bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–11–13
thirteen papers selected by
Ayesh Seneviratne, Western University
  1. Clonal hematopoiesis and bone marrow inflammation.
  2. Factors associated with clonal hematopoiesis and interaction with marrow environment.
  3. Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis.
  4. 2022 Jeffrey M. Hoeg Award Lecture: Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease.
  5. Clonal hematopoiesis in cardiovascular disease and therapeutic implications.
  6. Frailty After Cancer Surgery Among Older Adults: A Geriatric Oncology Perspective.
  7. T cell aging as a risk factor for autoimmunity.
  8. Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway.
  9. Frailty Among Asian Patients With Heart Failure.
  10. [Development of low-cost ex vivo hematopoietic stem cell expansion].
  11. YAP/TAZ dull the STING of aging.
  12. CRISPR cancer trial success paves the way for personalized treatments.
  13. Happy ageing by trusting our gut microbes.
  1. Transl Res. 2022 Nov 05. pii: S1931-5244(22)00246-8. [Epub ahead of print]
    Clonal hematopoiesis and bone marrow inflammation.
    Xinshu Xie, Meng Su, Kehan Ren, Xuezhen Ma, Zhiyi Lv, Zhaofeng Li, Yang Mei, Peng Ji.
      Clonal hematopoiesis (CH) occurs in hematopoietic stem cells with increased risks of progressing to hematologic malignancies. CH mutations are predominantly found in aged populations and correlate with an increased incidence of cardiovascular and other diseases. Increased lines of evidence demonstrate that CH mutations are closely related to the inflammatory bone marrow microenvironment. In this review, we summarize the recent advances in this topic starting from the discovery of CH and its mutations. We focus on the most commonly mutated and well-studied genes in CH and their contributions to the innate immune responses and inflammatory signaling, especially in the hematopoietic cells of bone marrow. We also aimed to discuss the interrelationship between inflammatory bone marrow microenvironment and CH mutations. Finally, we provide our perspectives on the challenges in the field and possible future directions to help understand the pathophysiology of CH.
    DOI:  https://doi.org/10.1016/j.trsl.2022.11.004
  2. J Bone Miner Metab. 2022 Nov 08.
    Factors associated with clonal hematopoiesis and interaction with marrow environment.
    Yasuhito Nannya.
      Clonal hematopoiesis (CH) is an expansion of clones in individuals without any hematologic abnormalities, often carrying the driver mutations implicated in myeloid tumors, such as DNMT3A, TET2, and ASXL1. Most notably, CH is an age-related event, accounting for ~ 10% of cases in people over 60 years old. CH may also be correlated with a previous history of cancer treatment with chemotherapeutic drugs/radiation and infection episodes. The link between aging and CH acquisition is best explained by the enhanced inflammatory level in the bone marrow environment, which in turn expands hematopoietic cell clones with mutations in myeloid drivers. This positive feedback accounts for not only increased incidence of subsequent myeloid tumors in CH carriers but also for increased all-cause mortality and cardiovascular diseases (CVD). Recent evidence from large-scale epidemiological studies with genetic profiles, and mice models that recapitulate hematopoietic clones harboring driver gene mutations has revealed the detailed pathophysiology of CH clones represented by specific driver mutations, especially regarding expansion mechanisms under environmental factors and how they alter the environment. This review introduces the current knowledge of CH with a special focus on its interaction with the marrow environment.
    Keywords:  Aging; Bone marrow environment; Clonal hematopoiesis
    DOI:  https://doi.org/10.1007/s00774-022-01380-0
  3. Blood. 2022 Nov 08. pii: blood.2022016832. [Epub ahead of print]
    Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis.
    María Piedad Menéndez-Gutiérrez, Jesús Porcuna, Ramesh C Nayak, Ana Paredes, Haixia Niu, Vanessa Núñez, Aditi Paranjpe, Manuel J Jose Gómez, Anukana Bhattacharjee, Daniel J Schnell, Fátima Sánchez-Cabo, John S S Welch, Nathan Salomonis, Jose Cancelas, Mercedes Ricote.
      Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Here, we show that dual deficiency for hematopoietic RXRa and RXRb induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRa and RXRb maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRa;RXRb-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXRa;RXRb-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.
    DOI:  https://doi.org/10.1182/blood.2022016832
  4. Arterioscler Thromb Vasc Biol. 2022 Nov 10.
    2022 Jeffrey M. Hoeg Award Lecture: Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease.
    Pradeep Natarajan.
      Chronologic age is the dominant risk factor for coronary artery disease but the features of aging promoting coronary artery disease are poorly understood. Advances in human genetics and population-based genetic profiling of blood cells have uncovered the surprising role of age-related subclinical leukemogenic mutations in blood cells, termed "clonal hematopoiesis of indeterminate potential," in coronary artery disease. Such mutations typically occur in DNMT3A, TET2, ASXL1, and JAK2. Murine and human studies prioritize the role of key inflammatory pathways linking clonal hematopoiesis with coronary artery disease. Increasingly larger, longitudinal, multiomics analyses are enabling further dissection into mechanistic insights. These observations expand the genetic architecture of coronary artery disease, now linking hallmark features of hematologic neoplasia with a much more common cardiovascular condition. Implications of these studies include the prospect of novel precision medicine paradigms for coronary artery disease.
    Keywords:  cardiovascular disease; clonal hematopoiesis; coronary artery disease; interleukin; mutation
    DOI:  https://doi.org/10.1161/ATVBAHA.122.318181
  5. Nat Cardiovasc Res. 2022 Feb;1(2): 116-124
    Clonal hematopoiesis in cardiovascular disease and therapeutic implications.
    Alan R Tall, Jose J Fuster.
      Clonal hematopoiesis arises from somatic mutations that provide a fitness advantage to hematopoietic stem cells and the outgrowth of clones of blood cells. Clonal hematopoiesis commonly involves mutations in genes that are involved in epigenetic modifications, signaling and DNA damage repair. Clonal hematopoiesis has emerged as a major independent risk factor in atherosclerotic cardiovascular disease, thrombosis and heart failure. Studies in mouse models of clonal hematopoiesis have shown an increase in atherosclerosis, thrombosis and heart failure, involving increased myeloid cell inflammatory responses and inflammasome activation. Although increased inflammatory responses have emerged as a common underlying principle, some recent studies indicate mutation-specific effects. The discovery of the association of clonal hematopoiesis with cardiovascular disease and the recent demonstration of benefit of anti-inflammatory treatments in human cardiovascular disease converge to suggest that anti-inflammatory treatments should be directed to individuals with clonal hematopoiesis. Such treatments could target specific inflammasomes, common downstream mediators such as IL-1β and IL-6, or mutations linked to clonal hematopoiesis.
    DOI:  https://doi.org/10.1038/s44161-021-00015-3
  6. J Natl Compr Canc Netw. 2022 Nov;pii: jnccn2011lw. [Epub ahead of print]20(11): 1276-1278
    Frailty After Cancer Surgery Among Older Adults: A Geriatric Oncology Perspective.
    Samuel Dubé, Shabbir M H Alibhai.
      
    DOI:  https://doi.org/10.6004/jnccn.2022.7086
  7. J Autoimmun. 2022 Nov 07. pii: S0896-8411(22)00155-X. [Epub ahead of print] 102947
    T cell aging as a risk factor for autoimmunity.
    Qingxiang Liu, Yanyan Zheng, Jorg J Goronzy, Cornelia M Weyand.
      Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur during the second half of life, counterintuitive to the concept of excess adaptive immunity driving immune-mediated tissue damage. T cells are particularly susceptible to aging-imposed changes, as they are under extreme proliferative pressure to fulfill the demands of clonal expansion and of homeostatic T cell repopulation. T cells in older adults have a footprint of genetic and epigenetic changes, lack mitochondrial fitness, and fail to maintain proteostasis, diverging them from host protection to host injury. Here, we review recent progress in understanding how the human T-cell system ages and the evidence detailing how T cell aging contributes to autoimmune conditions. T cell aging is now recognized as a risk determinant in two prototypic autoimmune syndromes; rheumatoid arthritis and giant cell arteritis. The emerging concept adds susceptibility to autoimmune and autoinflammatory disease to the spectrum of aging-imposed adaptations and opens new opportunities for immunomodulatory therapy by restoring the functional intactness of aging T cells.
