bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–05–29
fourteen papers selected by
Ayesh Seneviratne, Western University
  1. Nutrition and stem cell integrity in aging.
  2. Targeted LC-MS/MS-based metabolomics and lipidomics on limited hematopoietic stem cell numbers.
  3. In Beckett's words, by Beckett's thoughts: a narrative on ageing.
  4. Hypoxia and hemorheological properties in older individuals.
  5. Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities.
  6. Unraveling Pathways of Health and Lifespan with Integrated Multiomics Approaches.
  7. Schlafen2 is a regulator of quiescence in adult murine hematopoietic stem cells.
  8. Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation.
  9. Long-Term Hypercaloric Diet Consumption Exacerbates Age-Induced Dysmetabolism and Carotid Body Dysfunction: Beneficial Effects of CSN Denervation.
  10. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.
  11. Effectiveness of Homologous and Heterologous Covid-19 Boosters against Omicron.
  12. Mediterranean diet superior to low-fat diet for secondary prevention of CVD.
  13. HSCs perpetuate inflammation.
  14. Revealing the Longevity Code of Humans with up to Extreme Longevity in Guangxi Based on Physical Examination Indicators and Personalized Biomarkers of Aging.
  1. J Intern Med. 2022 May 28.
    Nutrition and stem cell integrity in aging.
    P J Stover, M S Field, H N Brawley, B Angelin, P O Iverson, G Frühbeck.
      Adult stem cells (SCs) represent the regenerative capacity of organisms throughout their lifespan. The maintenance of robust SC populations capable of renewing organs and physiological systems is one hallmark of healthy aging. The local environment of SCs, referred to as the niche, includes the nutritional milieu, which is essential to maintain the quantity and quality of SCs available for renewal and regeneration. There is increased recognition that SCs have unique metabolism and conditional nutrient needs compared to fully differentiated cells. However, the contribution of SC nutrition to overall human nutritional requirements is an understudied and underappreciated area of investigation. Nutrient needs vary across the lifespan and are modified by many factors including individual health, disease, physiological states including pregnancy, age, sex, and during recovery from injury. Although current nutrition guidance is generally derived for apparently healthy populations and to prevent nutritional deficiency diseases, there are increased efforts to establish nutrient-based and food-based recommendations based on reducing chronic disease. Understanding the dynamics of SC nutritional needs throughout the life span, including the role of nutrition in extending biological age by blunting biological systems decay, is fundamental to establishing food and nutrient guidance for chronic disease reduction and health maintenance. This review summarizes a 3-day symposium of the Marabou Foundation (www.marabousymposium.org) held to examine the metabolic properties and unique nutritional needs of adult SCs and their role in healthy aging and age-related chronic disease.
    Keywords:  aging; chronic disease; metabolism; nutrition; stem cells
    DOI:  https://doi.org/10.1111/joim.13507
  2. STAR Protoc. 2022 Jun 17. 3(2): 101408
    Targeted LC-MS/MS-based metabolomics and lipidomics on limited hematopoietic stem cell numbers.
    Katharina Schönberger, Michael Mitterer, Joerg M Buescher, Nina Cabezas-Wallscheid.
      Metabolism is important for the regulation of hematopoietic stem cells (HSCs) and drives cellular fate. Due to the scarcity of HSCs, it has been technically challenging to perform metabolome analyses gaining insight into HSC metabolic regulatory networks. Here, we present two targeted liquid chromatography-mass spectrometry approaches that enable the detection of metabolites after fluorescence-activated cell sorting when sample amounts are limited. One protocol covers signaling lipids and retinoids, while the second detects tricarboxylic acid cycle metabolites and amino acids. For complete details on the use and execution of this protocol, please refer to Schönberger et al. (2022).
    Keywords:  Mass Spectrometry; Metabolomics; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101408
  3. Br J Psychiatry. 2022 Jun;220(6): 329
    In Beckett's words, by Beckett's thoughts: a narrative on ageing.
    João Martins-Correia.
