bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–12–12
ten papers selected by
Ayesh Seneviratne, University of Toronto
  1. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging.
  2. CHIP: is clonal hematopoiesis a surrogate for aging and other disease?
  3. Mitophagy in aging and longevity.
  4. Clonal hematopoiesis and atherosclerotic cardiovascular disease: A primer.
  5. Role of Prohibitins in Aging and Therapeutic Potential Against Age-Related Diseases.
  6. Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection.
  7. Vascular Regulation of Hematopoietic Stem Cell Homeostasis, Regeneration, and Aging.
  8. How predictive is the finding of clonal hematopoiesis for the development of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML)?
  9. When are idiopathic and clonal cytopenias of unknown significance (ICUS or CCUS)?
  10. Mechanisms and Regulation of Cellular Senescence.
  1. Nat Aging. 2021 Jul;1 598-615
    An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging.
    Nazish Sayed, Yingxiang Huang, Khiem Nguyen, Zuzana Krejciova-Rajaniemi, Anissa P Grawe, Tianxiang Gao, Robert Tibshirani, Trevor Hastie, Ayelet Alpert, Lu Cui, Tatiana Kuznetsova, Yael Rosenberg-Hasson, Rita Ostan, Daniela Monti, Benoit Lehallier, Shai S Shen-Orr, Holden T Maecker, Cornelia L Dekker, Tony Wyss-Coray, Claudio Franceschi, Vladimir Jojic, François Haddad, José G Montoya, Joseph C Wu, Mark M Davis, David Furman.
      While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.
    DOI:  https://doi.org/10.1038/s43587-021-00082-y
  2. Hematology Am Soc Hematol Educ Program. 2021 Dec 10. 2021(1): 384-389
    CHIP: is clonal hematopoiesis a surrogate for aging and other disease?
    Lukasz P Gondek.
      Somatic mutations are an unavoidable consequence of aging tissues. Even though most mutations are functionally silent, some may affect genes critical to proper tissue self-renewal and differentiation, resulting in the outgrowth of affected cells, also known as clonal expansion. In hematopoietic tissue such clonal dominance is known as clonal hematopoiesis (CH). Sporadic CH is frequent in aging and affects over 10% of individuals beyond the fifth decade of life. It has been associated with an increased risk of hematologic malignancies and cardiovascular disease. In addition to aging, CH has been observed in other hematologic conditions and confers an adaptation of hematopoietic stem cells (HSCs) to various environmental stressors and cell-intrinsic defects. In the presence of extrinsic stressors such as genotoxic therapies, T-cell-mediated immune attack, or inflammation, somatic mutations may result in augmentation of HSC fitness. Such attuned HSCs can evade the environmental insults and outcompete their unadapted counterparts. Similarly, in inherited bone marrow failures, somatic mutations in HSCs frequently lead to the reversion of inherited defects. This may occur via the direct correction of germline mutations or indirect compensatory mechanisms. Occasionally, such adaptation may involve oncogenes or tumor suppressors, resulting in malignant transformation. In this brief article, we focus on the mechanisms of clonal dominance in various clinical and biological contexts.
    DOI:  https://doi.org/10.1182/hematology.2021000270
  3. IUBMB Life. 2021 Dec 10.
    Mitophagy in aging and longevity.
    Jing Guo, Wei-Chung Chiang.
      The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.
    Keywords:  aging; longevity; mitophagy
    DOI:  https://doi.org/10.1002/iub.2585
  4. Clin Investig Arterioscler. 2021 Dec 05. pii: S0214-9168(21)00139-X. [Epub ahead of print]
    Clonal hematopoiesis and atherosclerotic cardiovascular disease: A primer.
    María A Zuriaga, José J Fuster.
      Despite current standards of care, a considerable risk of atherosclerotic cardiovascular disease remains in both primary and secondary prevention. In this setting, clonal hematopoiesis driven by somatic mutations has recently emerged as a relatively common, potent and independent risk factor for atherosclerotic cardiovascular disease and other cardiovascular conditions. Experimental studies in mice suggest that mutations in TET2 and JAK2, which are among the most common in clonal hematopoiesis, increase inflammation and are causally connected to accelerated atherosclerosis development, which may explain the link between clonal hematopoiesis and increased cardiovascular risk. In this review, we provide an overview of our current understanding of this emerging cardiovascular risk factor.
    Keywords:  Aging; Atherosclerosis; CHIP; Inflammation; JAK2; TET2
    DOI:  https://doi.org/10.1016/j.arteri.2021.09.006
  5. Front Genet. 2021 ;12 714228
    Role of Prohibitins in Aging and Therapeutic Potential Against Age-Related Diseases.
    Misa Belser, David W Walker.
      A decline in mitochondrial function has long been associated with age-related health decline. Several lines of evidence suggest that interventions that stimulate mitochondrial autophagy (mitophagy) can slow aging and prolong healthy lifespan. Prohibitins (PHB1 and PHB2) assemble at the mitochondrial inner membrane and are critical for mitochondrial homeostasis. In addition, prohibitins (PHBs) have diverse roles in cell and organismal biology. Here, we will discuss the role of PHBs in mitophagy, oxidative phosphorylation, cellular senescence, and apoptosis. We will also discuss the role of PHBs in modulating lifespan. In addition, we will review the links between PHBs and diseases of aging. Finally, we will discuss the emerging concept that PHBs may represent an attractive therapeutic target to counteract aging and age-onset disease.
    Keywords:  PHB1; PHB2; age-related diseases; aging; prohibitin
    DOI:  https://doi.org/10.3389/fgene.2021.714228
  6. Nat Commun. 2021 Dec 08. 12(1): 7130
    Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection.
