bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–04–16
eightteen papers selected by
Ayesh Seneviratne, Western University
  1. Aryl hydrocarbon receptor (AhR) impairs circadian regulation: Impact on the aging process.
  2. The Roles of Myeloid Cells in Aging-related Liver Diseases.
  3. Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.
  4. Early path dominance as a principle for neurodevelopment.
  5. Cancer prevention with rapamycin.
  6. Targeting mTOR for Anti-Aging and Anti-Cancer Therapy.
  7. The Role of Inflammation in the Initiation and Progression of Myeloid Neoplasms.
  8. IL-27 attenuates IL-23 mediated inflammatory arthritis.
  9. Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging.
  10. Ageing-associated changes in transcriptional elongation influence longevity.
  11. Plasma metabolomic signatures of dual decline in memory and gait in older adults.
  12. Journal of Aging, Research & Lifestyle.
  13. Frailty level at discharge predicts mortality in older patients with Clostridioides difficile more accurately than age or disease severity.
  14. Editorial: Reviews in cancer metabolism.
  15. Mesenchymal Stromal Cells as a Driver of Inflammaging.
  16. Funding Life-Extension Research.
  17. MYB deficiency leads to myeloid neoplasia too.
  18. Immuno-oncology clinical trials take a turn beyond PD1/PDL1 inhibitors.
  1. Ageing Res Rev. 2023 Apr 07. pii: S1568-1637(23)00087-9. [Epub ahead of print]87 101928
    Aryl hydrocarbon receptor (AhR) impairs circadian regulation: Impact on the aging process.
    Antero Salminen.
      Circadian clocks control the internal sleep-wake rhythmicity of 24 h which is synchronized by the solar cycle. Circadian regulation of metabolism evolved about 2.5 billion years ago, i.e., the rhythmicity has been conserved from cyanobacteria and Archaea through to mammals although the mechanisms utilized have developed with evolution. While the aryl hydrocarbon receptor (AhR) is an evolutionarily conserved defence mechanism against environmental threats, it has gained many novel functions during evolution, such as the regulation of cell cycle, proteostasis, and many immune functions. There is robust evidence that AhR signaling impairs circadian rhythmicity, e.g., by interacting with the core BMAL1/CLOCK complex and disturbing the epigenetic regulation of clock genes. The maintenance of circadian rhythms is impaired with aging, disturbing metabolism and many important functions in aged organisms. Interestingly, it is known that AhR signaling promotes an age-related tissue degeneration, e.g., it is able to inhibit autophagy, enhance cellular senescence, and disrupt extracellular matrix. These alterations are rather similar to those induced by a long-term impairment of circadian rhythms. However, it is not known whether AhR signaling enhances the aging process by impairing circadian homeostasis. I will examine the experimental evidence indicating that AhR signaling is able to promote the age-related degeneration via a disruption of circadian rhythmicity.
    Keywords:  Ageing; IDO1; Immunosuppression; Kynurenine; Lifespan; Longevity
    DOI:  https://doi.org/10.1016/j.arr.2023.101928
  2. Int J Biol Sci. 2023 ;19(5): 1564-1578
    The Roles of Myeloid Cells in Aging-related Liver Diseases.
    Jinghao Yao, Yang Li, Hua Wang.
      Aging is a necessary process of life associated with various mechanisms, such as genomic instability, loss of proteostasis, deregulated nutrient sensing, and cellular senescence, causing progressive dysregulation of the microenvironment, organ homeostasis and biological functions. The hepatic microenvironment is essential for maintaining liver homeostasis, in which hepatocytes, sinusoidal endothelial cells, stellate cells and immune cells are closely associated with the development of aging-related liver diseases. There is increasing evidence that immunocytes, especially myeloid cells, are involved in aging-related liver diseases such as alcoholic liver disease, nonalcoholic liver disease, liver fibrosis or cirrhosis and liver cancer, becoming promising treatment targets of these diseases. This review summarizes the phenotypic and functional alterations associated with aging liver and myeloid cells, as well as the roles of myeloid cells in the progression of aging-related liver diseases.
