In recent years, the scientific community has witnessed a paradigm shift in understanding the fundamental role of cellular senescence in aging and cardiovascular disease. Once considered a mere consequence of aging, senescent cells have now emerged as pivotal drivers of tissue degeneration and chronic disease pathogenesis. Groundbreaking studies have revealed that the targeted elimination of senescent cells can not only delay the onset of natural and premature aging but also extend lifespan and restore organ function, rewriting the script of cardiovascular therapy and age-associated interventions.
Cellular senescence, characterized by a permanent cessation of cell division and a distinctive secretory profile known as the senescence-associated secretory phenotype (SASP), accumulates progressively with age. This senescent cell burden adversely impacts tissue homeostasis by impairing regenerative capacity and promoting inflammatory signaling that perpetuates senescence in neighboring cells. As a result, the strategic removal of these cells has emerged as a compelling anti-aging strategy, holding promise to rejuvenate aging tissues and mitigate cardiovascular disease progression.
The therapeutic potential of senolytics—drugs designed to selectively eliminate senescent cells—has garnered significant interest. Among the frontrunners, the combination of dasatinib, a tyrosine kinase inhibitor, and quercetin, a naturally occurring flavonoid, has demonstrated remarkable efficacy in preclinical models. For instance, this synergistic duo significantly reduces the expression of p16^INK4A, a key marker of senescence, clears radiation-induced senescent cardiomyocytes, and improves cardiac pump function in aged mice. These findings underscore the translational potential of senolytic therapies to combat cardiac aging and associated dysfunction.
Beyond senolytics, emerging research highlights the multifunctional roles of sirtuins—NAD+-dependent deacetylases and ribosyltransferases—in modulating aging and cardiovascular homeostasis. Mammalian sirtuins, comprising seven members with distinct subcellular localizations, regulate DNA repair, metabolic adaptation, cell cycle progression, and neuroprotection. Notably, SIRT2 downregulation correlates with accelerated cardiac aging in primates, with in vitro models confirming its protective role against cardiomyocyte senescence. Likewise, SIRT6 manifests broad-spectrum anti-aging effects, including telomere maintenance, genome stabilization, and inflammatory suppression, positioning it as a crucial target in cardiovascular longevity research.
In addition to intrinsic cellular regulators, metabolic factors such as homocysteine have been implicated in exacerbating cardiovascular aging. Elevated homocysteine levels promote vascular smooth muscle proliferation, endothelial dysfunction, oxidative stress, and extracellular matrix remodeling, collectively accelerating atherosclerosis. Intriguingly, folic acid supplementation mitigates these effects by lowering homocysteine concentrations, dampening oxidative stress, and repressing senescence markers p53-p21 and p16^INK4A. Animal studies corroborate its cardioprotective role, revealing reductions in ventricular hypertrophy, fibrosis, and apoptotic cardiomyocyte death, thereby offering a nutraceutical avenue for anti-aging cardiovascular interventions.
Recent advances also illuminate the critical role of metabolic pathways in cellular senescence. Serine biosynthesis, a glycolytic derivative pathway, emerges as a vital mechanism to forestall cardiovascular cell aging. Enhancing serine production could potentiate robust aging by maintaining cellular redox balance and supporting nucleotide synthesis, thereby curbing senescence onset. Complementarily, bromodomain-containing protein 4 (BRD4) has surfaced as an innovative molecular target. BRD4 influences chromatin architecture and gene expression, and its modulation exhibits profound effects on multiple aging-related pathologies, including cardiac dysfunction, highlighting the expanding repertoire of epigenetic targets in anti-senescence therapy.
While genetic and pharmacological routes dominate senescence management, cellular immunotherapy represents a cutting-edge frontier. Senescent cells’ intrinsic resistance to apoptosis has been exploited by developing Bcl-2/Bcl-xL inhibitors such as ABT-263, which selectively trigger apoptosis in these stubborn cells. Application of these agents remodels the tissue microenvironment, reactivates quiescent stem cells, and attenuates pathological fibrosis. Notably, engineered T cells targeting senescent-specific surface markers have achieved efficient and low-toxicity clearance in osteoarthritis and potentially cardiovascular disease models, foreshadowing a new era of precision immunotherapy for senescence-driven ailments.
