bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2024–03–03
eleven papers selected by
Ayesh Seneviratne, Western University
  1. Clonal hematopoiesis and autoimmunity.
  2. Role of mitochondrial potassium channels in ageing.
  3. Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.
  4. Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration.
  5. Response to: The information theory of aging has not been tested.
  6. Aging STINGs: mitophagy at the crossroads of neuroinflammation.
  7. Metformin reduces the clonal fitness of Dnmt3aR878H hematopoietic stem and progenitor cells by reversing their aberrant metabolic and epigenetic state.
  8. MtDNA deletions and aging.
  9. The information theory of aging has not been tested.
  10. Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies.
  11. Diet, Pace of Biological Aging, and Risk of Dementia in the Framingham Heart Study.
  1. Semin Hematol. 2024 Feb 02. pii: S0037-1963(24)00011-8. [Epub ahead of print]
    Clonal hematopoiesis and autoimmunity.
    Ashwin Kishtagari, Robert W Corty, Valeria Visconte.
      Clonal hematopoiesis (CH) has been associated with aging, occurring in about 10% of individuals aged >70 years, and immune dysfunction. Aged hematopoietic stem and progenitor cells exhibit pathological changes in immune function and activation of inflammatory pathways. CH clones commonly harbor a loss of function mutation in DNMT3A or TET2, which causes increased expression of inflammatory signaling genes, a proposed mechanism connected to CH and the development of age-related diseases. Additionally, inflammation may stress the hematopoietic compartment, driving the expansion of mutant clones. While the epidemiologic overlap between CH, hematologic malignancies, and atherosclerotic cardiovascular diseases has been reported, the mechanisms linking these concepts are largely unknown and merit much further investigation. Here, we review studies highlighting the interplay between CH, inflamm-aging, the immune system, and the prevalence of CH in autoimmune diseases.
    Keywords:  Autoimmune diseases; Clonal hematopoiesis; Dysregulation; Inflammation
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.01.012
  2. Mitochondrion. 2024 Feb 24. pii: S1567-7249(24)00015-1. [Epub ahead of print]76 101857
    Role of mitochondrial potassium channels in ageing.
    Lorenzo Flori, Jacopo Spezzini, Vincenzo Calderone, Lara Testai.
      Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life expectancy is also viewed as a condition in which many elderly will develop age-related diseases and disabilities, such as cardiovascular, metabolic, neurological and oncological ones. Currently, several recognized cellular hallmarks of senescence are taken in consideration to evaluate the level of biological ageing and are the topic to plan preventive/curative anti-ageing interventions, including genomic instability, epigenetic alterations, and mitochondrial dysfunction. In this scenario, alterations in the function/expression of mitochondrial ion channels have been found in ageing and associated to an impairment of calcium cycling and a reduced mitochondrial membrane potential. Although several ion channels have been described at mitochondrial level, undoubtedly the mitochondrial potassium (mitoK) channels are the most investigated. Therefore, this review summarized the evidence that sheds to light a correlation between age-related diseases and alteration of mitoK channels, focusing the attention of the main age-related diseases, i.e. cardiovascular, neurological and oncological ones.
    Keywords:  Age-related disease; Ageing; Dysfunction; Mitochondria; mitoK channels
    DOI:  https://doi.org/10.1016/j.mito.2024.101857
  3. iScience. 2024 Mar 15. 27(3): 109122
    Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.
    Jaime M Reyes, Ayala Tovy, Linda Zhang, Angelina S Bortoletto, Carina Rosas, Chun-Wei Chen, Sarah M Waldvogel, Anna G Guzman, Rogelio Aguilar, Sinjini Gupta, Ling Liu, Matthew T Buckley, Kalyani R Patel, Andrea N Marcogliese, Yumei Li, Choladda V Curry, Thomas Rando, Anne Brunet, Ronald J Parchem, Rachel E Rau, Margaret A Goodell.
      During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in DNA methyltransferase 3A (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between high-fat diet (HFD) and reduced DNMT3A in hematopoietic cells; strikingly, this combination led to weight gain. HFD amplified pro-inflammatory pathways and upregulated inflammation-associated genes in mutant cells along a pro-myeloid trajectory. Aberrant DNA methylation during myeloid differentiation and in response to HFD led to pro-inflammatory activation and maintenance of stemness genes. These findings suggest that reduced DNMT3A in hematopoietic cells contributes to weight gain, inflammation, and metabolic dysfunction, highlighting a role for DNMT3A loss in the development of metabolic disorders.
