bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–06–06
thirteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia.
  2. Symmetric and asymmetric activation of hematopoietic stem cells.
  3. Mitochondrial metabolism: powering new directions in acute myeloid leukemia.
  4. TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.
  5. Effect of Mobile-Based Lifestyle Intervention on Body Weight, Glucose and Lipid Metabolism among the Overweight and Obese Elderly Population in China: A Randomized Controlled Trial Protocol.
  6. Ceramides and Sphingosino-1-Phosphate in Obesity.
  7. JAK-STAT in Early Hematopoiesis and Leukemia.
  8. Aging of the progenitor cells that initiate prostate cancer.
  9. Metabolic syndrome in women with previous gestational diabetes.
  10. Extracellular Vesicles and Hematopoietic Stem Cell Aging.
  11. How Lipids Contribute to Autophagosome Biogenesis, a Critical Process in Plant Responses to Stresses.
  12. Age-Related Changes in Bone-Marrow Mesenchymal Stem Cells.
  13. Lipid metabolism and lipid-laden DCs downregulate NK cells.
  1. Mol Cell. 2021 May 25. pii: S1097-2765(21)00365-8. [Epub ahead of print]
    ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia.
    Daniela Di Marcantonio, Esteban Martinez, Joice S Kanefsky, Jacklyn M Huhn, Rashid Gabbasov, Anushk Gupta, John J Krais, Suraj Peri, YinFei Tan, Tomasz Skorski, Adrienne Dorrance, Ramiro Garzon, Aaron R Goldman, Hsin-Yao Tang, Neil Johnson, Stephen M Sykes.
      Metabolic reprogramming is a common feature of many human cancers, including acute myeloid leukemia (AML). However, the upstream regulators that promote AML metabolic reprogramming and the benefits conferred to leukemia cells by these metabolic changes remain largely unknown. We report that the transcription factor ATF3 coordinates serine and nucleotide metabolism to maintain cell cycling, survival, and the differentiation blockade in AML. Analysis of mouse and human AML models demonstrate that ATF3 directly activates the transcription of genes encoding key enzymatic regulators of serine synthesis, one-carbon metabolism, and de novo purine and pyrimidine synthesis. Total steady-state polar metabolite and heavy isotope tracing analyses show that ATF3 inhibition reduces de novo serine synthesis, impedes the incorporation of serine-derived carbons into newly synthesized purines, and disrupts pyrimidine metabolism. Importantly, exogenous nucleotide supplementation mitigates the anti-leukemia effects of ATF3 inhibition. Together, these findings reveal the dependence of AML on ATF3-regulated serine and nucleotide metabolism.
    Keywords:  AML; ATF3; ATF4; cell cycle; differentiation; leukemia; metabolism; purines; pyrimidines; serine
    DOI:  https://doi.org/10.1016/j.molcel.2021.05.008
  2. Curr Opin Hematol. 2021 Jul 01. 28(4): 262-268
    Symmetric and asymmetric activation of hematopoietic stem cells.
    Dirk Loeffler, Timm Schroeder.
       PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) are in an inactive quiescent state for most of their life. To replenish the blood system in homeostasis and after injury, they activate and divide. HSC daughter cells must then decide whether to return to quiescence and metabolic inactivity or to activate further to proliferate and differentiate and replenish lost blood cells. Although the regulation of HSC activation is not well understood, recent discoveries shed new light on involved mechanisms including asymmetric cell division (ACD).
    RECENT FINDINGS: HSC metabolism has emerged as a regulator of cell fates. Recent evidence suggests that cellular organelles mediating anabolic and catabolic processes can be asymmetrically inherited during HSC divisions. These include autophagosomes, mitophagosomes, and lysosomes, which regulate HSC quiescence. Their asymmetric inheritance has been linked to future metabolic and translational activity in HSC daughters, showing that ACD can regulate the balance between HSC (in)activity.
    SUMMARY: We discuss recent insights and remaining questions in how HSCs balance activation and quiescence, with a focus on ACD.
    DOI:  https://doi.org/10.1097/MOH.0000000000000644
  3. Leuk Lymphoma. 2021 Jun 01. 1-11
    Mitochondrial metabolism: powering new directions in acute myeloid leukemia.
    Ryan J Stubbins, Irina A Maksakov, David S Sanford, Arefeh Rouhi, Florian Kuchenbauer.
