bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022‒11‒27
twelve papers selected by
Ayesh Seneviratne
Western University
  1. Sedentary behavior and the biological hallmarks of aging.
  2. GVHD prevention by personalized nutrition.
  3. Major depression and the biological hallmarks of aging.
  4. Low c-Kit expression identifies primitive therapy-resistant CML stem cells.
  5. Multimorbidity, Frailty and Diabetes in Older People-Identifying Interrelationships and Outcomes.
  6. Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players.
  7. The Role of IL-6 in Cancer Cell Invasiveness and Metastasis-Overview and Therapeutic Opportunities.
  8. Mitochondrial genomic integrity and the nuclear epigenome in health and disease.
  9. Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
  10. Bone Marrow Immune Microenvironment in Myelodysplastic Syndromes.
  11. An evaluation of aging measures: from biomarkers to clocks.
  12. Fighting ageing with immune checkpoint blockade.
  1. Ageing Res Rev. 2022 Nov 21. pii: S1568-1637(22)00249-5. [Epub ahead of print] 101807
    Sedentary behavior and the biological hallmarks of aging.
    Jérémy Raffin, Philipe de Souto Barreto, Anne Pavy Le Traon, Bruno Vellas, Mylène Aubertin-Leheudre, Yves Rolland.
      While the benefits of physical exercise for a healthy aging are well-recognized, a growing body of evidence shows that sedentary behavior has deleterious health effects independently, to some extent, of physical activity levels. Yet, the increasing prevalence of sedentariness constitutes a major public health issue that contributes to premature aging but the potential cellular mechanisms through which prolonged immobilization may accelerate biological aging remain unestablished. This narrative review summarizes the impact of sedentary behavior using different models of extreme sedentary behaviors including bedrest, unilateral limb suspension and space travel studies, on the hallmarks of aging such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. We further highlight the remaining knowledge gaps that need more research in order to promote healthspan extension and to provide future contributions to the field of geroscience.
    Keywords:  Hallmarks of aging; bedrest; lower limb suspension; sedentary behavior; spaceflight
    DOI:  https://doi.org/10.1016/j.arr.2022.101807
  2. Blood. 2022 Nov 24. 140(21): 2190-2192
    GVHD prevention by personalized nutrition.
    Christoph K Stein-Thoeringer.
      
    DOI:  https://doi.org/10.1182/blood.2022017857
  3. Ageing Res Rev. 2022 Nov 18. pii: S1568-1637(22)00247-1. [Epub ahead of print] 101805
    Major depression and the biological hallmarks of aging.
    Erica C Lorenzo, George A Kuchel, Chia-Ling Kuo, Terrie E Moffitt, Breno S Diniz.
      Major depressive disorder (MDD) is characterized by psychological and physiological manifestations contributing to the disease severity and outcome. In recent years, several lines of evidence have suggested that individuals with MDD have an elevated risk of age-related adverse outcomes across the lifespan. This review provided evidence of a significant overlap between the biological abnormalities in MDD and biological changes commonly observed during the aging process (i.e., hallmarks of biological aging). Based on such evidence, we formulate a mechanistic model showing how abnormalities in the hallmarks of biological aging can be a common denominator and mediate the elevated risk of age-related health outcomes commonly observed in MDD. Finally, we proposed a roadmap for novel studies to investigate the intersection between the biology of aging and MDD, including the use of geroscience-guided interventions, such as senolytics, to delay or improve major depression by targeting biological aging.
    Keywords:  Major depression; biology of aging; cellular; geroscience; late-life depression; senescence
    DOI:  https://doi.org/10.1016/j.arr.2022.101805
  4. JCI Insight. 2022 Nov 22. pii: e157421. [Epub ahead of print]
    Low c-Kit expression identifies primitive therapy-resistant CML stem cells.
    Mansi Shah, Harish Kumar, Shaowei Qiu, Hui Li, Mason Harris, Jianbo He, Ajay Abraham, David K Crossman, Andrew Paterson, Robert S Welner, Ravi Bhatia.
      Despite the efficacy of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), malignant long-term hematopoietic stem cells (LT-HSC) persist as a source of relapse. However, LT-HSC are heterogenous and the most primitive, drug-resistant LT-HSC subpopulations are not well characterized. In normal hematopoiesis, self-renewal and long-term reconstitution capacity is enriched within LT-HSCs with low c-Kit expression (c-KitLow). Here, using a transgenic CML mouse model, we found that long-term engraftment and leukemogenic capacity were restricted to c-KitLow CML LT-HSC. CML LT-HSC demonstrated enhanced differentiation with expansion of mature progeny following exposure to the c-Kit ligand, stem cell factor (SCF). Conversely, SCF deletion led to depletion of normal LT-HSC but increase in c-KitLow and total CML LT-HSC with reduced generation of mature myeloid cells. CML c-KitLow LT-HSC showed reduced cell cycling, and expressed enhanced quiescence and inflammatory gene signatures. SCF administration led to enhanced depletion of CML primitive progenitors but not LT-HSC after TKI treatment. Human CML LT-HSC with low or absent c-Kit expression were markedly enriched after TKI treatment. We conclude that CML LT-HSC expressing low c-Kit levels are enriched for primitive, quiescent, drug-resistant leukemia initiating cells and represent a critical target for eliminating disease persistence.