      
    DOI:  https://doi.org/10.1192/bjp.2021.190
  4. Ageing Res Rev. 2022 May 18. pii: S1568-1637(22)00092-7. [Epub ahead of print]79 101650
    Hypoxia and hemorheological properties in older individuals.
    Antoine Raberin, Johannes Burtscher, Philippe Connes, Grégoire P Millet.
      Hypoxia is caused by insufficient oxygen availability for the organism leading to reduced oxygen delivery to tissues and cells. It has been regarded as a severe threat to human health and it is indeed implicated in pathophysiological mechanisms involved in the development and progression of many diseases. Nevertheless, the potential of controlled hypoxia interventions (i.e. hypoxia conditioning) for improving cardio-vascular health is gaining increased attention. However, blood rheology is often a forgotten factor for vascular health while aging and hypoxia exposure are both suspected to alter hemorheological properties. These changes in blood rheology may influence the benefits-risks balance of hypoxia exposure in older individuals. The benefits of hypoxia exposure for vascular health are mainly reported for healthy populations and the combined impact of aging and hypoxia on blood rheology could therefore be deleterious in older individuals. This review discusses evidence of hypoxia-related and aging-related changes in blood viscosity and its determinants. It draws upon an extensive literature search on the effects of hypoxia/altitude and aging on blood rheology. Aging increases blood viscosity mainly through a rise in plasma viscosity, red blood cell (RBC) aggregation and a decrease in RBC deformability. Hypoxia also causes an increase in RBC aggregation and plasma viscosity. In addition, hypoxia exposure may increase hematocrit and modulate RBC deformability, depending on the hypoxic dose, i.e, beneficial effect of intermittent hypoxia with moderate dose vs deleterious effect of chronic continuous or intermittent hypoxia or if the hypoxic dose is too high. Special attention is directed toward the risks vs. benefits of hemorheological changes during hypoxia exposure in older individuals, and its clinical relevance for vascular disorders.
    Keywords:  Aging; Altitude; Blood viscosity; Cardiovascular risks; Hemorheology; Hypoxia conditioning
    DOI:  https://doi.org/10.1016/j.arr.2022.101650
  5. J Pers Med. 2022 Apr 29. pii: 716. [Epub ahead of print]12(5):
    Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities.
    Paola Fernanda Ruiz-Aparicio, Jean-Paul Vernot.
      Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.
    Keywords:  AML; B-ALL; BM aging; MSCs senescence; leukaemia; leukemic microenvironment
    DOI:  https://doi.org/10.3390/jpm12050716
  6. Methods Mol Biol. 2022 ;2399 193-218
    Unraveling Pathways of Health and Lifespan with Integrated Multiomics Approaches.
    Miguel A Aon, Michel Bernier, Rafael de Cabo.
      Distinct and shared pathways of health and lifespan can be untangled following a concerted approach led by experimental design and a rigorous analytical strategy where the confounding effects of diet and feeding regimens can be dissected. In this chapter, we use integrated analysis of multiomics (transcriptomics-metabolomics) data in liver from mice to gain insight into pathways associated with improved health and survival. We identify a unique metabolic hub involving glycine-serine-threonine metabolism at the core of lifespan, and a pattern of shared pathways related to improved health.
    Keywords:  Computational systems biology; Diet; Gene and functional ontologies; Healthy aging; Integrated pathway analysis; Time-restricted feeding; Topology-based pathway network analysis
    DOI:  https://doi.org/10.1007/978-1-0716-1831-8_9
  7. Haematologica. 2022 May 26.
    Schlafen2 is a regulator of quiescence in adult murine hematopoietic stem cells.
    Sarah Warsi, Maria Dahl, Emma M K Smith, Anna Rydstrom, Els Mansell, Valgardur Sigurdsson, Julia Sjoberg, Shamit Soneji, Emma Rorby, Kavitha Siva, Tan H M Grahn, Yang Liu, Ulrika Blank, Goran Karlsson, Stefan Karlsson.
      Even though hematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. To investigate the role of Slfn2 in the regulation of HSCs we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSCs resulted in a significantly reduced regenerative capacity of HSCs in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSCs (as compared to WT HSCs) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus i dentifies S lfn2 as a n ov el a nd critical regulator of a dult H SCs and HSC quiescence.
