bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–02–27
seventeen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Aging and Clonal Behavior of Hematopoietic Stem Cells.
  2. Inflammation, Aging, and Cardiovascular Disease: JACC Review Topic of the Week.
  3. Health benefits of calorie restriction.
  4. What Clonal Hematopoiesis Can Teach Us About MDS.
  5. Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions.
  6. VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells.
  7. Implementing care for healthy ageing.
  8. Interleukin 6 as an energy allocator in muscle tissue.
  9. IDH1/2 mutations in acute myeloid leukemia.
  10. A BAX door to venetoclax resistance.
  11. Implementation Science: accelerating translation of clinical evidence into practice.
  12. COVID-19 Linked With Increased Incidence of Youth Diabetes.
  13. Flavonoids-Natural Gifts to Promote Health and Longevity.
  14. Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy.
  15. Geriatric assessment in older adults with Non-Hodgkin lymphoma: A Young International Society of Geriatric Oncology (YSIOG) review paper.
  16. Fourth dose of COVID vaccine offers only slight boost against Omicron infection.
  17. A phase II randomized study evaluating azacitidine versus conventional care regimens in newly diagnosed elderly Japanese patients with unfavorable acute myeloid leukemia.
  1. Int J Mol Sci. 2022 Feb 09. pii: 1948. [Epub ahead of print]23(4):
    Aging and Clonal Behavior of Hematopoietic Stem Cells.
    Masayuki Yamashita, Atsushi Iwama.
      Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism's life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence suggests that HSCs alter their function and become less active during organismal aging, leading ultimately to the disruption of hematopoietic homeostasis, such as anemia, perturbed immunity and increased propensity to hematological malignancies. Thus, understanding how HSCs alter their function during aging is a matter of critical importance to prevent or overcome these age-related changes in the blood system. Recent advances in clonal analysis have revealed the functional heterogeneity of murine HSC pools that is established upon development and skewed toward the clonal expansion of functionally poised HSCs during aging. In humans, next-generation sequencing has revealed age-related clonal hematopoiesis that originates from HSC subsets with acquired somatic mutations, and has highlighted it as a significant risk factor for hematological malignancies and cardiovascular diseases. In this review, we summarize the current fate-mapping strategies that are used to track and visualize HSC clonal behavior during development or after stress. We then review the age-related changes in HSCs that can be inherited by daughter cells and act as a cellular memory to form functionally distinct clones. Altogether, we link aging of the hematopoietic system to HSC clonal evolution and discuss how HSC clones with myeloid skewing and low regenerative potential can be expanded during aging.
    Keywords:  aging; clonal hematopoiesis; fate mapping; hematopoietic stem cells
    DOI:  https://doi.org/10.3390/ijms23041948
  2. J Am Coll Cardiol. 2022 Mar 01. pii: S0735-1097(21)08447-3. [Epub ahead of print]79(8): 837-847
    Inflammation, Aging, and Cardiovascular Disease: JACC Review Topic of the Week.
    Luca Liberale, Lina Badimon, Fabrizio Montecucco, Thomas F Lüscher, Peter Libby, Giovanni G Camici.
      Aging and inflammation both contribute pivotally to cardiovascular (CV) and cerebrovascular disease, the leading causes of death and disability worldwide. The concept of inflamm-aging recognizes that low-grade inflammatory pathways observed in the elderly contribute to CV risk. Understanding the mechanisms that link inflammation and aging could reveal new therapeutic targets and offer options to cope with the growing aging population worldwide. This review reports recent scientific advances in the pathways through which inflamm-aging mediates age-dependent decline in CV function and disease onset and considers critically the translational potential of such concepts into everyday clinical practice.
    Keywords:  cardiovascular disease; inflamm-aging; inflammation; vascular aging
    DOI:  https://doi.org/10.1016/j.jacc.2021.12.017
  3. Nat Med. 2022 Feb 24.
    Health benefits of calorie restriction.
    Karen O'Leary.
      
    Keywords:  Ageing; Inflammation; Nutrition; Translational research
    DOI:  https://doi.org/10.1038/d41591-022-00036-w
  4. Front Oncol. 2022 ;12 794021
    What Clonal Hematopoiesis Can Teach Us About MDS.