    Keywords:  Aging; Inflammation; Liver Disease; Microenvironment; Myeloid Cells
    DOI:  https://doi.org/10.7150/ijbs.82352
  3. Nat Commun. 2023 Apr 12. 14(1): 2070
    Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.
    N Zioni, A Akhiad Bercovich, N Chapal-Ilani, Tal Bacharach, N Rappoport, A Solomon, R Avraham, E Kopitman, Z Porat, M Sacma, G Hartmut, M Scheller, C Muller-Tidow, D Lipka, E Shlush, M Minden, N Kaushansky, Liran I Shlush.
      Both fatty bone marrow (FBM) and somatic mutations in hematopoietic stem cells (HSCs), also termed clonal hematopoiesis (CH) accumulate with human aging. However it remains unclear whether FBM can modify the evolution of CH. To address this question, we herein present the interaction between CH and FBM in two preclinical male mouse models: after sub-lethal irradiation or after castration. An adipogenesis inhibitor (PPARγ inhibitor) is used in both models as a control. A significant increase in self-renewal can be detected in both human and rodent DNMT3AMut-HSCs when exposed to FBM. DNMT3AMut-HSCs derived from older mice interacting with FBM have even higher self-renewal in comparison to DNMT3AMut-HSCs derived from younger mice. Single cell RNA-sequencing on rodent HSCs after exposing them to FBM reveal a 6-10 fold increase in DNMT3AMut-HSCs and an activated inflammatory signaling. Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrates an increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduce the selective advantage of DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 pathway.
    DOI:  https://doi.org/10.1038/s41467-023-36906-1
  4. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2218007120
    Early path dominance as a principle for neurodevelopment.
    Rostam M Razban, Jonathan Asher Pachter, Ken A Dill, Lilianne R Mujica-Parodi.
      We perform targeted attack, a systematic computational unlinking of the network, to analyze its effects on global communication across the brain network through its giant cluster. Across diffusion magnetic resonance images from individuals in the UK Biobank, Adolescent Brain Cognitive Development Study and Developing Human Connectome Project, we find that targeted attack procedures on increasing white matter tract lengths and densities are remarkably invariant to aging and disease. Time-reversing the attack computation suggests a mechanism for how brains develop, for which we derive an analytical equation using percolation theory. Based on a close match between theory and experiment, our results demonstrate that tracts are limited to emanate from regions already in the giant cluster and tracts that appear earliest in neurodevelopment are those that become the longest and densest.
    Keywords:  connectomics; dMRI; network neuroscience; percolation theory; statistical mechanics
    DOI:  https://doi.org/10.1073/pnas.2218007120
  5. Oncotarget. 2023 Apr 14. 14 342-350
    Cancer prevention with rapamycin.
    Mikhail V Blagosklonny.
      Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.
    Keywords:  aging; cancer; chemoprevention; lung; rapamycin
    DOI:  https://doi.org/10.18632/oncotarget.28410
  6. Molecules. 2023 Apr 01. pii: 3157. [Epub ahead of print]28(7):
    Targeting mTOR for Anti-Aging and Anti-Cancer Therapy.
    Wencheng Fu, Geng Wu.
      The balance between anabolism and catabolism is disrupted with aging, with the rate of anabolism being faster than that of catabolism. Therefore, mTOR, whose major function is to enhance anabolism and inhibit catabolism, has become a potential target of inhibition for anti-aging therapy. Interestingly, it was found that the downregulation of the mTOR signaling pathway had a lifespan-extending effect resembling calorie restriction. In addition, the mTOR signaling pathway promotes cell proliferation and has been regarded as a potential anti-cancer target. Rapamycin and rapalogs, such as everolimus, have proven to be effective in preventing certain tumor growth. Here, we reviewed the basic knowledge of mTOR signaling, including both mTORC1 and mTORC2. Then, for anti-aging, we cited a lot of evidence to discuss the role of targeting mTOR and its anti-aging mechanism. For cancer therapy, we also discussed the role of mTOR signaling in different types of cancers, including idiopathic pulmonary fibrosis, tumor immunity, etc. In short, we discussed the research progress and both the advantages and disadvantages of targeting mTOR in anti-aging and anti-cancer therapy. Hopefully, this review may promote more ideas to be generated for developing inhibitors of mTOR signaling to fight cancer and extend lifespan.
