bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–11–26
fiveteen papers selected by
Ayesh Seneviratne, Western University
  1. Transcriptional and Functional Consequences of Oncostatin M Signaling on Young Dnmt3a-Mutant Hematopoietic Stem Cells.
  2. Author Correction: Clonal hematopoiesis, aging and Alzheimer's disease.
  3. Is clonal hematopoiesis 'mostly harmless'?
  4. Looking at frailty and intrinsic capacity through a geroscience lens: the ICFSR & Geroscience Task Force.
  5. Quantification of healthspan in aging mice: Introducing FAMY and GRAIL.
  6. The lifelong natural history of clonal hematopoiesis and its links to myeloid malignancy.
  7. Hallmarks of ageing in human skeletal muscle and implications for understanding the pathophysiology of sarcopenia in women and men.
  8. Repurposing nucleoside reverse transcriptase inhibitors (NRTIs) to slow aging.
  9. These brain cells could influence how fast you eat - and when you stop.
  10. Toll-like receptor 4 (TLR4): new insight immune and aging.
  11. von Willebrand factor: aging is better?
  12. The Skin and Inflamm-Aging.
  13. Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.
  14. Mitochondrial DNA and Inflammation in Alzheimer's Disease.
  15. Cellular Senescence: A Troy Horse in Pulmonary Fibrosis.
  1. Exp Hematol. 2023 Nov 22. pii: S0301-472X(23)01768-X. [Epub ahead of print]
    Transcriptional and Functional Consequences of Oncostatin M Signaling on Young Dnmt3a-Mutant Hematopoietic Stem Cells.
    Logan S Schwartz, Kira A Young, Timothy M Stearns, Nathan Boyer, Kristina D Mujica, Jennifer J Trowbridge.
      Age-associated clonal hematopoiesis (CH) occurs due to somatic mutations accrued in hematopoietic stem cells (HSCs) that confer a selective growth advantage in the context of aging. The mechanisms by which CH-mutant HSCs gain this advantage with aging are not comprehensively understood. Using unbiased transcriptomic approaches, we identified Oncostatin M (OSM) signaling as a candidate contributor to age-related Dnmt3a-mutant CH. We found that Dnmt3a-mutant HSCs from young adult mice (3-6 months old) subjected to acute OSM stimulation do not demonstrate altered proliferation, apoptosis, hematopoietic engraftment, or myeloid differentiation. Dnmt3a-mutant HSCs from young mice do transcriptionally upregulate an inflammatory cytokine network in response to acute in vitro OSM stimulation as evidenced by significant upregulation of the genes encoding IL-6, IL-1β and TNFα. OSM-stimulated Dnmt3a-mutant HSCs also demonstrate upregulation of the anti-inflammatory genes Socs3, Atf3 and Nr4a1. In the context of an aged bone marrow (BM) microenvironment, Dnmt3a-mutant HSCs upregulate pro-inflammatory genes but not the anti-inflammatory genes Socs3, Atf3 and Nr4a1. The results from our studies suggest that aging may exhaust the regulatory mechanisms that HSCs employ to resolve inflammatory states in response to factors such as OSM.
    DOI:  https://doi.org/10.1016/j.exphem.2023.11.005
  2. Nat Med. 2023 Nov 20.
    Author Correction: Clonal hematopoiesis, aging and Alzheimer's disease.
    Pablo Sánchez Vela, Jennifer J Trowbridge, Ross L Levine.
      
    DOI:  https://doi.org/10.1038/s41591-023-02718-5
  3. Nat Genet. 2023 Nov 23.
    Is clonal hematopoiesis 'mostly harmless'?
      
    DOI:  https://doi.org/10.1038/s41588-023-01556-y
  4. Nat Aging. 2023 Nov 20.
    Looking at frailty and intrinsic capacity through a geroscience lens: the ICFSR & Geroscience Task Force.
    Philipe de Souto Barreto, Yves Rolland, Luigi Ferrucci, Hidenori Arai, Heike Bischoff-Ferrari, Gustavo Duque, Roger A Fielding, John R Beard, John Muscedere, Felipe Sierra, Bruno Vellas, Nathan K LeBrasseur.
      
    DOI:  https://doi.org/10.1038/s43587-023-00531-w
  5. bioRxiv. 2023 Nov 10. pii: 2023.11.07.566044. [Epub ahead of print]
    Quantification of healthspan in aging mice: Introducing FAMY and GRAIL.
