bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–11–12
thirteen papers selected by
Ayesh Seneviratne, Western University
  1. Centile curves for following intrinsic capacity across adulthood.
  2. Epigenetic roles in clonal hematopoiesis and aging kidney-related chronic kidney disease.
  3. 66Mouse models of accelerated aging in musculoskeletal research for assessing frailty, sarcopenia, and osteoporosis - a review.
  4. CD61 identifies a superior population of aged murine HSCs and is required to preserve quiescence and self-renewal.
  5. Lipid metabolism extinguishes cGAS-STING-induced inflammation.
  6. Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
  7. Introduction to Special Issue on 'Physiological and PA Evolutionary Mechanisms of Aging'.
  8. To promote healthy aging, focus on the environment.
  9. Mitophagy Activation by Urolithin A to Target Muscle Aging.
  10. A method to identify regulators of senolysis.
  11. Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.
  12. Lifestyle interventions to delay senescence.
  13. ATAC-clock: An aging clock based on chromatin accessibility.
  1. Nat Aging. 2023 Nov 10.
    Centile curves for following intrinsic capacity across adulthood.
      
    DOI:  https://doi.org/10.1038/s43587-023-00534-7
  2. Front Cell Dev Biol. 2023 ;11 1281850
    Epigenetic roles in clonal hematopoiesis and aging kidney-related chronic kidney disease.
    Yoshiyasu Ogura, Imari Mimura.
      Accumulation of somatic hematopoietic stem cell mutations with aging has been revealed by the recent genome-wide analysis. Clonal expansion, known as clonal hematopoiesis of indeterminate potential (CHIP), is a premalignant condition of hematological cancers. It is defined as the absence of definitive morphological evidence of a hematological neoplasm and occurrence of ≥2% of mutant allele fraction in the peripheral blood. In CHIP, the most frequently mutated genes are epigenetic regulators such as DNMT3A, TET2, and ASXL1. CHIP induces inflammation. CHIP is shown to be associated with not only hematological malignancy but also non-malignant disorders such as atherosclerosis, cardiovascular diseases and chronic liver disease. In addition, recent several large clinical trials have shown that CHIP is also the risk factor for developing chronic kidney disease (CKD). In this review article, we proposed novel findings about CHIP and CHIP related kidney disease based on the recent basic and clinical research. The possible mechanism of the kidney injury in CHIP is supposed to be due to the clonal expansion in both myeloid and lymphoid cell lines. In myeloid cell lines, the mutated macrophages increase the inflammatory cytokine level and induce chronic inflammation. It leads to epigenetic downregulation of kidney and macrophage klotho level. In lymphoid cell lines, CHIP might be related to monoclonal gammopathy of renal significance (MGRS). It describes any B cell or plasma cell clonal disorder that does not fulfill the criteria for cancer yet produces a nephrotoxic monoclonal immunoglobulin that leads to kidney injury or disease. MGRS causes M-protein related nephropathy frequently observed among aged CKD patients. It is important to consider the CHIP-related complications such as hematological malignancy, cardiovascular diseases and metabolic disorders in managing the elderly CKD patients. There are no established therapies for CHIP and CHIP-related CKD yet. However, recent studies have supported the development of effective CHIP therapies, such as blocking the expansion of aberrant HSCs and inhibiting chronic inflammation. In addition, drugs targeting the epigenetic regulation of Klotho in the kidney and macrophages might be therapeutic targets of CHIP in the kidney.
    Keywords:  CHIP; CKD; Klotho; aging; epigenetics
    DOI:  https://doi.org/10.3389/fcell.2023.1281850
  3. Ageing Res Rev. 2023 Nov 05. pii: S1568-1637(23)00277-5. [Epub ahead of print] 102118
    66Mouse models of accelerated aging in musculoskeletal research for assessing frailty, sarcopenia, and osteoporosis - a review.
    Dilara Yılmaz, Neashan Mathavan, Esther Wehrle, Gisela A Kuhn, Ralph Müller.
      Musculoskeletal aging encompasses the decline in bone and muscle function, leading to conditions such as frailty, osteoporosis, and sarcopenia. Unraveling the underlying molecular mechanisms and developing effective treatments are crucial for improving the quality of life for those affected. In this context, accelerated aging models offer valuable insights into these conditions by displaying the hallmarks of human aging. Herein, this review focuses on relevant mouse models of musculoskeletal aging with particular emphasis on frailty, osteoporosis, and sarcopenia. Among the discussed models, PolgA mice in particular exhibit hallmarks of musculoskeletal aging, presenting early-onset frailty, as well as reduced bone and muscle mass that closely resemble human musculoskeletal aging. Ultimately, findings from these models hold promise for advancing interventions targeted at age-related musculoskeletal disorders, effectively addressing the challenges posed by musculoskeletal aging and associated conditions in humans.
