bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–03–06
fiveteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss.
  2. The role of nutrition in inflammaging.
  3. Maladaptive trained immunity and clonal hematopoiesis as potential mechanistic links between periodontitis and inflammatory comorbidities.
  4. Tet-mediated DNA demethylation regulates specification of hematopoietic stem and progenitor cells during mammalian embryogenesis.
  5. More on BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.
  6. Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
  7. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine.
  8. Immune aging in killifish.
  9. NAD+ in COVID-19 and viral infections.
  10. Taking the STING out of acute myeloid leukemia through macrophage-mediated phagocytosis.
  11. Clonal compositions involving epigenetic regulator and splicing mutations in CHIP, CCUS, MDS, and CMML.
  12. 2.8 Nutrition in Pregnancy and Lactation.
  13. Adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomised trials.
  14. Endothelial MEKK3-KLF2/4 signaling integrates inflammatory and hemodynamic signals during definitive hematopoiesis.
  15. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming.
  1. EMBO Rep. 2022 Mar 01. e54262
    NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss.
    Claudia Morganti, Kyoko Ito, Chie Yanase, Amit Verma, Julie Teruya-Feldstein, Keisuke Ito.
      Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with morphologic dysplasia and a propensity to transform into overt acute myeloid leukemia (AML). Our analysis of two cohorts of 20 MDS and 49 AML with multi-lineage dysplasia patients shows a reduction in Nucleophosmin 1 (NPM1) expression in 70% and 90% of cases, respectively. A mouse model of Npm1 conditional knockout (cKO) in hematopoietic cells reveals that Npm1 loss causes premature aging of hematopoietic stem cells (HSCs). Mitochondrial activation in Npm1-deficient HSCs leads to aberrant activation of the NLRP3 inflammasome, which correlates with a developing MDS-like phenotype. Npm1 cKO mice exhibit shortened survival times, and expansion of both the intra- and extra-medullary myeloid populations, while evoking a p53-dependent response. After transfer into a p53 mutant background, the resulting Npm1/p53 double KO mice develop fatal leukemia within 6 months. Our findings identify NPM1 as a regulator of HSC aging and inflammation and highlight the role of p53 in MDS progression to leukemia.
    Keywords:  HSC aging; MDS; Nlrp3; Npm1; Tp53
    DOI:  https://doi.org/10.15252/embr.202154262
  2. Ageing Res Rev. 2022 Feb 24. pii: S1568-1637(22)00038-1. [Epub ahead of print]77 101596
    The role of nutrition in inflammaging.
    Paolo Di Giosia, Cosimo Andrea Stamerra, Paolo Giorgini, Tannaz Jamialahamdi, Alexandra E Butler, Amirhossein Sahebkar.
       BACKGROUND: Old age is characterized by a peculiar low-grade, chronic, and "sterile" inflammatory state, which has been termed "inflammaging." This is believed to substantially contribute to the pathogenesis of many age-related diseases and to the progression of the ageing process. An adequate nutritional status is of great importance for maintaining proper immune system functionality and preventing frailty in the elderly.
    METHODS: The purpose of this narrative review is to synthesize what is known about the interaction between inflammaging and nutrition, focusing on the role of the Mediterranean diet, gut microbiota and calorie restriction (CR) in reducing systemic inflammation and improving clinical outcomes.
    CONCLUSIONS: Dietary components may affect inflammation directly, counteracting the low grade age-related inflammation. In this regard, healthy diets, including the Mediterranean diet, are associated with lower concentrations of inflammatory mediators, like C-reactive protein (CRP) and Tumor Necrosis Factor-α (TNF-α), that are hallmarks of inflammaging. Among the components of a healthy diet, a higher intake of whole grains, vegetables and fruits, nuts and fish are all associated with lower inflammation. One area of promising research is the microbiome-ageing interaction. Indeed, dysbiosis plays a role in sub-optimal metabolism, immune function and brain function and contributes to the poor health and impaired well-being associated with ageing. Modulation of the gut microbiota has shown promising results in some disorders. Additionally, the discovery of several molecular pathways associated with ageing, and the characterization of the beneficial effects of calorie restriction (CR) in modulating metabolic pathways and preventing inflammation, should encourage research on CR mimetics, drugs able to promote lifespan and extend healthspan.
