bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023‒01‒22
twelve papers selected by
Ayesh Seneviratne
Western University
  1. Stem cell factors reverse signs of aging in mice.
  2. [Clonal hematopoiesis: causes and clinical implications].
  3. Targeting mitochondria to extend physically active lifespan.
  4. Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.
  5. The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging.
  6. Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism.
  7. Is aging a "Retro"spective event?
  8. Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment.
  9. Immune cells' ability to persist and replicate long outlives species lifespan.
  10. Fasting and fasting mimicking diets in cancer prevention and therapy.
  11. Management of inflammatory bowel diseases in older adults.
  12. Premature aging in childhood cancer survivors.
  1. Science. 2023 Jan 20. 379(6629): 224
    Stem cell factors reverse signs of aging in mice.
    Catherine Offord.
      Will reprogramming technique one day help people?
    DOI:  https://doi.org/10.1126/science.adg7353
  2. Z Gerontol Geriatr. 2023 Jan 20.
    [Clonal hematopoiesis: causes and clinical implications].
    Andreas Burchert.
      Clonal hematopoiesis of indeterminate potential (CHIP) refers to hematopoiesis from stem cells with mutations in leukemia-associated driver genes. These confer increased stress tolerance and expansive potential to stem cell clones. Patients with CHIP are hematologically healthy. The main risk factor for the development of CHIP is age or chronic inflammatory processes associated with aging, so-called "inflammaging". Therefore, the correlation of age-associated comorbidities with the detection of CHIP is not coincidental. CHIP is associated with, among other things, a significantly increased risk of cardiovascular disease and increased all-cause mortality. From a pathomechanistic perspective, CHIP leads to increased secretion of proinflammatory cytokines. It is also associated with a significantly increased risk of developing hematologic neoplasms. Thus, the treatment of CHIP could suppress the occurrence of hematologic neoplasms and prevent age-associated diseases.
    Keywords:  Cardiovascular comorbidity; Clonal hematopoiesis of indeterminate potential; Hematologic neoplasms; Inflammaging; Variant allele frequency
    DOI:  https://doi.org/10.1007/s00391-023-02162-7
  3. Aging (Albany NY). 2023 Jan 16. undefined
    Targeting mitochondria to extend physically active lifespan.
    Bumsoo Ahn.
      
    Keywords:  mitochondria; neurogenic atrophy; peroxiredoxin; retrograde effect; sarcopenia
    DOI:  https://doi.org/10.18632/aging.204494
  4. Nat Cell Biol. 2023 Jan;25(1): 30-41
    Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.
    Carl A Mitchell, Evgenia V Verovskaya, Fernando J Calero-Nieto, Oakley C Olson, James W Swann, Xiaonan Wang, Aurélie Hérault, Paul V Dellorusso, Si Yi Zhang, Arthur Flohr Svendsen, Eric M Pietras, Sietske T Bakker, Theodore T Ho, Berthold Göttgens, Emmanuelle Passegué.
      Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling. We find decreased numbers and functionality of osteoprogenitors at the endosteum and expansion of central marrow LepR+ mesenchymal stromal cells associated with deterioration of the sinusoidal vasculature. Together, they create a degraded and inflamed old bone marrow niche. Niche inflammation in turn drives the chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation and hinders haematopoietic regeneration. Moreover, we show how production of interleukin-1β (IL-1β) by the damaged endosteum acts in trans to drive the proinflammatory nature of the central marrow, with damaging consequences for the old blood system. Notably, niche deterioration, HSC dysfunction and defective regeneration can all be ameliorated by blocking IL-1 signalling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during ageing.
    DOI:  https://doi.org/10.1038/s41556-022-01053-0
  5. Biomolecules. 2023 Jan 13. pii: 165. [Epub ahead of print]13(1):
    The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging.
    Nekane Romero-García, Javier Huete-Acevedo, Cristina Mas-Bargues, Jorge Sanz-Ros, Mar Dromant, Consuelo Borrás.
      The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply inter-related and act together to drive the aging process. Altered intercellular communication is particularly relevant since it explains how damage at the cellular level translates into age-related loss of function at the organismal level. As the main effectors of intercellular communication, extracellular vesicles (EVs) might play a key role in the aggravation or mitigation of the hallmarks of aging. This review aims to summarize this role and to provide context for the multiple emerging EV-based gerotherapeutic strategies that are currently under study.
    Keywords:  aging; exosomes; extracellular vesicles; hallmarks
    DOI:  https://doi.org/10.3390/biom13010165
  6. Exp Hematol Oncol. 2023 Jan 18. 12(1): 11
    Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism.
