Heart failure with preserved ejection fraction is one of cardiology's most frustrating frontiers — affecting nearly half of all heart failure patients, with no therapy proven to cut mortality. A sweeping mechanistic review now argues that the aging biology of cellular senescence, long studied in cancer and neurodegeneration, sits at the very center of HFpEF's intractable pathophysiology, reframing it as a disease of biological aging rather than merely hemodynamic dysfunction.
The review synthesizes preclinical and clinical evidence showing that senescent cells accumulate in aging myocardium and release a coordinated storm of pro-inflammatory cytokines, proteases, and growth factors — collectively the senescence-associated secretory phenotype, or SASP. Specific SASP mediators, including IL-6, IL-1β, TGF-β, and MMP family proteins, were identified as mechanistic drivers of myocardial fibrosis, coronary microvascular dysfunction, and direct cardiomyocyte injury. The analysis distinguishes between two therapeutic intervention classes: senolytic agents, which selectively eliminate senescent cells (with dasatinib-plus-quercetin among the most studied combinations), and senomorphic compounds, which suppress SASP secretion without killing the senescent cell itself.
Placing this in broader context, the senolytic field has gained considerable momentum since murine studies demonstrated that clearing p16Ink4a-positive senescent cells extended healthspan dramatically. However, the translation to cardiac tissue poses unique challenges the review explicitly flags: senolytic drugs currently lack cardiac tissue specificity, raising concerns about off-target elimination of stress-adapted cells that may serve protective roles in remodeling myocardium. Equally problematic is the absence of validated circulating SASP biomarkers to guide dosing or confirm target engagement in clinical trials. These are not trivial hurdles. For a condition whose patient population skews elderly and multimorbid, systemic senolytic exposure carries real risk. This review is a rigorous, timely synthesis for the field — incremental in novelty given existing SASP literature, but potentially paradigm-clarifying for HFpEF specifically, where the biological aging framework has been underexplored therapeutically.
