The senescence-associated secretory phenotype and its physiological and pathological implications

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(12), P. 958 - 978

Published: April 23, 2024

Language: Английский

---

Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(12), P. 2111 - 2130

Published: Dec. 14, 2023

Abstract Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading fatal diseases. Senescent cells are main driver fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report cellular senescence, multiple types in mice humans characterized by the accumulation iron. We show vascular hemolytic injuries efficient triggering iron accumulation, which turn cause senescence promote fibrosis. Notably, find senescent persistently accumulate iron, even when surge extracellular has subdued. Indeed, under conditions exposed different senescence-inducing insults abundant ferritin-bound mostly within lysosomes, present high levels labile fuels generation reactive oxygen species SASP. Finally, demonstrate detection magnetic resonance imaging might allow non-invasive assessment burden kidneys patients with renal Our findings suggest plays central role fibrosis, initiating events may be independent identify metabolism potential therapeutic target for

Language: Английский

---

New Dawn for Atherosclerosis: Vascular Endothelial Cell Senescence and Death

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(20), P. 15160 - 15160

Published: Oct. 13, 2023

Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals metabolites in circulatory system. The senescence death ECs not only adverse outcomes, but also causal contributors endothelial dysfunction, an early risk marker atherosclerosis. pathophysiological process EC involves both structural functional changes has been linked various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, aberrant metabolite sensing signaling. Multiple forms have documented atherosclerosis, autophagic death, apoptosis, pyroptosis, NETosis, necroptosis, ferroptosis. Despite this, molecular mechanisms underlying or atherogenesis fully understood. To provide a comprehensive update on subject, this review examines historic latest findings alterations associated with different stages

Language: Английский

---

Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 794 - 794

Published: Jan. 8, 2024

Heart failure (HF) with preserved ejection fraction (HFpEF) is an increasingly frequent form and estimated to be the dominant of HF. On other hand, HFpEF a syndrome systemic involvement, it characterized by multiple cardiac extracardiac pathophysiological alterations. The increasing prevalence currently reaching epidemic levels, thereby making one greatest challenges facing cardiovascular medicine today. Compared HF reduced (HFrEF), medical attitude in case was relaxed towards disease, despite fact that much more complex, many problems related identification physiopathogenetic mechanisms optimal methods treatment. current challenge develop effective therapeutic strategies, because patients suffering from have symptoms quality life comparable those fraction, but specific medication for HFrEF ineffective this situation; this, we must first understand pathological detail correlate them clinical presentation. Another important aspect diversity can identified under umbrella syndrome. Thus, before being able test therapies, succeed grouping into several categories, called phenotypes, depending on pathways features. This narrative review critiques issues definition, etiology, features, pathophysiology HFpEF. We tried describe as possible biological phenotypes recognized literature order better approach reason limited effectiveness. also highlighted targeted latest research field.

Language: Английский

---

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

---

The Multifaceted Role of Endothelial Sirt1 in Vascular Aging: An Update

Cells, Journal Year: 2024, Volume and Issue: 13(17), P. 1469 - 1469

Published: Sept. 1, 2024

NAD+-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known be longevity regulators, and exerts a key role in prevention of vascular aging. By aging, expression levels Sirt1 decline with severe impact on function, such as rise endothelial dysfunction, which turn promotes development cardiovascular diseases. In this context, activity preventing senescence is particularly important. Given counteracting senescence, great efforts have been made deepen knowledge about intricate cross-talks interactions other molecules, order set up possible strategies boost prevent or treat The aim review provide proper background regulation function endothelium discuss recent advances regarding therapeutic targeting counteract

Language: Английский

---

Connecting epigenetics and inflammation in vascular senescence: state of the art, biomarkers and senotherapeutics

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 26, 2024

Vascular diseases pose major health challenges, and understanding their underlying molecular mechanisms is essential to advance therapeutic interventions. Cellular senescence, a hallmark of aging, cellular state characterized by cell-cycle arrest, senescence-associated secretory phenotype macromolecular damage, metabolic dysregulation. senescence has been demonstrated play key role in different vascular diseases, such as atherosclerosis, peripheral arterial disease, hypertension, stroke, diabetes, chronic venous ulcers. Even though was first described 1961, significant gaps persist comprehending the epigenetic driving its subsequent inflammatory response. Through comprehensive analysis, we aim elucidate these knowledge exploring network alterations that contribute senescence. In addition, describe consequent cascades triggered modifications. Finally, explore translational applications involving biomarkers emerging field senotherapy targeting this biological process.

