JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Xu, Ming; Tchkonia, Tamar; Ding, Husheng; Ogrodnik, Mikołaj; Lubbers, Ellen R.; Pirtskhalava, Tamar; White, Thomas A.; Johnson, Kurt O.; Stout, Michael B.; Mezera, Vojtěch; Giorgadze, Nino; Jensen, Michael D.; LeBrasseur, Nathan K.; Kirkland, James L.

doi:10.1073/pnas.1515386112

Cited by 568 publications

(497 citation statements)

References 67 publications

(82 reference statements)

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“…Interestingly, metformin, the effects of which include preventing NF-κB nuclear translocation, has been shown to reduce inflammation and oxidative stress and to promote health and increase lifespan in mice 131,132 . Activation of the Janus kinase (JAK)-STAT pathway has been found to lead to senescence and SASP, and inhibitors of this pathway have been shown to reprogramme SASP in adipocytes 133 . Importantly, IPF lung fibroblasts exhibit high STAT3 expression, and constitutively active STAT3 reduces proliferation and increases the expression of BCL-X L and BCL-2 in lung fibroblasts, suggesting that inhibitors of JAK-STAT might be useful to control senescence and SASP in IPF lungs 134 .…”

Section: Targets and Therapeutic Interventions For Senescencementioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

266

194

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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Section: Targets and Therapeutic Interventions For Senescencementioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

266

194

View full text Add to dashboard Cite

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“…This inflammatory status was attenuated by rapamycin treatment, and the inhibition of the inflammatory phenotype by rapamycin was correlated with an inhibition of the Stat3 pathway in both cell and mouse models (Xu et al ., 2015). By measuring the levels of p65/p50 in the nucleus vs. cytosol (Fig.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

et al. 2017

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SummarySenescent cells contribute to age‐related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild‐type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA‐β‐galactosidase (β‐gal) staining, senescence‐associated secretory phenotype (SASP), and p16 and p21 molecular markers. In Nrf2KO fibroblasts, however, rapamycin still decreased β‐gal staining and the SASP, but rapamycin did not activate the autophagy pathway or decrease p16 and p21 levels. These observations were further confirmed in vivo using Nrf2KO mice, where rapamycin treatment led to a decrease in β‐gal staining and pro‐inflammatory cytokines in serum and fat tissue; however, p16 levels were not significantly decreased in fat tissue. Consistent with literature demonstrating that the Stat3 pathway is linked to the production of SASP, we found that rapamycin decreased activation of the Stat3 pathway in cells or tissue samples from both WT and Nrf2KO mice. Our data thus suggest that cell senescence is a complex process that involves at least two arms, and rapamycin uses Nrf2 to regulate cell cycle arrest, but not the production of SASP.

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“…The components of the SASP have been shown to vary depending on the cell type, with differing levels of cytokines and other inflammatory mediators being found in epithelial cells and mesenchymal cells (Xu et al ., 2015). Indeed, we show here that senescent CD8 + T cells exhibited a SASP which differs to that reported for fibroblasts and B and NK cells, in that it is not defined by the expression of IL‐1β and IL‐6.…”

Section: Discussionmentioning

confidence: 99%

Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

et al. 2017

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SummaryCellular senescence is accompanied by a senescence‐associated secretory phenotype (SASP). We show here that primary human senescent CD8+ T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age‐associated inflammation. We found the CD8+ CD45RA + CD27− EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD8+ T cells once generated, they both adopt a unique secretory profile with no commonality to any other subset, aligning more closely with senescence than quiescence. Furthermore, we also show that the SASP observed in senescent CD8+ T cells is governed by p38 MAPK signalling.

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JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Cited by 568 publications

References 67 publications

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

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JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Cited by 568 publications

References 67 publications

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

Human CD8+EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

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Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK