The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice.

Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.

Blunting senescence boosts liver regeneration.

The mammalian liver possesses a unique capacity for regeneration. However, this regenerative potential declines with age due to unknown mechanisms. In this issue of Genes & Development, Ritschka and colleagues (pp. 489-494). compare liver regeneration upon partial hepatectomy in young and adult mice. Partial hepatectomy causes a transient increase in p21 in a subpopulation of hepatocytes that persists in adult mice. Remarkably, treatment with the BCL-2 family inhibitor ABT-737 blunts p21 expression, enhancing liver regeneration.

Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis.

BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are the key drivers of fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. HSCs are heterogenous, and a senescent subset of HSCs is implicated in hepatic fibrosis and HCC. Administration of anti-uPAR (urokinase-type plasminogen activator receptor) CAR T cells has been shown to deplete senescent HSCs and attenuate fibrosis in murine models. However, the comprehensive features of senescent HSCs in MASH, as well as their cellular ontogeny have not been characterized; hence, we aimed to comprehensively characterize and define the origin of HSCs in human and murine MASH. METHODS: To comprehensively characterize the phenotype and ontogeny of senescent HSCs in human and murine MASH, we integrated senescence-associated beta galactosidase activity with immunostaining, flow cytometry and single-nucleus RNA sequencing (snRNAseq). We integrated the immunohistochemical profile with a senescence score applied to snRNAseq data to characterize senescent HSCs and mapped the evolution of uPAR expression in MASH. RESULTS: Using pseudotime trajectory analysis, we establish that senescent HSCs arise from activated HSCs. While uPAR is expressed in MASH, the magnitude and cell-specificity of its expression evolve with disease stage. In early disease, uPAR is more specific to activated and senescent HSCs, while it is also expressed by myeloid-lineage cells, including Trem2+ macrophages and myeloid-derived suppressor cells, in late disease. Furthermore, we identify novel surface proteins expressed on senescent HSCs in human and murine MASH that could be exploited as therapeutic targets. CONCLUSIONS: These data define features of HSC senescence in human and murine MASH, establishing an important blueprint to target these cells as part of future antifibrotic therapies. IMPACT AND IMPLICATIONS: Hepatic stellate cells (HSCs) are the primary drivers of scarring in chronic liver diseases. As injury develops, a subset of HSCs become senescent; these cells are non-proliferative and pro-inflammatory, thereby contributing to worsening liver injury. Here we show that senescent HSCs are expanded in MASH (metabolic dysfunction-associated steatohepatitis) in humans and mice, and we trace their cellular origin from the activated HSC subset. We further characterize expression of uPAR (urokinase plasminogen activated receptor), a protein that marks senescent HSCs, and report that uPAR is also expressed by activated HSCs in early injury, and in immune cells as liver injury advances. We have integrated high-resolution single-nucleus RNA sequencing with immunostaining and flow cytometry to identify five other novel proteins expressed by senescent HSCs, including mannose receptor CD206, which will facilitate future therapeutic development.

Cellular senescence in acute kidney injury: Target and opportunity.

Acute kidney injury (AKI) is a common clinical disease with a high incidence and mortality rate. It typically arises from hemodynamic alterations, sepsis, contrast agents, and toxic drugs, instigating a series of events that culminate in tissue and renal damage. This sequence of processes often leads to acute renal impairment, prompting the initiation of a repair response. Cellular senescence is an irreversible arrest of the cell cycle. Studies have shown that renal cellular senescence is closely associated with AKI through several mechanisms, including the promotion of oxidative stress and inflammatory response, telomere shortening, and the down-regulation of klotho expression. Exploring the role of cellular senescence in AKI provides innovative therapeutic ideas for both the prevention and treatment of AKI. Furthermore, it has been observed that targeted removal of senescent cells in vivo can efficiently postpone senescence, resulting in an enhanced prognosis for diseases associated with senescence. This article explores the effects of common anti-senescence drugs senolytics and senostatic and lifestyle interventions on renal diseases, and mentions the rapid development of mesenchymal stem cells (MSCs). These studies have taken senescence-related research to a new level. Overall, this article comprehensively summarizes the studies on cellular senescence in AKI, aiming is to elucidate the relationship between cellular senescence and AKI, and explore treatment strategies to improve the prognosis of AKI.

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.

Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

Role of astrocyte senescence regulated by the non- canonical autophagy in the neuroinflammation associated to cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is a fatal neuroinflammatory syndrome caused (in humans) by the protozoa Plasmodium (P.) falciparum. Glial cell activation is one of the mechanisms that contributes to neuroinflammation in CM. RESULT: By studying a mouse model of CM (caused by P. berghei ANKA), we describe that the induction of autophagy promoted p21-dependent senescence in astrocytes and that CXCL-10 was part of the senescence-associated secretory phenotype. Furthermore, p21 expression was observed in post-mortem brain and peripheral blood samples from patients with CM. Lastly, we found that the depletion of senescent astrocytes with senolytic drugs abrogated inflammation and protected mice from CM. CONCLUSION: Our data provide evidence for a novel mechanism through which astrocytes could be involved in the neuropathophysiology of CM. p21 gene expression in blood cell and an elevated plasma CXCL-10 concentration could be valuable biomarkers of CM in humans. In the end, we believe senolytic drugs shall open up new avenues to develop newer treatment options.

Molecular mechanisms of aging and anti-aging strategies.

Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.

Targeting therapy-induced senescence as a novel strategy to combat chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting adverse effect of anticancer therapy that complicates the lifestyle of many cancer survivors. There is currently no gold-standard for the assessment or management of CIPN. Subsequently, understanding the underlying mechanisms that lead to the development of CIPN is essential for finding better pharmacological therapy. Therapy-induced senescence (TIS) is a form of senescence that is triggered in malignant and non-malignant cells in response to the exposure to chemotherapy. Recent evidence has also suggested that TIS develops in the dorsal root ganglia of rodent models of CIPN. Interestingly, several components of the senescent phenotype are commensurate with the currently established primary processes implicated in the pathogenesis of CIPN including mitochondrial dysfunction, oxidative stress, and neuroinflammation. In this article, we review the literature that supports the hypothesis that TIS could serve as a holistic mechanism leading to CIPN, and we propose the potential for investigating senotherapeutics as means to mitigate CIPN in cancer survivors.

Heart Disease and Ageing: The Roles of Senescence, Mitochondria, and Telomerase in Cardiovascular Disease.

During ageing molecular damage leads to the accumulation of several hallmarks of ageing including mitochondrial dysfunction, cellular senescence, genetic instability and chronic inflammation, which contribute to the development and progression of ageing-associated diseases including cardiovascular disease. Consequently, understanding how these hallmarks of biological ageing interact with the cardiovascular system and each other is fundamental to the pursuit of improving cardiovascular health globally. This review provides an overview of our current understanding of how candidate hallmarks contribute to cardiovascular diseases such as atherosclerosis, coronary artery disease and subsequent myocardial infarction, and age-related heart failure. Further, we consider the evidence that, even in the absence of chronological age, acute cellular stress leading to accelerated biological ageing expedites cardiovascular dysfunction and impacts on cardiovascular health. Finally, we consider the opportunities that modulating hallmarks of ageing offer for the development of novel cardiovascular therapeutics.

Cellular Senescence and Ageing.

Cellular senescence has become a subject of great interest within the ageing research field over the last 60 years, from the first observation in vitro by Leonard Hayflick and Paul Moorhead in 1961, to novel findings of phenotypic sub-types and senescence-like phenotype in post-mitotic cells. It has essential roles in wound healing, tumour suppression and the very first stages of human development, while causing widespread damage and dysfunction with age leading to a raft of age-related diseases. This chapter discusses these roles and their interlinking pathways, and how the observed accumulation of senescent cells with age has initiated a whole new field of ageing research, covering pathologies in the heart, liver, kidneys, muscles, brain and bone. This chapter will also examine how senescent cell accumulation presents in these different tissues, along with their roles in disease development. Finally, there is much focus on developing treatments for senescent cell accumulation in advanced age as a method of alleviating age-related disease. We will discuss here the various senolytic and senostatic treatment approaches and their successes and limitations, and the innovative new strategies being developed to address the differing effects of cellular senescence in ageing and disease.

Therapeutic Opportunities Presented by Modulation of Cellular Senescence.

