Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence

Hewitt, Graeme; Jurk, Diana; Marques, Francisco D.M.; Correia‐Melo, Clara; Hardy, Timothy; Gackowska, Agata; Anderson, Rosaleen J.; Taschuk, Morgan; Mann, Jelena; Passos, João F.

doi:10.1038/ncomms1708

Cited by 766 publications

(808 citation statements)

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“…5; Figs S3–6). In some cases, there were changes shortly after irradiation, consistent with potential acute responses to radiation, while senescence becomes established after days or weeks (Hewitt et al ., 2012). Bcl‐xl and Bcl‐2 increased in HUVECs, IMR90 cells, and MEFs but not preadipocytes, suggesting that senescent HUVECs, IMR90 cells, and MEFs might depend more on this pro‐survival pathway than N‐resistant preadipocytes.…”

Section: Resultsmentioning

confidence: 99%

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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SummaryClearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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Section: Resultsmentioning

confidence: 99%

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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“…However, since not all cells with DDR foci expressed high levels of α‐SMA in stress fibers (Supporting Information Figure S3d), our data also suggested that activation of the DDR alone is not sufficient for myofibroblast transdifferentiation and that other factors, such as timing of DDR induction or long‐term persistence of the DDR, are critical for activating the transdifferentiation program. As dysfunctional telomeres activate a persistent DDR while nontelomeric DSBs are repaired within minutes of being generated (Fumagalli et al, 2012; Hewitt et al, 2012), we tested whether fibroblasts are stimulated to transdifferentiate preferentially due to a persistent telomeric DDR. By simultaneously immunostaining TGF‐β1‐treated cells for α‐SMA expression and TIF formation, we discovered that the great majority of α‐SMA‐expressing myofibroblasts indeed displayed dysfunctional telomeres and were TIF positive (75%).…”

Section: Resultsmentioning

confidence: 99%

“…Significantly, telomere dysfunction‐induced senescence (TDIS) can also be triggered in the absence of continuous cell proliferation and in the absence of critical telomere shortening. For example, genotoxic stresses that cause DSB formation in telomeric repeats can rapidly activate TDIS, as telomeric breaks resist DNA repair activities (Fumagalli et al, 2012; Hewitt et al, 2012; Suram et al, 2012). Stresses that have been demonstrated to cause TDIS include oncogene expression (Patel, Suram, Mirani, Bischof, & Herbig, 2016; Suram et al, 2012), DNA replication stress (Boccardi et al, 2015; Fumagalli et al, 2012; Hewitt et al, 2012), and reactive oxygen species (ROS) (Boccardi et al, 2015), among others.…”

Section: Introductionmentioning

confidence: 99%

“…For example, genotoxic stresses that cause DSB formation in telomeric repeats can rapidly activate TDIS, as telomeric breaks resist DNA repair activities (Fumagalli et al, 2012; Hewitt et al, 2012; Suram et al, 2012). Stresses that have been demonstrated to cause TDIS include oncogene expression (Patel, Suram, Mirani, Bischof, & Herbig, 2016; Suram et al, 2012), DNA replication stress (Boccardi et al, 2015; Fumagalli et al, 2012; Hewitt et al, 2012), and reactive oxygen species (ROS) (Boccardi et al, 2015), among others. Whether generated due to progressive telomere erosion or due to DSB formation in telomeric repeats, telomere dysfunction activates a persistent DDR that is mediated by and dependent on p53, a transcription factor that not only trans‐activates DDR genes (Molchadsky, Rivlin, Brosh, Rotter, & Sarig, 2010), but also regulates a wide range of other biological activities including cell differentiation (Rivlin, Koifman, & Rotter, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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Cells that had undergone telomere dysfunction‐induced senescence secrete numerous cytokines and other molecules, collectively called the senescence‐associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF‐β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS‐dependent manner. Surprisingly, instead of activating cellular senescence, TGF‐β1‐induced telomere dysfunction caused fibroblasts to transdifferentiate into α‐SMA‐expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF‐β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF‐β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

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“…TAF + (telomere‐associated foci) nuclei were used as a marker of senescent cell burden (Hewitt et al ., 2012). TAF + nuclei were readily evident in subpopulations of cells in aorta (and localized in both endothelial and smooth muscle layers in the vessel wall) from vehicle‐treated mice (Fig.…”

Section: Can Chronic Senolytic Treatment Improve Age‐related Vascularmentioning

confidence: 99%

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

et al. 2016

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SummaryWhile reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long‐term senolytic treatment is unknown. To determine whether long‐term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF + cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK‐ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT–PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

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Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence

Cited by 766 publications

References 40 publications

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

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