bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–12–17
nine papers selected by
Ayesh Seneviratne, Western University
  1. Clonal Hematopoiesis and Transcatheter Aortic Valve Replacement: A Fatal Connection.
  2. Cellular senescence in brain aging and cognitive decline.
  3. Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.
  4. Are your organs ageing well? The blood holds clues.
  5. The role of cellular senescence in skin aging and age-related skin pathologies.
  6. Circulating cell-free nucleic acids of plasma in human aging, healthy aging and longevity: current state of knowledge.
  7. Longitudinal machine learning uncouples healthy aging factors from chronic disease risks.
  8. Frailty's influence on 30-day mortality in old critically ill ICU patients: a bayesian analysis evaluating the clinical frailty scale.
  9. GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. Reply.
  1. JACC Basic Transl Sci. 2023 Nov;8(11): 1436-1438
    Clonal Hematopoiesis and Transcatheter Aortic Valve Replacement: A Fatal Connection.
    Megan A Evans, Kenneth Walsh.
      
    Keywords:  CHIP; TET2; aortic valve disease; cardiovascular disease; inflammation
    DOI:  https://doi.org/10.1016/j.jacbts.2023.06.007
  2. Front Aging Neurosci. 2023 ;15 1281581
    Cellular senescence in brain aging and cognitive decline.
    Areez Shafqat, Saifullah Khan, Mohamed H Omer, Mahnoor Niaz, Ibrahem Albalkhi, Khaled AlKattan, Ahmed Yaqinuddin, Tamara Tchkonia, James L Kirkland, Shahrukh K Hashmi.
      Cellular senescence is a biological aging hallmark that plays a key role in the development of neurodegenerative diseases. Clinical trials are currently underway to evaluate the effectiveness of senotherapies for these diseases. However, the impact of senescence on brain aging and cognitive decline in the absence of neurodegeneration remains uncertain. Moreover, patient populations like cancer survivors, traumatic brain injury survivors, obese individuals, obstructive sleep apnea patients, and chronic kidney disease patients can suffer age-related brain changes like cognitive decline prematurely, suggesting that they may suffer accelerated senescence in the brain. Understanding the role of senescence in neurocognitive deficits linked to these conditions is crucial, especially considering the rapidly evolving field of senotherapeutics. Such treatments could help alleviate early brain aging in these patients, significantly reducing patient morbidity and healthcare costs. This review provides a translational perspective on how cellular senescence plays a role in brain aging and age-related cognitive decline. We also discuss important caveats surrounding mainstream senotherapies like senolytics and senomorphics, and present emerging evidence of hyperbaric oxygen therapy and immune-directed therapies as viable modalities for reducing senescent cell burden.
    Keywords:  aging; astrocyte senescence; cellular senescence; cognitive decline; microglia senescence; obesity; therapy-induced senescence (TIS); traumatic brain injury
    DOI:  https://doi.org/10.3389/fnagi.2023.1281581
  3. Nat Commun. 2023 Dec 07. 14(1): 8102
    Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.
    J McClatchy, R Strogantsev, E Wolfe, H Y Lin, M Mohammadhosseini, B A Davis, C Eden, D Goldman, W H Fleming, P Conley, G Wu, L Cimmino, H Mohammed, A Agarwal.
      Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1β is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1β promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1β administration, which is resisted by Tet2-deficient HSPCs, and thus IL1β enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1β-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.
    DOI:  https://doi.org/10.1038/s41467-023-43697-y
  4. Nature. 2023 Dec;624(7991): 237-238
    Are your organs ageing well? The blood holds clues.
    Max Kozlov.
      
    Keywords:  Ageing; Diseases; Medical research; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-03821-w
  5. Front Physiol. 2023 ;14 1297637
    The role of cellular senescence in skin aging and age-related skin pathologies.
    Toby Chin, Xin Er Lee, Pei Yi Ng, Yaelim Lee, Oliver Dreesen.
      Aging is the result of a gradual functional decline at the cellular, and ultimately, organismal level, resulting in an increased risk of developing a variety of chronic illnesses, such as cardiovascular disease, stroke, cancer and diabetes. The skin is the largest organ of the human body, and the site where signs of aging are most visible. These signs include thin and dry skin, sagging, loss of elasticity, wrinkles, as well as aberrant pigmentation. The appearance of these features is accelerated by exposure to extrinsic factors such as ultraviolet (UV) radiation or pollution, as well as intrinsic factors including time, genetics, and hormonal changes. At the cellular level, aging is associated with impaired proteostasis and an accumulation of macromolecular damage, genomic instability, chromatin reorganization, telomere shortening, remodelling of the nuclear lamina, proliferation defects and premature senescence. Cellular senescence is a state of permanent growth arrest and a key hallmark of aging in many tissues. Due to their inability to proliferate, senescent cells no longer contribute to tissue repair or regeneration. Moreover, senescent cells impair tissue homeostasis, promote inflammation and extracellular matrix (ECM) degradation by secreting molecules collectively known as the "senescence-associated secretory phenotype" (SASP). Senescence can be triggered by a number of different stimuli such as telomere shortening, oncogene expression, or persistent activation of DNA damage checkpoints. As a result, these cells accumulate in aging tissues, including human skin. In this review, we focus on the role of cellular senescence during skin aging and the development of age-related skin pathologies, and discuss potential strategies to rejuvenate aged skin.
    Keywords:  SASP; aging; lamin B1; senescence; senolytics; skin; wounds
    DOI:  https://doi.org/10.3389/fphys.2023.1297637
  6. Front Genet. 2023 ;14 1321280
    Circulating cell-free nucleic acids of plasma in human aging, healthy aging and longevity: current state of knowledge.
    Nicolas P Tessier, Lise M Hardy, Jean-François Deleuze, Alexandre How-Kit.
      Circulating cell-free nucleic acids (ccfNAs) of plasma are a remarkable source of genetic, epigenetic and transcriptomic materials originating from different cells, tissues and organs of an individual. They have been increasingly studied over the past decade as they can carry several important pieces of information about the health status of an individual, which makes them biomarkers of choice for non-invasive diagnosis of numerous diseases and health conditions. However, few studies have investigated variations of plasma ccfNAs in healthy subjects, particularly in relation to aging, healthy aging and longevity, despite the great variability of these biological processes among individuals. Here, we reviewed several studies that focused on the analysis of circulating cell-free DNA (ccfDNA) and microRNAs (ccfmiRNAs) during aging and in the elderly, including some on exceptionally long-lived individuals, i.e., centenarians. After a brief overview of the types, origins and functions of plasma ccfNAs, we described the variations of both ccfDNA and ccfmiRNAs during aging as well as the identification of several potential ccfDNA-based and ccfmiRNA-based biomarkers of aging, healthy aging and/or longevity. We finally highlighted some prospects offered by ccfNAs for the understanding and improvement of healthy aging and longevity.
    Keywords:  aging; centenarian; circulating cell-free DNA; circulating cell-free miRNA; circulating cell-free nucleic acids; healthy aging; longevity; plasma
    DOI:  https://doi.org/10.3389/fgene.2023.1321280
  7. Nat Aging. 2023 Dec 07.
    Longitudinal machine learning uncouples healthy aging factors from chronic disease risks.
    Netta Mendelson Cohen, Aviezer Lifshitz, Rami Jaschek, Ehud Rinott, Ran Balicer, Liran I Shlush, Gabriel I Barbash, Amos Tanay.
      To understand human longevity, inherent aging processes must be distinguished from known etiologies leading to age-related chronic diseases. Such deconvolution is difficult to achieve because it requires tracking patients throughout their entire lives. Here, we used machine learning to infer health trajectories over the entire adulthood age range using extrapolation from electronic medical records with partial longitudinal coverage. Using this approach, our model tracked the state of patients who were healthy and free from known chronic disease risk and distinguished individuals with higher or lower longevity potential using a multivariate score. We showed that the model and the markers it uses performed consistently on data from Israeli, British and US populations. For example, mildly low neutrophil counts and alkaline phosphatase levels serve as early indicators of healthy aging that are independent of risk for major chronic diseases. We characterize the heritability and genetic associations of our longevity score and demonstrate at least 1 year of extended lifespan for parents of high-scoring patients compared to matched controls. Longitudinal modeling of healthy individuals is thereby established as a tool for understanding healthy aging and longevity.
    DOI:  https://doi.org/10.1038/s43587-023-00536-5
  8. Ann Intensive Care. 2023 Dec 13. 13(1): 126
    Frailty's influence on 30-day mortality in old critically ill ICU patients: a bayesian analysis evaluating the clinical frailty scale.
    Bernhard Wernly, Raphael Romano Bruno, Michael Beil, Hans Flaatten, Malte Kelm, Sviri Sigal, Wojciech Szczeklik, Muhammed Elhadi, Michael Joannidis, Andreas Koköfer, Sandra Oeyen, Brian Marsh, Rui Moreno, Sarah Wernly, Susannah Leaver, Dylan W De Lange, Bertrand Guidet, Christian Jung.
       INTRODUCTION: Frailty is widely acknowledged as influencing health outcomes among critically ill old patients. Yet, the traditional understanding of its impact has predominantly been through frequentist statistics. We endeavored to explore this association using Bayesian statistics aiming to provide a more nuanced understanding of this multifaceted relationship.
    METHODS: Our analysis incorporated a cohort of 10,363 older (median age 82 years) patients from three international prospective studies, with 30-day all-cause mortality as the primary outcome. We defined frailty as Clinical Frailty Scale ≥ 5. A hierarchical Bayesian logistic regression model was employed, adjusting for covariables, using a range of priors. An international steering committee of registry members reached a consensus on a minimal clinically important difference (MCID).
    RESULTS: In our study, the 30-day mortality was 43%, with rates of 38% in non-frail and 51% in frail groups. Post-adjustment, the median odds ratio (OR) for frailty was 1.60 (95% CI 1.45-1.76). Frailty was invariably linked to adverse outcomes (OR > 1) with 100% probability and had a 90% chance of exceeding the minimal clinically important difference (MCID) (OR > 1.5). For the Clinical Frailty Scale (CFS) as a continuous variable, the median OR was 1.19 (1.16-1.22), with over 99% probability of the effect being more significant than 1.5 times the MCID. Frailty remained outside the region of practical equivalence (ROPE) in all analyses, underscoring its clinical importance regardless of how it is measured.
    CONCLUSIONS: This research demonstrates the significant impact of frailty on short-term mortality in critically ill elderly patients, particularly when the Clinical Frailty Scale (CFS) is used as a continuous measure. This approach, which views frailty as a spectrum, enables more effective, personalized care for this vulnerable group. Significantly, frailty was consistently outside the region of practical equivalence (ROPE) in our analysis, highlighting its clinical importance.
    DOI:  https://doi.org/10.1186/s13613-023-01223-9
  9. N Engl J Med. 2023 Dec 14. pii: 10.1056/NEJMc2311840#sa3. [Epub ahead of print]389(24): 2304-2305
    GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. Reply.
    Sean Wharton, Manige Konig.
      
    DOI:  https://doi.org/10.1056/NEJMc2311840
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