    DOI:  https://doi.org/10.3324/haematol.2021.279799
  8. Aging Cell. 2022 May 22. e13622
    Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation.
    Weizhe Zhong, Zhuqing Rao, Jian Xu, Yu Sun, Haoran Hu, Ping Wang, Yongxiang Xia, Xiongxiong Pan, Weiwei Tang, Ziyi Chen, Haoming Zhou, Xuehao Wang.
      Macrophage-stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age-related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia-reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Aging promoted the cytosolic leakage of macrophage mtDNA and enhanced STING activation, which was abrogated upon mtDNA depletion or cyclic GMP-AMP Synthase (cGAS) inhibition. Aged macrophages exhibited increased mitochondrial injury with impaired mitophagy. Mechanistically, a decline in the PTEN-induced kinase 1 (PINK1)/Parkin-mediated polyubiquitination of mitochondria was observed in aged macrophages. Pink1 overexpression reversed the inhibition of mitochondrial ubiquitination but failed to promote mitolysosome formation in the aged macrophages. Meanwhile, aging impaired lysosomal biogenesis and function in macrophages by modulating the mTOR/transcription factor EB (TFEB) signaling pathway, which could be reversed by Torin-1 treatment. Consequently, Pink1 overexpression in combination with Torin-1 treatment restored mitophagic flux and inhibited mtDNA/cGAS/STING activation in aged macrophages. Moreover, besides HR-induced metabolic stress, other types of oxidative and hepatotoxic stresses inhibited mitophagy and promoted the cytosolic release of mtDNA to activate STING signaling in aged macrophages. STING deficiency protected aged mice against diverse types of sterile inflammatory liver injuries. Our findings suggest that aging impairs mitophagic flux to facilitate the leakage of macrophage mtDNA into the cytosol and promotes STING activation, and thereby provides a novel potential therapeutic target for sterile inflammatory liver injury in aged patients.
    Keywords:  aging; macrophage; mitochondrial DNA; mitophagy; sterile inflammation; stimulator of interferon genes
    DOI:  https://doi.org/10.1111/acel.13622
  9. Front Physiol. 2022 ;13 889660
    Long-Term Hypercaloric Diet Consumption Exacerbates Age-Induced Dysmetabolism and Carotid Body Dysfunction: Beneficial Effects of CSN Denervation.
    Bernardete F Melo, Joana F Sacramento, Adriana M Capucho, Dinis Sampaio-Pires, Cláudia S Prego, Silvia V Conde.
      Carotid bodies (CBs) are metabolic sensors whose dysfunction is involved in the genesis of dysmetabolic states. Ageing induces significant alterations in CB function also prompting to metabolic deregulation. On the other hand, metabolic disease can accelerate ageing processes. Taking these into account, we evaluated the effect of long-term hypercaloric diet intake and CSN resection on age-induced dysmetabolism and CB function. Experiments were performed in male Wistar rats subjected to 14 or 44 weeks of high-fat high-sucrose (HFHSu) or normal chow (NC) diet and subjected to either carotid sinus nerve (CSN) resection or a sham procedure. After surgery, the animals were kept on a diet for more than 9 weeks. Metabolic parameters, basal ventilation, and hypoxic and hypercapnic ventilatory responses were evaluated. CB type I and type II cells, HIF-1α and insulin receptor (IR), and GLP-1 receptor (GLP1-R)-positive staining were analyzed by immunofluorescence. Ageing decreased by 61% insulin sensitivity in NC animals, without altering glucose tolerance. Short-term and long-term HFHSu intake decreased insulin sensitivity by 55 and 62% and glucose tolerance by 8 and 29%, respectively. CSN resection restored insulin sensitivity and glucose tolerance. Ageing decreased spontaneous ventilation, but short-term or long-term intake of HFHSu diet and CSN resection did not modify basal ventilatory parameters. HFHSu diet increased hypoxic ventilatory responses in young and adult animals, effects attenuated by CSN resection. Ageing, hypercaloric diet, and CSN resection did not change hypercapnic ventilatory responses. Adult animals showed decreased type I cells and IR and GLP-1R staining without altering the number of type II cells and HIF-1α. HFHSu diet increased the number of type I and II cells and IR in young animals without significantly changing these values in adult animals. CSN resection restored the number of type I cells in HFHSu animals and decreased IR-positive staining in all the groups of animals, without altering type II cells, HIF-1α, or GLP-1R staining. In conclusion, long-term hypercaloric diet consumption exacerbates age-induced dysmetabolism, and both short- and long-term hypercaloric diet intakes promote significant alterations in CB function. CSN resection ameliorates these effects. We suggest that modulation of CB activity is beneficial in exacerbated stages of dysmetabolism.
