Cellular Senescence: Defining a Path Forward

Cell, Год журнала: 2019, Номер 179(4), С. 813 - 827

Опубликована: Окт. 1, 2019

Язык: Английский

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Fisetin is a senotherapeutic that extends health and lifespan

EBioMedicine, Год журнала: 2018, Номер 36, С. 18 - 28

Опубликована: Сен. 29, 2018

Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent have been demonstrated play causal role driving aging and age-related diseases using genetic pharmacologic approaches. We previously that the combination dasatinib flavonoid quercetin potent senolytic improving numerous conditions including frailty, osteoporosis cardiovascular disease. The goal this study was identify flavonoids with more activity.

Язык: Английский

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An aged immune system drives senescence and ageing of solid organs

Nature, Год журнала: 2021, Номер 594(7861), С. 100 - 105

Опубликована: Май 12, 2021

Язык: Английский

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Cellular senescence: a key therapeutic target in aging and diseases

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(15)

Опубликована: Июль 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.

Язык: Английский

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Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Aging Cell, Год журнала: 2020, Номер 19(3)

Опубликована: Янв. 25, 2020

Abstract Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple mechanisms that protect the nuclear genome. Humans or mice reduced expression this enzyme rapidly due to increased levels spontaneous, Here, we asked whether corresponds an level senescent cells. p16 Ink4a p21 Cip1 mRNA were ~15‐fold peripheral lymphocytes from 4‐ 5‐month‐old Ercc1 −/∆ 2.5‐year‐old wild‐type (WT) mice, suggesting these animals exhibit similar biological age. elevated 10 13 tissues analyzed indicating where endogenous damage drives senescence vivo. Aged WT had increases same as mutant mice. Senescence‐associated β–galactosidase activity protein also progeroid aged while Lamin B1 diminished. In −/Δ luciferase reporter, bioluminescence rose steadily age, particularly lung, thymus, pancreas. These data illustrate occurs natural accelerated relative extent among tissues. Interestingly, was greater male until end life. The similarities between support conclusion repair‐deficient accurately model age‐related accumulation cells, albeit six‐times faster.

Язык: Английский

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Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span

The Annual Review of Pharmacology and Toxicology, Год журнала: 2020, Номер 61(1), С. 779 - 803

Опубликована: Сен. 30, 2020

Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation with damage. Senescent (Sncs) often develop senescence-associated secretory phenotype prompt immune clearance, which drives chronic sterile inflammation and plays causal role aging age-related diseases. Sncs accumulate age at anatomical sites disease. Thus, they are regarded as logical therapeutic target. Senotherapeutics new class drugs that selectively kill (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification clinical trial. Preclinical data indicate alleviate disease numerous organs, improve physical function resilience, all causes mortality, even if administered aged. Here, we review evidence drive disease, approaches identify optimize senotherapeutics, current status preclinical testing senolytics.

Язык: Английский

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The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

Nature Metabolism, Год журнала: 2021, Номер 3(12), С. 1706 - 1726

Опубликована: Дек. 6, 2021

Abstract Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation senescent cells, which develop senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component grape seed extract (GSE), increases healthspan lifespan mice through its action on cells. By screening library natural products, find GSE, PCC1 as one active components, have specific effects At low concentrations, appears to inhibit SASP formation, whereas it selectively kills cells at higher possibly promoting production reactive oxygen species mitochondrial dysfunction. In rodent models, depletes treatment-damaged tumour microenvironment enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration either irradiated, cell-implanted or naturally aged old alleviates physical dysfunction prolongs survival. We identify senotherapeutic agent vivo activity high potential further development clinical intervention delay, alleviate prevent pathologies.

Язык: Английский

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Cellular senescence: all roads lead to mitochondria

FEBS Journal, Год журнала: 2022, Номер 290(5), С. 1186 - 1202

Опубликована: Янв. 20, 2022

Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and pro-inflammatory phenotype, commonly known as the senescence-associated secretory phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues drives tissue dysfunction several age-related conditions. This has spurred academic community industry to identify new therapeutic interventions targeting this process. Mitochondrial often-unappreciated hallmark cellular senescence which plays important roles not only growth but also development SASP resistance cell-death. Here, we review supports role for mitochondria describe underlying mechanisms. Finally, propose detailed road map mitochondrial biology will be crucial guide future senotherapies.

Язык: Английский

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XJB-5-131 inhibited ferroptosis in tubular epithelial cells after ischemia−reperfusion injury

Cell Death and Disease, Год журнала: 2020, Номер 11(8)

Опубликована: Авг. 14, 2020

Abstract Regulated necrosis has been reported to exert an important role in the pathogenesis of various diseases, including renal ischemia-reperfusion (I/R) injury. Damage tubular epithelial cells and subsequent cell death initiate progression acute kidney injury (AKI) chronic disease (CKD). We found that ferroptosis appeared (TECs) human diseases upregulation proferroptotic gene ACSL4 was correlated with function patients XJB-5-131, which showed high affinity for TECs, attenuated I/R-induced inflammation mice by specifically inhibiting rather than necroptosis pyroptosis. Single-cell RNA sequencing (scRNA-seq) indicated ferroptosis-related genes were mainly expressed after I/R injury, while few necroptosis- pyroptosis-associated identified express this cluster cell. Taken together, plays inhibition XJB-5-131 is a promising therapeutic strategy protection against diseases.

Язык: Английский

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DNA damage—how and why we age?

eLife, Год журнала: 2021, Номер 10

Опубликована: Янв. 29, 2021

Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, increased risk morbidity and mortality. Many factors contribute aging, such as time-dependent accumulation macromolecular damage, including DNA damage. The integrity nuclear genome essential for cellular, tissue, organismal health. damage constant threat because nucleic acids are chemically unstable under physiological conditions vulnerable attack by endogenous environmental factors. To combat this, all organisms possess highly conserved mechanisms detect repair Persistent (genotoxic stress) triggers signaling cascades drive cells into apoptosis or senescence avoid replicating damaged genome. drawback these cancer avoidance promote aging. Here, we review evidence plays causal role We also provide genotoxic stress linked other cellular processes implicated drivers mitochondrial metabolic dysfunction, altered proteostasis inflammation. These links between genetic code pillars aging support notion could be root

Язык: Английский

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