bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–05–08
eleven papers selected by
Ayesh Seneviratne, Western University
  1. Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation.
  2. PLA2G7, caloric restriction and cardiovascular aging.
  3. Making sense of the ageing methylome.
  4. Ageing and cancer: a research gap to fill.
  5. Genetics of smoking and risk of clonal hematopoiesis.
  6. Geropathology. An inside view of biological aging.
  7. Letting go of damaged mitochondria.
  8. The Aging Of The US Prison Population: A Public Health Crisis.
  9. Venetoclax and acute myeloid leukaemia: an expanding new frontier.
  10. Clonal Hematopoiesis at the Crossroads of Inflammatory Bowel Diseases and Hematological Malignancies: A Biological Link?
  11. The Potential Role of m6A RNA Methylation in the Aging Process and Aging-Associated Diseases.
  1. Nat Cell Biol. 2022 May 05.
    Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation.
    Corbin E Meacham, Elise C Jeffery, Rebecca J Burgess, Charukesi D Sivakumar, Madison A Arora, Anne Marie Stanley, Emily M Colby, Genevieve M Crane, Zhiyu Zhao, Sean J Morrison.
      How are haematopoietic stem cells (HSCs) protected from inflammation, which increases with age and can deplete HSCs? Adiponectin, an anti-inflammatory factor that is not required for HSC function or haematopoiesis, promotes stem/progenitor cell proliferation after bacterial infection and myeloablation. Adiponectin binds two receptors, AdipoR1 and AdipoR2, which have ceramidase activity that increases upon adiponectin binding. Here we found that adiponectin receptors are non-cell-autonomously required in haematopoietic cells to promote HSC quiescence and self-renewal. Adiponectin receptor signalling suppresses inflammatory cytokine expression by myeloid cells and T cells, including interferon-γ and tumour necrosis factor. Without adiponectin receptors, the levels of these factors increase, chronically activating HSCs, reducing their self-renewal potential and depleting them during ageing. Pathogen infection accelerates this loss of HSC self-renewal potential. Blocking interferon-γ or tumour necrosis factor signalling partially rescues these effects. Adiponectin receptors are thus required in immune cells to sustain HSC quiescence and to prevent premature HSC depletion by reducing inflammation.
    DOI:  https://doi.org/10.1038/s41556-022-00909-9
  2. J Cardiovasc Aging. 2022 Apr;pii: 19. [Epub ahead of print]2(2):
    PLA2G7, caloric restriction and cardiovascular aging.
    Fang Cao, Richard T Lee.
      
    DOI:  https://doi.org/10.20517/jca.2022.08
  3. Nat Rev Genet. 2022 May 02.
    Making sense of the ageing methylome.
    Kirsten Seale, Steve Horvath, Andrew Teschendorff, Nir Eynon, Sarah Voisin.
      Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of individual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.
    DOI:  https://doi.org/10.1038/s41576-022-00477-6
  4. Mol Oncol. 2022 May 03.
    Ageing and cancer: a research gap to fill.
    Eric Solary, Nancy Abou-Zeid, Fabien Calvo.
      The complex mechanisms of ageing biology are increasingly understood. Interventions to reduce or delay ageing-associated diseases are emerging. Cancer is one of the diseases promoted by tissue ageing. A clockwise mutational signature is identified in many tumours. Ageing might be a modifiable cancer risk factor. To reduce the incidence of ageing-related cancer and to detect the disease at earlier stages, we need to understand better the links between ageing and tumours. When a cancer is established, geriatric assessment and measures of biological age might help to generate evidence-based therapeutic recommendations. In this approach, patients and care givers would include the respective weight to give to quality of life and survival in the therapeutic choices. The increasing burden of cancer in older patients requires new generations of researchers and geriatric oncologists to be trained, to properly address disease complexity in a multidisciplinary manner, and to reduce health inequities in this population of patients. In this review, we propose a series of research challenges to tackle in the next few years to better prevent, detect and treat cancer in older patients while preserving their quality of life.
    Keywords:  Ageing; Biological age; Cancer; Interception; Policies; Research
    DOI:  https://doi.org/10.1002/1878-0261.13222
  5. Sci Rep. 2022 May 04. 12(1): 7248
    Genetics of smoking and risk of clonal hematopoiesis.
    Michael G Levin, Tetsushi Nakao, Seyedeh M Zekavat, Satoshi Koyama, Alexander G Bick, Abhishek Niroula, Benjamin Ebert, Scott M Damrauer, Pradeep Natarajan.
      Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) represent two forms of clonal hematopoiesis where clones bearing expanded somatic mutations have been linked to both oncologic and non-oncologic clinical outcomes including atherosclerosis and all-cause mortality. Epidemiologic studies have highlighted smoking as an important driver of somatic mutations across multiple tissues. However, establishing the causal role of smoking in clonal hematopoiesis has been limited by observational study designs, which may suffer from confounding and reverse-causality. We performed two complementary analyses to investigate the role of smoking in mCAs and CHIP. First, using an observational study design among UK Biobank participants, we confirmed strong associations between smoking and mCAs. Second, using two-sample Mendelian randomization, smoking was strongly associated with mCA but not with CHIP. Overall, these results support a causal association between smoking and mCAs and suggest smoking may variably shape the fitness of clones bearing somatic mutations.
