bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–12–03
seventeen papers selected by
Ayesh Seneviratne, Western University
  1. COPIng with senescence.
  2. Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.
  3. Tangles, not TANGO: targeting tau aggregates.
  4. Mechanistic target of rapamycin in regulating macrophage function in inflammatory cardiovascular diseases.
  5. Leveraging AI to identify dual-purpose aging and disease targets.
  6. Targeting ABCA12-controlled ceramide homeostasis inhibits breast cancer stem cell function and chemoresistance.
  7. Editorial: (Osteo)sarcopenia & sarcopenic obesity, volume II.
  8. Frailty is related to serum inflammageing markers: results from the VITAL study.
  9. SIRT2 transgenic over-expression does not impact lifespan in mice.
  10. Association of Oral Health with Frailty, Malnutrition Risk and Functional Decline in Hospitalized Older Adults: A Cross-Sectional Study.
  11. How is Big Data reshaping preclinical aging research?
  12. eXplainable Artificial Intelligence (XAI) in aging clock models.
  13. Cellular senescence in brain aging and neurodegeneration.
  14. Geriatric assessment in Acute Myeloid Leukemia (AML).
  15. Editorial: Sarcopenia and frailty: the role of physical activity for better aging.
  16. Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.
  17. The Epigenetic Regulation of Quiescent in Stem Cells.
  1. Nat Cell Biol. 2023 Nov 27.
    COPIng with senescence.
    Stella Victorelli, João F Passos.
      
    DOI:  https://doi.org/10.1038/s41556-023-01276-9
  2. EMBO J. 2023 Nov 27. e112348
    Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.
    Yu Wei Zhang, Katharina Schönberger, Nina Cabezas-Wallscheid.
      During the last decades, remarkable progress has been made in further understanding the complex molecular regulatory networks that maintain hematopoietic stem cell (HSC) function. Cellular and organismal metabolisms have been shown to directly instruct epigenetic alterations, and thereby dictate stem cell fate, in the bone marrow. Epigenetic regulatory enzymes are dependent on the availability of metabolites to facilitate DNA- and histone-modifying reactions. The metabolic and epigenetic features of HSCs and their downstream progenitors can be significantly altered by environmental perturbations, dietary habits, and hematological diseases. Therefore, understanding metabolic and epigenetic mechanisms that regulate healthy HSCs can contribute to the discovery of novel metabolic therapeutic targets that specifically eliminate leukemia stem cells while sparing healthy HSCs. Here, we provide an in-depth review of the metabolic and epigenetic interplay regulating hematopoietic stem cell fate. We discuss the influence of metabolic stress stimuli, as well as alterations occurring during leukemic development. Additionally, we highlight recent therapeutic advancements toward eradicating acute myeloid leukemia cells by intervening in metabolic and epigenetic pathways.
    Keywords:  acute myeloid leukemia; epigenetics; hematopoietic stem cells; leukemia stem cells; metabolism
    DOI:  https://doi.org/10.15252/embj.2022112348
  3. Nat Aging. 2023 Nov 27.
    Tangles, not TANGO: targeting tau aggregates.
    Andrew M Stern, Reisa A Sperling.
      
    DOI:  https://doi.org/10.1038/s43587-023-00526-7
  4. J Mol Cell Cardiol. 2023 Nov 30. pii: S0022-2828(23)00166-9. [Epub ahead of print]186 111-124
    Mechanistic target of rapamycin in regulating macrophage function in inflammatory cardiovascular diseases.
    MariaSanta C Mangione, Jinhua Wen, Dian J Cao.
      The mechanistic target of rapamycin (mTOR) is evolutionarily conserved from yeast to humans and is one of the most fundamental pathways of living organisms. Since its discovery three decades ago, mTOR has been recognized as the center of nutrient sensing and growth, homeostasis, metabolism, life span, and aging. The role of dysregulated mTOR in common diseases, especially cancer, has been extensively studied and reported. Emerging evidence supports that mTOR critically regulates innate immune responses that govern the pathogenesis of various cardiovascular diseases. This review discusses the regulatory role of mTOR in macrophage functions in acute inflammation triggered by ischemia and in atherosclerotic cardiovascular disease (ASCVD) and heart failure with preserved ejection fraction (HFpEF), in which chronic inflammation plays critical roles. Specifically, we discuss the role of mTOR in trained immunity, immune senescence, and clonal hematopoiesis. In addition, this review includes a discussion on the architecture of mTOR, the function of its regulatory complexes, and the dual-arm signals required for mTOR activation to reflect the current knowledge state. We emphasize future research directions necessary to understand better the powerful pathway to take advantage of the mTOR inhibitors for innovative applications in patients with cardiovascular diseases associated with aging and inflammation.