      There has been an explosion of knowledge about the role of metabolism and the mitochondria in acute myeloid leukemia (AML). We have also recently seen several waves of novel therapies change the treatment landscape for AML, such as the selective B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. In this new context, we review the rapidly advancing literature on the role of metabolism and the mitochondria in AML pathogenesis, and how these are interwoven with the mechanisms of action for novel therapeutics in AML. We also review the role of oxidative phosphorylation (OxPhos) in maintaining leukemia stem cells (LSCs), how recurrent genomic alterations in AML alter downstream metabolism, and focus on how the BCL-2 pathway and the mitochondria are inextricably linked in AML. Thus, we provide an overview of the mitochondria and metabolism in the context of our new therapeutic world for AML and outline how targeting these vulnerabilities may produce novel therapeutic strategies.
    Keywords:  Acute myeloid leukemia; BCL-2; OxPhos; mitochondria; venetoclax therapy resistance
    DOI:  https://doi.org/10.1080/10428194.2021.1910685
  4. Eur J Clin Invest. 2021 Jun 02. e13600
    TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.
    Luca Liberale, Nicole R Bonetti, Yustina M Puspitasari, Ana Vukolic, Alexander Akhmedov, Candela Diaz-Cañestro, Stephan Keller, Fabrizio Montecucco, Mario Merlini, Aurora Semerano, Giacomo Giacalone, Marco Bacigaluppi, Maria Sessa, Frank Ruschitzka, Thomas F Lüscher, Peter Libby, Jürg H Beer, Giovanni G Camici.
       AIMS: Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target.
    METHODS: 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome.
    RESULTS: Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age.
    CONCLUSIONS: This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.
    Keywords:  TNF-α; ageing; inflamm-ageing; inflammation; ischaemic stroke; matrix metalloproteinases
    DOI:  https://doi.org/10.1111/eci.13600
  5. Int J Environ Res Public Health. 2021 May 01. pii: 4854. [Epub ahead of print]18(9):
    Effect of Mobile-Based Lifestyle Intervention on Body Weight, Glucose and Lipid Metabolism among the Overweight and Obese Elderly Population in China: A Randomized Controlled Trial Protocol.
    Yu Zhang, Xiaohui Guo, Na Zhang, Xinyu Yan, Muxia Li, Mingzhu Zhou, Hairong He, Yibin Li, Wen Guo, Man Zhang, Jianfen Zhang, Guansheng Ma.
      Background: Promotion of a healthy lifestyle is considered a good strategy for dealing with chronic diseases. Mobile-based lifestyle interventions have shown beneficial effects in the control and treatment of chronic diseases such as diabetes, obesity and metabolic syndrome. Current clinical trials for mobile-based lifestyle intervention were mainly conducted among non-elderly populations, thus well-designed trials performed among the elderly who are more susceptible to chronic diseases are needed. The study aims to assess the effect of the mobile-based lifestyle intervention on the improvement of body weight, glucose and lipid metabolism among overweight and obese elderly adults in China. Materials and Methods: Participants aged 60-80 years who are overweight or obese will be randomly assigned to receive mobile-based nutrition and exercise intervention, mobile-based exercise intervention and no intervention for 3 months. Before the intervention, participants will receive the training of the mobile application and sports bracelet. The primary outcome will be the between-group (three groups) difference in body mass index at the end of intervention. The secondary outcomes will include body composition, parameters of glucose and lipid metabolism, blood pressure, dietary data and physical activity data. All these outcomes will be assessed at baseline, day 45 and day 90. Ethics and dissemination: The trial has been approved by the Ethics Committee of Peking University Health Science Center (IRB00001052-18039).
    Keywords:  body weight; elderly population; glucose and lipid metabolism; mobile-based lifestyle intervention; overweight and obesity
    DOI:  https://doi.org/10.3390/ijerph18094854
  6. Front Endocrinol (Lausanne). 2021 ;12 635995
    Ceramides and Sphingosino-1-Phosphate in Obesity.
    Ilona Juchnicka, Mariusz Kuźmicki, Jacek Szamatowicz.
