bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–05–28
ten papers selected by
Ayesh Seneviratne, Western University
  1. Stress, Diet, Exercise: Common Environmental Factors and Their Impact on Epigenetic Age.
  2. Inflammasomes and Atherosclerosis: a Mixed Picture.
  3. RNA binding proteins in senescence: A potential common linker for age-related diseases?
  4. Clonal Hematopoiesis in Myeloproliferative Neoplasms Confers a Predisposition to both Thrombosis and Cancer.
  5. Cellular senescence and premature aging in Down Syndrome.
  6. Stem cell decoupling underlies impaired lymphoid development during aging.
  7. Regulation of hematopoietic stem cells differentiation, self-renewal, and quiescence through the mTOR signaling pathway.
  8. Building the case for mitochondrial transplantation as an anti-aging cardiovascular therapy.
  9. Red Blood Cell Membrane Fatty Acid Composition, Dietary Fatty Acid Intake and Diet Quality as Predictors of Inflammation in a Group of Australian Adults.
  10. IL-3 worsens MS.
  1. Ageing Res Rev. 2023 May 19. pii: S1568-1637(23)00115-0. [Epub ahead of print] 101956
    Stress, Diet, Exercise: Common Environmental Factors and Their Impact on Epigenetic Age.
    Fedor Galkin, Olga Kovalchuk, Diana Koldasbayeva, Alex Zhavoronkov, Evelyne Bischof.
      Epigenetic aging clocks have gained significant attention as a tool for predicting age-related health conditions in clinical and research settings. They have enabled geroscientists to study the underlying mechanisms of aging and assess the effectiveness of anti-aging therapies, including diet, exercise and environmental exposures. This review explores the effects of modifiable lifestyle factors' on the global DNA methylation landscape, as seen by aging clocks. We also discuss the underlying mechanisms through which these factors contribute to biological aging and provide comments on what these findings mean for people willing to build an evidence-based pro-longevity lifestyle.
    Keywords:  Longevity; Machine learning; aging; aging clocks; epigenetics; nutrition
    DOI:  https://doi.org/10.1016/j.arr.2023.101956
  2. Circ Res. 2023 May 26. 132(11): 1505-1520
    Inflammasomes and Atherosclerosis: a Mixed Picture.
    Alan R Tall, Karin E Bornfeldt.
      The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.
    Keywords:  cardiovascular diseases; clonal hematopoiesis; diabetes; inflammasomes; interleukin 1β; macrophages; mouse models
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.321637
  3. Ageing Res Rev. 2023 May 19. pii: S1568-1637(23)00117-4. [Epub ahead of print]88 101958
    RNA binding proteins in senescence: A potential common linker for age-related diseases?
    Angelica Varesi, Lucrezia Irene Maria Campagnoli, Annalisa Barbieri, Lorenzo Rossi, Giovanni Ricevuti, Ciro Esposito, Salvatore Chirumbolo, Nicoletta Marchesi, Alessia Pascale.
      Aging represents the major risk factor for the onset and/or progression of various disorders including neurodegenerative diseases, metabolic disorders, and bone-related defects. As the average age of the population is predicted to exponentially increase in the coming years, understanding the molecular mechanisms underlying the development of aging-related diseases and the discovery of new therapeutic approaches remain pivotal. Well-reported hallmarks of aging are cellular senescence, genome instability, autophagy impairment, mitochondria dysfunction, dysbiosis, telomere attrition, metabolic dysregulation, epigenetic alterations, low-grade chronic inflammation, stem cell exhaustion, altered cell-to-cell communication and impaired proteostasis. With few exceptions, however, many of the molecular players implicated within these processes as well as their role in disease development remain largely unknown. RNA binding proteins (RBPs) are known to regulate gene expression by dictating at post-transcriptional level the fate of nascent transcripts. Their activity ranges from directing primary mRNA maturation and trafficking to modulation of transcript stability and/or translation. Accumulating evidence has shown that RBPs are emerging as key regulators of aging and aging-related diseases, with the potential to become new diagnostic and therapeutic tools to prevent or delay aging processes. In this review, we summarize the role of RBPs in promoting cellular senescence and we highlight their dysregulation in the pathogenesis and progression of the main aging-related diseases, with the aim of encouraging further investigations that will help to better disclose this novel and captivating molecular scenario.
    Keywords:  Aging; Alzheimer’s disease; Cellular senescence; ELAVL; Neurodegeneration; RNA binding protein
    DOI:  https://doi.org/10.1016/j.arr.2023.101958
  4. Curr Hematol Malig Rep. 2023 May 24.
    Clonal Hematopoiesis in Myeloproliferative Neoplasms Confers a Predisposition to both Thrombosis and Cancer.