    Keywords:  Adult stem cells; Growth factors; Hematology; Leukemias; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.157421
  5. J Pers Med. 2022 Nov 16. pii: 1911. [Epub ahead of print]12(11):
    Multimorbidity, Frailty and Diabetes in Older People-Identifying Interrelationships and Outcomes.
    Alan J Sinclair, Ahmed H Abdelhafiz.
      Multimorbidity and frailty are highly prevalent in older people with diabetes. This high prevalence is likely due to a combination of ageing and diabetes-related complications and other diabetes-associated comorbidities. Both multimorbidity and frailty are associated with a wide range of adverse outcomes in older people with diabetes, which are proportionally related to the number of morbidities and to the severity of frailty. Although, the multimorbidity pattern or cluster of morbidities that have the most adverse effect are not yet well defined, it appears that mental health disorders enhance the multimorbidity-related adverse outcomes. Therefore, comprehensive diabetes guidelines that incorporate a holistic approach that includes screening and management of mental health disorders such as depression is required. The adverse outcomes predicted by multimorbidity and frailty appear to be similar and include an increased risk of health care utilisation, disability and mortality. The differential effect of one condition on outcomes, independent of the other, still needs future exploration. In addition, prospective clinical trials are required to investigate whether interventions to reduce multimorbidity and frailty both separately and in combination would improve clinical outcomes.
    Keywords:  diabetes; frailty; multimorbidity; older people; outcomes
    DOI:  https://doi.org/10.3390/jpm12111911
  6. Cells. 2022 Nov 15. pii: 3607. [Epub ahead of print]11(22):
    Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players.
    Youssef Siblini, Farès Namour, Abderrahim Oussalah, Jean-Louis Guéant, Céline Chéry.
      Stem cells are a population of undifferentiated cells with self-renewal and differentiation capacities. Normal and cancer stem cells share similar characteristics in relation to their stemness properties. One-carbon metabolism (OCM), a network of interconnected reactions, plays an important role in this dependence through its role in the endogenous synthesis of methionine and S-adenosylmethionine (SAM), the universal donor of methyl groups in eukaryotic cells. OCM genes are differentially expressed in stem cells, compared to their differentiated counterparts. Furthermore, cultivating stem cells in methionine-restricted conditions hinders their stemness capacities through decreased SAM levels with a subsequent decrease in histone methylation, notably H3K4me3, with a decrease in stem cell markers. Stem cells' reliance on methionine is linked to several mechanisms, including high methionine flux or low endogenous methionine biosynthesis. In this review, we provide an overview of the recent discoveries concerning this metabolic dependence and we discuss the mechanisms behind them. We highlight the influence of SIRT1 on SAM synthesis and suggest a role of PGC-1α/PPAR-α in impaired stemness produced by methionine deprivation. In addition, we discuss the potential interest of methionine restriction in regenerative medicine and cancer treatment.
    Keywords:  S-adenosylmethionine; cancer stem cells; methionine; methionine dependence; normal stem cells; peroxisome proliferator-activated receptor alpha; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; sirtuin 1; stemness
    DOI:  https://doi.org/10.3390/cells11223607
  7. Cells. 2022 Nov 21. pii: 3698. [Epub ahead of print]11(22):
    The Role of IL-6 in Cancer Cell Invasiveness and Metastasis-Overview and Therapeutic Opportunities.
    Magdalena Rašková, Lukáš Lacina, Zdeněk Kejík, Anna Venhauerová, Markéta Skaličková, Michal Kolář, Milan Jakubek, Daniel Rosel, Karel Smetana, Jan Brábek.
      Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression.
    Keywords:  IL-6; cancer; metastasis
    DOI:  https://doi.org/10.3390/cells11223698
  8. Front Endocrinol (Lausanne). 2022 ;13 1059085
    Mitochondrial genomic integrity and the nuclear epigenome in health and disease.
    Amanda L Morin, Phyo W Win, Angela Z Lin, Christina A Castellani.