    Jayna J Mistry, Charlotte Hellmich, Jamie A Moore, Aisha Jibril, Iain Macaulay, Mar Moreno-Gonzalez, Federica Di Palma, Naiara Beraza, Kristian M Bowles, Stuart A Rushworth.
      Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete. Using mouse models, we show that inducible CD36 is required for free fatty acid uptake by HSCs during acute infection, allowing the metabolic transition from glycolysis towards β-oxidation. Mechanistically, high CD36 levels promote FFA uptake, which enables CPT1A to transport fatty acyl chains from the cytosol into the mitochondria. Without CD36-mediated FFA uptake, the HSCs are unable to enter the cell cycle, subsequently enhancing mortality in response to bacterial infection. These findings enhance our understanding of HSC metabolism in the bone marrow microenvironment, which supports the expansion of HSCs during pathogenic challenge.
    DOI:  https://doi.org/10.1038/s41467-021-27460-9
  7. Curr Stem Cell Rep. 2021 ;7(4): 194-203
    Vascular Regulation of Hematopoietic Stem Cell Homeostasis, Regeneration, and Aging.
    Pradeep Ramalingam, Jason M Butler, Michael G Poulos.
       Purpose of Review: Hematopoietic stem cells (HSCs) sit at the top of the hierarchy that meets the daily burden of blood production. HSC maintenance relies on extrinsic cues from the bone marrow (BM) microenvironment to balance stem cell self-renewal and cell fate decisions. In this brief review, we will highlight the studies and model systems that define the centralized role of BM vascular endothelium in modulating HSC activity in health and stress.
    Recent Findings: The BM microenvironment is composed of a diverse array of intimately associated vascular and perivascular cell types. Recent dynamic imaging studies, coupled with single-cell RNA sequencing (scRNA-seq) and functional readouts, have advanced our understanding of the HSC-supportive cell types and their cooperative mechanisms that govern stem cell fate during homeostasis, regeneration, and aging. These findings have established complex and discrete vascular microenvironments within the BM that express overlapping and unique paracrine signals that modulate HSC fate.
    Summary: Understanding the spatial and reciprocal HSC-niche interactions and the molecular mechanisms that govern HSC activity in the BM vascular microenvironment will be integral in developing therapies aimed at ameliorating hematological disease and supporting healthy hematopoietic output.
    Keywords:  Aging; HSC niche; HSC regeneration; Inflammaging; Inflammation; Vascular niche
    DOI:  https://doi.org/10.1007/s40778-021-00198-2
  8. Best Pract Res Clin Haematol. 2021 Dec;pii: S1521-6926(21)00092-X. [Epub ahead of print]34(4): 101327
    How predictive is the finding of clonal hematopoiesis for the development of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML)?
    David P Steensma.
      Clonal hematopoiesis (CH) - a biological state in which one or a small number of hematopoietic stem or progenitor cells contribute disproportionately to blood cell production, usually as a result of somatic gene mutations in the stem cells - is often considered to be a precursor to myeloid neoplasia, especially myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, the majority of people with CH never develop an overt myeloid neoplasm, and CH can be a precursor to lymphoid cancers as well as myeloid neoplasms. In addition, CH increases all-cause mortality and augments the risk of several non-neoplastic medical conditions, including atherosclerotic cardiovascular disease. CH can arise during aging, or in the context of an inherited marrow failure syndrome, aplastic anemia, or hematopoietic cell transplantation. Risk factors for progression of CH to myeloid neoplasia include larger clone size; the presence of a TP53, IDH1/2, or splicing mutation; multiple mutations; and associated cytopenias or abnormal red blood cell indices. The receipt of genotoxic chemotherapy or radiation, which can promote clonal expansion of mutant clones at the expense of healthy progenitor cells, may result in therapy-related MDS/AML.
    Keywords:  Clonal evolution; Clonal hematopoiesis; Myelodysplastic syndromes; Prognosis; Somatic mutations
    DOI:  https://doi.org/10.1016/j.beha.2021.101327
  9. Hematology Am Soc Hematol Educ Program. 2021 Dec 10. 2021(1): 399-404
    When are idiopathic and clonal cytopenias of unknown significance (ICUS or CCUS)?
    Afaf E W G Osman.
      Rapid advances in sequencing technology have led to the identification of somatic mutations that predispose a significant subset of the aging population to myeloid malignancies. Recently recognized myeloid precursor conditions include clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of unknown significance (CCUS). These conditions can present diagnostic challenges and produce unwarranted anxiety in some instances. While the risk of progression to myeloid malignancies is very low in CHIP, true CCUS confers an exponential increase in risk. Idiopathic cytopenia of unknown significance (IDUS) lacks the predisposing genetic mutations and has a variable course. In this review we define the early myeloid precursor conditions and their risk of progression. We present our diagnostic approach to patients with unexplained cytopenias and discuss the clinical consequences of CHIP and CCUS.
    DOI:  https://doi.org/10.1182/hematology.2021000272
  10. Int J Mol Sci. 2021 Dec 06. pii: 13173. [Epub ahead of print]22(23):
    Mechanisms and Regulation of Cellular Senescence.
    Lauréline Roger, Fanny Tomas, Véronique Gire.
      Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.
    Keywords:  DNA damage signaling; aging; cell cycle arrest; cellular senescence; epigenetic and chromatin changes; metabolism alteration; mitochondrial dysfunction; senescence-associated secretory phenotype; transcriptome signature
    DOI:  https://doi.org/10.3390/ijms222313173
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