    Deyu Huang, Yingli Han, Tian Tang, Lin Yang, Penglei Jiang, Wenchang Qian, Zhaoru Zhang, Xinyue Qian, Xin Zeng, Pengxu Qian.
      BACKGROUND: Adult hematopoietic stem cells (HSCs) homeostasis is critically important in maintaining lifelong hematopoiesis. However, how adult HSCs orchestrate its homeostasis remains not fully understood. Imprinted gene Dlk1 has been shown to play critical role in mouse embryonic hematopoiesis and in regulation of stem cells, but its physiological roles in adult HSCs are unknown.METHODS: We performed gene expression analysis of Dlk1, and constructed conditional Dlk1 knockout (KO) mice by crossing Mx1 cre mice with Dlkflox/flox mice. Western blot and quantitative PCR were used to detect Dlk1 KO efficiency. Flow cytometry was performed to investigate the effects of Dlk1 KO on HSCs, progenitors and linage cells in primary mice. Competitive HSCs transplantation and secondary transplantation was used to examine the effects of Dlk1 KO on long-term hematopoietic repopulation potential of HSCs. RNA-Seq and cell metabolism assays was used to determine the underlying mechanisms.
    RESULTS: Dlk1 was highly expressed in adult mice long-term HSCs (LT-HSCs) relative to progenitors and mature lineage cells. Dlk1 KO in adult mice HSCs drove HSCs enter active cell cycle, and expanded phenotypical LT-HSCs, but undermined its long-term hematopoietic repopulation potential. Dlk1 KO resulted in an increase in HSCs' metabolic activity, including glucose uptake, ribosomal translation, mitochondrial metabolism and ROS production, which impaired HSCs function. Further, Dlk1 KO in adult mice HSCs attenuated Notch signaling, and re-activation of Notch signaling under Dlk1 KO decreased the mitochondrial activity and ROS production, and rescued the changes in frequency and absolute number of HSCs. Scavenging ROS by antioxidant N-acetylcysteine could inhibit mitochondrial metabolic activity, and rescue the changes in HSCs caused by Dlk1 KO.
    CONCLUSION: Our study showed that Dlk1 played an essential role in maintaining HSC homeostasis, which is realized by governing cell cycle and restricting mitochondrial metabolic activity.
    Keywords:  Dlk1; HSC transplantation; HSCs; Mitochondrial metabolism; Notch
    DOI:  https://doi.org/10.1186/s40164-022-00369-9
  7. Cell. 2023 Jan 19. pii: S0092-8674(22)01583-5. [Epub ahead of print]186(2): 233-235
    Is aging a "Retro"spective event?
    Nirmalya Dasgupta, Peter D Adams.
      Reactivation of endogenous retroviruses (ERVs), the relics of ancient infections, has been implicated in a number of disease contexts. In this issue of Cell, Liu et al. show how reactivation of ERVs in old age can induce senescence. This awakening of ERVs is associated with their epigenetic derepression and contributes to age-associated chronic inflammation.
    DOI:  https://doi.org/10.1016/j.cell.2022.12.040
  8. Biomedicines. 2023 Jan 11. pii: 189. [Epub ahead of print]11(1):
    Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment.
    Ferenc Sipos, Györgyi Műzes.
      Inflammatory processes and cancer stem cells (CSCs) are increasingly recognized as factors in the development of tumors. Emerging evidence indicates that CSCs are associated with cancer properties such as metastasis, treatment resistance, and disease recurrence. However, the precise interaction between CSCs and the immune microenvironment remains unexplored. Although evasion of the immune system by CSCs has been extensively studied, new research demonstrates that CSCs can also control and even profit from the immune response. This review provides an overview of the reciprocal interplay between CSCs and tumor-infiltrating immune cells, collecting pertinent data about how CSCs stimulate leukocyte reprogramming, resulting in pro-tumor immune cells that promote metastasis, chemoresistance, tumorigenicity, and even a rise in the number of CSCs. Tumor-associated macrophages, neutrophils, Th17 and regulatory T cells, mesenchymal stem cells, and cancer-associated fibroblasts, as well as the signaling pathways involved in these pro-tumor activities, are among the immune cells studied. Although cytotoxic leukocytes have the potential to eliminate CSCs, immune evasion mechanisms in CSCs and their clinical implications are also known. We intended to compile experimental findings that provide direct evidence of interactions between CSCs and the immune system and CSCs and the inflammatory milieu. In addition, we aimed to summarize key concepts in order to comprehend the cross-talk between CSCs and the tumor microenvironment as a crucial process for the effective design of anti-CSC therapies.