    Keywords:  Caloric restriction; Immunosenescence; Inflammaging; Intermitting fasting; Mediterranean diet; Microbioma; Nutrition
    DOI:  https://doi.org/10.1016/j.arr.2022.101596
  3. Periodontol 2000. 2022 Mar 04.
    Maladaptive trained immunity and clonal hematopoiesis as potential mechanistic links between periodontitis and inflammatory comorbidities.
    George Hajishengallis, Xiaofei Li, Kimon Divaris, Triantafyllos Chavakis.
      Periodontitis is bidirectionally associated with systemic inflammatory disorders. The prevalence and severity of this oral disease and linked comorbidities increases with aging. Here, we review two newly emerged concepts, trained innate immunity (TII) and clonal hematopoiesis of indeterminate potential (CHIP), which together support a potential hypothesis on how periodontitis affects and is affected by comorbidities and why the susceptibility to periodontitis and comorbidities increases with aging. Given that chronic diseases are largely triggered by the action of inflammatory immune cells, modulation of their bone marrow precursors, the hematopoietic stem and progenitor cells (HSPCs), may affect multiple disorders that emerge as comorbidities. Such alterations in HSPCs can be mediated by TII and/or CHIP, two non-mutually exclusive processes sharing a bias for enhanced myelopoiesis and production of innate immune cells with heightened proinflammatory potential. TII is a state of elevated immune responsiveness based on innate immune (epigenetic) memory. Systemic inflammation can initiate TII in the bone marrow via sustained rewiring of HSPCs, which thereby display a skewing toward the myeloid lineage, resulting in generation of hyper-reactive or "trained" myeloid cells. CHIP arises from aging-related somatic mutations in HSPCs, which confer a survival and proliferation advantage to the mutant HSPCs and give rise to an outsized fraction of hyper-inflammatory mutant myeloid cells in the circulation and tissues. This review discusses emerging evidence that supports the notion that TII and CHIP may underlie a causal and age-related association between periodontitis and comorbidities. A holistic mechanistic understanding of the periodontitis-systemic disease connection may offer novel diagnostic and therapeutic targets for treating inflammatory comorbidities.
    Keywords:  aging; clonal hematopoiesis; comorbidities; hematopoietic stem cells; periodontitis; trained immunity
    DOI:  https://doi.org/10.1111/prd.12421
  4. Sci Adv. 2022 Mar 04. 8(9): eabm3470
    Tet-mediated DNA demethylation regulates specification of hematopoietic stem and progenitor cells during mammalian embryogenesis.
    Liyang Ma, Qin Tang, Xin Gao, Joun Lee, Run Lei, Masako Suzuki, Deyou Zheng, Keisuke Ito, Paul S Frenette, Meelad M Dawlaty.
      Ten-eleven translocation (Tet) enzymes promote DNA demethylation by oxidizing 5-methylcytosine. They are expressed during development and are essential for mouse gastrulation. However, their postgastrulation functions are not well established. We find that global or endothelial-specific loss of all three Tet enzymes immediately after gastrulation leads to reduced number of hematopoietic stem and progenitor cells (HSPCs) and lethality in mid-gestation mouse embryos. This is due to defects in specification of HSPCs from endothelial cells (ECs) that compromise primitive and definitive hematopoiesis. Mechanistically, loss of Tet enzymes in ECs led to hypermethylation and down-regulation of NFκB1 and master hematopoietic transcription factors (Gata1/2, Runx1, and Gfi1b). Restoring Tet catalytic activity or overexpression of these factors in Tet-deficient ECs rescued hematopoiesis defects. This establishes Tet enzymes as activators of hematopoiesis programs in ECs for specification of HSPCs during embryogenesis, which is distinct from their roles in adult hematopoiesis, with implications in deriving HSPCs from pluripotent cells.
    DOI:  https://doi.org/10.1126/sciadv.abm3470
  5. N Engl J Med. 2022 Mar 02. pii: 10.1056/NEJMc2201556#sa2. [Epub ahead of print]386(12):
    More on BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.