    Keywords:  aging; anti-aging; anti-cancer therapy; cancer; mTOR; mTOR inhibition; senescence
    DOI:  https://doi.org/10.3390/molecules28073157
  7. Blood Cancer Discov. 2023 Apr 13. OF1-OF13
    The Role of Inflammation in the Initiation and Progression of Myeloid Neoplasms.
    Juan Carlos Balandrán, Audrey Lasry, Iannis Aifantis.
      Myeloid malignancies are devastating hematologic cancers with limited therapeutic options. Inflammation is emerging as a novel driver of myeloid malignancy, with important implications for tumor composition, immune response, therapeutic options, and patient survival. Here, we discuss the role of inflammation in normal and malignant hematopoiesis, from clonal hematopoiesis to full-blown myeloid leukemia. We discuss how inflammation shapes clonal output from hematopoietic stem cells, how inflammation alters the immune microenvironment in the bone marrow, and novel therapies aimed at targeting inflammation in myeloid disease.
    SIGNIFICANCE: Inflammation is emerging as an important factor in myeloid malignancies. Understanding the role of inflammation in myeloid transformation, and the interplay between inflammation and other drivers of leukemogenesis, may yield novel avenues for therapy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-22-0176
  8. Clin Immunol. 2023 Apr 08. pii: S1521-6616(23)00106-7. [Epub ahead of print] 109327
    IL-27 attenuates IL-23 mediated inflammatory arthritis.
    Ritu Sarin, Ran Gu, Zahra Jalali, Emanual Maverakis, Maria Tsokos, Iannis E Adamopoulos.
      Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17 differentiation but the IL-27 effect on myeloid cells is less studied. Herein we demonstrate that IL-27 inhibits IL-23-induced inflammation associated not only with Th17 cells but also with myeloid cell infiltration in the joints and splenic myeloid populations of CD11b+ GR1+ and CD3-CD11b+CD11c-GR1- cells. The IL-27 anti-inflammatory response was associated with reduced levels of myeloid cells in the spleen and bone marrow. Overall, our data demonstrate that IL-27 has an immunosuppressive role that affects IL-23-dependent myelopoiesis in the bone marrow and its progression to inflammatory arthritis and plays a crucial role in controlling IL-23 driven joint inflammation by negatively regulating the expansion of myeloid cell subsets.
    Keywords:  Inflammatory arthritis; Interleukin 23; Interleukin 27; Osteoclasts
    DOI:  https://doi.org/10.1016/j.clim.2023.109327
  9. Cells. 2023 Mar 24. pii: 998. [Epub ahead of print]12(7):
    Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging.
    Mingjia Cheng, Weihao Yuan, Alireza Moshaverinia, Bo Yu.
      Advanced age is a shared risk factor for many chronic and debilitating skeletal diseases including osteoporosis and periodontitis. Mesenchymal stem cells develop various aging phenotypes including the onset of senescence, intrinsic loss of regenerative potential and exacerbation of inflammatory microenvironment via secretory factors. This review elaborates on the emerging concepts on the molecular and epigenetic mechanisms of MSC senescence, such as the accumulation of oxidative stress, DNA damage and mitochondrial dysfunction. Senescent MSCs aggravate local inflammation, disrupt bone remodeling and bone-fat balance, thereby contributing to the progression of age-related bone diseases. Various rejuvenation strategies to target senescent MSCs could present a promising paradigm to restore skeletal aging.
    Keywords:  aging; bone regeneration; senescence; stem cells
    DOI:  https://doi.org/10.3390/cells12070998
  10. Nature. 2023 Apr 12.
    Ageing-associated changes in transcriptional elongation influence longevity.
    Cédric Debès, Antonios Papadakis, Sebastian Grönke, Özlem Karalay, Luke S Tain, Athanasia Mizi, Shuhei Nakamura, Oliver Hahn, Carina Weigelt, Natasa Josipovic, Anne Zirkel, Isabell Brusius, Konstantinos Sofiadis, Mantha Lamprousi, Yu-Xuan Lu, Wenming Huang, Reza Esmaillie, Torsten Kubacki, Martin R Späth, Bernhard Schermer, Thomas Benzing, Roman-Ulrich Müller, Adam Antebi, Linda Partridge, Argyris Papantonis, Andreas Beyer.
      Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.
    DOI:  https://doi.org/10.1038/s41586-023-05922-y
  11. Geroscience. 2023 Apr 13.
    Plasma metabolomic signatures of dual decline in memory and gait in older adults.
    Qu Tian, Michelle D Shardell, Pei-Lun Kuo, Toshiko Tanaka, Eleanor M Simonsick, Ruin Moaddel, Susan M Resnick, Luigi Ferrucci.
      Older adults experiencing dual decline in memory and gait have greater dementia risk than those with memory or gait decline only, but mechanisms are unknown. Dual decline may indicate specific pathophysiological pathways to dementia which can be reflected by circulating metabolites. We compared longitudinal changes in plasma metabolite biomarkers of older adults with and without dual decline in the Baltimore Longitudinal Study of Aging (BLSA). Participants were grouped into 4 phenotypes based on annual rates of decline in verbal memory and gait speed: no decline in memory or gait, memory decline only, gait decline only, and dual decline. Repeated measures of plasma metabolomics were measured by biocrates p500 kit during the same time of memory and gait assessments. In BLSA, 18 metabolites differed across groups (q-value < 0.05). Metabolites differentially abundant were enriched for lysophosphatidylcholines (lysoPC C18:0,C16:0,C17:0,C18:1,C18:2), ceramides (d18:2/24:0,d16:1/24:0,d16:1/23:0), and amino acids (glycine) classes. Compared to no decline, the dual decline group showed greater declines in lysoPC C18:0, homoarginine synthesis, and the metabolite module containing mostly triglycerides, and showed a greater increase in indoleamine 2,3-dioxygenase (IDO) activity. Metabolites distinguishing dual decline and no decline groups were implicated in metabolic pathways of the aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, histidine metabolism, and sphingolipid metabolism. Older adults with dual decline exhibit the most extensive alterations in metabolic profiling of lysoPCs, ceramides, IDO activity, and homoarginine synthesis. Alterations in these metabolites may indicate mitochondrial dysfunction, compromised immunity, and elevated burden of cardiovascular and kidney pathology.
    Keywords:  Dementia risk; Dual decline; Gait decline; Memory decline; Metabolomics
    DOI:  https://doi.org/10.1007/s11357-023-00792-8
  12. JAR Life. 2023 ;12 1-3
    Journal of Aging, Research & Lifestyle.
    Ara S Khachaturian.
      
    DOI:  https://doi.org/10.14283/jarlife.2023.1
  13. Eur Geriatr Med. 2023 Apr 13.
    Frailty level at discharge predicts mortality in older patients with Clostridioides difficile more accurately than age or disease severity.
    Tone Rubak, Simon Mark Dahl Baunwall, Merete Gregersen, Troels Kjærskov Hansen, Jeppe Bakkestrøm Rosenbæk, Lise Tornvig Erikstrup, Christian Lodberg Hvas, Else Marie Skjøde Damsgaard.
       PURPOSE: Clostridioides difficile infection (CDI) has a high mortality among older patients. Identification of older patients with CDI in increased mortality risk is important to target treatment and thereby reduce mortality. The aim of this study was to investigate mortality rates and compare frailty levels at discharge, measured by the record-based Multidimensional Prognostic Index (MPI), with age and severity of CDI as mortality predictors in patients with CDI diagnosed during hospitalisation.
    METHODS: This was a population-based cohort study from Central Denmark Region, Denmark, including all patients  ≥ 60 years with a positive CD toxin test without prior infection and diagnosed from 1 January to 31 December 2018. Frailty level, estimated from the electronic medical record, was defined as low, moderate, or severe frailty. CDI severity was graded according to international guidelines. Primary outcome was 90-day mortality.
    RESULTS: We included 457 patients with median age 77 years (interquartile range 69-84) and females (49%). Overall, 90-day mortality was 28%, and this was associated with age (hazard ratio (HR): 2.71 (95% confidence interval 1.64-4.47)), CDI severity (HR 4.58 (3.04-6.88)) and frailty (HR 10.15 (4.06-25.36)). Frailty was a better predictor of 90-day mortality than both age (p < 0.001) and CDI severity (p = 0.04) with a receiver operating characteristic curve area of 77%.