Cellular senescence is a permanent state of growth arrest coupled with profound changes in phenotype that can be triggered by multiple extrinsic or intrinsic stimuli. Senescence is a process-level example of the evolution of ageing mechanisms through antagonistic pleiotropy and plays a primary role in tumour suppression, although evidence is mounting for its involvement in other fundamental physiological processes. Evidence from human premature ageing diseases and from transgenic mice in which it is possible to specifically delete senescent cells is consistent with a model in which the accumulation of senescent cells through the life course is responsible for later life chronic disease and impairment. The removal of senescent cells or their reversion to a phenotypically benign state is thus an important emerging goal of translational medicine.Modern bioinformatic approaches based on text mining have compiled co-mentions of cell senescence and age-related diseases allowing an impartial ranking of the impairments most closely associated with this process. Following this schema, the evidence for the involvement of senescence in several highly ranked pathologies is reviewed, alongside potential methods for the ablation of senescent cells or their reversion to their primary phenotype with polyphenolics or inhibitors of p38 MAP kinase. Lastly, the potential for senescence to act as a barrier to the development of bioartificial organs designed to treat some of these conditions is discussed.

Introduction: Progression of the Science of Ageing.

We outline the progression of ageing research from ancient history to present day geroscience. Calorie restriction, genetic mutations, and the involvement of the sirtuins are highlighted, along with pharmaceutical interventions, in particular rapamycin. At the cellular level, replicative senescence and telomere shortening are presented in the history of ageing studies. We discuss the roles of macromolecular damage in ageing including damage to nuclear, and mitochondrial DNA, epigenetic and protein damage. The importance inflammation during ageing "inflammageing" is becoming increasingly recognized. Omics-based biomarkers are now proving to be a promising approach, along with comparative studies on long-lived animals. The science is getting closer to understanding the mechanisms of ageing and developing reliable interventions to improve human health.

Cellular senescence in the pathogenesis of ovarian dysfunction.

The follicular microenvironment is crucial for normal ovarian function, and intra-ovarian factors, in coordination with gonadotropins, contribute to its regulation. Recent research has revealed that the accumulation of senescent cells worsens the adverse environment of various tissues and plays critical roles in chronological aging and various pathological conditions. Cellular senescence involves cell-cycle arrest, a senescence-associated secretory phenotype (SASP), macromolecular damage, and dysmetabolism. In this review, I summarize the latest knowledge regarding the role of cellular senescence in pathological conditions in the ovary, in the context of reproduction. Specifically, cellular senescence is known to impair follicular and oocyte health in cisplatin- and cyclophosphamide-induced primary ovarian insufficiency and to contribute to the pathogenesis of polycystic ovary syndrome (PCOS). In addition, cellular senescence is induced during the decline in ovarian reserve that is associated with chronological aging, endometriosis, psychological stress, and obesity, but it remains unclear whether it plays a causative role in these conditions. Finally, I discuss the potential for use of cellular senescence as a novel therapeutic target. The modification of SASP using a senomorphic and/or the elimination of senescent cells using a senolytic represent promising therapeutic strategies. Further elucidation of the role of cellular senescence in the effects of various insults on ovarian reserve, including chronological aging, as well as in pathogenesis of ovarian pathologies, including PCOS, may facilitate a new era of reproductive medicine.

Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies.

The improvement of human living conditions has led to an increase in average life expectancy, creating a new social and medical problem-aging, which diminishes the overall quality of human life. The aging process of the body begins with the activation of effector signaling pathways of aging in cells, resulting in the loss of their normal functions and deleterious effects on the microenvironment. This, in turn, leads to chronic inflammation and similar transformations in neighboring cells. The cumulative retention of these senescent cells over a prolonged period results in the deterioration of tissues and organs, ultimately leading to a reduced quality of life and an elevated risk of mortality. Among the most promising methods for addressing aging and age-related illnesses are pharmacological, genetic, and cellular therapies. Elevating the activity of aging-suppressing genes, employing specific groups of native and genetically modified cells, and utilizing senolytic medications may offer the potential to delay aging and age-related ailments over the long term. This review explores strategies and advancements in the field of anti-aging therapies currently under investigation, with a particular emphasis on gene therapy involving adeno-associated vectors and cell-based therapeutic approaches.

Senescence in Adipose-Derived Stem Cells: Biological Mechanisms and Therapeutic Challenges.

Adipose tissue-derived stem cells (ADSCs) represent a subset of the mesenchymal stem cells in every adipose compartment throughout the body. ADSCs can differentiate into various cell types, including chondrocytes, osteocytes, myocytes, and adipocytes. Moreover, they exhibit a notable potential to differentiate in vitro into cells from other germinal lineages, including endothelial cells and neurons. ADSCs have a wide range of clinical applications, from breast surgery to chronic wounds. Furthermore, they are a promising cell population for future tissue-engineering uses. Accumulating evidence indicates a decreased proliferation and differentiation potential of ADSCs with an increasing age, increasing body mass index, diabetes mellitus, metabolic syndrome, or exposure to radiotherapy. Therefore, the recent literature thoroughly investigates this cell population's senescence mechanisms and how they can hinder its possible therapeutic applications. This review will discuss the biological mechanisms and the physio-pathological causes behind ADSC senescence and how they can impact cellular functionality. Moreover, we will examine the possible strategies to invert these processes, re-establishing the full regenerative potential of this progenitor population.