    Dudley W Lamming.
      The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, is an urgent priority of geroscience research. The lack of agreed-upon quantitative metrics for measuring healthspan in aging mice has slowed progress in identifying interventions that do not simply increase lifespan, but also healthspan. Here, we define FAMY (Frailty-Adjusted Mouse Years) and GRAIL (Gauging Robust Aging when Increasing Lifespan) as new summary statistics for quantifying healthspan in mice. FAMY is based entirely on a widely utilized clinical frailty index, while GRAIL incorporates frailty, widely utilized healthspan assays, and information about the hallmarks of aging. Both metrics are conceptually similar to quality-adjusted life years (QALY), a widely-utilized measure of disease burden in humans, and can be readily calculated from data acquired during longitudinal and cross-sectional studies of mouse aging. We find that interventions generally thought to promote health, including calorie restriction, robustly improve healthspan as measured by FAMY and GRAIL. Finally, we show that use of GRAIL provides new insights, and identify dietary restriction of protein or isoleucine as an intervention that promotes healthspan but not longevity in female HET3 mice. We suggest that the routine integration of these measures into studies of aging in mice will allow the identification and development of interventions that promote healthy aging even in the absence of increased lifespan.
    DOI:  https://doi.org/10.1101/2023.11.07.566044
  6. Blood. 2023 Nov 22. pii: blood.2023019964. [Epub ahead of print]
    The lifelong natural history of clonal hematopoiesis and its links to myeloid malignancy.
    Margarete A Fabre, George S Vassiliou.
      The study of somatic mutations and the associated clonal mosaicism across the human body has transformed our understanding of ageing and its links to cancer. In proliferative human tissues, stem cells compete for dominance and those with an advantage expand clonally in relation to their peers. In the hematopoietic system, such expansion is termed clonal hematopoiesis (CH). The forces driving competition, namely heterogeneity of the hematopoietic stem cell (HSC) pool and attrition of the HSC environment, become increasingly prominent with age. As a result, CH becomes progressively more common through life, to the point of becoming essentially ubiquitous. We are beginning to unravel the specific intra- and extra-cellular factors underpinning clonal behavior, with somatic mutations in specific driver genes, inflammation, telomere maintenance, extraneous exposures and inherited genetic variation among the important players. The inevitability of CH with age, combined with its unequivocal links to myeloid cancers, poses a scientific and clinical challenge. Specifically, we need to decipher the factors determining clonal behavior and to develop prognostic tools to identify those at high risk of malignant progression, for whom preventive interventions may be warranted. Here, we discuss how recent advances in our understanding of the natural history of CH have provided important insights into these processes and helped define future avenues of investigation.
    DOI:  https://doi.org/10.1182/blood.2023019964
  7. Clin Sci (Lond). 2023 Nov 29. 137(22): 1721-1751
    Hallmarks of ageing in human skeletal muscle and implications for understanding the pathophysiology of sarcopenia in women and men.
    Antoneta Granic, Karen Suetterlin, Tea Shavlakadze, Miranda D Grounds, Avan A Sayer.
      Ageing is a complex biological process associated with increased morbidity and mortality. Nine classic, interdependent hallmarks of ageing have been proposed involving genetic and biochemical pathways that collectively influence ageing trajectories and susceptibility to pathology in humans. Ageing skeletal muscle undergoes profound morphological and physiological changes associated with loss of strength, mass, and function, a condition known as sarcopenia. The aetiology of sarcopenia is complex and whilst research in this area is growing rapidly, there is a relative paucity of human studies, particularly in older women. Here, we evaluate how the nine classic hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication contribute to skeletal muscle ageing and the pathophysiology of sarcopenia. We also highlight five novel hallmarks of particular significance to skeletal muscle ageing: inflammation, neural dysfunction, extracellular matrix dysfunction, reduced vascular perfusion, and ionic dyshomeostasis, and discuss how the classic and novel hallmarks are interconnected. Their clinical relevance and translational potential are also considered.
    Keywords:  hallmarks of ageing; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1042/CS20230319
  8. Ageing Res Rev. 2023 Nov 19. pii: S1568-1637(23)00291-X. [Epub ahead of print]92 102132
    Repurposing nucleoside reverse transcriptase inhibitors (NRTIs) to slow aging.
    Thomas Brochard, Rebecca L McIntyre, Riekelt H Houtkooper, Andrei Seluanov, Vera Gorbunova, Georges E Janssens.