    Keywords:  Atherosclerosis; Inflammation; Ischemia; Macrophage; mTOR
    DOI:  https://doi.org/10.1016/j.yjmcc.2023.10.011
  5. Expert Opin Ther Targets. 2023 Dec 01. 1-4
    Leveraging AI to identify dual-purpose aging and disease targets.
    Geoffrey Ho Duen Leung, Chun Wai Wong, Frank W Pun, Alex Aliper, Feng Ren, Alex Zhavoronkov.
      
    Keywords:  Artificial intelligence; aging; dual-purpose target; longevity
    DOI:  https://doi.org/10.1080/14728222.2023.2288270
  6. Sci Adv. 2023 Dec;9(48): eadh1891
    Targeting ABCA12-controlled ceramide homeostasis inhibits breast cancer stem cell function and chemoresistance.
    Jihong Cui, John R Christin, Julie A Reisz, Francesca Isabelle Cendali, Rahul Sanawar, Marcelo Coutinho De Miranda, Angelo D'Alessandro, Wenjun Guo.
      Cancer stem cells (CSCs) drive tumor growth, metastasis, and chemoresistance. While emerging evidence suggests that CSCs have a unique dependency on lipid metabolism, the functions and regulation of distinct lipid species in CSCs remain poorly understood. Here, we developed a stem cell factor SOX9-based reporter for isolating CSCs in primary tumors and metastases of spontaneous mammary tumor models. Transcriptomic analyses uncover that SOX9high CSCs up-regulate the ABCA12 lipid transporter. ABCA12 down-regulation impairs cancer stemness and chemoresistance. Lipidomic analyses reveal that ABCA12 maintains cancer stemness and chemoresistance by reducing intracellular ceramide abundance, identifying a CSC-associated function of ABCA subfamily transporter. Ceramide suppresses cancer stemness by inhibiting the YAP-SOX9 signaling pathway in CSCs. Increasing ceramide levels in tumors enhances their sensitivity to chemotherapy and prevents the enrichment of SOX9high CSCs. In addition, SOX9high and ABCA12high cancer cells contribute to chemoresistance in human patient-derived xenografts. These findings identify a CSC-suppressing lipid metabolism pathway that can be exploited to inhibit CSCs and overcome chemoresistance.
    DOI:  https://doi.org/10.1126/sciadv.adh1891
  7. Front Endocrinol (Lausanne). 2023 ;14 1309645
    Editorial: (Osteo)sarcopenia & sarcopenic obesity, volume II.
    Ifigenia Kostoglou-Athanassiou, Lambros Athanassiou, Panagiotis Athanassiou, Stefano Masiero, Yannis Dionyssiotis.
      
    Keywords:  diagnosis; exercise; osteoporosis; sarcopenia; sarcopenic obesity
    DOI:  https://doi.org/10.3389/fendo.2023.1309645
  8. Immun Ageing. 2023 Nov 27. 20(1): 68
    Frailty is related to serum inflammageing markers: results from the VITAL study.
    Yannick van Sleen, Sudarshan A Shetty, Marieke van der Heiden, Milou C A Venema, Nicolas Gutiérrez-Melo, Erik J M Toonen, Josine van Beek, Anne-Marie Buisman, Debbie van Baarle, Delphine Sauce.