    DOI:  https://doi.org/10.1038/s41598-022-09604-z
  6. Aging Pathobiol Ther. 2022 ;4(1): 23-24
    Geropathology. An inside view of biological aging.
    Warren Ladiges.
      The geropathology concept assumes all age-related lesions are relevant, which allows the ability to grade each lesion in an organ with a severity score resulting in a quantitative value. Because aging pet cats have similar age-related diseases as older humans, knowledge of histopathology occurring during aging would be invaluable to determine how age-related lesions progress with increasing age and the connection with comorbidities. The ability to use the severity of specific organ geropathology to predict biological aging would provide new approaches to study pathways of aging and their role in the development of age-related diseases in animal models.
    Keywords:  Alzheimer’s disease; Geropathology; age-related diseases; age-related lesions; domestic cats; pathways of aging; standard lesion curve
    DOI:  https://doi.org/10.31491/APT.2022.03.078
  7. Sci Signal. 2022 May 03. 15(732): eabq7456
    Letting go of damaged mitochondria.
    Wei Wong.
      Thermogenesis requires that macrophages digest damaged mitochondria released by brown adipocytes.
    DOI:  https://doi.org/10.1126/scisignal.abq7456
  8. Health Aff (Millwood). 2022 May;41(5): 622-627
    The Aging Of The US Prison Population: A Public Health Crisis.
    Jonathan S Bor.
      As the proportion of older adults in the nation's prisons grows, policy makers struggle to meet their health and social needs.
    DOI:  https://doi.org/10.1377/hlthaff.2022.00280
  9. Lancet Haematol. 2022 May 02. pii: S2352-3026(22)00136-3. [Epub ahead of print]
    Venetoclax and acute myeloid leukaemia: an expanding new frontier.
    Kieran D Sahasrabudhe, Alice S Mims.
      
    DOI:  https://doi.org/10.1016/S2352-3026(22)00136-3
  10. Front Oncol. 2022 ;12 873896
    Clonal Hematopoiesis at the Crossroads of Inflammatory Bowel Diseases and Hematological Malignancies: A Biological Link?
    Cosimo Cumbo, Francesco Tarantini, Antonella Zagaria, Luisa Anelli, Crescenzio Francesco Minervini, Nicoletta Coccaro, Giuseppina Tota, Luciana Impera, Elisa Parciante, Maria Rosa Conserva, Immacolata Redavid, Paola Carluccio, Mario Delia, Annamaria Giordano, Maria Chiara Longo, Tommasina Perrone, Antonella Russo Rossi, Giorgina Specchia, Pellegrino Musto, Francesco Albano.
      Inflammatory bowel diseases (IBDs) are a group of chronic conditions of the gastrointestinal tract in which nationwide studies have revealed a higher risk of hematological malignancies (HMs). Clonal hematopoiesis (CH) is a premalignant condition defined by the presence of an acquired somatic mutation characterized by a variant allele frequency (VAF) of ≥2%, in a gene frequently associated with HMs. A growing body of evidence suggests a correlation between inflammation and CH; its occurrence in the context of IBD has been previously demonstrated. With the aim to assess CH possible co-occurrence in patients with an IBD associated with HMs, we performed a targeted next-generation sequencing analysis in a cohort of thirteen patients who were referred to our center with IBD associated with HMs. Eleven (85%) patients showed one or more mutations in CH-associated genes; DNMT3A was the most frequently mutated gene, followed by ASXL1 and JAK2. These results may suggest that the mechanisms at the basis of the inflammatory environment could potentially select for the growth of hematopoietic clones harboring specific mutations. In this context, CH emergence may be boosted by the proinflammatory IBD environment, thus acting as a biological link between IBD and the HM onset. If these data are confirmed, IBD patients screened and positive for CH should undergo a hematologic follow-up to assess the risk of developing HM. Future study will clarify the relationship between these conditions.
    Keywords:  ASXL1; DNMT3A; JAK2; clonal hematopoiesis; hematological malignancies; inflammatory bowel diseases
    DOI:  https://doi.org/10.3389/fonc.2022.873896
  11. Front Genet. 2022 ;13 869950
    The Potential Role of m6A RNA Methylation in the Aging Process and Aging-Associated Diseases.
    Jin Sun, Bokai Cheng, Yongkang Su, Man Li, Shouyuan Ma, Yan Zhang, Anhang Zhang, Shuang Cai, Qiligeer Bao, Shuxia Wang, Ping Zhu.
      N6-methyladenosine (m6A) is the most common and conserved internal eukaryotic mRNA modification. m6A modification is a dynamic and reversible post-transcriptional regulatory modification, initiated by methylase and removed by RNA demethylase. m6A-binding proteins recognise the m6A modification to regulate gene expression. Recent studies have shown that altered m6A levels and abnormal regulator expression are crucial in the ageing process and the occurrence of age-related diseases. In this review, we summarise some key findings in the field of m6A modification in the ageing process and age-related diseases, including cell senescence, autophagy, inflammation, oxidative stress, DNA damage, tumours, neurodegenerative diseases, diabetes, and cardiovascular diseases (CVDs). We focused on the biological function and potential molecular mechanisms of m6A RNA methylation in ageing and age-related disease progression. We believe that m6A modification may provide a new target for anti-ageing therapies.
    Keywords:  N6-methyladenosine; RNA methylation; aging; aging-related disease; epigenetics
    DOI:  https://doi.org/10.3389/fgene.2022.869950
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