      Repurposing drugs already approved in the clinic to be used off-label as geroprotectors, compounds that combat mechanisms of aging, are a promising way to rapidly reduce age-related disease incidence in society. Several recent studies have found that a class of drugs-nucleoside reverse transcriptase inhibitors (NRTIs)-originally developed as treatments for cancers and human immunodeficiency virus (HIV) infection, could be repurposed to slow the aging process. Interestingly, these studies propose complementary mechanisms that target multiple hallmarks of aging. At the molecular level, NRTIs repress LINE-1 elements, reducing DNA damage, benefiting the hallmark of aging of 'Genomic Instability'. At the organellar level, NRTIs inhibit mitochondrial translation, activate ATF-4, suppress cytosolic translation, and extend lifespan in worms in a manner related to the 'Loss of Proteostasis' hallmark of aging. Meanwhile, at the cellular level, NRTIs inhibit the P2X7-mediated activation of the inflammasome, reducing inflammation and improving the hallmark of aging of 'Altered Intercellular Communication'. Future development of NRTIs for human aging health will need to balance out toxic side effects with the beneficial effects, which may occur in part through hormesis.
    Keywords:  Aging; Geroprotectors; Intervention; Mitohormesis; NRTIs
    DOI:  https://doi.org/10.1016/j.arr.2023.102132
  9. Nature. 2023 Nov 22.
    These brain cells could influence how fast you eat - and when you stop.
    Carissa Wong.
      
    Keywords:  Brain; Metabolism; Neuroscience; Nutrition
    DOI:  https://doi.org/10.1038/d41586-023-03679-y
  10. Immun Ageing. 2023 Nov 24. 20(1): 67
    Toll-like receptor 4 (TLR4): new insight immune and aging.
    Hyo-Jin Kim, Hyemin Kim, Jeong-Hyung Lee, Cheol Hwangbo.
      TLR4, a transmembrane receptor, plays a central role in the innate immune response. TLR4 not only engages with exogenous ligands at the cellular membrane's surface but also interacts with intracellular ligands, initiating intricate intracellular signaling cascades. Through MyD88, an adaptor protein, TLR4 activates transcription factors NF-κB and AP-1, thereby facilitating the upregulation of pro-inflammatory cytokines. Another adapter protein linked to TLR4, known as TRIF, autonomously propagates signaling pathways, resulting in heightened interferon expression. Recently, TLR4 has garnered attention as a significant factor in the regulation of symptoms in aging-related disorders. The persistent inflammatory response triggered by TLR4 contributes to the onset and exacerbation of these disorders. In addition, alterations in TLR4 expression levels play a pivotal role in modifying the manifestations of age-related diseases. In this review, we aim to consolidate the impact of TLR4 on cellular senescence and aging-related ailments, highlighting the potential of TLR4 as a novel therapeutic target that extends beyond immune responses.
    Keywords:  Age-related disease; Aging; Cellular senescence; TLR4
    DOI:  https://doi.org/10.1186/s12979-023-00383-3
  11. J Thromb Haemost. 2023 Dec;pii: S1538-7836(23)00660-8. [Epub ahead of print]21(12): 3357-3359
    von Willebrand factor: aging is better?
    Jenny Goudemand, Sophie Susen.
      
    DOI:  https://doi.org/10.1016/j.jtha.2023.09.001
  12. Biology (Basel). 2023 Nov 02. pii: 1396. [Epub ahead of print]12(11):
    The Skin and Inflamm-Aging.
    Rashi Agrawal, Anne Hu, Wendy B Bollag.
      With its unique anatomical location facing both the external and internal environment, the skin has crucial functions, including shielding the body from damage caused by ultraviolet radiation and chemicals, preventing water loss, acting as a primary barrier against pathogens, participating in metabolic processes like vitamin D production and temperature control and relaying information to the body through sensory and proprioceptor nerves. Like all organ systems, skin is known to undergo multiple changes with aging. A better understanding of the mechanisms that mediate aging-related skin dysfunction may allow the creation of targeted therapeutics that have beneficial effects not only on aged skin but also on other organs and tissues that experience a loss of or decline in function with aging. The skin is the largest organ of the body and can contribute to serum inflammatory mediator levels. One alteration known to occur with age is an impairment of skin barrier function; since disruption of the barrier is known to induce inflammation, skin may be a major contributor to the sustained, sub-clinical systemic inflammation associated with aging. Such "inflamm-aging" may underlie many of the deleterious changes observed in aged individuals. This review explores the role of age-related skin changes, skin inflammation and inflamm-aging.