    Irenaeus C C Chan, Brian J Wiley, Kelly L Bolton.
      Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Recent work has elucidated how the development and cellular fitness of CH is shaped by aging, environmental exposures, and the germline (inherited) genetic background of an individual. This in turn has provided valuable insights into the pathogenesis of MNs including MDS. Here, in this review, we discuss the genetic origins of CH, the environmental stressors that influence CH, and the implications of CH on health outcomes including MDS. Since MNs have shared risk factors and underlying biology, most of our discussion regarding the implications of CH surrounds MN in general rather than focusing specifically on MDS. We conclude with future directions and areas of investigation including how intervention studies of CH might inform future therapeutic approaches to MN including MDS.
    Keywords:  clonal hematopoiesis (CH); environmental risk; genetic predisposition; myelodysplastic syndrome (MDS); myeloid neoplasm
    DOI:  https://doi.org/10.3389/fonc.2022.794021
  5. Cells. 2022 Feb 15. pii: 675. [Epub ahead of print]11(4):
    Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions.
    Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Francesco P Damiano, Cecilia Bucci, Emanuele Marzetti.
      Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components-in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions.
    Keywords:  exosomes; extracellular vesicles; inflamm-aging; mitochondrial damage; mitochondrial dynamics; mitochondrial-derived vesicles; mitochondrial-lysosomal axis; mitophagy; oxidative stress; senescence
    DOI:  https://doi.org/10.3390/cells11040675
  6. Nat Cell Biol. 2022 Feb 24.
    VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells.
    Sandra Pinho, Qiaozhi Wei, Maria Maryanovich, Dachuan Zhang, Juan Carlos Balandrán, Halley Pierce, Fumio Nakahara, Anna Di Staulo, Boris A Bartholdy, Jianing Xu, Daniel K Borger, Amit Verma, Paul S Frenette.
      Haematopoietic stem cells (HSCs) home to the bone marrow via, in part, interactions with vascular cell adhesion molecule-1 (VCAM1)1-3. Once in the bone marrow, HSCs are vetted by perivascular phagocytes to ensure their self-integrity. Here we show that VCAM1 is also expressed on healthy HSCs and upregulated on leukaemic stem cells (LSCs), where it serves as a quality-control checkpoint for entry into bone marrow by providing 'don't-eat-me' stamping in the context of major histocompatibility complex class-I (MHC-I) presentation. Although haplotype-mismatched HSCs can engraft, Vcam1 deletion, in the setting of haplotype mismatch, leads to impaired haematopoietic recovery due to HSC clearance by mononuclear phagocytes. Mechanistically, VCAM1 'don't-eat-me' activity is regulated by β2-microglobulin MHC presentation on HSCs and paired Ig-like receptor-B (PIR-B) on phagocytes. VCAM1 is also used by cancer cells to escape immune detection as its expression is upregulated in multiple cancers, including acute myeloid leukaemia (AML), where high expression associates with poor prognosis. In AML, VCAM1 promotes disease progression, whereas VCAM1 inhibition or deletion reduces leukaemia burden and extends survival. These results suggest that VCAM1 engagement regulates a critical immune-checkpoint gate in the bone marrow, and offers an alternative strategy to eliminate cancer cells via modulation of the innate immune tolerance.
    DOI:  https://doi.org/10.1038/s41556-022-00849-4
  7. BMJ Glob Health. 2022 Feb;pii: e007778. [Epub ahead of print]7(2):
    Implementing care for healthy ageing.
    Matteo Cesari, Yuka Sumi, Zee A Han, Monica Perracini, Hyobum Jang, Andrew Briggs, Jotheeswaran Amuthavalli Thiyagarajan, Ritu Sadana, Anshu Banerjee.
