Cellular senescence: a key therapeutic target in aging and diseases

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(15)

Published: July 31, 2022

Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary disrupts tissue homeostasis, resulting loss repair regeneration. The use transgenic mouse models which SnCs be genetically ablated has established key role for driving age-related disease. Importantly, senotherapeutics have been developed pharmacologically eliminate SnCs, termed senolytics, or suppress SASP other markers senescence, senomorphics. Based on extensive preclinical studies as well small clinical trials demonstrating benefits senotherapeutics, multiple are under way. This Review discusses diseases, strategies target approaches discover advances senolytics.

Language: Английский

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Identification and characterization of Cardiac Glycosides as senolytic compounds

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 21, 2019

Abstract Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence aging and offer therapeutic interventions. Here we report identification Cardiac Glycosides (CGs) as a family compounds senolytic activity. CGs, by targeting Na+/K+ATPase pump, cause disbalanced electrochemical gradient within cell causing depolarization acidification. Senescent cells present slightly depolarized plasma membrane higher concentrations H+, making them more susceptible to action CGs. These vulnerabilities can be exploited for purposes evidenced vivo eradication tumors xenografted mice after treatment combination senogenic drug. The effect CGs is also effective elimination senescence-induced lung fibrosis. This experimental approach allows that could potentially used develop treatments against age-related diseases.

Language: Английский

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Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction

Aging Cell, Journal Year: 2019, Volume and Issue: 18(3)

Published: March 28, 2019

Abstract Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging associated with an increased prevalence coronary artery and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate tissues, including heart, contribute to age‐related pathologies. However, role senescence recovery MI has not been investigated. In this study, we demonstrate that treatment aged mice senolytic drug, navitoclax, eliminates cardiomyocytes attenuates profibrotic protein expression mice. Importantly, clearance improved remodelling diastolic function as well overall survival MI. These data provide proof‐of‐concept evidence are major contributors impaired mortality senolytics potential new therapeutic avenue for

Language: Английский

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Immune Cells and Immunotherapy for Cardiac Injury and Repair

Circulation Research, Journal Year: 2021, Volume and Issue: 128(11), P. 1766 - 1779

Published: May 27, 2021

Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, full understanding why the heart fails to fully recover function after acute injury, progressive failure frequently ensues, elusive. No therapeutics, short transplantation, have emerged reliably halt or reverse inexorable progression in majority patients once it has become clinically evident. To date, most pharmacological interventions focused on modifying hemodynamics (reducing afterload, controlling blood pressure volume) cardiac myocyte function. However, important contributions immune system normal response recently as exciting areas investigation. Therapeutic aimed at harnessing power cells hold promise for new treatment avenues disease. Here, we review its contribution fibrosis, potential therapies affect repair.

Language: Английский

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Macrophage Related Chronic Inflammation in Non-Healing Wounds

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: June 16, 2021

Persistent hyper-inflammation is a distinguishing pathophysiological characteristic of chronic wounds, and macrophage malfunction considered as major contributor thereof. In this review, we describe the origin heterogeneity macrophages during wound healing, compare function in healing non-healing wounds. We consider extrinsic intrinsic factors driving dysregulation, review systemic topical therapeutic approaches for restoration response. Multidimensional analysis highlighted through integration various high-throughput technologies, used to assess diversity activation states well cellular communication wound. This research fills gaps current literature provides promising interventions

Language: Английский

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Cellular Senescence in Cardiovascular Diseases: A Systematic Review

Aging and Disease, Journal Year: 2022, Volume and Issue: 13(1), P. 103 - 103

Published: Jan. 1, 2022

Aging is a prominent risk factor for cardiovascular diseases, which the leading cause of death around world. Recently, cellular senescence has received potential attention as promising target in preventing including acute myocardial infarction, atherosclerosis, cardiac aging, pressure overload-induced hypertrophy, heart regeneration, hypertension, and abdominal aortic aneurysm. Here, we discuss mechanisms underlying describe involvement senescent cells (including cardiomyocytes, endothelial cells, vascular smooth muscle fibroblasts/myofibroblasts T cells) age-related diseases. Then, highlight targets (SIRT1 mTOR) that regulating disorders. Furthermore, review evidence can exert both beneficial detrimental implications diseases on context-dependent manner. Finally, summarize emerging pro-senescent or anti-senescent interventions their therapeutic