    Tiziano Barbui, Antonello Gavazzi, Edoardo Sciatti, Maria Chiara Finazzi, Arianna Ghirardi, Greta Carioli, Alessandra Carobbio.
       PURPOSE OF REVIEW: This review focuses on vascular complications associated with chronic myeloproliferative neoplasms (MPN) and more specifically aims to discuss the clinical and biological evidence supporting the existence of a link between clonal hematopoiesis, cardiovascular events (CVE), and solid cancer (SC).
    RECENT FINDINGS: The MPN natural history is driven by uncontrolled clonal myeloproliferation sustained by acquired somatic mutations in driver (JAK2, CALR, and MPL) and non-driver genes, involving epigenetic (e.g., TET2, DNMT3A) regulators, chromatin regulator genes (e.g., ASXL1, EZH2), and splicing machinery genes (e.g., SF3B1). The genomic alterations and additional thrombosis acquired risk factors are determinants for CVE. There is evidence that clonal hematopoiesis can elicit a chronic and systemic inflammation status that acts as driving force for the development of thrombosis, MPN evolution, and second cancer (SC). This notion may explain the mechanism that links arterial thrombosis in MPN patients and subsequent solid tumors. In the last decade, clonal hematopoiesis of indeterminate potential (CHIP) has been detected in the general population particularly in the elderly and initially found in myocardial infarction and stroke, rising the hypothesis that the inflammatory status CHIP-associated could confer predisposition to both cardiovascular diseases and cancer. In summary, clonal hematopoiesis in MPN and CHIP confer a predisposition to cardiovascular events and cancer through chronic and systemic inflammation. This acquisition could open new avenues for antithrombotic therapy both in MPNs and in general population by targeting both clonal hematopoiesis and inflammation.
    Keywords:  Cancer; Clonal hematopoiesis of indeterminate potential; Disease progression; Inflammation; Myeloproliferative neoplasms; Thrombosis
    DOI:  https://doi.org/10.1007/s11899-023-00697-5
  5. Mech Ageing Dev. 2023 May 24. pii: S0047-6374(23)00050-7. [Epub ahead of print] 111824
    Cellular senescence and premature aging in Down Syndrome.
    Lianli Peng, Alireza A Baradar, Julio Aguado, Ernst Wolvetang.
      Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21, resulting in cognitive impairment, physical abnormalities, and an increased risk of age-related co-morbidities. Individuals with DS exhibit accelerated aging, which has been attributed to several cellular mechanisms, including cellular senescence, a state of irreversible cell cycle arrest that is associated with aging and age-related diseases. Emerging evidence suggests that cellular senescence may play a key role in the pathogenesis of DS and the development of age-related disorders in this population. Importantly, cellular senescence may be a potential therapeutic target in alleviating age-related DS pathology. Here, we discuss the importance of focusing on cellular senescence to understand accelerated aging in DS. We review the current state of knowledge regarding cellular senescence and other hallmarks of aging in DS, including its putative contribution to cognitive impairment, multi-organ dysfunction, and premature aging phenotypes.
    Keywords:  Cellular senescence; Down Syndrome; Premature Aging
    DOI:  https://doi.org/10.1016/j.mad.2023.111824
  6. Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2302019120
    Stem cell decoupling underlies impaired lymphoid development during aging.
    Geunhyo Jang, Stephania Contreras Castillo, Eduardo Esteva, Samik Upadhaya, Jue Feng, Nicholas M Adams, Elodie Richard, Rajeshwar Awatramani, Catherine M Sawai, Boris Reizis.
      Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with preferential megakaryocytic and/or myeloid potential ("myeloid bias"). Here, we tested this notion using inducible genetic labeling and tracing of HSCs in unmanipulated animals. We found that the endogenous HSC population in old mice shows reduced differentiation into all lineages including lymphoid, myeloid, and megakaryocytic. Single-cell RNA sequencing and immunophenotyping (CITE-Seq) showed that HSC progeny in old animals comprised balanced lineage spectrum including lymphoid progenitors. Lineage tracing using the aging-induced HSC marker Aldh1a1 confirmed the low contribution of old HSCs across all lineages. Competitive transplantations of total bone marrow cells with genetically marked HSCs revealed that the contribution of old HSCs was reduced, but compensated by other donor cells in myeloid cells but not in lymphocytes. Thus, the HSC population in old animals becomes globally decoupled from hematopoiesis, which cannot be compensated in lymphoid lineages. We propose that this partially compensated decoupling, rather than myeloid bias, is the primary cause of the selective impairment of lymphopoiesis in older mice.
    Keywords:  aging; hematopoietic stem cells; lymphopoiesis
    DOI:  https://doi.org/10.1073/pnas.2302019120
  7. Front Cell Dev Biol. 2023 ;11 1186850
    Regulation of hematopoietic stem cells differentiation, self-renewal, and quiescence through the mTOR signaling pathway.