      Obesity is a growing worldwide problem, especially in developed countries. This disease adversely affects the quality of life and notably contributes to the development of type 2 diabetes, metabolic syndrome, and cardiovascular disorders. It is characterised by excessive lipids accumulation in the subcutaneous and visceral adipose tissue. Considering the secretory function of adipose tissue, this leads to impaired adipokines and cytokines release. Changes in adipose tissue metabolism result in chronic inflammation, pancreatic islets dysfunction and peripheral insulin resistance. In addition to saturating various adipocytes, excess lipids are deposited into non-adipose peripheral tissues, which disturbs cell metabolism and causes a harmful effect known as lipotoxicity. Fatty acids are metabolised into bioactive lipids such as ceramides, from which sphingolipids are formed. Ceramides and sphingosine-1-phosphate (S1P) are involved in intracellular signalling, cell proliferation, migration, and apoptosis. Studies demonstrate that bioactive lipids have a crucial role in regulating insulin signalling pathways, glucose homeostasis and β cell death. Data suggests that ceramides may have an opposite cellular effect than S1P; however, the role of S1P remains controversial. This review summarises the available data on ceramide and sphingolipid metabolism and their role in obesity.
    Keywords:  S1P; adipose tissue; ceramides; obesity; sphingolipids
    DOI:  https://doi.org/10.3389/fendo.2021.635995
  7. Front Cell Dev Biol. 2021 ;9 669363
    JAK-STAT in Early Hematopoiesis and Leukemia.
    Eirini Sofia Fasouli, Eleni Katsantoni.
      Hematopoietic stem cells (HSCs) produce all the terminally differentiated blood cells and are controlled by extracellular signals from the microenvironment, the bone marrow (BM) niche, as well as intrinsic cell signals. Intrinsic signals include the tightly controlled action of signaling pathways, as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Activation of JAK-STAT leads to phosphorylation of members of the STAT family to regulate proliferation, survival, and self-renewal of HSCs. Mutations in components of the JAK-STAT pathway are linked with defects in HSCs and hematologic malignancies. Accumulating mutations in HSCs and aging contribute to leukemia transformation. Here an overview of hematopoiesis, and the role of the JAK-STAT pathway in HSCs and in the promotion of leukemic transformation is presented. Therapeutic targeting of JAK-STAT and clinical implications of the existing research findings are also discussed.
    Keywords:  JAK-STAT; STAT5; STATs; hematopoiesis; hematopoietic stem cells; leukemia
    DOI:  https://doi.org/10.3389/fcell.2021.669363
  8. Cancer Lett. 2021 May 28. pii: S0304-3835(21)00238-X. [Epub ahead of print]515 28-35
    Aging of the progenitor cells that initiate prostate cancer.
    Jack Freeland, Preston D Crowell, Jenna M Giafaglione, Paul C Boutros, Andrew S Goldstein.
      Many organs experience a loss of tissue mass and a decline in regenerative capacity during aging. In contrast, the prostate continues to grow in volume. In fact, age is the most important risk factor for prostate cancer. However, the age-related factors that influence the composition, morphology and molecular features of prostate epithelial progenitor cells, the cells-of-origin for prostate cancer, are poorly understood. Here, we review the evidence that prostate luminal progenitor cells are expanded with age. We explore the age-related changes to the microenvironment that may influence prostate epithelial cells and risk of transformation. Finally, we raise a series of questions about models of aging and regulators of prostate aging which need to be addressed. A fundamental understanding of aging in the prostate will yield critical insights into mechanisms that promote the development of age-related prostatic disease.
    Keywords:  Epithelium; Microenvironment; Mutations; Old; Organoid
    DOI:  https://doi.org/10.1016/j.canlet.2021.05.014
  9. Sci Rep. 2021 Jun 02. 11(1): 11558
    Metabolic syndrome in women with previous gestational diabetes.
    Karsten Kaiser, Michael Festersen Nielsen, Ervin Kallfa, Greta Dubietyte, Finn Friis Lauszus.