      Frailty describes an age-associated state in individuals with an increased vulnerability and less resilience against adverse outcomes. To score frailty, studies have employed the questionnaires, such as the SF-36 and EQ-5D-3L, or the Frailty Index, a composite score based on deficit accumulation. Furthermore, ageing of the immune system is often accompanied by a state of low-grade inflammation (inflammageing). Here, we aimed to associate 29 circulating markers of inflammageing with frailty measures in a prospective cohort study to understand the mechanisms underlying ageing.Frailty measures and inflammageing markers were assessed in 317 participants aged 25-90. We determined four different measures of frailty: the Frailty Index based on 31 deficits, the EQ-5D-3L and two physical domains of the SF-36. Serum/plasma levels of inflammageing markers and CMV/EBV seropositivity were measured using different techniques: Quanterix, Luminex or ELISA.All four measures of frailty strongly correlated with age and BMI. Nineteen biomarkers correlated with age, some in a linear fashion (IL-6, YKL-40), some only in the oldest age brackets (CRP), and some increased at younger ages and then plateaued (CCL2, sIL-6R). After correcting for age, biomarkers, such as IL-6, CRP, IL-1RA, YKL-40 and elastase, were associated with frailty. When corrected for BMI, the number of associations reduced further.In conclusion, inflammageing markers, particularly markers reflecting innate immune activation, are related to frailty. These findings indicate that health decline and the accumulation of deficits with age is accompanied with a low-grade inflammation which can be detected by specific inflammatory markers.
    Keywords:  Ageing; Biomarkers; Body Mass Index; Cytomegalovirus; Frailty; Inflammation
    DOI:  https://doi.org/10.1186/s12979-023-00391-3
  9. Aging Cell. 2023 Nov 27. e14027
    SIRT2 transgenic over-expression does not impact lifespan in mice.
    Lindsay E Wu, Corrine E Fiveash, Nicholas L Bentley, Myung-Jin Kang, Hemna Govindaraju, Jayne A Barbour, Brendan P Wilkins, Sarah E Hancock, Romanthi Madawala, Abhijit Das, Hassina Massudi, Catherine Li, Lynn-Jee Kim, Ashley S A Wong, Maria B Marinova, Ghazal Sultani, Abhirup Das, Neil A Youngson, David G Le Couteur, David A Sinclair, Nigel Turner.
      The NAD+ -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role for sirtuin-2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under-expressed. Here, we sought to test whether SIRT2 over-expression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high-fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2-Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity.
    Keywords:  aging; aging biology; healthspan; lifespan; longevity; sirtuin 2 (SIRT2); sirtuins
    DOI:  https://doi.org/10.1111/acel.14027
  10. J Frailty Aging. 2023 ;12(4): 277-283
    Association of Oral Health with Frailty, Malnutrition Risk and Functional Decline in Hospitalized Older Adults: A Cross-Sectional Study.
    J Chew, J Q Chia, K K Kyaw, J K Fu, J Ang, Y P Lim, K Y Ang, H N Tan, W S Lim.
       BACKGROUND: Poor oral health is known to be associated with adverse outcomes, but the frequency and impact of poor oral health on older adults in the acute inpatient setting has been less well studied.
    OBJECTIVES: We examined the association between oral health, frailty, nutrition and functional decline in hospitalized older adults.
    DESIGN: Retrospective cross-sectional study.
    SETTING AND PARTICIPANTS: We included data from 465 inpatients (mean age 79.2±8.3 years) admitted acutely to a tertiary hospital.
    METHODS: We evaluated oral health using the Revised Oral Assessment Guide (ROAG), frailty using the Clinical Frailty Scale (CFS), malnutrition risk using the Nutritional Screening Tool (NST) and functional status using a modified Katz Activities of Daily Living (ADL) scale. We examined cross-sectional associations of oral health with frailty, malnutrition risk and functional decline on admission, followed by multivariate logistic regression models evaluating the association between poor oral health and the aforementioned outcomes.
    RESULTS: 343 (73.8%), 100 (21.5%) and 22 (4.7%) were classified as low, moderate and high risk on the ROAG, respectively. Poorer oral health was associated with greater severity of frailty, functional decline on admission and malnutrition risk. Abnormalities in ROAG domains of voice changes, swallowing difficulty, xerostomia, lips and tongue appearance were more frequently present at greater severity of frailty. Poor oral health was associated with frailty [odds ratio (OR): 1.76, 95% confidence interval (CI) 1.05-2.97; P=0.034]; malnutrition risk [OR: 2.76, 95% CI 1.46-5.19, P=0.002] and functional decline [OR: 1.62, 95% CI 1.01-2.59, P=0.046].