      Bidirectional crosstalk between the nuclear and mitochondrial genomes is essential for proper cell functioning. Mitochondrial DNA copy number (mtDNA-CN) and heteroplasmy influence mitochondrial function, which can influence the nuclear genome and contribute to health and disease. Evidence shows that mtDNA-CN and heteroplasmic variation are associated with aging, complex disease, and all-cause mortality. Further, the nuclear epigenome may mediate the effects of mtDNA variation on disease. In this way, mitochondria act as an environmental biosensor translating vital information about the state of the cell to the nuclear genome. Cellular communication between mtDNA variation and the nuclear epigenome can be achieved by modification of metabolites and intermediates of the citric acid cycle and oxidative phosphorylation. These essential molecules (e.g. ATP, acetyl-CoA, ɑ-ketoglutarate and S-adenosylmethionine) act as substrates and cofactors for enzymes involved in epigenetic modifications. The role of mitochondria as an environmental biosensor is emerging as a critical modifier of disease states. Uncovering the mechanisms of these dynamics in disease processes is expected to lead to earlier and improved treatment for a variety of diseases. However, the influence of mtDNA-CN and heteroplasmy variation on mitochondrially-derived epigenome-modifying metabolites and intermediates is poorly understood. This perspective will focus on the relationship between mtDNA-CN, heteroplasmy, and epigenome modifying cofactors and substrates, and the influence of their dynamics on the nuclear epigenome in health and disease.
    Keywords:  DNA methylation; aging; disease; epigenome; histone acetylation; metabolism; mitochondrial DNA
    DOI:  https://doi.org/10.3389/fendo.2022.1059085
  9. Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01564-9. [Epub ahead of print]41(8): 111690
    Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.
    Yahyah Aman, Annmary Paul Erinjeri, Nikolaos Tataridas-Pallas, Rhianna Williams, Rachel Wellman, Hannah Chapman, John Labbadia.
      The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.
    Keywords:  CP: Cell biology; Caenorhabditis elegans; HSF-1; HSP90; MTCH-1; aging; mitochondria; molecular chaperones; programmed cell death; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111690
  10. Cancers (Basel). 2022 Nov 17. pii: 5656. [Epub ahead of print]14(22):
    Bone Marrow Immune Microenvironment in Myelodysplastic Syndromes.
    Olga Kouroukli, Argiris Symeonidis, Periklis Foukas, Myrto-Kalliopi Maragkou, Eleni P Kourea.
      The BM, the major hematopoietic organ in humans, consists of a pleiomorphic environment of cellular, extracellular, and bioactive compounds with continuous and complex interactions between them, leading to the formation of mature blood cells found in the peripheral circulation. Systemic and local inflammation in the BM elicit stress hematopoiesis and drive hematopoietic stem cells (HSCs) out of their quiescent state, as part of a protective pathophysiologic process. However, sustained chronic inflammation impairs HSC function, favors mutagenesis, and predisposes the development of hematologic malignancies, such as myelodysplastic syndromes (MDS). Apart from intrinsic cellular mechanisms, various extrinsic factors of the BM immune microenvironment (IME) emerge as potential determinants of disease initiation and evolution. In MDS, the IME is reprogrammed, initially to prevent the development, but ultimately to support and provide a survival advantage to the dysplastic clone. Specific cellular elements, such as myeloid-derived suppressor cells (MDSCs) are recruited to support and enhance clonal expansion. The immune-mediated inhibition of normal hematopoiesis contributes to peripheral cytopenias of MDS patients, while immunosuppression in late-stage MDS enables immune evasion and disease progression towards acute myeloid leukemia (AML). In this review, we aim to elucidate the role of the mediators of immune response in the initial pathogenesis of MDS and the evolution of the disease.
    Keywords:  BM; CHIP; HSC niche; MDS; MDSC; immune dysregulation; immunosuppression; inflamm-aging; microenvironment; pathogenesis
    DOI:  https://doi.org/10.3390/cancers14225656
  11. Biogerontology. 2022 Nov 23.
    An evaluation of aging measures: from biomarkers to clocks.
    Qingyi Wang, Tongyao Hou, Qiwen Wang, Jiamin He, Lan Wang, Jianmin Si, Shujie Chen.
      With the increasing number of aged population and growing burden of healthy aging demands, a rational standard for evaluation aging is in urgent need. The advancement of medical testing technology and the prospering of artificial intelligence make it possible to evaluate the biological status of aging from a more comprehensive view. In this review, we introduced common aging biomarkers and concluded several famous aging clocks. Aging biomarkers reflect changes in the organism at a molecular or cellular level over time while aging clocks tend to be more of a generalization of the overall state of the organism. We expect to construct a framework for aging evaluation measurement from both micro and macro perspectives. Especially, population-specific aging clocks and multi-omics aging clocks may better fit the demands to evaluate aging in a comprehensive and multidimensional manner and make a detailed classification to represent different aging rates at tissue/organ levels. This framework will promisingly provide a crucial basis for disease diagnosis and intervention assessment in geroscience.
    Keywords:  Aging; Biological-age; Biomarkers; Machine learning; Multi-omics
    DOI:  https://doi.org/10.1007/s10522-022-09997-4
  12. Nat Rev Drug Discov. 2022 Nov 23.
    Fighting ageing with immune checkpoint blockade.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-022-00194-z
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