bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–08–07
thirteen papers selected by
Ayesh Seneviratne, Western University
  1. Mitochondrial Deep Dive into Hematopoietic Stem Cell Dormancy: Not Much Glycolysis but Plenty of Sluggish Lysosomes.
  2. Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells.
  3. The impact of inflammation-induced tumor plasticity during myeloid transformation.
  4. Early Growth Response Factor 1 in Aging Hematopoietic Stem Cells and Leukemia.
  5. New horizons in life extension, healthspan extension and exceptional longevity.
  6. Zebrafish models of inflammation in hematopoietic development and disease.
  7. Peripheral inflammation marker relationships to cognition in healthy older adults - A systematic review.
  8. Passive Remote Monitoring and Aging in Place: A Scoping Review.
  9. Intersection of Inflammation and Senescence in the Aging Lung Stem Cell Niche.
  10. Cellular senescence: the good, the bad and the unknown.
  11. TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging.
  12. Life-space, frailty, and health-related quality of life.
  13. Tieing together loose ends: telomere instability in cancer and aging.
  1. Exp Hematol. 2022 Jul 28. pii: S0301-472X(22)00577-X. [Epub ahead of print]
    Mitochondrial Deep Dive into Hematopoietic Stem Cell Dormancy: Not Much Glycolysis but Plenty of Sluggish Lysosomes.
    Jiajing Qiu, Saghi Ghaffari.
      The discovery of hematopoietic stem cells (HSCs) heterogeneity have had major implications for investigations of hematopoietic stem cell disorders, clonal hematopoiesis and HSC aging. More recent studies of the heterogeneity of HSC organelles have begun to provide additional insights into the HSC behavior with far reaching ramifications for mechanistic understanding of aging of HSCs and stem cell-derived diseases. Mitochondrial heterogeneity has been explored to expose HSC subsets with distinct properties and functions. Here we review some of the recent advances in these lines of studies that challenged the classical view of glycolysis in HSCs and led to the identification of lysosomes as dynamic pivotal switch in controlling HSC quiescence vs. activation beyond their function in autophagy.
    DOI:  https://doi.org/10.1016/j.exphem.2022.07.299
  2. Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00297-1. [Epub ahead of print]29(8): 1156-1158
    Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells.
    Sarah S Burns, Reuben Kapur.
      In the current issue of Cell Stem Cell, Bogeska et al. demonstrate that repeated exposures to inflammation cause indelible and specific functional compromise and accelerated aging of long-term hematopoietic stem cells (LT-HSCs). This study proposes the notion that the cumulative inflammatory events over the course of an organism's lifespan may irreversibly damage LT-HSCs.
    DOI:  https://doi.org/10.1016/j.stem.2022.07.002
  3. Cancer Discov. 2022 Aug 04. pii: CD-21-1146. [Epub ahead of print]
    The impact of inflammation-induced tumor plasticity during myeloid transformation.
    Anna Yeaton, Geraldine Cayanan, Sanam Loghavi, Igor Dolgalev, Emmett M Leddin, Christian E Loo, Hedieh Torabifard, Deedra Nicolet, Jingjing Wang, Kate Corrigan, Varvara Paraskevopoulou, Daniel T Starczynowski, Eric Wang, Omar Abdel-Wahab, Aaron D Viny, Richard M Stone, John C Byrd, Olga A Guryanova, Rahul M Kohli, G Andres Cisneros, Aristotelis Tsirigos, Ann-Kathrin Eisfeld, Iannis Aifantis, Maria Guillamot.
      Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated pre-leukemic cells. Individuals with CH are at an increased risk of developing hematopoietic malignancies. Here, we describe a novel animal model carrying a recurrent TET2 missense mutation, frequently found in CH and leukemic patients. In a fashion similar to CH, animals show signs of disease late in life when they develop a wide range of myeloid neoplasms, including acute myeloid leukemia (AML). Using single cell transcriptomic profiling of the bone marrow, we show that disease progression in aged animals correlates with an enhanced inflammatory response and the emergence of an aberrant inflammatory monocytic cell population. The gene signature characteristic of this inflammatory population is associated to poor prognosis in AML patients. Our study illustrates an example of collaboration between a genetic lesion found in CH and inflammation, leading to transformation and the establishment of blood neoplasms.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1146
  4. Front Cell Dev Biol. 2022 ;10 925761
    Early Growth Response Factor 1 in Aging Hematopoietic Stem Cells and Leukemia.
    Rohan Kulkarni.
