Cellular senescence in ageing: from mechanisms to therapeutic opportunities

Nature Reviews Molecular Cell Biology, Год журнала: 2020, Номер 22(2), С. 75 - 95

Опубликована: Дек. 16, 2020

Язык: Английский

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Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

Cell Research, Год журнала: 2020, Номер 30(7), С. 574 - 589

Опубликована: Апрель 27, 2020

Abstract Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives age-related phenotypes. The clearance senescent cells is expected decrease chronic, low-grade inflammation improve repair capacity, thus attenuating the decline physical function organisms. However, selective effective different types has proven challenging. Herein, we developed prodrug strategy design new compound based on increased activity lysosomal β-galactosidase (β-gal), primary characteristic cells. Our SSK1 specifically activated by β-gal eliminates mouse human independently senescence inducers types. In mice, our effectively cleared tissues, decreased senescence- age-associated gene signatures, attenuated local systemic inflammation, restored function. results demonstrate that can be leveraged selectively eliminate cells, providing novel develop anti-aging interventions.

Язык: Английский

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Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

Aging Cell, Год журнала: 2020, Номер 19(4)

Опубликована: Март 31, 2020

Abstract Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation senolytic therapies to human is hampered by their suboptimal specificity cells and important toxicities that narrow therapeutic windows. We have previously shown the high levels senescence‐associated lysosomal β‐galactosidase (SA‐β‐gal) found within be exploited specifically release tracers cargoes from galactose‐encapsulated nanoparticles these cells. Here, we show galacto‐conjugation BCL‐2 family inhibitor Navitoclax results a potent prodrug (Nav‐Gal), preferentially activated SA‐β‐gal wide range cell types. Nav‐Gal selectively induces apoptosis has higher index than (through reduced activation nonsenescent cells). enhances cytotoxicity standard senescence‐inducing chemotherapy (cisplatin) A549 lung Concomitant treatment cisplatin vivo eradication significantly reduces tumour growth. Importantly, Navitoclax‐induced platelet murine blood samples treated ex vivo, thrombocytopenia at therapeutically effective concentrations Taken together, provide potentially versatile strategy generating prodrugs toxicities.

Язык: Английский

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Aging of the cells: Insight into cellular senescence and detection Methods

European Journal of Cell Biology, Год журнала: 2020, Номер 99(6), С. 151108 - 151108

Опубликована: Июль 12, 2020

Язык: Английский

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Connective Tissue and Fibroblast Senescence in Skin Aging

Journal of Investigative Dermatology, Год журнала: 2021, Номер 141(4), С. 985 - 992

Опубликована: Фев. 7, 2021

There is increasing evidence that skin aging significantly enforced by the accumulation of senescent dermal fibroblasts. Various stressors damaging macromolecules inside and outside fibroblasts are responsible. In addition, NK cells fail to adequately remove (SEN) from tissues. SEN release proinflammatory, tissue degrading senescent-associated secretory phenotype factors vesicles with distinct cargo impact on their endogenous niche spread senescence aging. this review, we will further discuss less noticed facets, including plasticity fibroblast phenotypes, underestimated extracellular matrix itself, depletion subsets homeostasis

Язык: Английский

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The Cancer SENESCopedia: A delineation of cancer cell senescence

Cell Reports, Год журнала: 2021, Номер 36(4), С. 109441 - 109441

Опубликована: Июль 1, 2021

Cellular senescence is characterized as a stable proliferation arrest that can be triggered by multiple stresses. Most knowledge about senescent cells obtained from studies in primary cells. However, features may different cancer cells, since the pathways are involved induction often deregulated cancer. We report here comprehensive analysis of transcriptome and senolytic responses panel 13 cell lines rendered two distinct compounds. show response to agents composition senescence-associated secretory phenotype more influenced origin than trigger. Using machine learning, we establish SENCAN gene expression classifier for detection samples. The profiles available an interactive online Cancer SENESCopedia.

Язык: Английский

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Theranostic Fluorescent Probes

Chemical Reviews, Год журнала: 2024, Номер 124(5), С. 2699 - 2804

Опубликована: Фев. 29, 2024

The ability to gain spatiotemporal information, and in some cases achieve control, the context of drug delivery makes theranostic fluorescent probes an attractive intensely investigated research topic. This interest is reflected steep rise publications on topic that have appeared over past decade. Theranostic probes, their various incarnations, generally comprise a fluorophore linked masked drug, which released as result certain stimuli, with both intrinsic extrinsic stimuli being reported. release then signaled by emergence signal. Importantly, use appropriate fluorophores has enabled not only this emerging fluorescence marker for but also provided modalities useful photodynamic, photothermal, sonodynamic therapeutic applications. In review we highlight recent work particular focus are activated tumor microenvironments. We summarize efforts develop other applications, such neurodegenerative diseases antibacterials. celebrates diversity designs reported date, from discrete small-molecule systems nanomaterials. Our aim provide insights into potential clinical impact still-emerging direction.

Язык: Английский

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The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

Antioxidants, Год журнала: 2022, Номер 11(7), С. 1224 - 1224

Опубликована: Июнь 22, 2022

Cellular senescence is an irreversible state of cell cycle arrest occurring in response to stressful stimuli, such as telomere attrition, DNA damage, reactive oxygen species, and oncogenic proteins. Although beneficial protective several physiological processes, excessive senescent burden has been involved various pathological conditions including aging, tissue dysfunction chronic diseases. Oxidative stress (OS) can drive due a loss balance between pro-oxidant stimuli antioxidant defences. Therefore, the identification characterization compounds capable preventing or counteracting phenotype major interest. However, despite considerable number studies, comprehensive overview main molecules OS-induced still lacking. Here, besides brief description molecular mechanisms implicated OS-mediated we review discuss role enzymes, mitochondria-targeting compounds, vitamins, carotenoids, organosulfur nitrogen non-protein molecules, minerals, flavonoids, non-flavonoids with anti-aging potential, therefore offering insights into innovative lifespan-extending approaches.

Язык: Английский

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Discovering small-molecule senolytics with deep neural networks

Nature Aging, Год журнала: 2023, Номер 3(6), С. 734 - 750

Опубликована: Май 4, 2023

Язык: Английский

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A near-IR ratiometric fluorescent probe for the precise tracking of senescence: a multidimensional sensing assay of biomarkers in cell senescence pathways

Chemical Science, Год журнала: 2024, Номер 15(15), С. 5681 - 5693

Опубликована: Янв. 1, 2024

A NIR fluorescent probe for monitoring senescence was developed with SA-β-gal and HClO as targets under high lysosomal pH conditions. The precise tracking of cellular/ in vivo achieved a ratiometric sensing pattern.

Язык: Английский

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