a proinflammatory and prothrombotic profile. Senescent cells are found in aged tissues where they remain metabolically active but are unable to proliferate despite the presence of mitogens.

In AF, the role of senescence in atrial remodeling and the development of a prothrombotic state remains unclear. Using a model of atrial endothelial cells, we recently demonstrated that thrombin, a key determinant of thrombogenicity during atrial fibrillation, promotes atrial endothelial cells senescence and the acquisition of the senescence-associated secretory phenotype, characterized by enhanced expression levels of vascular cell adhesion molecule (VCAM)-1, tissue factor (TF), transforming growth factor (TGF-β), and metalloproteinases (MMP-2 and MMP-9).

In this study, we investigated the link between AF and senescence markers through the assessment of protein expression in the tissue lysates of human appendages from patients in AF, including paroxysmal (PAF) or permanent AF (PmAF), and in sinus rhythm (SR). The major findings of the study indicated that the progression of AF is strongly related to the human atrial senescence burden as determined by p53 and p16 expression. The stepwise increase of senescence (p53, p16), prothrombotic (TF), and proremodeling (MMP-9) markers observed in the right atrial appendages of patients in SR, PAF, and PmAF points toward multiple interactions in the human atrium that enhance the senescence burden, atrial extracellular matrix remodeling, thrombogenicity, and other putative mediators involved in the progression of AF.

Link: https://doi.org/10.3390/jcm9010036

Comments

Biohackers considering senolytic therapy for afib and heart failure need to be careful of cardiac toxicity. The entry below explains the concern well.
I quote:
" The cardiac toxicity is probably due to high tissue concentration and inhibition of cardiac mitochrondria-- exactly what is happening in senolytic therapy and anti-cancer-stem cell therapy. We can probably expect that the therapeutic window of all drugs that work this way, is not that large. At doses a few times what kills cancer stem cells and senile cells, we start to get effects on normal cells. If that's in your heart, it's not something you can tolerate for a few days, like cancer "chemo." Instead you might be dead from just momentary problems."

https://forum.age-reversal.net/t/m2dxq7/azithromycin-zithromax-as-senolytic-a-note-of-caution

Posted by: August 33 at January 7th, 2020 6:57 AM

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