Senescence and senotherapeutics: a new field in cancer therapy

Pharmacology & Therapeutics, Journal Year: 2018, Volume and Issue: 193, P. 31 - 49

Published: Aug. 16, 2018

Cellular senescence is a stress response mechanism ensuring homeostasis. Its temporal activation during embryonic development or normal adult life linked with beneficial properties. In contrast, persistent (chronic) seems to exert detrimental effects fostering aging and age-related disorders, such as cancer. Due the lack of reliable marker able detect in vivo, its precise impact diseases large extent still undetermined. A novel reagent termed GL13 (SenTraGorTM) that we developed, allowing recognition any type biological material, emerges powerful tool study phenomenon vivo. Exploiting advantages this methodological approach, scientists will be connect aggressive behavior human malignancies, tolerance chemotherapy classical Hodgkin Lymphoma Langerhans Cell Histiocytosis. The latter depicts importance developing new rapidly expanding field senotherapeutic agents targeting driving cell death senescent cells. We discuss detail current progress exciting area senotherapeutics suggest future perspectives applications.

Language: Английский

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Cyclin G1 and TASCC regulate kidney epithelial cell G ₂ -M arrest and fibrotic maladaptive repair

Science Translational Medicine, Journal Year: 2019, Volume and Issue: 11(476)

Published: Jan. 23, 2019

Cyclin G1 regulates G 2 -M arrest in proximal tubular cells, promoting a TASCC-induced secretory phenotype, fibrosis, and kidney disease progression.

Language: Английский

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Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Aging and Age-Related Diseases.

PubMed, Journal Year: 2019, Volume and Issue: 42(12), P. 821 - 827

Published: Dec. 31, 2019

Aging is the most important single risk factor for many chronic diseases such as cancer, metabolic syndrome, and neurodegenerative disorders. Targeting aging itself might, therefore, be a better strategy than targeting each disease individually enhancing human health. Although much should achieved completely understanding biological basis of aging, cellular senescence now believed to mainly contribute organismal via two independent, yet not mutually exclusive mechanisms: on one hand, stem cells leads exhaustion thus decreases tissue regeneration. On other senescent secrete proinflammatory cytokines, chemokines, growth factors, proteases, collectively termed senescence-associated secretory phenotype (SASP), which causes inflammation dysfunction. Much effort has been recently made therapeutically target detrimental effects including selectively eliminating (senolytics) modulating secretome (senostatics). Here, we discuss current progress limitations in molecular mechanisms senolytics senostatics therapeutic strategies applying them. Furthermore, propose how these novel interventions treatment could improved, based lessons learned from cancer treatment.

Language: Английский

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The bright side of fibroblasts: molecular signature and regenerative cues in major organs

npj Regenerative Medicine, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 10, 2021

Fibrosis is a pathologic process characterized by the replacement of parenchymal tissue large amounts extracellular matrix, which may lead to organ dysfunction and even death. Fibroblasts are classically associated fibrosis repair, seldom regeneration. However, accumulating evidence supports pro-regenerative role fibroblasts in different organs. While some organs rely on for maintaining stem cell niches, others depend fibroblast activity, particularly secreted molecules that promote adhesion, migration, proliferation, guide regenerative process. Herein we provide an up-to-date overview fibroblast-derived signaling across discuss how this capacity become compromised with aging. We further introduce new paradigm therapies based reverting adult fetal/neonatal-like phenotype.

Language: Английский

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Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research

Nutrients, Journal Year: 2020, Volume and Issue: 12(5), P. 1344 - 1344

Published: May 8, 2020

It has been thought that caloric restriction favors longevity and healthy aging where autophagy plays a vital role. However, decreases during can lead to the development of aging-associated diseases such as cancer, diabetes, neurodegeneration, etc. was shown be induced by mechanical or chemical stress. In this regard, various pharmacological compounds were proposed, including natural polyphenols. Apart from ability induce autophagy, polyphenols, resveratrol, are capable modulating expression pro- anti-apoptotic factors, neutralizing free radical species, affecting mitochondrial functions, chelating redox-active transition metal ions, preventing protein aggregation. Moreover, polyphenols have advantages compared inducers due their intrinsic bio-compatibility safety. context, considered potential therapeutic tool for either part diet separate (supplements). This review discusses epigenetic aspect underlying molecular mechanism an anti-aging remedy. addition, recent advances studies on NAD-dependent deacetylase sirtuin-1 (SIRT1) regulation role senescence-associated secretory phenotype (SASP) in cells senescence highlighted well. that, also revised latest information how help improve function modulate apoptosis (programmed cell death).

