bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–10–15
eight papers selected by
Ayesh Seneviratne, Western University
  1. Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.
  2. Metabolites in aging and aging-relevant diseases: Frailty, sarcopenia and cognitive decline.
  3. The Third Annual Symposium of the Midwest Aging Consortium.
  4. Exercise mitigates Age-related Metabolic Diseases by improving Mitochondrial Dysfunction.
  5. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  6. The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
  7. How Nutrition Regulates Hematopoietic Stem Cell Features.
  8. Mitochondria: A Potential Rejuvenation Tool against Aging.
  1. Annu Rev Pathol. 2023 Oct 13.
    Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.
    Rashmi Kanagal-Shamanna, David B Beck, Katherine R Calvo.
      Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-051222-122724
  2. Geriatr Gerontol Int. 2023 Oct 13.
    Metabolites in aging and aging-relevant diseases: Frailty, sarcopenia and cognitive decline.
    Hiroshi Kondoh, Masahiro Kameda.
      Aging shows biologically complex features with high individual variability, which reflects the exposure to several stimuli and the adaptation to them. Among them, metabolic changes are well observed as consequences or possible causes of aging. Calorie restriction extends organismal life span in experimental models. Several metabolites; for example, resveratrol or nicotinamide mononucleotide, are reported to mimic calorie restriction effects in vivo. Metabolomic research would be useful to evaluate metabolites as biomarkers in aging-relevant events and to identify metabolic regulation of aging. We recently developed the metabolomic approach for whole blood analysis, which functions as strong tool for this purpose. We review the update findings in aging-relevant metabolites detected by this method. Geriatr Gerontol Int 2023; ••: ••-••.
    Keywords:  aging; frailty; metabolites
    DOI:  https://doi.org/10.1111/ggi.14684
  3. J Gerontol A Biol Sci Med Sci. 2023 Oct 07. pii: glad239. [Epub ahead of print]
    The Third Annual Symposium of the Midwest Aging Consortium.
    Andrea Keller, Hua Bai, Scott Budinger, Susan Eliazer, Malene Hansen, Adam R Konopka, Luisa Morales-Nebreda, Charles P Najt, Veena Prahlad, Stella Victorelli, Colby J Vorland, Rong Yuan, Timothy W Rhoads, Maria M Mihaylova.
      The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The 3rd annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States. This report summarizes the work presented during a virtual conference across topics in aging biology, including immune function in lung - particularly timely given the COVID-19 pandemic - along with the role of metabolism and nutrient regulated pathways in cellular function with age, the influence of senescence on stem cell function and inflammation, and our evolving understanding of the mechanisms underlying observation of sex dimorphism in aging-related outcomes. The symposium focused on early-stage and emerging investigators, while including keynote presentations from leaders in the biology of aging field, highlighting the diversity and strength of aging research in the Midwest.
    Keywords:  Aging; geroscience; metabolism
    DOI:  https://doi.org/10.1093/gerona/glad239
  4. Ageing Res Rev. 2023 Oct 11. pii: S1568-1637(23)00246-5. [Epub ahead of print] 102087
    Exercise mitigates Age-related Metabolic Diseases by improving Mitochondrial Dysfunction.
    Dandan Jia, Zhenjun Tian, Ru Wang.
      The benefits of regular physical activity are related to delaying and reversing the onset of ageing and age-related disorders, including cardiomyopathy, neurodegenerative diseases, cancer, obesity, diabetes, and fatty liver diseases. However, the molecular mechanisms of the benefits of exercise or physical activity on ageing and age-related disorders remain poorly understood. Mitochondrial dysfunction is implicated in the pathogenesis of ageing and age-related metabolic diseases. Mitochondrial health is an important mediator of cellular function. Therefore, exercise alleviates metabolic diseases in individuals with advancing ageing and age-related diseases by the remarkable promotion of mitochondrial biogenesis and function. Exerkines are identified as signaling moieties released in response to exercise. Exerkines released by exercise have potential roles in improving mitochondrial dysfunction in response to age-related disorders. This review comprehensive summarizes the benefits of exercise in metabolic diseases, linking mitochondrial dysfunction to the onset of age-related diseases. Using relevant examples utilizing this approach, the possibility of designing therapeutic interventions based on these molecular mechanisms is addressed.
    Keywords:  age-related diseases; ageing; exerkines; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.arr.2023.102087
  5. Nature. 2023 Oct 11.
    Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
    DOI:  https://doi.org/10.1038/s41586-023-06621-4
  6. Exp Hematol. 2023 Oct 11. pii: S0301-472X(23)01736-8. [Epub ahead of print]
    The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
    Marie-Dominique Filippi.
      Hematopoietic stem cells (HSCs) have the properties to self-renew and/or differentiate into all mature blood cell lineages. The fate decisions to generate progeny that retain stemness properties or that commit to differentiation is a fundamental process to maintain tissue homeostasis and must be tightly regulated in order to prevent HSC overgrowth or exhaustion. HSC fate decisions are inherently coupled to cell division. The transition from quiescence to activation is accompanied by major metabolic and mitochondrial changes that are important for cell cycle entry for balanced decisions between self-renewal and differentiation. In this review, we discuss the current understanding of the role of mitochondrial metabolism in HSC transition from quiescence to activation and fate decisions.
    DOI:  https://doi.org/10.1016/j.exphem.2023.10.001
  7. Exp Hematol. 2023 Oct 08. pii: S0301-472X(23)01735-6. [Epub ahead of print]
    How Nutrition Regulates Hematopoietic Stem Cell Features.
    Katharina Schönberger, Nina Cabezas-Wallscheid.
      Our dietary choices significantly impact all the cells in our body. Increasing evidence suggests that diet-derived metabolites influence hematopoietic stem cell (HSC) metabolism and function, thereby actively modulating blood homeostasis. This is of particular relevance since regulating the metabolic activity of HSCs is crucial for maintaining stem cell fitness and mitigating the risk of hematological disorders. In this review, we examine the current scientific knowledge of the impact of the diet on stemness features, and we specifically highlight the established mechanisms by which dietary components modulate metabolic and transcriptional programs in adult HSCs. Gaining a deeper understanding of how nutrition influences our HSC compartment may pave the way for targeted dietary interventions with the potential to decelerate aging and improve the effectiveness of transplantation and cancer therapies.
    Keywords:  Diet; Metabolism; Stem Cells (hematopoietic stem cells)
    DOI:  https://doi.org/10.1016/j.exphem.2023.09.008
  8. Aging Dis. 2023 Oct 03.
    Mitochondria: A Potential Rejuvenation Tool against Aging.
    Qian Hua Phua, Shi Yan Ng, Boon-Seng Soh.
      Aging is a complex physiological process encompassing both physical and cognitive decline over time. This intricate process is governed by a multitude of hallmarks and pathways, which collectively contribute to the emergence of numerous age-related diseases. In response to the remarkable increase in human life expectancy, there has been a substantial rise in research focusing on the development of anti-aging therapies and pharmacological interventions. Mitochondrial dysfunction, a critical factor in the aging process, significantly impacts overall cellular health. In this extensive review, we will explore the contemporary landscape of anti-aging strategies, placing particular emphasis on the promising potential of mitotherapy as a ground-breaking approach to counteract the aging process. Moreover, we will investigate the successful application of mitochondrial transplantation in both animal models and clinical trials, emphasizing its translational potential. Finally, we will discuss the inherent challenges and future possibilities of mitotherapy within the realm of aging research and intervention.
    DOI:  https://doi.org/10.14336/AD.2023.0712
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