    Keywords:  ageing; carotid body; carotid sinus nerve; hypercaloric diets; insulin receptor; metabolic disease
    DOI:  https://doi.org/10.3389/fphys.2022.889660
  10. Signal Transduct Target Ther. 2022 May 25. 7(1): 162
    Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.
    Xin Li, Jiaqiang Wang, LeYun Wang, Yuanxu Gao, Guihai Feng, Gen Li, Jun Zou, Meixin Yu, Yu Fei Li, Chao Liu, Xue Wei Yuan, Ling Zhao, Hong Ouyang, Jian-Kang Zhu, Wei Li, Qi Zhou, Kang Zhang.
      Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. We applied artificial intelligence to predict the protein structure of ELOVL2 and the interaction with its substrate. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key aging phenotypes at both cellular and physiological level. Furthermore, restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells; this indicates a conservative mechanism in both human and mouse. Taken together, we revealed an epigenetic-metabolism axis contributing to aging and illustrate the power of an AI-based approach in structure-function studies.
    DOI:  https://doi.org/10.1038/s41392-022-00964-6
  11. N Engl J Med. 2022 May 25.
    Effectiveness of Homologous and Heterologous Covid-19 Boosters against Omicron.
    Emma K Accorsi, Amadea Britton, Nong Shang, Katherine E Fleming-Dutra, Ruth Link-Gelles, Zachary R Smith, Gordana Derado, Joseph Miller, Stephanie J Schrag, Jennifer R Verani.
      
    DOI:  https://doi.org/10.1056/NEJMc2203165
  12. Nat Rev Cardiol. 2022 May 27.
    Mediterranean diet superior to low-fat diet for secondary prevention of CVD.
    Gregory B Lim.
      
    DOI:  https://doi.org/10.1038/s41569-022-00727-4
  13. Nat Immunol. 2022 May 27.
    HSCs perpetuate inflammation.
    Ioana Visan.
      
    DOI:  https://doi.org/10.1038/s41590-022-01234-x
  14. Biomed Res Int. 2022 ;2022 2810379
    Revealing the Longevity Code of Humans with up to Extreme Longevity in Guangxi Based on Physical Examination Indicators and Personalized Biomarkers of Aging.
    He Li, Minhong Ren, Qianzu He, Jie Gao, Quanyang Li.
       Background: The pursuit of health and longevity is the eternal theme of humanity. Guangxi has a remarkable phenomenon of longevity in long-lived regions and ranks with the highest number of longevity villages in China, thus providing a natural advantage for health longevity research.
    Methods: In this study, we selected 117 natives of a longevity area in Guangxi, covering a large age range (38-118 years old) as subjects to measure peripheral leukocyte telomere length (LTL). Nineteen physical examination indicators and two inflammatory factor levels were measured.
    Results: Pearson's analysis revealed a significant negative correlation between age and LTL (r = -0.3694, p = 0.003), as well as alanine aminotransferase, albumin, total bilirubin, direct bilirubin, γ-glutamyltransferase, triglycerides, Interleukin-10, and tumor necrosis factor type-α. Systolic blood pressure and blood urea nitrogen were positively correlated with age. In addition, LTL decreased in people aged 38-89 years, and an upward trend was observed in people aged older than 90 years.
    Conclusions: Longevity individuals have characteristics, such as longer LTL, good hepatic function, and lower triglycerides and inflammation levels.
    DOI:  https://doi.org/10.1155/2022/2810379
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