The path toward clinical translation of senescence-targeted therapies remains challenging yet tantalizing. Clinical trials investigating senolytic drugs and T-cell immunotherapies for cardiovascular diseases are underway, but the safety, efficacy, and long-term effects require rigorous evaluation. Despite encouraging preclinical data, widespread application necessitates overcoming hurdles related to senescent cell heterogeneity, off-target effects, and individualized responses—objectives propelled by cutting-edge single-cell technologies illuminating cellular diversity within aging tissues.
Single-cell RNA sequencing (scRNA-seq) has revolutionized our capacity to decipher the intricate heterogeneity of senescent cells. This technology enables the unbiased classification of cellular subpopulations based on transcriptional profiles, uncovering rare and previously unrecognized subtypes. For example, distinct CD8 T cell subpopulations with divergent senescence trajectories were recently characterized, refining our understanding of immune aging. The development of the SenCID algorithm, a machine learning-powered tool for senescent cell identification, leverages human single-cell transcriptomics to categorize senescence into discrete states, facilitating targeted therapeutic development.
In the cardiac milieu, single-nucleus RNA sequencing has unraveled complex fibroblast heterogeneity linked to age-related fibrosis. Specific fibroblast subsets enriched in aged hearts express genes associated with anti-angiogenesis and inflammation, contributing to vascular dysfunction via paracrine SASP factors like IL-6 and Serpine2. Moreover, progenitor cell populations exhibit diminished regenerative capacity with age, exacerbating fibrosis through chemokine and TGF-β pathways, thereby defining molecular targets for rejuvenating cardiac repair.
At the genomic level, single-cell whole-genome sequencing (scWGS) exposes the accumulation of somatic mutations as a hallmark of cardiac aging. Elderly cardiomyocytes harbor a significantly higher burden of single-nucleotide variants than neonatal counterparts, underpinning the genetic fragility acquired during aging. These insights underscore the multifactorial nature of cardiac senescence encompassing transcriptomic, epigenetic, and genomic alterations, necessitating integrated therapeutic paradigms.
Complementary to cellular analyses, plasma proteomics offers a systemic window into biological aging. Dynamic shifts in plasma protein compositions reveal critical inflection points in human aging, with biomarkers such as GDF15 and IGFBP4 implicated in key regulatory networks. By charting these systemic signatures, proteomic profiling enhances early diagnostic capabilities and sculpting personalized treatment strategies targeting the senescence axis.
As we stand on the cusp of a new dawn in aging and cardiovascular medicine, the intersection of molecular biology, immunotherapy, genomics, and bioinformatics heralds transformative possibilities. The precise dissection of senescent cell heterogeneity has unveiled actionable targets and unveiled the plasticity of aging tissues. While challenges remain—from defining universal senescence markers to ensuring clinical safety—the momentum is undeniable. Harnessing these insights could enable interventions that not only extend lifespan but importantly, healthspan, mitigating the burden of cardiovascular disease and enhancing quality of life across the aging population.
The journey from bench to bedside for anti-senescence therapies promises to redefine therapeutic landscapes and rejuvenate aging hearts. Future research integrating single-cell profiling, molecular targeting, and immune modulation will accelerate the design of precision therapies tailored to individual senescent cell profiles and disease phenotypes. This holistic approach may finally unlock the elusive fountain of youth at the cellular level, charting a course toward durable cardiovascular health in an aging world.
Subject of Research: Cellular senescence and its role and targeting in cardiovascular disease and aging
Article Title: The role of cellular senescence in cardiovascular disease
Article References: Xu, C., Qiu, Z., Guo, Q. et al. The role of cellular senescence in cardiovascular disease. Cell Death Discov. 11, 431 (2025). https://doi.org/10.1038/s41420-025-02720-5
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02720-5
Keywords: Cellular senescence, cardiovascular disease, senolytics, sirtuins, senescence-associated secretory phenotype, single-cell RNA sequencing, BRD4, immunotherapy, cardiac aging, homocysteine, folic acid, serine biosynthesis
Tags: anti-aging interventions in cardiovascular healthcellular senescence and heart diseasechronic disease pathogenesis and senescencedasatinib and quercetin combination therapyimpact of cellular senescence on tissue regenerationinflammatory signaling in aging cellsrejuvenation of aging tissuesrole of senescent cells in agingsenescence-associated secretory phenotypesenolytics and agingtargeted elimination of senescent cellstherapeutic strategies for cardiovascular disease