    Keywords:  Musculoskeletal aging; PolgA; accelerated aging mouse models; frailty; osteoporosis; sarcopenia
    DOI:  https://doi.org/10.1016/j.arr.2023.102118
  4. Blood Adv. 2023 Nov 08. pii: bloodadvances.2023011585. [Epub ahead of print]
    CD61 identifies a superior population of aged murine HSCs and is required to preserve quiescence and self-renewal.
    Natalia Skinder, Irene Sanz Fernández, Albertien Dethmers-Ausema, Ellen Weersing, Gerald de Haan.
      Aging leads to a decline in function of hematopoietic stem cells (HSCs) and increases susceptibility to hematological disease. We found CD61 to be highly expressed in aged murine HSCs. Here we investigate the role of CD61 in identifying distinct subpopulations of aged HSCs and assess how expression of CD61 affects stem cell function. We show that HSCs with high expression of CD61 are functionality superior and retain self-renewal capacity in serial transplantations. In primary transplantations aged CD61High HSCs function similarly compared to young HSCs. CD61High HSCs are more quiescent compared to their CD61Low counterparts. We also show that in aged BM CD61High and CD61Low HSCs are transcriptomically distinct populations. Collectively, our research identifies CD61 as a key player in maintaining stem cell quiescence, ensuring the preservation of their functional integrity and potential during aging. Moreover, CD61 emerges as a marker to prospectively isolate a superior, highly dormant population of young and aged HSCs, making it a valuable tool both in fundamental and clinical research.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011585
  5. Nat Rev Immunol. 2023 Nov 03.
    Lipid metabolism extinguishes cGAS-STING-induced inflammation.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-023-00962-x
  6. Nat Aging. 2023 Nov 09.
    Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
    Chrysa Nikopoulou, Niklas Kleinenkuhnen, Swati Parekh, Tonantzi Sandoval, Christoph Ziegenhain, Farina Schneider, Patrick Giavalisco, Kat-Folz Donahue, Anna Juliane Vesting, Marcel Kirchner, Mihaela Bozukova, Christian Vossen, Janine Altmüller, Thomas Wunderlich, Rickard Sandberg, Vangelis Kondylis, Achim Tresch, Peter Tessarz.
      Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.
    DOI:  https://doi.org/10.1038/s43587-023-00513-y
  7. Exp Gerontol. 2023 Nov 06. pii: S0531-5565(23)00245-0. [Epub ahead of print] 112324
    Introduction to Special Issue on 'Physiological and PA Evolutionary Mechanisms of Aging'.
    Gustavo Barja, Reinald Pamplona.
      What are the structural components and physiological mechanisms determining the aging process? Can the different mechanisms described in aging biology converge into a core of coordinated aging effectors? Why some human beings, for instance, can reach 115-122 years of age while rats can live at best a maximum of 4 years? Can the aging rate be modified? How much can human lifespan be extended? Is aging a programmed or non-programmed process? This special issue includes invited articles to explore the physiological mechanisms of aging, and both classical and updated hypotheses on the evolutionary meaning of aging. Breakthroughs in aging-related research are currently unveiling longevity factors highly conserved during evolution of animal species and are discovering details on how and why molecular and cellular processes decline during physiologically normal aging. Investigations in model organisms and humans are uncovering potential approaches to extend not only mean individual survival but also species maximum (from here on) longevity. Experimental Gerontology presents this Special Issue (SI) highlighting recent advances in the mechanistic understanding of longevity, aging and interventions that extend lifespan. This SI includes invited articles to address most of the reasonably well known physiological mechanisms of aging, and tries to evaluate the available evidence supporting or not the different opposed hypotheses on the biological evolution of aging, why aging exists at all?. The SI is composed of ten peer reviewed invited reviews and primary research articles, covering basic concepts on aging biology and species longevity, with a special specific focus on mitochondrial function, mitROS production (mitROSp), mitDNA damage and caloric restriction; autophagy; the role of dietary antioxidants; the only drug that has consistently demonstrated (ITP/NIA/NIH program performed at three independent laboratories) that increases longevity in mammals over that of normal controls: rapamycin; heterochronic parabiosis; secondary inflammaging; the role of epigenetics in the control of a cellular nuclear aging program, and the hypothetical existence of peripheral and central aging clocks.
    DOI:  https://doi.org/10.1016/j.exger.2023.112324
  8. Nat Aging. 2023 Nov 09.
    To promote healthy aging, focus on the environment.
    Daniel W Belsky, Andrea A Baccarelli.