      The WHO concept of Healthy Ageing (ie, the process of developing and maintaining the functional ability that enables well-being in older age) has initiated a global discussion about the need for shifting paradigms to reorient health and social services towards person-centred and coordinated models of care. In particular, the integration of health and social care services is critical to provide the basis for comprehensive information sharing and service delivery to support the evolution of the older person over time. The capability to monitor and respond to an older person's changing health and social care needs will enable prompt and personalised health and social care plans to be implemented.The implementation of an integrated care approach involves all the settings where persons age, but also requires a concerted action among micro (clinical), meso (service delivery) and macro (system) level. The community is of particular relevance given the primary objective of "ageing in place". However, from the perspective of the continuum of care and services acting synergistically, all health and social care settings (including long-term care facilities and hospitals) need to evolve and embrace an integrated way of operating to support functional ability in older people, while maximising resource and information sharing efficiencies.In this paper, we explain that government actions to promote well-being in older age should be built on a seamless continuum of care starting from the assessment of the older person's intrinsic capacity and functional ability with the final aim of providing care aligned with the individual's needs and priorities.
    Keywords:  health policies and all other topics; public health
    DOI:  https://doi.org/10.1136/bmjgh-2021-007778
  8. Nat Metab. 2022 Feb 24.
    Interleukin 6 as an energy allocator in muscle tissue.
    Timothy M Kistner, Bente K Pedersen, Daniel E Lieberman.
      Extensive research has shown that interleukin 6 (IL-6) is a multifunctional molecule that is both proinflammatory and anti-inflammatory, depending on the context. Here, we combine an evolutionary perspective with physiological data to propose that IL-6's context-dependent effects on metabolism reflect its adaptive role for short-term energy allocation. This energy-allocation role is especially salient during physical activity, when skeletal muscle releases large amounts of IL-6. We predict that during bouts of physical activity, myokine IL-6 fulfills the three main characteristics of a short-term energy allocator: it is secreted from muscle in response to an energy deficit, it liberates somatic energy through lipolysis and it enhances muscular energy uptake and transiently downregulates immune function. We then extend this model of energy allocation beyond myokine IL-6 to reinterpret the roles that IL-6 plays in chronic inflammation, as well as during COVID-19-associated hyperinflammation and multiorgan failure.
    DOI:  https://doi.org/10.1038/s42255-022-00538-4
  9. Blood Res. 2022 Feb 24.
    IDH1/2 mutations in acute myeloid leukemia.
    Ja Min Byun, Seung-Joo Yoo, Hyeong-Joon Kim, Jae-Sook Ahn, Youngil Koh, Jun Ho Jang, Sung-Soo Yoon.
      The mutational and epigenetic landscape of acute myeloid leukemia (AML) has become increasingly well understood in recent years, informing on biological targets for precision medicine. Among the most notable findings was the recognition of mutational hot-spots in the isocitrate dehydrogenase (IDH) genes. In this review, we provide an overview on the IDH1/2 mutation landscape in Korean AML patients, and compare it with available public data. We also discuss the role of IDH1/2 mutations as biomarkers and drug targets. Taken together, occurrence of IDH1/2 mutations is becoming increasingly important in AML treatment, thus requiring thorough examination and follow-up throughout the clinical course of the disease.
    Keywords:  Acute myeloid leukemia; Biomarker; Drug target; IDH; Korean
    DOI:  https://doi.org/10.5045/br.2021.2021152
  10. Blood. 2022 Feb 24. 139(8): 1124-1126
    A BAX door to venetoclax resistance.
    Franco Izzo, Dan A Landau.
      
    DOI:  https://doi.org/10.1182/blood.2021013788
  11. Hepatology. 2022 Feb 19.
    Implementation Science: accelerating translation of clinical evidence into practice.
    Michael L Volk.
      
    DOI:  https://doi.org/10.1002/hep.32415
  12. JAMA. 2022 Feb 22. 327(8): 711
    COVID-19 Linked With Increased Incidence of Youth Diabetes.
    Bridget M Kuehn.
      
    DOI:  https://doi.org/10.1001/jama.2022.0936
  13. Int J Mol Sci. 2022 Feb 16. pii: 2176. [Epub ahead of print]23(4):
    Flavonoids-Natural Gifts to Promote Health and Longevity.
    Xiaolan Fan, Ziqiang Fan, Ziyue Yang, Tiantian Huang, Yingdong Tong, Deying Yang, Xueping Mao, Mingyao Yang.
      The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.