      Aging is associated with various hematological disorders and a higher risk of myeloproliferative disorders. An aged hematopoietic system can be characterized by decreased immune function and increased myeloid cell production. Hematopoietic stem cells (HSCs) regulate the production of blood cells throughout life. The self-renewal and regenerative potential of HSCs determine the quality and quantity of the peripheral blood cells. External signals from the microenvironment under different conditions determine the fate of the HSCs to proliferate, self-renew, differentiate, or remain quiescent. HSCs respond impromptu to a vast array of extracellular signaling cascades such as cytokines, growth factors, or nutrients, which are crucial in the regulation of HSCs. Early growth response factor 1 (EGR1) is one of the key transcription factors controlling HSC proliferation and their localization in the bone marrow (BM) niche. Downregulation of Egr1 activates and recruits HSCs for their proliferation and differentiation to produce mature blood cells. Increased expression of Egr1 is implicated in immuno-aging of HSCs. However, dysregulation of Egr1 is associated with hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML). Here, we summarize the current understanding of the role of EGR1 in the regulation of HSC functionality and the manifestation of leukemia. We also discuss the alternative strategies to rejuvenate the aged HSCs by targeting EGR1 in different settings.
    Keywords:  HSC activation; HSC rejuvenation; aged HSCs; early growth response 1 (EGR1); hematopoitic stem cells; leukemia
    DOI:  https://doi.org/10.3389/fcell.2022.925761
  5. Age Ageing. 2022 Aug 02. pii: afac156. [Epub ahead of print]51(8):
    New horizons in life extension, healthspan extension and exceptional longevity.
    David G Le Couteur, Nir Barzilai.
      Many common chronic diseases and syndromes are ageing-related. This raises the prospect that therapeutic agents that target the biological changes of ageing will prevent or delay multiple diseases with a single therapy. Gerotherapeutic drugs are those that target pathways involved in ageing, with the aims of reducing the burden of ageing-related diseases and increasing lifespan and healthspan. The approach to discovering gerotherapeutic drugs is similar to that used to discover drugs for diseases. This includes screening for novel compounds that act on receptors or pathways that influence ageing or repurposing of drugs currently available for other indications. A novel approach involves studying populations with exceptional longevity, in order to identify genes variants linked with longer lifespan and could be targeted by drugs. Metformin, rapamycin and precursors of nicotinamide adenine dinucleotide are amongst the frontrunners of gerotherapeutics that are moving into human clinical trials to evaluate their effects on ageing. There are also increasing numbers of potential gerotherapeutic drugs in the pipeline or being studied in animal models. A key hurdle is designing clinical trials that are both feasible and can provide sufficient clinical evidence to support licencing and marketing of gerotherapeutic drugs.
    Keywords:  ageing; ageing biology; exceptional longevity; gerotherapeutic; metformin; nicotinamide adenine dinucleotide; older people; rapamycin
    DOI:  https://doi.org/10.1093/ageing/afac156
  6. Front Cell Dev Biol. 2022 ;10 955658
    Zebrafish models of inflammation in hematopoietic development and disease.
    Sarada Ketharnathan, Vinothkumar Rajan, Sergey V Prykhozhij, Jason N Berman.
      Zebrafish offer an excellent tool for studying the vertebrate hematopoietic system thanks to a highly conserved and rapidly developing hematopoietic program, genetic amenability, optical transparency, and experimental accessibility. Zebrafish studies have contributed to our understanding of hematopoiesis, a complex process regulated by signaling cues, inflammation being crucial among them. Hematopoietic stem cells (HSCs) are multipotent cells producing all the functional blood cells, including immune cells. HSCs respond to inflammation during infection and malignancy by proliferating and producing the blood cells in demand for a specific scenario. We first focus on how inflammation plays a crucial part in steady-state HSC development and describe the critical role of the inflammasome complex in regulating HSC expansion and balanced lineage production. Next, we review zebrafish studies of inflammatory innate immune mechanisms focusing on interferon signaling and the downstream JAK-STAT pathway. We also highlight insights gained from zebrafish models harbouring genetic perturbations in the role of inflammation in hematopoietic disorders such as bone marrow failure, myelodysplastic syndrome, and myeloid leukemia. Indeed, inflammation has been recently identified as a potential driver of clonal hematopoiesis and leukemogenesis, where cells acquire somatic mutations that provide a proliferative advantage in the presence of inflammation. Important insights in this area come from mutant zebrafish studies showing that hematopoietic differentiation can be compromised by epigenetic dysregulation and the aberrant induction of signaling pathways.