      To build health equity for an aging world marked by dramatic disparities in healthy lifespan between countries, regions and population groups, research at the intersections of biology, toxicology and the social and behavioral sciences points the way: to promote healthy aging, focus on the environment. In this Perspective, we suggest that ideas and tools from the emerging field of geroscience offer opportunities to advance the environmental science of aging. Specifically, the capacity to measure the pace and progress of biological processes of aging within individuals from relatively young ages makes it possible to study how changing environments can change aging trajectories from early in life, in time to prevent or delay aging-related disease and disability and build aging health equity.
    DOI:  https://doi.org/10.1038/s43587-023-00518-7
  9. Calcif Tissue Int. 2023 Nov 05.
    Mitophagy Activation by Urolithin A to Target Muscle Aging.
    Julie Faitg, Davide D'Amico, Chris Rinsch, Anurag Singh.
      The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. During aging, mitophagy levels decline and negatively impact skeletal muscle performance. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline.
    Keywords:  Aging; Mitochondria; Mitophagy; Muscle health; Urolithin A
    DOI:  https://doi.org/10.1007/s00223-023-01145-5
  10. Nat Aging. 2023 Nov 09.
    A method to identify regulators of senolysis.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-023-00529-4
  11. Nat Genet. 2023 Nov 06.
    Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.
    Simon N Stacey, Florian Zink, Gisli H Halldorsson, Lilja Stefansdottir, Sigurjon A Gudjonsson, Gudmundur Einarsson, Grimur Hjörleifsson, Thjodbjorg Eiriksdottir, Anna Helgadottir, Gyda Björnsdottir, Thorgeir E Thorgeirsson, Thorunn A Olafsdottir, Ingileif Jonsdottir, Solveig Gretarsdottir, Vinicius Tragante, Magnus K Magnusson, Hakon Jonsson, Julius Gudmundsson, Sigurgeir Olafsson, Hilma Holm, Daniel F Gudbjartsson, Patrick Sulem, Agnar Helgason, Unnur Thorsteinsdottir, Laufey Tryggvadottir, Thorunn Rafnar, Pall Melsted, Magnus Ö Ulfarsson, Brynjar Vidarsson, Gudmar Thorleifsson, Kari Stefansson.
      Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.
    DOI:  https://doi.org/10.1038/s41588-023-01555-z
  12. Biomed J. 2023 Nov 02. pii: S2319-4170(23)00113-0. [Epub ahead of print] 100676
    Lifestyle interventions to delay senescence.
    Jan Martel, David M Ojcius, John D Young.
      Senescence is a condition of cell cycle arrest that increases inflammation and contributes to the development of chronic diseases in the aging human body. While several compounds described as senolytics and senomorphics produce health benefits by reducing the burden of senescence, less attention has been devoted to lifestyle interventions that produce similar effects. We describe here the effects of exercise, nutrition, caloric restriction, intermittent fasting, phytochemicals from natural products, prebiotics and probiotics, and adequate sleep on senescence in model organisms and humans. These interventions can be integrated within a healthy lifestyle to reduce senescence and inflammation and delay the consequences of aging.
    Keywords:  Caloric restriction; Exercise; Metformin; Nutrition; Phytochemicals; Senescence
    DOI:  https://doi.org/10.1016/j.bj.2023.100676
  13. Geroscience. 2023 Nov 04.
    ATAC-clock: An aging clock based on chromatin accessibility.
    Francesco Morandini, Cheyenne Rechsteiner, Kevin Perez, Viviane Praz, Guillermo Lopez Garcia, Laura C Hinte, Ferdinand von Meyenn, Alejandro Ocampo.
      The establishment of aging clocks highlighted the strong link between changes in DNA methylation and aging. Yet, it is not known if other epigenetic features could be used to predict age accurately. Furthermore, previous studies have observed a lack of effect of age-related changes in DNA methylation on gene expression, putting the interpretability of DNA methylation-based aging clocks into question. In this study, we explore the use of chromatin accessibility to construct aging clocks. We collected blood from 159 human donors and generated chromatin accessibility, transcriptomic, and cell composition data. We investigated how chromatin accessibility changes during aging and constructed a novel aging clock with a median absolute error of 5.27 years. The changes in chromatin accessibility used by the clock were strongly related to transcriptomic alterations, aiding clock interpretation. We additionally show that our chromatin accessibility clock performs significantly better than a transcriptomic clock trained on matched samples. In conclusion, we demonstrate that the clock relies on cell-intrinsic chromatin accessibility alterations rather than changes in cell composition. Further, we present a new approach to construct epigenetic aging clocks based on chromatin accessibility, which bear a direct link to age-related transcriptional alterations, but which allow for more accurate age predictions than transcriptomic clocks.
    Keywords:  ATAC sequencing; Aging; Biomarker; Chromatin accessibility; Epigenetic clock
    DOI:  https://doi.org/10.1007/s11357-023-00986-0
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