    Bai Ling, Yunyang Xu, Siyuan Qian, Ze Xiang, Shihai Xuan, Jian Wu.
      Hematopoietic stem cells (HSCs) are important for the hematopoietic system because they can self-renew to increase their number and differentiate into all the blood cells. At a steady state, most of the HSCs remain in quiescence to preserve their capacities and protect themselves from damage and exhaustive stress. However, when there are some emergencies, HSCs are activated to start their self-renewal and differentiation. The mTOR signaling pathway has been shown as an important signaling pathway that can regulate the differentiation, self-renewal, and quiescence of HSCs, and many types of molecules can regulate HSCs' these three potentials by influencing the mTOR signaling pathway. Here we review how mTOR signaling pathway regulates HSCs three potentials, and introduce some molecules that can work as the regulator of HSCs' these potentials through the mTOR signaling. Finally, we outline the clinical significance of studying the regulation of HSCs three potentials through the mTOR signaling pathway and make some predictions.
    Keywords:  differentiation; hematopoietic stem cells (HSCS); mTOR; quiescence; self-renewal
    DOI:  https://doi.org/10.3389/fcell.2023.1186850
  8. Front Cardiovasc Med. 2023 ;10 1141124
    Building the case for mitochondrial transplantation as an anti-aging cardiovascular therapy.
    Colwyn A Headley, Philip S Tsao.
      Mitochondrial dysfunction is a common denominator in both biological aging and cardiovascular disease (CVD) pathology. Understanding the protagonist role of mitochondria in the respective and independent progressions of CVD and biological aging will unravel the synergistic relationship between biological aging and CVD. Moreover, the successful development and implementation of therapies that can simultaneously benefit mitochondria of multiple cell types, will be transformational in curtailing pathologies and mortality in the elderly, including CVD. Several works have compared the status of mitochondria in vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in CVD dependent context. However, fewer studies have cataloged the aging-associated changes in vascular mitochondria, independent of CVD. This mini review will focus on the present evidence related to mitochondrial dysfunction in vascular aging independent of CVD. Additionally, we discuss the feasibility of restoring mitochondrial function in the aged cardiovascular system through mitochondrial transfer.
    Keywords:  ROS; aging; cardiovascular system; endothelial cells; mitochondrial stress; oxidative stress; vascular smooth muscle cells
    DOI:  https://doi.org/10.3389/fcvm.2023.1141124
  9. Nutrients. 2023 May 21. pii: 2405. [Epub ahead of print]15(10):
    Red Blood Cell Membrane Fatty Acid Composition, Dietary Fatty Acid Intake and Diet Quality as Predictors of Inflammation in a Group of Australian Adults.
    Erin D Clarke, Jordan Stanford, Jessica J A Ferguson, Lisa G Wood, Clare E Collins.
      Evidence suggests that diet can play a role in modulating systemic inflammation. This study aims to examine the relationship between fatty acids (FAs) (self-reported dietary intake and red blood cell (RBC) membrane fatty acid concentrations), three diet quality scores, and the plasma concentrations of inflammatory markers (interleukin-6, IL-6; tumour necrosis factor alpha, TNF-α; and C-reactive protein, CRP) in a group of Australian adults (n = 92). Data were collected on their demographic characteristics, health status, supplement intake, dietary intake, RBC-FAs and plasma inflammatory markers over a nine-month period. Mixed-effects models were used to determine the relationship between RBC-FAs, dietary intake of FAs, diet quality scores and inflammatory markers to determine which variable most strongly predicted systemic inflammation. A significant association was identified between dietary saturated fat intake and TNF-α (β = 0.01, p < 0.05). An association was also identified between RBC membrane saturated fatty acids (SFA) and CRP (β = 0.55, p < 0.05). Inverse associations were identified between RBC membrane monounsaturated fatty acids (MUFAs) (β = -0.88, p < 0.01), dietary polyunsaturated fatty acids (PUFAs) (β = -0.21, p < 0.05) and CRP, and the Australian Eating Survey Modified Mediterranean Diet (AES-MED) score and IL-6 (β = -0.21, p < 0.05). In summary, using both objective and subjective measures of fat intake and diet quality, our study has confirmed a positive association between saturated fat and inflammation, while inverse associations were observed between MUFAs, PUFAs, the Mediterranean diet, and inflammation. Our results provide further evidence that manipulating diet quality, in particular fatty acid intake, may be useful for reducing chronic systemic inflammation.
    Keywords:  diet quality; fatty acids; inflammation
    DOI:  https://doi.org/10.3390/nu15102405
  10. Nat Immunol. 2023 May 22.
    IL-3 worsens MS.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-023-01534-w
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