Language: Английский

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Role of cellular senescence in inflammation and regeneration

Inflammation and Regeneration, Journal Year: 2024, Volume and Issue: 44(1)

Published: June 3, 2024

Abstract Cellular senescence is the state in which cells undergo irreversible cell cycle arrest and acquire diverse phenotypes. It has been linked to chronic inflammation fibrosis various organs as well individual aging. Therefore, eliminating senescent emerged a potential target for extending healthy lifespans. plays beneficial role many biological processes, including embryonic development, wound healing, tissue regeneration, mediated by activation of stem cells. comprehensive understanding cellular senescence, both its detrimental effects, critical developing safe effective treatment strategies This review provides an overview pathological roles with particular focus on or functions among roles.

Language: Английский

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Focus on senescence: Clinical significance and practical applications

Journal of Internal Medicine, Journal Year: 2024, Volume and Issue: 295(5), P. 599 - 619

Published: March 6, 2024

Abstract The older population is increasing worldwide, and life expectancy continuously rising, predominantly thanks to medical technological progress. Healthspan refers the number of years an individual can live in good health. From a gerontological viewpoint, mission extend spent health, promoting well‐being minimizing impact aging‐related diseases slow aging process. Biologically, malleable process characterized by intra‐ inter‐individual heterogeneous dynamic balance between accumulating damage repair mechanisms. Cellular senescence key component this process, with senescent cells different tissues organs, leading age‐related disease susceptibility over time. Removing from body or slowing down burden rate has been proposed as efficient way reduce age‐dependent deterioration. In animal models, senotherapeutic molecules lifespan either senolytic senomorphic activity. Much research shows that dietary physical activity‐driven lifestyle interventions protect against senescence. This narrative review aims summarize current knowledge on targeting risk models their translational potential for humans. We focused studies have examined role senotherapeutics modifying burdens. concludes general discussion mechanisms underlying unique trajectory its implications future research.

Language: Английский

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Senescence and senolytics in cardiovascular disease: Promise and potential pitfalls

Mechanisms of Ageing and Development, Journal Year: 2021, Volume and Issue: 198, P. 111540 - 111540

Published: July 6, 2021

Ageing is the biggest risk factor for impaired cardiovascular health, with disease being cause of death in 40 % individuals over 65 years old. associated an increased prevalence atherosclerosis, coronary artery stenosis and subsequent myocardial infarction, thoracic aortic aneurysm, valvular heart failure. An accumulation senescence inflammation, caused by senescence-associated secretory phenotype, have been implicated aetiology progression these age-associated diseases. Recently it has demonstrated that compounds targeting components anti-apoptotic pathways expressed senescent cells can preferentially induce to apoptosis termed senolytics. In this review, we discuss evidence demonstrating contributes disease, a particular focus on studies indicate promise senotherapy. Based data suggest novel indications senolytics as treatment diseases which yet be studied context Finally, while potential benefits are encouraging, several complications may result from senolytic treatment. We, therefore, consider challenges system.

Language: Английский

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The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: May 31, 2022

Abstract Background The global population of older individuals is growing, and ageing a key risk factor for atherosclerotic cardiovascular diseases. Abnormal accumulation senescent cells can cause potentially deleterious effects on the organism with age. As vital marker cellular senescence, senescence-associated secretory phenotype (SASP) novel mechanism to link senescence atherosclerosis. Main body In this review, we concretely describe characteristics SASP its regulation mechanisms. Importantly, provide perspectives how promote from different types have roles in atherosclerosis progression. significant mediator harmful cells, it play pro-atherogenic role by producing inflammation immune dysfunction. Furthermore, deliver signals surrounding vascular gradually contributing development Finally, focus variety therapeutic strategies aimed reduce burden elderly targeting inhibiting regulatory mechanisms SASP. Conclusion This review systematically summarizes multiple contribute exploration new opportunities.

Language: Английский

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