      To evaluate the incidence and timing of the diagnosis of metabolic syndrome in a cohort of Danish women after a pregnancy with gestational diabetes (GDM) to estimate the optimum time for preventative actions in relation to metabolic syndrome (MetS). In this follow-up study, 435 women were included from a consecutive cohort with prior history of GDM. Data on dyslipidemia, hypertension and other cardiovascular disorders (CVD) were extracted from the electronic patient journal. Any antidiabetic, cardiovascular and cholesterol-lowering medicine was ascertained in the national prescription database. Similarly, any blood test taken was evaluated. We defined a patient having MetS if the criteria of the WHO based definition of diabetes or impaired glucose regulation were met. Further, we added as alternative for glucose intolerance, a glycosylated hemoglobin (HbA1c) > 44 mmol/mol or the former level ≥ 6.5%. Further, dyslipidemia, lipid lowering medications, BMI > 30 kg/m2 or antihypertensive treatment were used. For MetS outcome, diagnosis or medication for CVD was registered. All women were followed for median 5.7 years (range 0; 9). The incidence of MetS was 28%. Thirteen percent of these qualified already within one year after pregnancy for the diagnosis of MetS. Postpartum MetS was detected after a median of 3 years (range 0; 7 years); further, 36 (8%) had been diagnosed with manifest diabetes after pregnancy. The diagnosis of postpartum MetS was strongly associated with the prevalence of manifest diabetes. Six years after pregnancy the rate of metabolic syndrome was more than tripled (25 vs. 89%, no DM vs manifest DM, RR: 6.7; 95% CI 2.7-17, p < 0.001). At 40 years the MetS rate nearly tripled if manifest DM was diagnosed (26 vs. 78%, no DM vs. manifest DM, RR: 3.3, 95% CI 1.8-6, p < 0.001). We found that GDM and later on manifest DM in women increase the risk of metabolic syndrome. There seems to be a window of opportunity before the early thirties where it would be especially beneficial to begin preventive efforts in women with GDM.
    DOI:  https://doi.org/10.1038/s41598-021-90832-0
  10. Arterioscler Thromb Vasc Biol. 2021 Jun 03. ATVBAHA120314643
    Extracellular Vesicles and Hematopoietic Stem Cell Aging.
    Laura R Goldberg.
      Extracellular vesicles (EVs), important mediators of intercellular communication, play a critical role in modulating hematopoiesis within the bone marrow microenvironment. Although few studies have explicitly examined the connections between EVs and hematopoietic stem cell (HSC) aging, there is a growing body of evidence that implicates EVs in numerous age-related biologic processes and diseases. This, coupled with their tremendous capacity to influence hematopoiesis, suggests EVs may be key mediators of HSC aging. This review provides an overview of the effects of aging on HSCs, the role of EVs in aging in general, and then details key work in EV modulation of normal and malignant hematopoiesis, with a particular focus on how these effects may translate into the ability of EVs to drive HSC aging. Finally, it describes an exciting emerging literature that provides direct evidence for EV modulation of HSC phenotypes during natural aging and highlights their potential in HSC rejuvenation. Taken collectively, this body of research has profound implications for the future of HSC aging studies. More clearly defining how EVs modify HSC function in an age-dependent fashion and determining the molecular mechanisms by which they drive these age-related HSC phenotype changes will undoubtedly yield innovative strategies to delay or even reverse age-related hematologic dysfunction.
    Keywords:  aging; extracellular vesicles; hematopoiesis; phenotype; stem cell
    DOI:  https://doi.org/10.1161/ATVBAHA.120.314643
  11. Cells. 2021 May 21. pii: 1272. [Epub ahead of print]10(6):
    How Lipids Contribute to Autophagosome Biogenesis, a Critical Process in Plant Responses to Stresses.
    Rodrigo Enrique Gomez, Josselin Lupette, Clément Chambaud, Julie Castets, Amélie Ducloy, Jean-Luc Cacas, Céline Masclaux-Daubresse, Amélie Bernard.
      Throughout their life cycle, plants face a tremendous number of environmental and developmental stresses. To respond to these different constraints, they have developed a set of refined intracellular systems including autophagy. This pathway, highly conserved among eukaryotes, is induced by a wide range of biotic and abiotic stresses upon which it mediates the degradation and recycling of cytoplasmic material. Central to autophagy is the formation of highly specialized double membrane vesicles called autophagosomes which select, engulf, and traffic cargo to the lytic vacuole for degradation. The biogenesis of these structures requires a series of membrane remodeling events during which both the quantity and quality of lipids are critical to sustain autophagy activity. This review highlights our knowledge, and raises current questions, regarding the mechanism of autophagy, and its induction and regulation upon environmental stresses with a particular focus on the fundamental contribution of lipids. How autophagy regulates metabolism and the recycling of resources, including lipids, to promote plant acclimation and resistance to stresses is further discussed.
    Keywords:  ATG proteins; ER-stress; autophagosomes; autophagy; environmental stresses; lipids
    DOI:  https://doi.org/10.3390/cells10061272
  12. Cells. 2021 May 21. pii: 1273. [Epub ahead of print]10(6):
    Age-Related Changes in Bone-Marrow Mesenchymal Stem Cells.
    Valentina A Babenko, Denis N Silachev, Tatyana I Danilina, Kirill V Goryunov, Irina B Pevzner, Ljubava D Zorova, Vasily A Popkov, Valery P Chernikov, Egor Y Plotnikov, Gennady T Sukhikh, Dmitry B Zorov.