    Keywords:  Epigenetics; Immunology; Physiology; Stem cells research; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109122
  4. Nat Aging. 2024 Mar 01.
    Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration.
    Isabelle R de Luzy, Michael K Lee, William C Mobley, Lorenz Studer.
      Age remains the central risk factor for many neurodegenerative diseases including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Although the mechanisms of aging are complex, the age-related accumulation of senescent cells in neurodegeneration is well documented and their clearance can alleviate disease-related features in preclinical models. Senescence-like characteristics are observed in both neuronal and glial lineages, but their relative contribution to aging and neurodegeneration remains unclear. Human pluripotent stem cell-derived neurons provide an experimental model system to induce neuronal senescence. However, the extensive heterogeneity in the profile of senescent neurons and the methods to assess senescence remain major challenges. Here, we review the evidence of cellular senescence in neuronal aging and disease, discuss human pluripotent stem cell-based model systems used to investigate neuronal senescence and propose a panel of cellular and molecular hallmarks to characterize senescent neurons. Understanding the role of neuronal senescence may yield novel therapeutic opportunities in neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s43587-024-00586-3
  5. Cell. 2024 Feb 29. pii: S0092-8674(24)00051-5. [Epub ahead of print]187(5): 1103-1105
    Response to: The information theory of aging has not been tested.
    Jae-Hyun Yang, Motoshi Hayano, Luis A Rajman, David A Sinclair.
      
    DOI:  https://doi.org/10.1016/j.cell.2024.01.014
  6. Autophagy. 2024 Feb 27.
    Aging STINGs: mitophagy at the crossroads of neuroinflammation.
    Juan Ignacio Jiménez-Loygorri, Patricia Boya.
      Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in non-selective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an in vitro model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.
    Keywords:  Inflammation; PINK1; Parkin; mitochondria; mtDNA; retina
    DOI:  https://doi.org/10.1080/15548627.2024.2322421
  7. Res Sq. 2024 Feb 06. pii: rs.3.rs-3874821. [Epub ahead of print]
    Metformin reduces the clonal fitness of Dnmt3aR878H hematopoietic stem and progenitor cells by reversing their aberrant metabolic and epigenetic state.
    Steven Chan, Mohsen Hosseini, Veronique Voisin, Ali Chegini, Angelica Varesi, Severine Cathelin, Dhanoop Manikoth Ayyathan, Alex Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie Haines, Angelo D'Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, Luigi Naldini, Federico Gaiti, Shraddha Pai, Aaron Schimmer, Gary Bader, John Dick, Stephanie Z Xie, Jennifer Trowbridge.
      Clonal hematopoiesis (CH) arises when a hematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type (WT) HSCs, resulting in its clonal expansion. Individuals with CH are at an increased risk of developing hematologic neoplasms and a range of age-related inflammatory illnesses1-3. Therapeutic interventions that suppress the expansion of mutant HSCs have the potential to prevent these CH-related illnesses; however, such interventions have not yet been identified. The most common CH driver mutations are in the DNA methyltransferase 3 alpha (DNMT3A) gene with arginine 882 (R882) being a mutation hotspot. Here we show that murine hematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, which is equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with WT cells and are dependent on this metabolic reprogramming for their competitive advantage. Importantly, treatment with metformin, an oral anti-diabetic drug with inhibitory activity against complex I in the electron transport chain (ETC), reduced the fitness of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we discovered that metformin acts by enhancing the methylation potential in Dnmt3aR878H/+ HSPCs and reversing their aberrant DNA CpG methylation and histone H3K27 trimethylation (H3K27me3) profiles. Metformin also reduced the fitness of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against illnesses associated with DNMT3AR882 mutation-driven CH in humans.
    DOI:  https://doi.org/10.21203/rs.3.rs-3874821/v1
  8. Front Aging. 2024 ;5 1359638
    MtDNA deletions and aging.
    Charlotte Sprason, Trudy Tucker, David Clancy.