    Keywords:  Autoimmune disease; Giant cell arteritis; Immune aging; Inflammaging; Rheumatoid arthritis; T cell aging
    DOI:  https://doi.org/10.1016/j.jaut.2022.102947
  8. EMBO Rep. 2022 Nov 07. e54729
    Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway.
    Srdjan Grusanovic, Petr Danek, Maria Kuzmina, Miroslava K Adamcova, Monika Burocziova, Romana Mikyskova, Karolina Vanickova, Sladjana Kosanovic, Jana Pokorna, Milan Reinis, Tomas Brdicka, Meritxell Alberich-Jorda.
      Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.
    Keywords:  IL-6/Jak/Stat3; chronic inflammation; chronic multifocal osteomyelitis; hematopoietic stem cells; niche
    DOI:  https://doi.org/10.15252/embr.202254729
  9. JACC Asia. 2021 Dec;1(3): 314-316
    Frailty Among Asian Patients With Heart Failure.
    Christy N Taylor, Hanna K Gaggin.
      
    Keywords:  Asia; frailty; frailty index; heart failure; outcomes
    DOI:  https://doi.org/10.1016/j.jacasi.2021.11.002
  10. Rinsho Ketsueki. 2022 ;63(10): 1422-1429
    [Development of low-cost ex vivo hematopoietic stem cell expansion].
    Takaharu Kimura, Satoshi Yamazaki.
      Hematopoietic stem cells (HSC) have self-renewal as well as multilineage differentiation capacity and maintain hematopoiesis throughout life. HSC transplantation (HSCT) is performed as a curative therapy for hematopoietic malignancies and nonmalignant hematopoietic disorders. Furthermore, bone marrow, mobilized peripheral blood, and cord blood are available sources for HSCT. HLA compatibility is the most critical factor for a successful HSCT. The HSC number in a graft is also invaluable for engraftment. Moreover, it is challenging to obtain an abundant number of HSC for patients with obesity, particularly, in cord blood. HSC ex vivo expansion is an appropriate solution for this problem. Extrinsic factors to expand and maintain HSCs, such as cytokines are identified from analysis of HSCs and their niche. Thus, HSC ex vivo expansion is improved by adding them in culture medium; however, it is still difficult for therapeutic applications. Recently, several small molecular compounds have been reported to facilitate ex vivo expansion of HSC. Clinical trials that transplant ex vivo expanded cord blood have been already expanded, and some trials demonstrate reduction of time to hematopoietic recovery. Thus, we anticipate that ex vivo expanded cord blood transplantation will be applied widely in the future.
    Keywords:  Ex vivo expansion; Hematopoietic stem cell transplantation; Polyvinyl alcohol; Small molecule compounds
    DOI:  https://doi.org/10.11406/rinketsu.63.1422
  11. J Cardiovasc Aging. 2022 ;pii: 44. [Epub ahead of print]2
    YAP/TAZ dull the STING of aging.
    Jamie Francisco, Dominic P Del Re.
      
    DOI:  https://doi.org/10.20517/jca.2022.33
  12. Nature. 2022 Nov 10.
    CRISPR cancer trial success paves the way for personalized treatments.
    Heidi Ledford.
      
    Keywords:  CRISPR-Cas9 genome editing; Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-022-03676-7
  13. Biochem Biophys Res Commun. 2022 Dec 10. pii: S0006-291X(22)01276-1. [Epub ahead of print]633 88-91
    Happy ageing by trusting our gut microbes.
    Anusha Jayaraman, Sven Pettersson.
      The human gut microbiota comprises of trillions of micro-organisms in the gut some which secrete metabolites that play a pivotal role in supporting optimal body and organ functions. These dynamic and malleable gut microbes share a bidirectional relationship with their hosts that supports health in an age- and sex-dependent manner. Disruption of the gut microbiota or decrease in their diversity and richness due to unhealthy changes in lifestyle, diet or social disconnection, always results in unwanted outcomes on the host health which fuel chronic disease symptoms including neurodegenerative diseases. Thus, impairment of gut microbiota composition, results in organ decline that accelerates an individual's biological ageing. Here we review evidence supporting the bidirectional relationships between the gut microbiota and biological ageing.
    DOI:  https://doi.org/10.1016/j.bbrc.2022.09.026
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