      The use of stem cells is part of a strategy for the treatment of a large number of diseases. However, the source of the original stem cells for use is extremely important and determines their therapeutic potential. Mesenchymal stromal cells (MSC) have proven their therapeutic effectiveness when used in a number of pathological models. However, it remains an open question whether the chronological age of the donor organism affects the effectiveness of the use of MSC. The asymmetric division of stem cells, the result of which is some residential stem cells acquiring a non-senile phenotype, means that stem cells possess an intrinsic ability to preserve juvenile characteristics, implying an absence or at least remarkable retardation of senescence in stem cells. To test whether residential MSC senesce, we evaluated the physiological changes in the MSC from old rats, with a further comparison of the neuroprotective properties of MSC from young and old animals in a model of traumatic brain injury. We found that, while the effect of administration of MSC on lesion volume was minimal, functional recovery was remarkable, with the highest effect assigned to fetal cells; the lowest effect was recorded for cells isolated from adult rats and postnatal cells, having intermediate potency. MSC from the young rats were characterized by a faster growth than adult MSC, correlating with levels of proliferating cell nuclear antigen (PCNA). However, there were no differences in respiratory activity of MSC from young and old rats, but young cells showed much higher glucose utilization than old ones. Autophagy flux was almost the same in both types of cells, but there were remarkable ultrastructural differences in old and young cells.
    Keywords:  aging; glucose utilization; glycolysis; mesenchymal stromal cells; mitochondria; oxidative phosphorylation; proliferation; senescence; stem; therapy; traumatic brain injury
    DOI:  https://doi.org/10.3390/cells10061273
  13. Metabolism. 2021 May 26. pii: S0026-0495(21)00100-1. [Epub ahead of print] 154800
    Lipid metabolism and lipid-laden DCs downregulate NK cells.
    Xiangyu Hu, Xiaoqin Jia, Cong Xu, Yingying Wei, Zhengbing Wang, George Liu, Qiang You, Guotao Lu, Weijuan Gong.
       OBJECTIVE: Apolipoprotein C-III (Apoc3) is a key component of triglyceride-rich lipoproteins (TRL). The Apoc3-transgenic mice are characterized by high levels of plasma triglyceride and free fatty acids (FFAs). Apoc3 stimulates human monocytes via activation of the NLRP3 inflammasome. Considering the NK cell downregulation in obese individuals and the possible stimulatory-effects of macrophages, variations of NK cell functions and underlying mechanisms were investigated in mice with Apoc3-induced hyperlipidemia.
    METHODS: Variations of activities and glycolipid metabolism in NK cells of the Apoc3-transgenic mice with hyperlipidemia were detected. Molecular mechanisms of lipid-induced metabolic-reprogramming in NK cells were analyzed based on the transcriptome sequencing. Finally, effects of DCs in mice with hyperlipidemia on NK cell functions were determined.
    RESULTS: Impaired number and function of NK cells in Apoc3TG mice was involved with the increased fatty acid oxidation and decreased glycolysis. Increased uptake of FFAs in Apoc3TG-NK cells contributed to the peroxisome proliferator-activated receptor (PPAR) activation and the downstream PTEN-AKT-mTOR/FOXO1 signaling pathway. Inhibition of PPAR or CPT1α only partly reversed the IFN-γ production of Apoc3TG-NK cells, but completely restored IFN-γ secretion by palmitic acid-treated NK cells ex vivo, indicating that other factors contributed to the Apoc3TG-NK cell downregulation. Meanwhile, Apoc3TG-DCs, which contained more lipids in the cytoplasm, depended on reactive oxygen species (ROS) to increase the expressions PD-L1, TGF-β1, and NKG2D ligands and suppress NK cell activities. DCs of the Apoc3TG-CD36-/+ hybrid mice with less intracellular lipids and ROS production could not inhibit NK cells, indicating that intracellular FFAs promoted the immune-modulatory function of DCs.
    CONCLUSIONS: The downregulation of NK cell activities in individuals with Apoc3-induced hyperlipidemia was due to the increased fatty acid oxidation in NK cells and the bystander suppression caused by lipid-laden DCs. The dual recovery function of NK cells and DCs would improve the prognosis of patients with metabolic syndrome.
    Keywords:  Apoc3; Dendritic cell; Downregulation; Fatty acid oxidation; NK cell
    DOI:  https://doi.org/10.1016/j.metabol.2021.154800
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