From immunosenescence to diastolic dysfunction: tracing the senescence cascade in heart failure with preserved ejection fraction

This editorial refers to ‘Pharmacological clearance of senescent cells reduces inflammation, endothelial damage and cardiac fibrosis in HFpEF’, by E.D. Silva et al., https://doi.org/10.1093/cvr/cvaf208. In this issue of Cardiovascular Research, Nascimento et al., provide further compelling evidence supporting a role for senescence, and the senescence associated secretory phenotype (SASP), in the pathophysiology of cardiovascular disease and senescence-induced remodelling (SIR).1 Prior studies have demonstrated that both acute and chronic cardiac stress can drive myocardial cell senescence and consequently structural remodelling.2–6 Nascimento et al. extend these concepts to a cardiometabolic model of heart failure with preserved ejection fraction (HFpEF). HFpEF is a highly prevalent, clinically heterogeneous syndrome that now accounts for over half of all heart failure cases globally, underscoring the relevance of these findings. In this context, the authors utilized the ZSF1-Obese rat model, which recapitulates many features of human HFpEF, to longitudinally characterize senescence in multiple cell types across disease progression. Their data provide a novel paradigm wherein cellular senescence is a central pathogenic driver in HFpEF; however, the initial trigger for SIR appears to be the induction of senescence within the immune cell compartment. Senescent immune cells precipitate a state of systemic inflammation via their SASP and promote heightened recruitment of immune cells into the myocardium. This inflammatory influx in turn drives secondary senescence in resident cardiac cell populations, including endothelial cells and fibroblasts. The induction of myocardial senescence is hypothesized to contribute to the observed vascular rarefaction (loss of small blood vessels) and myofibroblast differentiation, with the culmination of this multi-cellular senescence cascade being maladaptive myocardial remodelling and impaired diastolic function. This sequence of senescence-driven events exemplifies the emerging concept of SIR and is depicted schematically in Figure 1. Complementing these preclinical studies, clinical data from patients suffering from HFpEF demonstrated elevated levels of circulating senescent leukocytes which correlated with established clinical disease markers such as higher B-type natriuretic peptide (BNP) levels and increased pulmonary artery systolic pressure. Together these data strongly support the hypothesis that senescence in immune and endothelial cells is a key driver of HFpEF, by sustaining chronic inflammation and impairing normal vascular homeostasis, ultimately promoting cardiac dysfunction. Senescence as a central driver of HFpEF pathophysiology and the therapeutic potential of senolytics. A cascade of cellular senescence contributes to HFpEF; initially, metabolic dysfunction triggers immunosenescence, leading to systemic inflammation mediated by SASP. Immune cell recruitment promotes secondary senescence in resident myocardial cells, including endothelial cells and fibroblasts. Endothelial cell activation further increases immune cell recruitment and infiltration. These events lead to vascular rarefaction and fibrosis via myofibroblast differentiation, and ultimately this senescence induced remodelling impacts diastolic function. Therapeutic intervention with the senolytic navitoclax effectively reduces senescent cell burden, decreases inflammatory cytokine levels, and improves endothelial function and attenuates myocardial fibrosis. Additionally, early administration improves extracardiac outcomes. However, questions remain regarding (Q1) the initial mechanism by which metabolic dysfunction initiates immunosenescence, (Q2) the relative contribution to maladaptive remodelling and phenotype of the different senescent myocardial cell lineages, and weather other myocardial cell lineages such as cardiomyocytes, pericytes and neuronal cells are involved in the senescence cascade. (Q3) the systemic influence of myocardial senescence once established. Created with BioRender.com To test the therapeutic potential of this hypothesis and to provide a causal link between senescence and HFpEF, the authors employed navitoclax (ABT-263), a senolytic agent that selectively induces apoptosis in senescent cells by inhibiting anti-apoptotic proteins BCL-2 and BCL-xL.7 In both early (pre-HFpEF) and late (post-HFpEF onset) treatment schedules, navitoclax administration led to a marked reduction in senescent cell burden, attenuated inflammatory cytokine levels, improved endothelial function, and significantly reduced myocardial fibrosis. Early treatment also improved extracardiac parameters including exercise tolerance, renal function and reduced pulmonary oedema, whereas late treatment did not (Figure 1). Importantly, restoration of endothelial integrity following navitoclax therapy supports the hypothesis that senescent endothelial cells hinder microvascular proliferation, and their removal may permit angiogenic repair. These findings align with previous studies in ischemia–reperfusion injury models, where navitoclax enhanced capillary density and cardiac repair.2 Overall, these results highlight the capacity of senolytics to not only clear dysfunctional endothelial cells but also foster regenerative environments supportive of vascular health. This study holds particular significance given the therapeutic stagnation in HFpEF, where most interventions remain palliative. The authors’ demonstration that early senolytic intervention yields superior outcomes underscores the value of early disease detection and positions senescence-targeting therapies as viable strategies for upstream disease modification. The work by Nascimento et al. represents an important contribution to the evolving narrative that highlights cellular senescence as a central and common pathological process in the development and progression of maladaptive cardiac remodelling, and positions senescence as a therapeutic target. Moreover, the observed correlation between senescent immune cells and clinical HFpEF biomarkers highlights the potential utility of quantifying circulating senescent cell populations or SASP components as prognostic indicators for patient stratification and monitoring. Nonetheless, important caveats remain (Figure 1). While navitoclax is a potent senolytic, its non-specific mechanism of action may lead to off-target effects, including thrombocytopenia. As the authors suggest, pharmacological strategies including the use of senolytic nanoparticles,8 senolytic prodrugs9 or the use of novel senomorphic agents that protect against senescence10 may provide a better route to clinical translation. Further, the precise identity of the senescent cell populations responsible for driving disease remains incompletely defined. In this study a comprehensive assessment of immune, endothelial and fibroblast cellular senescence was performed, however, to fully resolve which cell populations are induced to senescence and to determine if all senescent cells contribute equally to disease pathophysiology and through the same mechanisms, will require advanced technologies. Single-cell transcriptomics and senescence reporter models will be invaluable for dissecting cell-specific contributions and for developing targeted delivery strategies. Additionally, the systemic influence of myocardial senescence and SASP at later disease stages remains unresolved. Finally, while the data supports the initiation event being induction of immunosenescence, the mechanisms by which metabolic dysfunction initiates immunosenescence are yet to be defined. Understanding this early axis may unlock additional therapeutic windows to target the metabolic–immune interface in HFpEF. Nascimento and colleagues present a compelling case for cellular senescence as a modifiable driver of HFpEF and establish proof-of-concept for senolytic therapy in preclinical models. By demonstrating both mechanistic insight and therapeutic potential, this study contributes meaningfully to the emerging field of senescence-targeting strategies in cardiovascular disease. Future work integrating basic, translational, and clinical research will be crucial to realise the promise of this approach and to bring precision senotherapeutics into clinical practice. This work was supported by the British Heart Foundation [PG/22/10788 and PG/23/11571]. There are no new data associated with this article.