    Keywords:  JAK-STAT signaling pathway; bone marrow failure disorders; clonal hematopoiesis; hematopoietic stem and progenitor cell (HSPC); inflammasome; inflammation; interferon; zebrafish
    DOI:  https://doi.org/10.3389/fcell.2022.955658
  7. Psychoneuroendocrinology. 2022 Jul 13. pii: S0306-4530(22)00211-6. [Epub ahead of print]144 105870
    Peripheral inflammation marker relationships to cognition in healthy older adults - A systematic review.
    Masoumeh Tangestani Fard, Karen M Savage, Con K Stough.
      Several cognitive domains show decline with increasing age, which is associated with poorer work performance and reduced quality of life. As many nations show a rise in the number of citizens aged over 60 years, the study of the mechanisms underlying age-related cognitive functional reductions, such as inflammation, is important. Inflammaging has been implicated in progressive minor decline through to dementia typologies, with peripheral cytokine patterns investigated for their potential role in cognitive function. Assessing the relationship between these markers and cognitive performance could elucidate mechanisms with aging beyond neuropathologies. The research literature suggests peripheral cytokines/chemokines such as interleukin-6 and c-reactive protein are associated with cognitive processing. In this systematic review, we examine the evidence for a relationship between a range of peripheral inflammatory markers and domains of cognitive function in healthy older adults. To do this, a literature search was conducted using the following databases: SCOPUS, PubMed, Web of Science, and PsycINFO. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Twenty-nine studies met our inclusion criteria. Although a wide range of systemic inflammatory biomarkers were examined, IL-6 and CRP were the most studied. The evidence suggests an inverse inflammatory biomarker-cognitive function relationship whereby elevations in most cytokines were associated with poorer performance across cognitive domains. The findings contribute to our understanding of peripheral inflammation and domains of cognitive function, offering insight into inflammaging processes.
    Keywords:  Cognition; Cognitive decline; Cytokine; Inflammaging; Inflammation; Memory
    DOI:  https://doi.org/10.1016/j.psyneuen.2022.105870
  8. Can J Aging. 2022 Aug 01. 1-13
    Passive Remote Monitoring and Aging in Place: A Scoping Review.
    Emily Read, Cora Woolsey, Lorie Donelle, Lori Weeks, Norma Chinho.
      Passive remote monitoring is a relatively new technology that may support older adults to age in place. However, current knowledge about the effectiveness of this technology in extending older adults' independence is lacking. Therefore, we conducted a scoping review of studies examining passive remote monitoring to systematically synthesize evidence about the technology's effectiveness as an intervention. Our initial search of Embase, CINAHL, PubMed, and Scopus databases identified 486 unique articles. Of these, 14 articles met our inclusion criteria. Results show that passive remote monitoring technologies are being used in innovative and diverse ways to support older adults aging in place and their caregivers. More high-quality research on this topic is needed.
    Keywords:  aging; aging in place; aidants; caregivers; community-dwelling older adults; home care; in-home monitoring technology; personnes âgées vivant dans la communauté; soins à domicile; technologie de surveillance à domicile; vieillir sur place; vieillissement
    DOI:  https://doi.org/10.1017/S0714980822000198
  9. Front Cell Dev Biol. 2022 ;10 932723
    Intersection of Inflammation and Senescence in the Aging Lung Stem Cell Niche.
    Nancy C Allen, Nabora S Reyes, Jin Young Lee, Tien Peng.
      Aging is the final stage of development with stereotyped changes in tissue morphology. These age-related changes are risk factors for a multitude of chronic lung diseases, transcending the diverse pathogenic mechanisms that have been studied in disease-specific contexts. Two of the hallmarks of aging include inflammation and cellular senescence, which have been attributed as drivers of age-related organ decline. While these two age-related processes are often studied independently in the same tissue, there appears to be a reciprocal relationship between inflammation and senescence, which remodels the aging tissue architecture to increase susceptibility to chronic diseases. This review will attempt to address the "chicken or the egg" question as to whether senescence drives inflammation in the aging lung, or vice versa, and whether the causality of this relationship has therapeutic implications for age-related lung diseases.
    Keywords:  SASP; aging; inflammation; senescence; stem cell niche
    DOI:  https://doi.org/10.3389/fcell.2022.932723
  10. Nat Rev Nephrol. 2022 Aug 03.
    Cellular senescence: the good, the bad and the unknown.
    Weijun Huang, LaTonya J Hickson, Alfonso Eirin, James L Kirkland, Lilach O Lerman.
      Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.
