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Lookup NU author(s): Dr Marco Trevisan, Dr Rachael RedgraveORCiD, Professor Gavin RichardsonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Ageing is a major risk factor for cardiovascular disease and is associated with progressive deterioration in myocardial structure, metabolism, and function. Increasing evidence supports a causal role for the accumulation of senescent cells within the myocardium in driving age associated cardiac dysfunction (PMID: 32996233, PMID: 30920115). Consistent with this, our work has demonstrated that senescence accumulates across multiple myocardial cell populations with age and that targeted elimination of senescent cells, genetically or pharmacologically, attenuates myocardial remodelling, enhances stress resilience, and improves diastolic function (PMID: 30920115, PMID: 30737209). While these and other studies (PMID: 34237321) highlight the therapeutic potential of senolytic strategies, the cell-type specific mechanisms through which senescent cell clearance reshapes myocardial biology remain poorly defined. A key barrier is computational: senolytic effects must be resolved from mixed-cell transcriptomes into cell-type-specific, pathway-level programmes using replicate-aware single cell approaches.To address this, we performed single nucleus RNA sequencing on hearts from young ~4-month-old and aged ~23-month-old mice treated with vehicle or navitoclax (16 hearts, n=4 per group). Navitoclax was provided cyclically for 1 month at 50 mg kg−1 day−1 (figure 1A), which previously was observed to reduce fibrosis/hypertrophy and improved diastolic function in aged mice (PMID: 30920115). Hearts were collected within 2.5 hours. A workflow using Scanpy was applied (QC, Scrublet, kNN/UMAP, Leiden, marker annotation) with replicate-aware pseudobulk DE (DESeq2-style NB) and pre-ranked pathway enrichment.Pseudobulk DE (aged vs young) highlighted cardiomyopathy/heart failure, hypertrophy, myocardial infarction and diabetes associated cardiac dysfunction gene sets, and ageing signatures from human GTEx heart datasets. These enrichments were largely lost following navitoclax; vascular ageing signatures from human blood vessel datasets reversed direction, suggesting a shift towards a more youthful vascular state.Cell-type resolution (Leiden + marker mapping; figure 1B) pinpointed fibroblasts and endothelial cells as dominant drivers, with cardiomyocyte stress-adaptation (‘translation/ribosome and RNA quality-control pathways increased; mitochondrial metabolism and circadian programmes reduced) attenuated by navitoclax. Collectively, these analyses place senescent-cell clearance as a microenvironment-targeted strategy: navitoclax reverses profibrotic fibroblast ECM/PDGF programmes and endothelial inflammatory/senescent signalling while partially normalising cardiomyocyte metabolism/circadian control. This cell-type map identifies tractable pathways and biomarkers to stratify ageing hearts and guide senolytic combination therapies for HFpEF and remodelling, linking transcriptome to phenotype in aged myocardium.doi.org/10.1136/heartjnl-2026-BCS.323
Author(s): Trevisan-Herraz M, Redgrave R, Richardson GD
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.323
DOI: 10.1136/heartjnl-2026-BCS.323
ePrints DOI: 10.57711/8xnw-sx40
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