    CONCLUSION: The 90-day mortality among older patients with CDI in a Danish region is 28%. Frailty measured by record-based MPI at discharge outperforms age and disease severity markers in predicting mortality in older patients with CDI.
    Keywords:  Aged; Clostridioides difficile; Frailty; Mortality
    DOI:  https://doi.org/10.1007/s41999-023-00772-3
  14. Front Oncol. 2023 ;13 1167484
    Editorial: Reviews in cancer metabolism.
    Nadia Jacobo-Herrera, Bela Ozsvari.
      
    Keywords:  cancer metabolism; metabolic reprogramming; metabolic therapy; mitochondria; resistance mechanisms
    DOI:  https://doi.org/10.3389/fonc.2023.1167484
  15. Int J Mol Sci. 2023 Mar 28. pii: 6372. [Epub ahead of print]24(7):
    Mesenchymal Stromal Cells as a Driver of Inflammaging.
    Svetlana Lyamina, Denis Baranovskii, Ekaterina Kozhevnikova, Tatiana Ivanova, Sergey Kalish, Timur Sadekov, Ilya Klabukov, Igor Maev, Vadim Govorun.
      Life expectancy and age-related diseases burden increased significantly over the past few decades. Age-related conditions are commonly discussed in a very limited paradigm of depleted cellular proliferation and maturation with exponential accumulation of senescent cells. However, most recent evidence showed that the majority of age-associated ailments, i.e., diabetes mellitus, cardiovascular diseases and neurodegeneration. These diseases are closely associated with tissue nonspecific inflammation triggered and controlled by mesenchymal stromal cell secretion. Mesenchymal stromal cells (MSCs) are known as the most common type of cells for therapeutic approaches in clinical practice. Side effects and complications of MSC-based treatments increased interest in the MSCs secretome as an alternative concept for validation tests in regenerative medicine. The most recent data also proposed it as an ideal tool for cell-free regenerative therapy and tissue engineering. However, senescent MSCs secretome was shown to hold the role of 'key-driver' in inflammaging. We aimed to review the immunomodulatory effects of the MSCs-secretome during cell senescence and provide eventual insight into the interpretation of its beneficial biological actions in inflammaging-associated diseases.
    Keywords:  MSC-secretome; SASP; immunomodulatory; pro-inflammatory cytokines
    DOI:  https://doi.org/10.3390/ijms24076372
  16. Cold Spring Harb Perspect Med. 2023 Apr 10. pii: a041208. [Epub ahead of print]
    Funding Life-Extension Research.
    Mehmood Khan.
      While the worldwide trend in life expectancy continues to increase slightly overall, the trend for the last few decades in developed countries is that more people are spending more years in poor health with multiple chronic comorbidities. These chronic conditions in aging populations consume high proportions of national healthcare budgets. The relatively young field of longevity research, after accumulating insights into the mechanisms of aging and producing dramatic laboratory demonstrations of life extension in some organisms, is entering the translational phase. This phase, through clinical trials, will confirm or refute the "geroscience hypothesis" that drugs can change the trajectory of the processes of aging within cells, and ultimately in living humans. At the same time, traditional funding patterns do not favor such visionary "moonshot" research, which, despite the potential for ultimately providing benefits for everyone, offers little prospect for rapid return on investment and high probabilities for early phase failure. New radical funding strategies incentivizing innovation will have to be called into play.
    DOI:  https://doi.org/10.1101/cshperspect.a041208
  17. Blood. 2023 Apr 13. 141(15): 1786-1787
    MYB deficiency leads to myeloid neoplasia too.
    Thomas J Gonda.
      
    DOI:  https://doi.org/10.1182/blood.2022019533
  18. Nat Rev Drug Discov. 2023 Apr 14.
    Immuno-oncology clinical trials take a turn beyond PD1/PDL1 inhibitors.
    Ana Rosa Saez-Ibanez, Samik Upadhaya, Jay Campbell.
      
    DOI:  https://doi.org/10.1038/d41573-023-00066-0
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