Language: Английский

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Early Vascular Ageing and Cellular Senescence in Chronic Kidney Disease

Computational and Structural Biotechnology Journal, Journal Year: 2019, Volume and Issue: 17, P. 721 - 729

Published: Jan. 1, 2019

Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by progressive vascular disease, systemic inflammation, muscle wasting and frailty. The predominant early (EVA) process mediated medial calcification (VC) results in marked discrepancy between chronological biological age CKD. Though the exact underlying mechanisms VC EVA are not fully elucidated, accumulating evidence indicates that cellular senescence - subsequent chronic inflammation through senescence-associated secretary phenotype (SASP) plays fundamental role its initiation progression. In this review, we discuss pathophysiological links CKD, with focus on media VC, potential anti-ageing therapeutic strategies senolytic drugs targeting

Language: Английский

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PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state

Thorax, Journal Year: 2019, Volume and Issue: 74(8), P. 749 - 760

Published: June 10, 2019

Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha ( PPARGC1A , encoding PGC1α), master regulator of biogenesis, diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts sorted from bleomycin-injured mice were used evaluate the expression function PGC1α. In vitro PGC1α manipulation was performed by small interfering RNA knockdown or overexpression. Fibroblast activation assessed quantitative PCR, Western blotting, matrix deposition, secreted cytokine array, immunofluorescence traction force microscopy. Mitochondrial Seahorse analyzer mitochondria mass number flow cytometry, DNA quantification transmission electron microscopy (TEM). We found that levels are stably repressed fibroblasts. After bleomycin injury young mice, drops transiently but then increases prior resolution. contrast, fails recover aged with persistent fibrosis. alone normal reduces while enhancing contractile synthetic activation, senescence-related gene soluble profibrotic prosenescence signalling. Re-expression ameliorates all these pathological cellular functions. Pharmacological treatment rosiglitazone, not thyroid hormone, elevated attenuated sustained repression beneficial effects its rescue identifies as an important fibroblast’s state IPF.

Language: Английский

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Accelerated Kidney Aging in Diabetes Mellitus

Oxidative Medicine and Cellular Longevity, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 24

Published: July 28, 2020

With aging, the kidney undergoes inexorable and progressive changes in structural functional performance. These aging-related alterations are more obvious serious diabetes mellitus (DM). Renal accelerated aging under DM conditions is associated with multiple stresses such as accumulation of advanced glycation end products (AGEs), hypertension, oxidative stress, inflammation. The main hallmarks cellular senescence diabetic kidneys include cyclin-dependent kinase inhibitors, telomere shortening, nephropathy-associated secretory phenotype. Lysosome-dependent autophagy antiaging proteins Klotho Sirt1 play a fundamental role DM, among which autophagy-lysosome system convergent mechanism pathways involved renal conditions. Metformin inhibitor sodium-glucose cotransporter 2 recommended due to their effects independent antihyperglycemia, besides angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Additionally, diet intervention including low protein AGEs antioxidants suggested for patients nephropathy (DN). However, long-term benefits still need further study. Exploring interactive relationships Klotho, Sirt1, may provide insight into better satisfying urgent medical needs elderly DN.

Language: Английский

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Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 11, 2020

Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed a state of accelerated premature aging. Aging share common characteristic features with increased cellular senescence, conserved program characterized by an irreversible cell cycle arrest altered transcriptome secretome. While developmental senescence acute may positively contribute to the fine-tuning embryogenesis injury repair, when unresolved promptly, plays crucial role in fibrogenesis progression. Senescent cells elicit their fibrogenic actions primarily secreting assortment inflammatory profibrotic factors known senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent could promising new target for therapeutic intervention senotherapy, which includes depleting cells, modulating SASP restoration inhibitors. this review, we discuss current understanding mechanism fibrosis. We also highlight potential options targeting treatment CKD.

Language: Английский

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Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: July 7, 2020

Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney (AKI), increases the risk of delayed graft function (DGF), primes donor for rejection, and contributes to long-term loss. In last decade, epidemiological studies have linked even mild episodes AKI chronic disease (CKD) progression, innate immunity seems play crucial role. The ischemic insult triggers an inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well tubular epithelial (TECs). Among PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like (NLRs), inflammasomes, pivotal role in shaping inflammation TEC repair, response IRI. These represent promising targets modulate extent inflammation, but also gatekeepers tissue protecting against AKI-to-CKD progression. Despite important considerations timely use therapeutics, context IRI, treatment options are limited lack understanding intra- intercellular mechanisms associated with activation impact adaptive repair. Accumulating evidence suggests TEC-associated shapes stress through regulation immunometabolism. Engagement provides TECs metabolic flexibility necessary plasticity during This could significantly affect pathogenic processes within TECs, such cell death, mitochondrial damage, senescence, pro-fibrotic cytokine secretion, well-known exacerbate fibrosis. article overview past 5 years research experimental human focus cascade events activated hypoxic damage TECs: from programmed death (PCD) dysfunction-mediated rewiring maladaptive repair progression Finally, we will discuss crosstalk between metabolism observed therapeutic potential clinical research.

Language: Английский

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