    Keywords:  cancer stem cells; cancer-associated fibroblasts; inflammation; leukocyte reprogramming; regulatory T cells; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/biomedicines11010189
  9. Nature. 2023 Jan 18.
    Immune cells' ability to persist and replicate long outlives species lifespan.
      
    Keywords:  Ageing; Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-022-04529-z
  10. Trends Cancer. 2023 Jan 14. pii: S2405-8033(22)00268-0. [Epub ahead of print]
    Fasting and fasting mimicking diets in cancer prevention and therapy.
    Olga Blaževitš, Maira Di Tano, Valter D Longo.
      Fasting mimicking diets (FMDs) are emerging as effective dietary interventions with the potential to improve healthspan and decrease the incidence of cancer and other age-related diseases. Unlike chronic dietary restrictions or water-only fasting, FMDs represent safer and less challenging options for cancer patients. FMD cycles increase protection in healthy cells while sensitizing cancer cells to various therapies, partly by generating complex environments that promote differential stress resistance (DSR) and differential stress sensitization (DSS), respectively. More recent data indicate that FMD cycles enhance the efficacy of a range of drugs targeting different cancers in mice by stimulating antitumor immunity. Here, we report on the effects of FMD cycles on cancer prevention and treatment and the mechanisms implicated in these effects.
    Keywords:  cancer treatment; differential stress resistance (DSR); differential stress sensitization (DSS); fasting mimicking diet
    DOI:  https://doi.org/10.1016/j.trecan.2022.12.006
  11. Lancet Gastroenterol Hepatol. 2023 Jan 17. pii: S2468-1253(22)00358-2. [Epub ahead of print]
    Management of inflammatory bowel diseases in older adults.
    Siddharth Singh, Brigid S Boland, Tine Jess, Alison A Moore.
      The burden of inflammatory bowel disease (IBD) in older adults (ie, aged over 60 years old) is increasing due to a combination of an ageing population with compounding prevalence of IBD and increasing incidence of elderly-onset (ie, onset over the age of over 60 years) IBD. Despite the increasing prevalence of IBD, there is a paucity of evidence on which to base management of older adults with IBD, leading to substantial variability in care. This population is under-represented in clinical trials and has a high burden of chronic corticosteroid use, low uptake of steroid-sparing immunosuppressive agents, and high rates of unplanned health-care use and disability. Management of IBD in older adults requires carefully weighing an individual patient's risk of IBD-related complications, IBD-directed immunosuppressive therapy, and non-IBD comorbidities. A deeper understanding of biological and functional age, dynamic risk stratification strategies (including frailty-based risk assessment tools), comparative effectiveness and safety of current therapies and treatment strategies, and shared decision making to inform treatment goals and targets is needed to improve outcomes in older adults with IBD. In this Review, we discuss the epidemiology, natural history, pathophysiology, and medical and surgical management of older individuals living with IBD and identify key research gaps and approaches to address them.
    DOI:  https://doi.org/10.1016/S2468-1253(22)00358-2
  12. Oncol Lett. 2023 Feb;25(2): 43
    Premature aging in childhood cancer survivors.
    Jarmila Kruseova, Andrea Zichova, Tomas Eckschlager.
      Progress in medicine has increased the survival time of children suffering from cancer; >80% of patients survive for at least 5 years from the end of treatment. However, there are late effects of anticancer therapy, which accompany this success. Two-thirds of childhood cancer survivors (CCSs) have at least one late effect (any side effects or complications of anticancer treatment that appear months to years after the completion of treatment), e.g. endocrinopathies, cardiovascular diseases or subsequent cancers, and half of these late effects are serious or life threatening. These late consequences of childhood cancer treatment pose a serious health, social and economic problem. A common mechanism for developing a number of late effects is the onset of premature biological aging, which is associated with the early onset of chronic diseases and death. Cellular senescence in cancer survivors is caused by therapy that can induce chromosomal aberrations, mutations, telomere shortening, epigenetic alterations and mitochondrial dysfunctions. The mechanisms of accelerated aging in cancer survivors have not yet been fully clarified. The measurement of biological age in survivors can help improve the understanding of aging mechanisms and identify risk factors for premature aging. However, to the best of our knowledge, no single marker for the evaluation of biological or functional age is known, so it is therefore necessary to measure the consequences of anticancer treatment using complex assessments. The present review presents an overview of premature aging in CCSs and of the mechanisms involved in its development, focusing on the association of senescence and late effects.
    Keywords:  aging-related diseases; childhood cancer survivors; late effects; premature aging
    DOI:  https://doi.org/10.3892/ol.2022.13629
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