      Aging is the major risk factor in most of the leading causes of mortality worldwide, yet its fundamental causes mostly remain unclear. One of the clear hallmarks of aging is mitochondrial dysfunction. Mitochondria are best known for their roles in cellular energy generation, but they are also critical biosynthetic and signaling organelles. They also undergo multiple changes with organismal age, including increased genetic errors in their independent, circular genome. A key group of studies looking at mice with increased mtDNA mutations showed that premature aging phenotypes correlated with increased deletions but not point mutations. This generated an interest in mitochondrial deletions as a potential fundamental cause of aging. However, subsequent studies in different models have yielded diverse results. This review summarizes the research on mitochondrial deletions in various organisms to understand their possible roles in causing aging while identifying the key complications in quantifying deletions across all models.
    Keywords:  aging; mitochondria; mitochondrial DNA; mitochondrial DNA deletions; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fragi.2024.1359638
  9. Cell. 2024 Feb 29. pii: S0092-8674(24)00050-3. [Epub ahead of print]187(5): 1101-1102
    The information theory of aging has not been tested.
    James A Timmons, Charles Brenner.
      
    DOI:  https://doi.org/10.1016/j.cell.2024.01.013
  10. Aging Dis. 2024 Feb 27.
    Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies.
    Liyao Zheng, Shipei He, Hong Wang, Jinling Li, Yuanyuan Liu, Sijia Liu.
      Cellular senescence is characterized by the permanent arrest of cell proliferation and is a response to endogenous and exogenous stress. The continuous accumulation of senescent cells (SnCs) in the body leads to the development of aging and age-related diseases (such as neurodegenerative diseases, cancer, metabolic diseases, cardiovascular diseases, and osteoarthritis). In the face of the growing challenge of aging and age-related diseases, several compounds have received widespread attention for their potential to target SnCs. As a result, senolytics (compounds that selectively eliminate SnCs) and senomorphics (compounds that alter intercellular communication and modulate the behavior of SnCs) have become hot research topics in the field of anti-aging. In addition, strategies such as combination therapies and immune-based approaches have also made significant progress in the field of anti-aging therapy. In this article, we discuss the latest research on anti-aging targeting SnCs and gain a deeper understanding of the mechanism of action and impact of different anti-aging strategies on aging and age-related diseases, with the aim of providing more effective references and therapeutic ideas for clinical anti-aging treatment in the face of the ever-grave challenges of aging and age-related diseases.
    DOI:  https://doi.org/10.14336/AD.2024.0206
  11. Ann Neurol. 2024 Feb 26.
    Diet, Pace of Biological Aging, and Risk of Dementia in the Framingham Heart Study.
    Aline Thomas, Calen P Ryan, Avshalom Caspi, Zhonghua Liu, Terrie E Moffitt, Karen Sugden, Jiayi Zhou, Daniel W Belsky, Yian Gu.
       OBJECTIVE: People who eat healthier diets are less likely to develop dementia, but the biological mechanism of this protection is not well understood. We tested the hypothesis that healthy diet protects against dementia because it slows the pace of biological aging.
    METHODS: We analyzed Framingham Offspring Cohort data. We included participants ≥60 years-old, free of dementia and having dietary, epigenetic, and follow-up data. We assessed healthy diet as long-term adherence to the Mediterranean-Dash Intervention for Neurodegenerative Delay diet (MIND, over 4 visits spanning 1991-2008). We measured the pace of aging from blood DNA methylation data collected in 2005-2008 using the DunedinPACE epigenetic clock. Incident dementia and mortality were defined using study records compiled from 2005 to 2008 visit through 2018.
    RESULTS: Of n = 1,644 included participants (mean age 69.6, 54% female), n = 140 developed dementia and n = 471 died over 14 years of follow-up. Greater MIND score was associated with slower DunedinPACE and reduced risks for dementia and mortality. Slower DunedinPACE was associated with reduced risks for dementia and mortality. In mediation analysis, slower DunedinPACE accounted for 27% of the diet-dementia association and 57% of the diet-mortality association.
    INTERPRETATION: Findings suggest that slower pace of aging mediates part of the relationship of healthy diet with reduced dementia risk. Monitoring pace of aging may inform dementia prevention. However, a large fraction of the diet-dementia association remains unexplained and may reflect direct connections between diet and brain aging that do not overlap other organ systems. Investigation of brain-specific mechanisms in well-designed mediation studies is warranted. ANN NEUROL 2024.
    DOI:  https://doi.org/10.1002/ana.26900
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