    Raya Leibowitz, Efrat Schurr, Omer Hirsch.
      
    DOI:  https://doi.org/10.1056/NEJMc2201556
  6. Elife. 2022 Mar 02. pii: e75658. [Epub ahead of print]11
    Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
    Qingqing Liu, Catherine E Chang, Alexandra C Wooldredge, Benjamin Fong, Brian K Kennedy, Chuankai Zhou.
      Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.
    Keywords:  S. cerevisiae; cell biology
    DOI:  https://doi.org/10.7554/eLife.75658
  7. Nat Neurosci. 2022 Mar 03.
    Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine.
    Omar Mossad, Bérénice Batut, Bahtiyar Yilmaz, Nikolaos Dokalis, Charlotte Mezö, Elisa Nent, Lara Susann Nabavi, Melanie Mayer, Feres José Mocayar Maron, Joerg M Buescher, Mercedes Gomez de Agüero, Antal Szalay, Tim Lämmermann, Andrew J Macpherson, Stephanie C Ganal-Vonarburg, Rolf Backofen, Daniel Erny, Marco Prinz, Thomas Blank.
      Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression. The absence of gut microbiota diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia from the brains of aged mice. Unbiased metabolomic analyses of serum and brain tissue revealed the accumulation of N6-carboxymethyllysine (CML) in the microglia of the aging brain. CML mediated a burst of reactive oxygen species and impeded mitochondrial activity and ATP reservoirs in microglia. We validated the age-dependent rise in CML levels in the sera and brains of humans. Finally, a microbiota-dependent increase in intestinal permeability in aged mice mediated the elevated levels of CML. This study adds insight into how specific features of microglia from aged mice are regulated by the gut microbiota.
    DOI:  https://doi.org/10.1038/s41593-022-01027-3
  8. Lab Anim (NY). 2022 Mar;51(3): 76
    Immune aging in killifish.
    Alexandra Le Bras.
      
    DOI:  https://doi.org/10.1038/s41684-022-00934-z
  9. Trends Immunol. 2022 Feb 11. pii: S1471-4906(22)00025-4. [Epub ahead of print]
    NAD+ in COVID-19 and viral infections.
    Minyan Zheng, Michael B Schultz, David A Sinclair.
      NAD+, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19). In this Opinion, we suggest that interventions that boost NAD+ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD+ concentrations and risk factors for poor COVID-19 outcomes, including aging and common comorbidities. Mechanistically, we outline how viral infections can further deplete NAD+ and its roles in antiviral defense and inflammation. We also describe how coronaviruses can subvert NAD+-mediated actions via genes that remove NAD+ modifications and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Finally, we explore ongoing approaches to boost NAD+ concentrations in the clinic to putatively increase antiviral responses while curtailing hyperinflammation.
    Keywords:  COVID-19; NAD(+); immune responses; inflammation
    DOI:  https://doi.org/10.1016/j.it.2022.02.001
  10. J Clin Invest. 2022 Mar 01. pii: e157434. [Epub ahead of print]132(5):
    Taking the STING out of acute myeloid leukemia through macrophage-mediated phagocytosis.
    William Brian Dalton, Gabriel Ghiaur, Linda Ms Resar.
      Macrophages within the bone marrow (BM) microenvironment take on unexpected roles in acute myeloid leukemia (AML) as reported by Moore and colleagues in this issue of the JCI. In contrast to solid tumors, where tumor-associated macrophages frequently assume an immunosuppressive phenotype that promotes tumor progression, this study revealed that BM macrophages repressed leukemia expansion in AML through a pathway called LC3-associated phagocytosis (LAP). After phagocytosis of dead and dying leukemic cells, including the mitochondria within the leukemic blasts, mitochondrial DNA activated stimulator of IFN genes (STING), leading to inflammatory signals that enhanced phagocytosis and restrained leukemic cell expansion. These findings unveil the modulation of macrophage-mediated phagocytosis via LAP as a potential therapeutic strategy directed at the BM microenvironment in AML.