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity-A Narrative Review.

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic ß cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid ß-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging.

Targeting tumor cell senescence and polyploidy as potential therapeutic strategies.

Senescence is a unique state of growth arrest that develops in response to a plethora of cellular stresses, including replicative exhaustion, oxidative injury, and genotoxic insults. Senescence has been implicated in the pathogenesis of multiple aging-related pathologies, including cancer. In cancer, senescence plays a dual role, initially acting as a barrier against tumor progression by enforcing a durable growth arrest in premalignant cells, but potentially promoting malignant transformation in neighboring cells through the secretion of pro-tumorigenic drivers. Moreover, senescence is induced in tumor cells upon exposure to a wide variety of conventional and targeted anticancer drugs (termed Therapy-Induced Senescence-TIS), representing a critical contributing factor to therapeutic outcomes. As with replicative or oxidative senescence, TIS manifests as a complex phenotype of macromolecular damage, energetic dysregulation, and altered gene expression. Senescent cells are also frequently polyploid. In vitro studies have suggested that polyploidy may confer upon senescent tumor cells the ability to escape from growth arrest, thereby providing an additional avenue whereby tumor cells escape the lethality of anticancer treatment. Polyploidy in tumor cells is also associated with persistent energy production, chromatin remodeling, self-renewal, stemness and drug resistance - features that are also associated with escape from senescence and conversion to a more malignant phenotype. However, senescent cells are highly heterogenous and can present with variable phenotypes, where polyploidy is one component of a complex reversion process. Lastly, emerging efforts to pharmacologically target polyploid tumor cells might pave the way towards the identification of novel targets for the elimination of senescent tumor cells by the incorporation of senolytic agents into cancer therapeutic strategies.

Drug mechanism enrichment analysis improves prioritization of therapeutics for repurposing.

BACKGROUND: There is a pressing need for improved methods to identify effective therapeutics for diseases. Many computational approaches have been developed to repurpose existing drugs to meet this need. However, these tools often output long lists of candidate drugs that are difficult to interpret, and individual drug candidates may suffer from unknown off-target effects. We reasoned that an approach which aggregates information from multiple drugs that share a common mechanism of action (MOA) would increase on-target signal compared to evaluating drugs on an individual basis. In this study, we present drug mechanism enrichment analysis (DMEA), an adaptation of gene set enrichment analysis (GSEA), which groups drugs with shared MOAs to improve the prioritization of drug repurposing candidates. RESULTS: First, we tested DMEA on simulated data and showed that it can sensitively and robustly identify an enriched drug MOA. Next, we used DMEA on three types of rank-ordered drug lists: (1) perturbagen signatures based on gene expression data, (2) drug sensitivity scores based on high-throughput cancer cell line screening, and (3) molecular classification scores of intrinsic and acquired drug resistance. In each case, DMEA detected the expected MOA as well as other relevant MOAs. Furthermore, the rankings of MOAs generated by DMEA were better than the original single-drug rankings in all tested data sets. Finally, in a drug discovery experiment, we identified potential senescence-inducing and senolytic drug MOAs for primary human mammary epithelial cells and then experimentally validated the senolytic effects of EGFR inhibitors. CONCLUSIONS: DMEA is a versatile bioinformatic tool that can improve the prioritization of candidates for drug repurposing. By grouping drugs with a shared MOA, DMEA increases on-target signal and reduces off-target effects compared to analysis of individual drugs. DMEA is publicly available as both a web application and an R package at https://belindabgarana.github.io/DMEA .

The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice.

BACKGROUND: Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. The present study aimed to determine the therapeutic effect of the second-generation TKI Dasatinib on lipid accumulation and cardiac function in obese, type 2 diabetic mice. We also assessed if the drug impacts extra-cardiac fat tissue depots. METHODS: Two studies on 21-week-old male obese leptin receptor mutant BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Unpaired parametric or non-parametric tests were used to compare two and multiple groups as appropriate. RESULTS: Dasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment. CONCLUSIONS: Our findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function. Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.