    Keywords:  aging; flavonoids; health span; macromolecular damage
    DOI:  https://doi.org/10.3390/ijms23042176
  14. Int J Mol Sci. 2022 Feb 12. pii: 2054. [Epub ahead of print]23(4):
    Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy.
    Mark F McCarty.
      Macroautophagy is a "cell cleansing" process that rids cells of protein aggregates and damaged organelles that may contribute to disease pathogenesis and the dysfunctions associated with aging. Measures which boost longevity and health span in rodents typically up-regulate macroautophagy, and it has often been suggested that safe strategies which can promote this process in humans may contribute to healthful aging. The kinase ULK1 serves as a trigger for autophagy initiation, and the transcription factors TFEB, FOXO1, ATF4 and CHOP promote expression of a number of proteins which mediate macroautophagy. Nutraceutical or dietary measures which stimulate AMPK, SIRT1, eIF5A, and that diminish the activities of AKT and mTORC1, can be expected to boost the activities of these pro-autophagic factors. The activity of AMPK can be stimulated with the phytochemical berberine. SIRT1 activation may be achieved with a range of agents, including ferulic acid, melatonin, urolithin A, N1-methylnicotinamide, nicotinamide riboside, and glucosamine; correction of ubiquinone deficiency may also be useful in this regard, as may dietary strategies such as time-restricted feeding or intermittent fasting. In the context of an age-related decrease in cellular polyamine levels, provision of exogenous spermidine can boost the hypusination reaction required for the appropriate post-translational modification of eIF5A. Low-protein plant-based diets could be expected to increase ATF4 and CHOP expression, while diminishing IGF-I-mediated activation of AKT and mTORC1. Hence, practical strategies for protecting health by up-regulating macroautophagy may be feasible.
    Keywords:  AMPK; N1-methylnicotinamide; SIRT1; autophagy; berberine; ferulic acid; glucosamine; macroautophagy; melatonin; nicotinamide riboside; plant-based diets; ubiquinone; urolithin A
    DOI:  https://doi.org/10.3390/ijms23042054
  15. J Geriatr Oncol. 2022 Feb 22. pii: S1879-4068(22)00020-0. [Epub ahead of print]
    Geriatric assessment in older adults with Non-Hodgkin lymphoma: A Young International Society of Geriatric Oncology (YSIOG) review paper.
    Othman Salim Akhtar, Li-Wen Huang, Mazie Tsang, Pallawi Torka, Kah Poh Loh, Vicki A Morrison, Raul Cordoba.
      Non-Hodgkin lymphoma (NHL) is a disease of older adults, with a median age at diagnosis of 67 years. Treatment in older adults with NHL is challenging. The aging process is associated with a decline in functional reserve that varies among individuals, and results in an increasing risk of treatment-related toxicity and mortality. Chronological age and performance status fail to capture the multidimensional and heterogeneous nature of the aging process. A geriatric assessment (GA) screens multiple geriatric domains and provides a more accurate assessment of functional reserve. Several abbreviated GA tools have been developed for use in oncology clinics and help identify patients at high risk for chemotherapy-related toxicity and mortality. In this review, we explore GA tools validated for use in patients with NHL. We discuss the evidence behind GA-guided treatment in NHL and present a suggested approach to assessing frailty in this patient population.
    Keywords:  Frailty; Geriatric assessment; Lymphoma; Non-Hodgkin lymphoma; Older adults
    DOI:  https://doi.org/10.1016/j.jgo.2022.02.005
  16. Nature. 2022 Feb 23.
    Fourth dose of COVID vaccine offers only slight boost against Omicron infection.
    Smriti Mallapaty.
      
    Keywords:  Epidemiology; Immunology; Medical research; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-022-00486-9
  17. Int J Hematol. 2022 Feb 24.
    A phase II randomized study evaluating azacitidine versus conventional care regimens in newly diagnosed elderly Japanese patients with unfavorable acute myeloid leukemia.
    Study Group
      A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients.
    Keywords:  Acute myeloid leukemia; Azacitidine; Front-line therapy; Japanese patients; Phase 2 study
    DOI:  https://doi.org/10.1007/s12185-022-03307-x
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