Intestinal stem cells acquire premature senescence and senescence associated secretory phenotype concurrent with persistent DNA damage after heavy ion radiation in mice

Kumar, Santosh; Suman, Shubhankar; Fornace, Albert J.; Datta, Kamal

doi:10.18632/aging.102043

Cited by 34 publications

(36 citation statements)

References 60 publications

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“…In addition, intestinal epithelial organoids derived from aged mice also showed consistent upregulation of senescence markers such as SA-β-gal activity and p21 as compared to organoids derived from younger organisms (Uchida et al, 2018). Intestinal epithelial stem cells of old mice expressed enhanced mRNA levels of genes associated with cellular senescence and oxidative stress (Moorefield et al, 2017), and radiation exposure also induced premature cellular senescence and SASP phenotype in intestinal stem cells in vivo (Kumar et al, 2019b). It is thus evident that intestinal epithelial as well as stem cells exhibit age-dependent cellular senescence which can contribute to known functional alterations and disruption of gastrointestinal homeostasis.…”

Section: Gut Microbiome and Cellular Senescencementioning

confidence: 86%

“…It is thus evident that intestinal epithelial as well as stem cells exhibit age-dependent cellular senescence which can contribute to known functional alterations and disruption of gastrointestinal homeostasis. Moreover, the chronic SASP secreted by senescent intestinal cells can promote inflammatory environment and/or oncogenic transformation which can have harmful effects on gut permeability, immune activation as well as the gut microbiome composition (Kumar et al, 2019b;Sharma et al, 2021) (Figure 3). A breakthrough study demonstrated the effects of a dysbiotic gut in the development of SASP and its deleterious effects.…”

Section: Gut Microbiome and Cellular Senescencementioning

confidence: 99%

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Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: An Emerging Frontier

Sharma¹

2021

Preprint

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The significance of diversity, composition, and functional attributes of the gut microbiota is recognized in human health and disease. Studies have also shown that the gut microbiota is related to human aging, and a causal relationship between gut microflora dysbiosis and chronic age-related disorders is also becoming apparent. Further, emerging evidence indicates that age-associated changes in the gut microbiome are predictors of human survival and longevity. Recent advances in our understanding of the cellular and molecular aspects of biological aging have revealed a cellular senescence-centric view of the aging process. However, the association between gut microbiome and cellular senescence is only beginning to be understood. The present review provides an integrative view of the emerging relationship between the gut microbiome and cellular senescence in aging and disease. Evidence relating to microbiome-mediated modulation of senescent cells, as well as senescent cells-mediated changes in intestinal homeostasis have been discussed. Unanswered questions and future research directions have also been deliberated to truly ascertain the relationship of the gut microbiome and cellular senescence for developing microbiome-based age-delaying and longevity promoting therapies.

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Section: Gut Microbiome and Cellular Senescencementioning

confidence: 86%

Section: Gut Microbiome and Cellular Senescencementioning

confidence: 99%

Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: An Emerging Frontier

Sharma¹

2021

Preprint

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“…Data from this study are reminiscent of those from studies of intestinal stem cells from aged mice which demonstrate that senescent stem cells accumulate in intestinal crypts as mice age. (6,13) Accumulation of senescent cells is thought to contribute to decreased functional capacity, dysregulation of proliferation, and altered regenerative ability of ISC. (14,15) This leads us to consider that senescent cells could accumulate in small intestinal crypts following treatment with genotoxic agents, such as doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin Induces Senescence in Intestinal Epithelial Cells

Biraud

Cortes

Cray

et al. 2021

Preprint

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Doxorubicin treatment induces DNA damage and apoptosis in rapidly dividing cell types like intestinal epithelial cells. This has been demonstrated both in vivo and in vitro. In certain cell types some cells do not undergo DNA damage-induced apoptosis in response to doxorubicin but instead become senescent. Induction of senescence in these cells can lead to dysfunction and chronic inflammation, which can lead to more damage. We questioned whether a single dose of doxorubicin would be able to induce apoptosis and senescence in intestinal epithelial cells in vitro. For these studies, we exposed IEC-6 small intestinal epithelial cells to doxorubicin to evaluate whether senescence is induced in a relatively homogeneous population of intestinal epithelial cells. Although some cells underwent apoptosis, those that did not showed traits of senescence. Our studies showed that doxorubicin treatment increased cell size and increased expression of senescence-associated β-galactosidase. Concomitantly, we observed increased mRNA expression of several genes associated with a senescence-associated secretory phenotype including IL-6, Ptges, Faim2, and Cdkn1a and decreased expression of Sirt1. We also observed release of HMGB1, a cellular alarmin, from treated cells. Together, these data suggest that doxorubicin induces senescence in intestinal epithelial cells. Furthermore, our data indicate that cellular responses to a DNA damaging agent, such as doxorubicin, can differ within a population of cells suggesting differing levels of sensitivity within a relatively homogenous cell population. Further studies are needed to delineate the mechanisms that determine whether a cell moves down an apoptotic or senescent pathway following DNA damage.

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“…And in the gut, ROS as a signal molecule, is majorly produced in mitochondrial, would stimulate inflammatory signal and plays a central role in colitis [54]. Overproduction of proinflammatory cytokine and ROS would amplify immune signal and exacerbate the breakdown of the epithelium [8,9,55]. Hence, controlling inflammation and oxidative is an effective way to treat IBD in clinical trials [8,56].…”

Section: Discussionmentioning

confidence: 99%

GPA Peptide-Induced Nur77 Localization at Mitochondria Inhibits Inflammation and Oxidative Stress through Activating Autophagy in the Intestine

Deng

Liu

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. Nur77, belongs to the NR4A subfamily of nuclear hormone receptors, plays a critical role in controlling the pathology of colitis. The aim of this study is to investigate the protection effect and mechanism of Gly-Pro-Ala (GPA) peptide, isolated from fish skin gelatin hydrolysate, in a mouse model of dextran sulfate sodium- (DSS-) induced colitis and intestinal epithelial cells (IECs) stimulated by lipopolysaccharide (LPS). In vivo, GPA treatment alleviates DSS-induced weight loss, disease activity index (DAI) increase, colon length shortening, and colonic pathological damage. Production of proinflammatory cytokines, ROS, and MDA is significantly decreased by GPA treatment. In vitro, GPA significantly inhibits proinflammatory cytokine production, cytotoxicity, ROS, and MDA in IECs. Furthermore, GPA induces autophagy to suppress inflammation and oxidative stress. GPA promotes Nur77 translocation from the nucleus to mitochondria where it facilitates Nur77 interaction with TRAF6 and p62, leading to the induction of autophagy. In addition, GPA contributed to the maintenance of tight junction architecture in vivo and in vitro. Taken together, GPA, as a Nur77 modulator, could exert anti-inflammatory and antioxidant effects by inducing autophagy in IECs, suggesting that GPA may be promising for the prevention of colitis.

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Intestinal stem cells acquire premature senescence and senescence associated secretory phenotype concurrent with persistent DNA damage after heavy ion radiation in mice

Cited by 34 publications

References 60 publications

Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: An Emerging Frontier

Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: An Emerging Frontier

Doxorubicin Induces Senescence in Intestinal Epithelial Cells

GPA Peptide-Induced Nur77 Localization at Mitochondria Inhibits Inflammation and Oxidative Stress through Activating Autophagy in the Intestine

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