Senolytic and senomorphic agent procyanidin C1 alleviates structural and functional decline in the aged retina.

Increased cellular senescence burden contributes in part to age-related organ dysfunction and pathologies. In our study, using mouse models of natural aging, we observed structural and functional decline in the aged retina, which was accompanied by the accumulation of senescent cells and senescence-associated secretory phenotype factors. We further validated the senolytic and senomorphic properties of procyanidin C1 (PCC1) both in vitro and in vivo, the long-term treatment of which ameliorated age-related retinal impairment. Through high-throughput single-cell RNA sequencing (scRNA-seq), we comprehensively characterized the retinal landscape after PCC1 administration and deciphered the molecular basis underlying the senescence burden increment and elimination. By exploring the scRNA-seq database of age-related retinal disorders, we revealed the role of cellular senescence and the therapeutic potential of PCC1 in these pathologies. Overall, these results indicate the therapeutic effects of PCC1 on the aged retina and its potential use for treating age-related retinal disorders.

Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy.

Cancer is daunting pathology with remarkable breadth and scope, spanning genetics, epigenetics, proteomics, metalobomics and cell biology. Cellular senescence represents a stress-induced and essentially irreversible cell fate associated with aging and various age-related diseases, including malignancies. Senescent cells are characterized of morphologic alterations and metabolic reprogramming, and develop a highly active secretome termed as the senescence-associated secretory phenotype (SASP). Since the first discovery, senescence has been understood as an important barrier to tumor progression, as its induction in pre-neoplastic cells limits carcinogenesis. Paradoxically, senescent cells arising in the tumor microenvironment (TME) contribute to tumor progression, including augmented therapeutic resistance. In this article, we define typical forms of senescent cells commonly observed within the TME and how senescent cells functionally remodel their surrounding niche, affect immune responses and promote cancer evolution. Furthermore, we highlight the recently emerging pipelines of senotherapies particularly senolytics, which can selectively deplete senescent cells from affected organs in vivo and impede tumor progression by restoring therapeutic responses and securing anticancer efficacies. Together, co-targeting cancer cells and their normal but senescent counterparts in the TME holds the potential to achieve increased therapeutic benefits and restrained disease relapse in future clinical oncology.

Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs.

BACKGROUND & AIMS: Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. METHODS: A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. RESULTS: The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. CONCLUSIONS: Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.

Chemical Strategies for the Detection and Elimination of Senescent Cells.

Cellular senescence can be defined as an irreversible stopping of cell proliferation that arises in response to various stress signals. Cellular senescence is involved in diverse physiological and pathological processes in different tissues, exerting effects on processes as differentiated as embryogenesis, tissue repair and remodeling, cancer, aging, and tissue fibrosis. In addition, the development of some pathologies, aging, cancer, and other age-related diseases has been related to senescent cell accumulation. Due to the complexity of the senescence phenotype, targeting senescent cells is not trivial, is challenging, and is especially relevant for in vivo detection in age-related diseases and tissue samples. Despite the elimination of senescent cells (senolysis) using specific drugs (senolytics) that have been shown to be effective in numerous preclinical disease models, the clinical translation is still limited due to the off-target effects of current senolytics and associated toxicities. Therefore, the development of new chemical strategies aimed at detecting and eliminating senescent cells for the prevention and selective treatment of senescence-associated diseases is of great interest. Such strategies not only will contribute to a deeper understanding of this rapidly evolving field but also will delineate and inspire new possibilities for future research.In this Account, we report our recent research in the development of new chemical approaches for the detection and elimination of senescent cells based on new probes, nanoparticles, and prodrugs. The designed systems take advantage of the over-representation in senescent cells of certain biomarkers such as ß-galactosidase and lipofuscin. One- and two-photon probes, for higher tissue penetration, have been developed. Moreover, we also present a renal clearable fluorogenic probe for the in vivo detection of the ß-galactosidase activity, allowing for correlation with the senescent burden in living animals. Moreover, as an alternative to molecular-based probes, we also developed nanoparticles for senescence detection. Besides, we describe advances in new therapeutic agents to selectively eradicate senescent cells using ß-galactosidase activity-sensitive gated nanoparticles loaded with cytotoxic or senolytic agents or new prodrugs aiming to increase the selectivity and reduction of off-target toxicities of current drugs. Moreover, new advances therapies have been applied in vitro and in vivo. Studies with the probes, nanoparticles, and prodrugs have been applied in several in vitro and in vivo models of cancer, fibrosis, aging, and drug-induced cardiotoxicity in which senescence plays an important role. We discuss the benefits of these chemical strategies toward the development of more specific and sophisticated probes, nanoparticles, and prodrugs targeting senescent cells.

