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Lookup NU author(s): Lily Mathison, Professor Gavin RichardsonORCiD, Laura BoothORCiD, Dr Rachael RedgraveORCiD, Steven White, Professor Viktor KorolchukORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Senescence is a complex cellular state usually associated with cell cycle arrest in mitotic cells yet is also recognised in post-mitotic cells including cardiomyocytes (CMs). Literature suggests that CM senescence is associated with CDKN1A (p21) and/or CDKN2A (p16) expression and increased myocardial senescence, at least in part, drives cardiovascular disease (CVD) including age-related myocardial remodelling due to a proinflammatory phenotype termed the senescence-associated secretory phenotype (SASP). Importantly, murine data from our group showed improved cardiac function after targeting senescent cells, proving the potential of clearance as a therapeutic. Using human donor tissues and snRNAseq we are beginning to obtain evidence that while both p21 and p16 are observed in the human heart they may represent distinct populations as they are rarely observed in the same cell, correlate with different disease markers and are found at different expression levels in the same tissue (figure 1). We have begun to characterise the molecular pathways of biomarkers p21 and p16, which will provide specific targets for mitigating cardiac ageing, through utilization of in vitro models of human CMs, fibroblasts and endothelial cells.AC16 CMs were transduced with p21/p16 using lentiviral Tet-on vectors. Tet-on induction was observed during doxycycline dose responses, and time-point analyses were measured using both comparative gene expression and protein analyses. Secretion profile analyses will also be conducted. Switching p21 and/or p16 on/off in the transduced cells allows us to analyse feedback loops and distinguish the reversibility of the senescent phenotype. Future use of hiPSCs (human-induced Pluripotent Stem Cells) differentiated into CMs, endothelial cells or fibroblasts will confirm whether senescence is uniform across human myocardium.After Tet-on induction of p21-transduced CMs, an increase in expression of both transgene and endogenous p21 was observed, alongside increased expression of GDF-15, a component of CM SASP and a biomarker of CVD, and PURPL, a p53-induced long non-coding RNA associated with DNA damage responses and growth arrest linked to senescence. Although preliminary, this allows ongoing work to assess other specific mechanisms activated by a p21-positive feedback loop, and downstream effects through activation/inhibition of transgenes. Experiments will be mirrored in p16-transduced CMs, and derivatives of hiPSCs. We plan to compare the two senescent profiles using an omics approach.Results from p21-transduced CMs solidify the magnitude of the impact of p21-driven senescence in CM microenvironment. Further findings surrounding wider-spread effects and specific mechanisms, such as mitochondrial damage, will allow us to characterise exact senescence pathways, especially observing the difference in p21 and p16-driven senescence. Findings from this work will generate important insights for future developments of anti-ageing therapeutics.
Author(s): Mathison L, Richardson GD, Booth L, Redgrave RE, White S, Korolchuk V
Publication type: Article
Publication status: Published
Journal: Heart
Year: 2026
Volume: 112
Issue: Suppl 1
Print publication date: 09/06/2026
Online publication date: 09/06/2026
Acceptance date: 01/05/2026
Date deposited: 01/07/2026
ISSN (print): 1355-6037
ISSN (electronic): 1468-201X
Publisher: BMJ Group
URL: https://doi.org/10.1136/heartjnl-2026-BCS.300
DOI: 10.1136/heartjnl-2026-BCS.300
ePrints DOI: 10.57711/2r83-pd92
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