bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2024–09–01
twelve papers selected by
Ayesh Seneviratne, Western University
  1. How clonal hematopoiesis promotes inflammation at a single-cell level.
  2. Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.
  3. What accelerates brain ageing? This AI 'brain clock' points to answers.
  4. The promise of machine learning approaches to capture cellular senescence heterogeneity.
  5. Genetic causes and cardiovascular consequences of clonal hematopoiesis in the UK Biobank.
  6. Intrinsic capacity and aging: advances in research and clinical practice.
  7. Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?
  8. Clinical and Therapeutic Implications of Clonal Hematopoiesis.
  9. Molecular Signaling and Clinical Implications in the Human Aging-cancer Cycle.
  10. The Art of Healthy Aging.
  11. Daily briefing: Five patterns of brain atrophy associated with ageing and Alzheimer's.
  12. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
  1. Nat Cardiovasc Res. 2023 Sep;2(9): 801-802
    How clonal hematopoiesis promotes inflammation at a single-cell level.
    Nicholas W Chavkin, Megan A Evans, Kenneth Walsh.
      
    DOI:  https://doi.org/10.1038/s44161-023-00323-w
  2. Cell Stem Cell. 2024 Aug 21. pii: S1934-5909(24)00285-6. [Epub ahead of print]
    Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.
    Changhong Du, Chaonan Liu, Kuan Yu, Shuzhen Zhang, Zeyu Fu, Xinliang Chen, Weinian Liao, Jun Chen, Yimin Zhang, Xinmiao Wang, Mo Chen, Fang Chen, Mingqiang Shen, Cheng Wang, Shilei Chen, Song Wang, Junping Wang.
      Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.
    Keywords:  NADPH; SHMT2; ferroptosis; hematopoietic stem cell; heterogeneity; ionizing radiation; mitochondrial serine catabolism; myelosuppressive injury
    DOI:  https://doi.org/10.1016/j.stem.2024.07.009
  3. Nature. 2024 Aug 27.
    What accelerates brain ageing? This AI 'brain clock' points to answers.
    Julian Nowogrodzki.
      
    Keywords:  Ageing; Brain; Epidemiology; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-024-02770-2
  4. Nat Aging. 2024 Aug 26.
    The promise of machine learning approaches to capture cellular senescence heterogeneity.
    Imanol Duran, Cleo L Bishop, Jesús Gil, Ryan Wallis.
      
    DOI:  https://doi.org/10.1038/s43587-024-00703-2
  5. Nat Cardiovasc Res. 2023 Jan;2(1): 13-15
    Genetic causes and cardiovascular consequences of clonal hematopoiesis in the UK Biobank.
    J Scott Beeler, Alexander G Bick, Kelly L Bolton.
      
    DOI:  https://doi.org/10.1038/s44161-022-00198-3
  6. J Nutr Health Aging. 2024 Aug;pii: S1279-7707(24)00423-8. [Epub ahead of print]28(8): 100336
    Intrinsic capacity and aging: advances in research and clinical practice.
    Philipe de Souto Barreto.
      
    DOI:  https://doi.org/10.1016/j.jnha.2024.100336
  7. Aging Cell. 2024 Aug 26. e14296
    Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?
    Antentor O Hinton, Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano.
      The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity-including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks-may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.
    Keywords:  aging; mitochondria; organelle contacts; protein targeting; structure
    DOI:  https://doi.org/10.1111/acel.14296
  8. Annu Rev Genomics Hum Genet. 2024 Aug;25(1): 329-351
    Clinical and Therapeutic Implications of Clonal Hematopoiesis.
    Giulia Petrone, Isik Turker, Pradeep Natarajan, Kelly L Bolton.
      Clonal hematopoiesis (CH) is an age-related process whereby hematopoietic stem and progenitor cells (HSPCs) acquire mutations that lead to a proliferative advantage and clonal expansion. The most commonly mutated genes are epigenetic regulators, DNA damage response genes, and splicing factors, which are essential to maintain functional HSPCs and are frequently involved in the development of hematologic malignancies. Established risk factors for CH, including age, prior cytotoxic therapy, and smoking, increase the risk of acquiring CH and/or may increase CH fitness. CH has emerged as a novel risk factor in many age-related diseases, such as hematologic malignancies, cardiovascular disease, diabetes, and autoimmune disorders, among others. Future characterization of the mechanisms driving CH evolution will be critical to develop preventative and therapeutic approaches.
    Keywords:  cardiovascular disease; cellular therapy; clonal hematopoiesis; hematologic malignancies; management of clonal hematopoiesis
    DOI:  https://doi.org/10.1146/annurev-genom-120722-100409
  9. Semin Cancer Biol. 2024 Aug 26. pii: S1044-579X(24)00061-0. [Epub ahead of print]
    Molecular Signaling and Clinical Implications in the Human Aging-cancer Cycle.
    Abdol-Hossein Rezaeian, Wenyi Wei.
      It is well documented that aging is associated with cancer, and likewise, cancer survivors display accelerated aging. As the number of aging individuals and cancer survivors continues to grow, it raises additional concerns across society. Therefore, unraveling the molecular mechanisms of aging in tissues is essential to developing effective therapies to fight the aging and cancer diseases in cancer survivors and cancer patients. Indeed, cellular senescence is a critical response, or a natural barrier to suppress the transition of normal cells into cancer cells, however, hypoxia which is physiologically required to maintain the stem cell niche, is increased by aging and inhibits senescence in tissues. Interestingly, oxygen restriction or hypoxia increases longevity and slows the aging process in humans, but hypoxia can also drive angiogenesis to facilitate cancer progression. In addition, cancer treatment is considered as one of the major reasons that drive cellular senescence, subsequently followed by accelerated aging. Several clinical trials have recently evaluated inhibitors to eliminate senescent cells. However, some mechanisms of aging typically can also block cancer cell growth and progression, which might require careful strategy for better clinical outcomes. Here we describe the molecular regulation of aging and cancer in crosstalk with DNA damage and hypoxia signaling pathways in cancer patients and cancer survivors. We also update several therapeutic strategies that might be critical in reversing the cancer treatment-associated aging process.
    Keywords:  aging; cancer; hypoxia; senescence; therapeutic strategies
    DOI:  https://doi.org/10.1016/j.semcancer.2024.08.003
  10. Am J Nurs. 2024 Sep 01. 124(9): 5
    The Art of Healthy Aging.
    Christine Moffa.
      It's never too early to think about growing older.
    DOI:  https://doi.org/10.1097/01.NAJ.0001050740.61781.e5
  11. Nature. 2024 Aug 20.
    Daily briefing: Five patterns of brain atrophy associated with ageing and Alzheimer's.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02750-6
  12. Nat Commun. 2024 Aug 27. 15(1): 7378
    Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
    Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.
      The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51363-0
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