Cellular senescence of granulosa cells in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated ß-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.

Application potential of senolytics in clinical treatment.

Of the factors studied in individual ageing, the accumulation of senescent cells has been considered as an essential cause of organ degeneration to eventually initiate age-related diseases. Cellular senescence is attributed to the accumulation of damage for an inducement in the activation of cell cycle inhibitory pathways, resulting the cell permanently withdraw from the cell proliferation cycle. Further, senescent cells will activate the inflammatory factor secretion pathway to promote the development of various age-related diseases. Senolytics, a small molecule compound, can delay disease development and extend mammalian lifespan. The evidence from multiple trials shows that the targeted killing of senescent cells has a significant clinical application for the treatment of age-related diseases. In addition, senolytics are also significant for the development of ageing research in solid organ transplantation, which can fully develop the potential of elderly organs and reduce the age gap between demand and supply. We conclude that the main characteristics of cellular senescence, the anti-ageing drug senolytics in the treatment of chronic diseases and organ transplantation, and the latest clinical progress of related researches in order to provide a theoretical basis for the prevention and treatment of ageing and related diseases.

Therapeutic Potential of Senolytics in Cardiovascular Disease.

Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the leading cause of death in 40% of individuals over 65 years old. Ageing is associated with both an increased prevalence of cardiovascular disease including heart failure, coronary artery disease, and myocardial infarction. Furthermore, ageing is associated with a poorer prognosis to these diseases. Genetic models allowing the elimination of senescent cells revealed that an accumulation of senescence contributes to the pathophysiology of cardiovascular ageing and promotes the progression of cardiovascular disease through the expression of a proinflammatory and profibrotic senescence-associated secretory phenotype. These studies have resulted in an effort to identify pharmacological therapeutics that enable the specific elimination of senescent cells through apoptosis induction. These senescent cell apoptosis-inducing compounds are termed senolytics and their potential to ameliorate age-associated cardiovascular disease is the focus of this review.

Potential Use of Senolytics for Pharmacological Targeting of Precancerous Lesions.

Senescence is a cell state that contributes to several homeostatic and pathologic processes. In addition to being induced in somatic cells in response to replicative exhaustion (replicative senescence) as part of organismal aging, senescence can also be triggered prematurely by oncogene hyperactivation or tumor suppressor dysfunction [oncogene-induced senescence (OIS)]. Consequently, senescent cells comprise a major component of precancerous lesions of skin, oral mucosa, nasopharynx, prostate, gut, and lung. Unfortunately, invasive (or minimally invasive) interventions are currently the only available approach employed to eradicate premalignant lesions that carry the potential for cancer progression. Senolytics are a newly emerging drug class capable of selectively eliminating senescent cells. Although senolytics have been successfully demonstrated to mitigate a myriad of aging-related pathologies and to cull senescent cancer cells, there is a paucity of evidence for the potential use of senolytics as a novel approach to eliminate oncogene-induced senescent cells. This Emerging Concepts commentary will 1) summarize evidence in established models of OIS including B-Raf-induced nevi, transgenic lung cancer, and pancreatic adenocarcinoma models, as well as evidence from clinical precancerous lesions; 2) suggest that OIS is targetable; and 3) propose the utilization of senolytic agents as a revolutionary means to interfere with the ability of senescent premalignant cells to progress to cancer in vitro and in vivo If proven to be effective, senolytics will represent an emerging tool to pharmacologically treat precancerous lesions. SIGNIFICANCE STATEMENT: The treatment of premalignant lesions is largely based on the utilization of invasive (or minimally invasive) measures. Oncogene-induced senescence (OIS) is one form of senescence that occurs in response to oncogene overexpression in somatic cells and is present in precancerous lesions. Although the contribution of OIS to disease progression is undetermined, recent evidence suggests that senescent cells are permissive for malignant transformation. Accordingly, the pharmacological targeting of oncogene-induced senescent cells could potentially provide a novel, less invasive, means for the treatment of premalignant disease.

Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis.

