Link Between Senescence and Cell Fate: Senescence-Associated Secretory Phenotype and Its Effects on Stem Cell Fate Transition

Pan, Yu; Gu, Zhenzhen; Lyu, Yansi; Yang, Yi; Chung, Manhon; Pan, Xiaohua; Cai, Sa

doi:10.1089/rej.2022.0021

Cited by 9 publications

(9 citation statements)

References 113 publications

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“…2a) 28 . We first interrogated the metabolic pattern of glucose upon uptake by senescent cells, as glucose is supposed to act as a principal contributor to the TCA cycle when cells enter senescence, a stage that allows cells to sustain metabolic activity 29 . Experimental data from analysis of mitochondrial dynamics and cellular bioenergetics with the gas chromatography-mass spectrometry (GC-MS) indicated significantly elevated glycolytic activity in senescent human stromal cells, as reflected by enhanced production of metabolites including but not limited to dihydroxyacetone phosphate (DHAP), glyceraldehyde-3-phosphate (GAP) and 3-phosphoglycerate (3-PG) (Fig.…”

Section: Senescent Cells Exhibit a Distinct Profile Of Glucose Metabo...mentioning

confidence: 99%

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Dou

Long

et al. 2023

Preprint

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Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here we highlight upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon cellular senescence, a tendency adversely correlated with cancer patient survival after chemotherapy. Senescent cells exhibit increased aerobic glycolysis and enhanced lactate production, but subject to reversal upon PDK4 inhibition. Distinct from the cancer cell-featured Warburg effect, however, senescent cells sustain mitochondrial respiration and redox activity, adopting a special form of metabolic reprogramming. Media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro, while targeting PDK4 causes tumor regression in vivo. The metabolite lactate causes NOX1 upregulation and ROS production in mitochondrion-disabled cells, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype (SASP). In preclinical trials, PDK4 intervention alleviates physical dysfunction and prevents age-associated frailty, conditions frequently observed in advanced life. Together, our study substantiates the hypercatabolic nature of senescent cells, and reveals a metabolic link between cellular senescence, lactate production, chronological aging and age-related pathologies including but not limited to cancer.

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Section: Senescent Cells Exhibit a Distinct Profile Of Glucose Metabo...mentioning

confidence: 99%

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Dou

Long

et al. 2023

Preprint

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“…38 Transient exposure to SASP promotes repair by inducing differentiation and enhancing cell plasticity, however, prolonged exposure to SASP can inhibit this process by decreasing differentiation capability and destroying stem cell niches. 39 Gastric mucosal atrophy is a long-term pathological process. Cai et al found that CXCR2 was mainly distributed at the base of the glands, implying that the stem cells in the bottom of the glands underwent senescence, the p53-p21 signaling pathway may be the key to the CXCR2-mediated enhancement of the senescence of gastric epithelial cells, 40 they also showed that in addition to CAG patients, high p21 expression was also observed in gastric mucosa of IM patients.…”

Section: Cellul Ar S Ene Scen Ce and H Pylori -P Os Itive Chroni C A...mentioning

confidence: 99%

“…Mucosal glands of H. pylori ‐positive CAG patients also secrete a large amount of C‐X‐C motif chemokine receptor 2 (CXCR2), a SASP 38 . Transient exposure to SASP promotes repair by inducing differentiation and enhancing cell plasticity, however, prolonged exposure to SASP can inhibit this process by decreasing differentiation capability and destroying stem cell niches 39 . Gastric mucosal atrophy is a long‐term pathological process.…”

Section: Cellular Senescence and H Pylori‐positive Chronic Atrophic G...mentioning

confidence: 99%

Helicobacter pylori‐positive chronic atrophic gastritis and cellular senescence

Zheng

Zhu

et al. 2022

Helicobacter

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Background Chronic atrophic gastritis (CAG) is a pathological stage in the Correa’s cascade, whereby Helicobacter pylori (H. pylori) infection is the primary cause. Cellular senescence is an inducing factor for cancer occurrence and cellular senescence is an obvious phenomenon in gastric mucosal tissues of H. pylori‐positive CAG patients. Methods In this review, we collated the information on cellular senescence and H. pylori‐positive CAG. Results At present, only a few studies have observed the effect of cellular senescence on precancerous lesions. In combination with the latest research, this review has collated the information on cellular senescence and H. pylori‐positive CAG from four aspects‐ telomere shortening, DNA methylation, increased reacive oxygen species (ROS) production, and failure of autophagy. Conclusion This is expected to be helpful for exploring the relevant mechanisms underlying inflammatory cancerous transformation and formulating appropriate treatment strategies.

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“…3a) 30 . We first interrogated the metabolic pattern of glucose upon uptake by senescent cells, as glucose is supposed to act as a principal contributor to the TCA cycle when cells enter senescence, a stage that is considered metabolically active 31 . Experimental data from assessment of mitochondrial dynamics and cellular bioenergetics with the XF24 Extracellular Flux analyzer (Seahorse bioanalyzer) indicated significantly elevated glycolytic activity in senescent human stromal cells, as reflected by enhanced production of metabolites including but not limited to dihydroxyacetone phosphate (DHAP), glyceraldehyde-3-phosphate (GAP) and 3-phosphoglycerate (3-PG) (Fig.…”

Section: Senescent Cells Exhibit a Distinct Profile Of Glucose Metabo...mentioning

confidence: 99%

Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance

Dou

Long

Liu

et al. 2022

Preprint

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Cellular senescence is a state of stable growth arrest, usually accompanied by development of the senescence-associated secretory phenotype (SASP). Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence (GIS), PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured Warburg effect, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Pharmacologically targeting PDK4 restrains the adverse effects of PDK4 in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Together, our study substantiates the hypercatabolic nature of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies including but not limited to cancer.

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Link Between Senescence and Cell Fate: Senescence-Associated Secretory Phenotype and Its Effects on Stem Cell Fate Transition

Cited by 9 publications

References 113 publications

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Helicobacter pylori‐positive chronic atrophic gastritis and cellular senescence

Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance

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