    DOI:  https://doi.org/10.1172/JCI157434
  11. Leuk Res. 2022 Feb 22. pii: S0145-2126(22)00044-3. [Epub ahead of print] 106818
    Clonal compositions involving epigenetic regulator and splicing mutations in CHIP, CCUS, MDS, and CMML.
    Zhuoer Xie, Gina Campestri, Terra Lasho, Christy Finke, Marissa Li, Moritz Binder, Jenna Fernandez, Horatiu Olteanu, Kaaren K Reichard, Rhett Ketterling, Mark Litzow, Ayalew Tefferi, Abhishek Mangaonkar, Naseema Gangat, Al-Kali Aref, Mrinal M Patnaik.
      
    Keywords:  CCUS; CHIP; CMML; Clonal Compositions; Clonal Hematopoiesis; Epigenetic Regulator Genes; MDS; Splicing Genes
    DOI:  https://doi.org/10.1016/j.leukres.2022.106818
  12. World Rev Nutr Diet. 2022 ;124 189-196
    2.8 Nutrition in Pregnancy and Lactation.
    Lenka Malek, Merryn Netting, Maria Makrides.
      
    Keywords:  Lactation; Nutrition; Pregnancy
    DOI:  https://doi.org/10.1159/000516720
  13. BMJ Open. 2022 Mar 02. 12(3): e048502
    Adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomised trials.
    Ariel Izcovich, Reed Alexander Siemieniuk, Jessica Julia Bartoszko, Long Ge, Dena Zeraatkar, Elena Kum, Anila Qasim, Assem M Khamis, Bram Rochwerg, Thomas Agoritsas, Derek K Chu, Shelley L McLeod, Reem A Mustafa, Per Vandvik, Romina Brignardello-Petersen.
       BACKGROUND: To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19.
    METHODS: We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach.
    RESULTS: We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo.
    DISCUSSION: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.
    Keywords:  COVID-19; adverse events; infectious diseases
    DOI:  https://doi.org/10.1136/bmjopen-2020-048502
  14. Blood. 2022 Mar 04. pii: blood.2021013934. [Epub ahead of print]
    Endothelial MEKK3-KLF2/4 signaling integrates inflammatory and hemodynamic signals during definitive hematopoiesis.
    Yiqing Yang, Melanie Mumau, Joanna Tober, Qin Zhu, Laura Bennett, Courtney Hong, Derek Chou Sung, Thomas Collins Stevenson Keller, Yasin Uzun, Peng Gao, Swapnil Shewale, Mei Chen, Jisheng Yang, Xiaowen Chen, Steven A Thomas, Kai Tan, Nancy A Speck, Mark L Kahn.
      The hematopoietic stem cells (HSCs) that produce blood for the lifetime of an animal arise from RUNX1+ hemogenic endothelial cells (HECs) in the embryonic vasculature through a process of endothelial-to-hematopoietic transition (EHT). Studies have identified inflammatory mediators and fluid shear forces as critical environmental stimuli for EHT, raising the question of how such diverse inputs are integrated to drive HEC specification. Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid shear forces and inflammatory mediators, and plays roles in cardiovascular development and disease that have been linked to both stimuli. Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for the specification of RUNX1+ HECs in both the yolk sac and dorsal aorta of the mouse embryo and for their transition to intra-aortic hematopoietic cluster cells (IAHCs). The inflammatory mediators lipopolysaccharide and interferon gamma increase RUNX1+ HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis.
    DOI:  https://doi.org/10.1182/blood.2021013934
  15. Aging Cell. 2022 Mar 02. e13578
    Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming.
    Dafni Chondronasiou, Diljeet Gill, Lluc Mosteiro, Rocio G Urdinguio, Antonio Berenguer-Llergo, Mònica Aguilera, Sylvere Durand, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Abad, Daniel E Martin-Herranz, Camille Stephan-Otto Attolini, Neus Prats, Guido Kroemer, Mario F Fraga, Wolf Reik, Manuel Serrano.
      The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.
    Keywords:  OSKM; Yamanaka; aging; epigenetic clocks; pluripotency; reprogramming; transcriptomic clocks
    DOI:  https://doi.org/10.1111/acel.13578
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