OBJECTIVE: Intervertebral disc degeneration (IDD) represents major cause of low back pain. Quercetin (QUE) is one of the approved senolytic agents. In this study, we evaluated the protective effects of QUE on IDD development and its underlying mechanism. METHODS: Effects of senolytic agent QUE on the viability of nucleus pulposus cells (NPCs) were measured by CCK-8 assays and EdU staining. The senescence associated secreted phenotype (SASP) factors expressions were measured by qPCR, western blot, and ELISA; and NF-κB pathway was detected by immunofluorescence and western blot. Molecular docking was applied to predict the interacting protein of QUE; while Nrf2 was knocked down by siRNAs to confirm its role in QUE regulated senescence phenotype. X-ray, MRI, Hematoxylin-Eosin and Safranin O-Fast green staining were performed to evaluate the therapeutic effects of QUE on IDD in the puncture-induced rat model. RESULTS: In in vitro experiments, QUE inhibited SASP factors expression and senescence phenotype in IL-1ß-treated NPCs. Mechanistically, QUE suppressed IL-1ß induced activation of the NF-κB pathway cascades; it was also demonstrated in molecular docking and knock down studies that QUE might bind to Keap1-Nrf2 complex to suppress NF-κB pathway. In vivo, QUE ameliorated the IDD process in the puncture-induced rat model. CONCLUSIONS: Together the present work suggests that QUE inhibits SASP factors expression and senescence phenotype in NPCs and ameliorates the progression of IDD via the Nrf2/NF-κB axis, which supports senolytic agent QUE as a potential therapeutic agent for the treatment of IDD.

Senolytics: A Novel Strategy for Neuroprotection in ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.

Senolytic Therapy for Cerebral Ischemia-Reperfusion Injury.

Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.

Biomolecular Evaluation of Piceatannol's Effects in Counteracting the Senescence of Mesenchymal Stromal Cells: A New Candidate for Senotherapeutics?

Several investigations on senescence and its causative role in aging have underscored the importance of developing senotherapeutics, a field focused on killing senescent cells and/or preventing their accumulation within tissues. Using polyphenols in counteracting senescence may facilitate the development of senotherapeutics given their presence in the human diet, their confirmed tolerability and absence of severe side effects, and their role in preventing senescence and inducing the death of senescent cells. Against that background, we evaluated the effect of piceatannol, a natural polyphenol, on the senescence of mesenchymal stromal cells (MSCs), which play a key role in the body's homeostasis. Among our results, piceatannol reduced the number of senescent cells both after genotoxic stress that induced acute senescence and in senescent replicative cultures. Such senotherapeutics activity, moreover, promoted the recovery of cell proliferation and the stemness properties of MSCs. Altogether, our findings demonstrate piceatannol's effectiveness in counteracting senescence by targeting its associated pathways and detecting and affecting P53-dependent and P53-independent senescence. Our study thus suggests that, given piceatannol's various mechanisms to accomplish its pleiotropic activities, it may be able to counteract any senescent phenotypes.

Effects and Related Mechanisms of the Senolytic Agent ABT-263 on the Survival of Irradiated A549 and Ca9-22 Cancer Cells.

Senolytic agents eliminate senescent cells and are expected to reduce senescent cell-mediated adverse effects in cancer therapy. However, the effects of senolytic agents on the survival of irradiated cancer cells remain unknown. Here, the effects of the senolytic agent ABT-263 on the survival of irradiated A549 and Ca9-22 cancer cells were investigated. ABT-263 was added to the culture medium after irradiation. SA-ß-gal activity and cell size, which are hallmarks of cell senescence, were evaluated using a flow cytometer. The colony-forming assay and annexin V staining were performed to test cell survival. We first confirmed that radiation increased the proportion of cells with high SA-ß-gal activity and that ABT-263 decreased it. Of note, ABT-263 decreased the survival of irradiated cancer cells and increased the proportion of radiation-induced annexin V+ cells. Furthermore, the caspase inhibitor suppressed the ABT-263-induced decrease in the survival of irradiated cells. Intriguingly, ABT-263 decreased the proportion of SA-ß-gal low-activity/large cells in the irradiated A549 cells, which was recovered by the caspase inhibitor. Together, these findings suggest that populations maintaining the ability to proliferate existed among the irradiated cancer cells showing senescence-related features and that ABT-263 eliminated the population, which led to decreased survival of irradiated cancer cells.

Biochemical and Cellular Characterization of New Radio-Resistant Cell Lines Reveals a Role of Natural Flavonoids to Bypass Senescence.