Language: Английский

---

Senescent cells as a target for anti-aging interventions: From senolytics to immune therapies

Journal of Translational Internal Medicine, Journal Year: 2025, Volume and Issue: 13(1), P. 33 - 47

Published: Feb. 1, 2025

Aging and age-related diseases are major drivers of multimorbidity mortality worldwide. Cellular senescence is a hallmark aging. The accumulation senescent cells causally associated with pathogenesis various age-associated disorders. Due to their promise for alleviating disorders extending healthspan, therapeutic strategies targeting (senotherapies) as means combat aging have received much attention over the past decade. Among conventionally used approaches, one usage small-molecule compounds specifically exhibit cytotoxicity toward or inhibit deleterious effects senescence-associated secretory phenotype (SASP). Alternatively, there immunotherapies directed at surface antigens upregulated in (seno-antigens), including chimeric antigen receptor (CAR) therapies senolytic vaccines. This review gives an update current status discovery development therapies, translational progress from preclinical clinical trials. We highlight challenges faced by senotherapeutic context heterogeneity, aim offering novel perspectives future anti-aging interventions aimed enhancing healthy longevity.

Language: Английский

---

The contribution of endothelial cells to tissue fibrosis

Current Opinion in Rheumatology, Journal Year: 2023, Volume and Issue: 36(1), P. 52 - 60

Published: Aug. 10, 2023

Purpose of review Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity mortality rates. Growing evidence indicates that common cellular molecular mechanisms may drive diverse cause affecting different organs. The scope this to highlight recent findings in support for important role vascular endothelial cells the pathogenesis fibrosis, a special focus systemic sclerosis as prototypic multisystem fibrotic disorder. Recent Although transition fibroblasts chronically activated myofibroblasts widely considered central profibrotic switch, cell involvement development progression has been recognized over last few years. Endothelial can contribute process either directly by acting source through endothelial-to-myofibroblast (EndMT) concomitant microvascular rarefaction, or indirectly becoming senescent and/or secreting variety proinflammatory mediators consequent fibroblast activation recruitment inflammatory/immune further promote fibrosis. Summary An in-depth understanding underlying EndMT acquisition secretory phenotype will provide rationale novel reprogramming-based therapeutic approaches prevent treat

Language: Английский

---

Potential Clinical Implications of Senotherapies for Cardiovascular Disease

Circulation Journal, Journal Year: 2023, Volume and Issue: 88(3), P. 277 - 284

Published: Oct. 25, 2023

Aging is a major risk factor for cardiovascular diseases (CVDs) and accumulating evidence indicates that biological aging has significant effect on the onset progression of CVDs. In recent years, therapies targeting senescent cells (senotherapies), particularly senolytics selectively eliminate cells, have been developed show promise treating geriatric syndromes age-associated diseases, including 2 pilot studies published in 2019 senolytic combination, dasatinib plus quercetin, improved physical function patients with idiopathic pulmonary fibrosis eliminated from adipose tissue diabetic kidney disease. More than 30 clinical trials using are currently underway or planned. preclinical CVD models, appear to improve heart failure, ischemic disease, valvular atherosclerosis, aortic aneurysm, vascular dysfunction, dialysis arteriovenous fistula patency, pre-eclampsia. Because senotherapies completely different strategies existing treatment paradigms, they might alleviate which there no current effective treatments could be used addition enhance efficacy. Moreover, delay, prevent, treat multiple elderly reduce polypharmacy, because target fundamental mechanisms. We comprehensively summarize about CVDs discuss future prospects their application.

Language: Английский

---