    Keywords:  aging; atopic dermatitis; epidermal barrier; epidermis; inflammation; keratinocytes; psoriasis; skin; xerosis
    DOI:  https://doi.org/10.3390/biology12111396
  13. JCI Insight. 2023 Nov 22. pii: e174290. [Epub ahead of print]8(22):
    Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.
    Kun Jia, Jing Tian, Tienju Wang, Lan Guo, Zhenyu Xuan, Russell H Swerdlow, Heng Du.
      Mitochondria are critical for neurophysiology, and mitochondrial dysfunction constitutes a characteristic pathology in both brain aging and Alzheimer disease (AD). Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid β 42 (Aβ42) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD. Experiments using a mouse model expressing nonmutant humanized Aβ (humanized Aβ-knockin [hAβ-KI] mice) confirmed the association of increased intramitochondrial sequestration of Aβ42 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk-bearing context. Also, in comparison with global cerebral Aβ, intramitochondrial Aβ was relatively preserved from activated microglial phagocytosis in aged hAβ-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial Aβ sequestration renders synaptic mitochondrial dysfunction in the transitional stage between normal aging and AD. Mitochondrial dysfunction in both brain aging and the prodromal stage of AD may follow a continuous transition in response to escalated intraneuronal, especially intramitochondrial Aβ, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging.
    Keywords:  Aging; Alzheimer disease; Mitochondria; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.174290
  14. Curr Issues Mol Biol. 2023 Oct 25. 45(11): 8586-8606
    Mitochondrial DNA and Inflammation in Alzheimer's Disease.
    Giacoma Galizzi, Marta Di Carlo.
      Mitochondrial dysfunction and neuroinflammation are implicated in the pathogenesis of most neurodegenerative diseases, such as Alzheimer's disease (AD). In fact, although a growing number of studies show crosstalk between these two processes, there remain numerous gaps in our knowledge of the mechanisms involved, which requires further clarification. On the one hand, mitochondrial dysfunction may lead to the release of mitochondrial damage-associated molecular patterns (mtDAMPs) which are recognized by microglial immune receptors and contribute to neuroinflammation progression. On the other hand, inflammatory molecules released by glial cells can influence and regulate mitochondrial function. A deeper understanding of these mechanisms may help identify biomarkers and molecular targets useful for the treatment of neurodegenerative diseases. This review of works published in recent years is focused on the description of the mitochondrial contribution to neuroinflammation and neurodegeneration, with particular attention to mitochondrial DNA (mtDNA) and AD.
    Keywords:  Alzheimer’s disease; DAMPs; glia; microglia; mitochondria; mitochondrial dysfunction; mtDNA; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3390/cimb45110540
  15. Int J Mol Sci. 2023 Nov 16. pii: 16410. [Epub ahead of print]24(22):
    Cellular Senescence: A Troy Horse in Pulmonary Fibrosis.
    Ruyan Wan, Lan Wang, Miaomiao Zhu, Wenwen Li, Yudi Duan, Guoying Yu.
      Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by myofibroblast abnormal activation and extracellular matrix deposition. However, the pathogenesis of PF remains unclear, and treatment options are limited. Epidemiological studies have shown that the average age of PF patients is estimated to be over 65 years, and the incidence of the disease increases with age. Therefore, PF is considered an age-related disease. A preliminary study on PF patients demonstrated that the combination therapy of the anti-senescence drugs dasatinib and quercetin improved physical functional indicators. Given the global aging population and the role of cellular senescence in tissue and organ aging, understanding the impact of cellular senescence on PF is of growing interest. This article systematically summarizes the causes and signaling pathways of cellular senescence in PF. It also objectively analyzes the impact of senescence in AECs and fibroblasts on PF development. Furthermore, potential intervention methods targeting cellular senescence in PF treatment are discussed. This review not only provides a strong theoretical foundation for understanding and manipulating cellular senescence, developing new therapies to improve age-related diseases, and extending a healthy lifespan but also offers hope for reversing the toxicity caused by the massive accumulation of senescence cells in humans.
    Keywords:  cellular senescence; pathogenesis; pulmonary fibrosis; treatment
    DOI:  https://doi.org/10.3390/ijms242216410
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