Cancer is one of the main causes of death worldwide, and, among the most frequent cancer types, osteosarcoma accounts for 56% of bone neoplasms observed in children and colorectal cancer for 10.2% of tumors diagnosed in the adult population. A common and frequent hurdle in cancer treatment is the emergence of resistance to chemo- and radiotherapy whose biological causes are largely unknown. In the present work, human osteosarcoma (SAOS) and colorectal adenocarcinoma (HT29) cell lines were γ-irradiated at doses mimicking the sub-lethal irradiation in clinical settings to obtain two radio-resistant cellular sub-populations named SAOS400 and HT500, respectively. Since "therapy-induced senescence" (TIS) is often associated with tumor response to radiotherapy in cancer cells, we measured specific cellular and biochemical markers of senescence in SAOS400 and HT500 cells. In detail, both cell lines were characterized by a higher level of expression of cyclin-dependent kinase inhibitors p16INK4 and p21CIP1 and increased positivity to SAß-gal (senescence-associated ß-galactosidase) with respect to parental cells. Moreover, the intracellular levels of reactive oxygen species in the resistant cells were significantly lower compared to the parental counterparts. Subsequently, we demonstrated that senolytic agents were able to sensitize SAOS400 and HT500 to cell death induced by γ-irradiation. Employing two natural flavonoids, fisetin and quercetin, and a BH3-mimetic, ABT-263/navitoclax, we observed that their association with γ-irradiation significantly reduced the expression of p16INK4, p21CIP1 and synergistically (combination index < 1) increased cell death compared to radiation mono-alone treatments. The present results reinforce the potential role of senolytics as adjuvant agents in cancer therapy.

In the land of not-unhappiness: On the state-of-the-art of targeting aging and age-related diseases by biomedical research.

The concept of the Land of Not-Unhappiness refers to the potential achievement of eliminating the pathologies of the aging process. To inform of how close we are to settling in the land, we summarize and review the achievements of research on anti-aging interventions over the last hundred years with a specific focus on strategies that slow down metabolism, compensate for aging-related losses, and target a broad range of age-related diseases. We critically evaluate the existing interventions labeled as "anti-aging," such as calorie restriction, exercise, stem cell administration, and senolytics, to provide a down-to-earth evaluation of their current applicability in counteracting aging. Throughout the text, we have maintained a light tone to make it accessible to non-experts in biogerontology, and provide a broad overview for those considering conducting studies, research, or seeking to understand the scientific basis of anti-aging medicine.

Cellular senescence in normal physiology.

Long associated with aging, senescent cells can promote health and have physiological roles.

Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.

Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.

A pipeline for senolytics.

There is intense interest in identifying compounds that selectively kill senescent cells, termed senolytics, for ameliorating age-related comorbidities. However, screening for senolytic compounds currently relies on primary cells or cell lines where senescence is induced in vitro. Given the complexity of senescent cells across tissues and diseases, this approach may not target the senescent cells that develop under specific conditions in vivo. In this issue of the JCI, Lee et al. describe a pipeline for high-throughput drug screening of senolytic compounds where senescence was induced in vivo and identify the HSP90 inhibitor XL888 as a candidate senolytic to treat idiopathic pulmonary fibrosis.

Nanocarriers for natural polyphenol senotherapeutics.

Senescence is a heterogenous and dynamic process in which various cell types undergo cell-cycle arrest due to cellular stressors. While senescence has been implicated in aging and many human pathologies, therapeutic interventions remain inadequate due to the absence of a comprehensive set of biomarkers in a context-dependent manner. Polyphenols have been investigated as senotherapeutics in both preclinical and clinical settings. However, their use is hindered by limited stability, toxicity, modest bioavailability, and often inadequate concentration at target sites. To address these limitations, nanocarriers such as polymer nanoparticles and lipid vesicles can be utilized to enhance the efficacy of senolytic polyphenols. Focusing on widely studied senolytic agents-specifically fisetin, quercetin, and resveratrol-we provide concise summaries of their physical and chemical properties, along with an overview of preclinical and clinical findings. We also highlight common signaling pathways and potential toxicities associated with these agents. Addressing challenges linked to nanocarriers, we present examples of senotherapeutic delivery to various cell types, both with and without nanocarriers. Finally, continued research and development of senolytic agents and nanocarriers are encouraged to reduce the undesirable effects of senescence on different cell types and organs. This review underscores the need for establishing reliable sets of senescence biomarkers that could assist in evaluating the effectiveness of current and future senotherapeutic candidates and nanocarriers.

The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology.

AIMS: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS: AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. CONCLUSION: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.