    DOI:  https://doi.org/10.1038/s41581-022-00601-z
  11. J Dent Res. 2022 Aug 02. 220345221110108
    TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging.
    E Albuquerque-Souza, K E Crump, K Rattanaprukskul, Y Li, B Shelling, X Xia-Juan, M Jiang, S E Sahingur.
      TLR9 is a critical nucleic acid sensing receptor in mediating periodontitis and periodontitis-associated comorbidities. Emerging evidence implicates TLR9 as a key sensor during aging, although its participation in periodontal aging is unexplored. Here, we investigated whether TLR9-mediated host responses can promote key hallmarks of aging, inflammaging, and senescence, in the course of periodontitis using a multipronged approach comprising clinical and preclinical studies. In a case-control model, we found increased TLR9 gene expression in gingival tissues of older (≥55 y) subjects with periodontitis compared to older healthy subjects as well as those who are younger (<55 y old) with and without the disease. Mechanistically, this finding was supported by an in vivo model in which wild-type (WT) and TLR9-/- mice were followed for 8 to 10 wk (young) and 18 to 22 mo (aged). In this longitudinal model, aged WT mice developed severe alveolar bone resorption when compared to their younger counterpart, whereas aged TLR9-/- animals presented insignificant bone loss when compared to the younger groups. In parallel, a boosted inflammaging milieu exhibiting higher expression of inflammatory/osteoclast mediators (Il-6, Rankl, Cxcl8) and danger signals (S100A8, S100A9) was noted in gingival tissues of aged WT mice compared to the those of aged TLR9-/- mice. Consistently, WT aged mice displayed an increase in prosenescence balance as measured by p16INK4a/p19ARF ratio compared to the younger groups and aged TLR9-/- animals. Ex vivo experiments with bone marrow-derived macrophages primed by TLR9 ligand (ODN 1668) further corroborated in vivo and clinical data and showed enhanced inflammatory-senescence circuit followed by increased osteoclast differentiation. Together, these findings reveal first systematic evidence implicating TLR9 as one of the drivers of periodontitis during aging and functioning by boosting a deleterious inflammaging/senescence environment. This finding calls for further investigations to determine whether targeting TLR9 will improve periodontal health in an aging population.
    Keywords:  S100 proteins; cellular senescence; macrophages; nucleic acids; periodontitis; toll-like receptor 9
    DOI:  https://doi.org/10.1177/00220345221110108
  12. BMC Geriatr. 2022 Aug 06. 22(1): 646
    Life-space, frailty, and health-related quality of life.
    Petronella Chitalu, Alex Tsui, Samuel D Searle, Daniel Davis.
       INTRODUCTION: Life-space and frailty are closely linked to health-related quality of life and understanding their inter-relationship could indicate potential intervention targets for improving quality of life. We set out to examine the relationship between frailty and life-space and their relative impact on quality of life measures.
    METHODS: Using cross-sectional data from a population-representative cohort of people aged ≥ 70 years, we assessed quality of life with the EuroQol Health Index tool (5-levels) (EQ-5D-5L). We also undertook a life-space assessment and derived a frailty index. Linear regression models estimated EQ-5D-5L scores (dependent variable) using life-space assessment, frailty index and interactions between them. All models were adjusted by age, sex, lifestyle, and social care factors.
    RESULTS: A higher EQ-5D Index was associated with higher life-space (0.02 per life-space assessment score, 95%CI: 0.01 to 0.03, p < 0.01) and decreasing frailty (-0.1 per SD, 95%CI: -0.1 to -0.1, p < 0.01). There was evidence of an interaction between life-space and frailty, where the steepest gradient for life-space and EQ-5D was in those with the highest frailty (interaction term = 0.02 per SD of frailty, 95%CI: 0.01 to 0.03, p < 0.01).
    CONCLUSION: Individuals with the highest frailty were twice as likely to have higher quality of life in association with a larger life-space. Interventions designed to improve quality of life in frail older people could focus on increasing a person's life-space.
    Keywords:  Epidemiology; Frailty; Life-space; Quality of life
    DOI:  https://doi.org/10.1186/s12877-022-03355-2
  13. Mol Oncol. 2022 Aug 03.
    Tieing together loose ends: telomere instability in cancer and aging.
    Gustavo Borges, Mélanie Criqui, Lea Harrington.
      Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure, and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re-addition of G-rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.
    Keywords:  Telomeres; aging; cancer; genome instability; senescence; telomerase reverse transcriptase
    DOI:  https://doi.org/10.1002/1878-0261.13299
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