    CONCLUSIONS: Poor oral health is significantly associated with frailty, malnutrition risk and functional decline in older inpatients. Oral health evaluation, as part of a comprehensive geriatric assessment may be a target for interventions to improve outcomes. Further research including longitudinal outcomes and effectiveness of specific interventions targeted at oral health are warranted in older adults in the inpatient setting.
    Keywords:  Oral health; frailty; hospitalized; inpatient; nutrition; outcomes
    DOI:  https://doi.org/10.14283/jfa.2023.33
  11. Lab Anim (NY). 2023 Dec;52(12): 289-314
    How is Big Data reshaping preclinical aging research?
    Maria Emilia Fernandez, Jorge Martinez-Romero, Miguel A Aon, Michel Bernier, Nathan L Price, Rafael de Cabo.
      The exponential scientific and technological progress during the past 30 years has favored the comprehensive characterization of aging processes with their multivariate nature, leading to the advent of Big Data in preclinical aging research. Spanning from molecular omics to organism-level deep phenotyping, Big Data demands large computational resources for storage and analysis, as well as new analytical tools and conceptual frameworks to gain novel insights leading to discovery. Systems biology has emerged as a paradigm that utilizes Big Data to gain insightful information enabling a better understanding of living organisms, visualized as multilayered networks of interacting molecules, cells, tissues and organs at different spatiotemporal scales. In this framework, where aging, health and disease represent emergent states from an evolving dynamic complex system, context given by, for example, strain, sex and feeding times, becomes paramount for defining the biological trajectory of an organism. Using bioinformatics and artificial intelligence, the systems biology approach is leading to remarkable advances in our understanding of the underlying mechanism of aging biology and assisting in creative experimental study designs in animal models. Future in-depth knowledge acquisition will depend on the ability to fully integrate information from different spatiotemporal scales in organisms, which will probably require the adoption of theories and methods from the field of complex systems. Here we review state-of-the-art approaches in preclinical research, with a focus on rodent models, that are leading to conceptual and/or technical advances in leveraging Big Data to understand basic aging biology and its full translational potential.
    DOI:  https://doi.org/10.1038/s41684-023-01286-y
  12. Ageing Res Rev. 2023 Nov 27. pii: S1568-1637(23)00303-3. [Epub ahead of print] 102144
    eXplainable Artificial Intelligence (XAI) in aging clock models.
    Alena Kalyakulina, Igor Yusipov, Alexey Moskalev, Claudio Franceschi, Mikhail Ivanchenko.
      XAI is a rapidly progressing field of machine learning, aiming to unravel the predictions of complex models. XAI is especially required in sensitive applications, e.g. in health care, when diagnosis, recommendations and treatment choices might rely on the decisions made by artificial intelligence systems. AI approaches have become widely used in aging research as well, in particular, in developing biological clock models and identifying biomarkers of aging and age-related diseases. However, the potential of XAI here awaits to be fully appreciated. We discuss the application of XAI for developing the "aging clocks" and present a comprehensive analysis of the literature categorized by the focus on particular physiological systems.
    Keywords:  age-related diseases; aging; explainable artificial intelligence; longevity; machine learning
    DOI:  https://doi.org/10.1016/j.arr.2023.102144
  13. Ageing Res Rev. 2023 Nov 27. pii: S1568-1637(23)00300-8. [Epub ahead of print] 102141
    Cellular senescence in brain aging and neurodegeneration.
    L S Melo Dos Santos, M Trombetta-Lima, Eggen Bjl, M Demaria.
      Cellular senescence is a state of terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory phenotype. In the brain, senescent cells naturally accumulate during aging and at sites of age-related pathologies. Here, we discuss the recent advances in understanding the accumulation of senescent cells in brain aging and disorders. Here we highlight the phenotypical heterogeneity of different senescent brain cell types, highlighting the potential importance of subtype-specific features for physiology and pathology. We provide a comprehensive overview of various senescent cell types in naturally occurring aging and the most common neurodegenerative disorders. Finally, we critically discuss the potential of adapting senotherapeutics to improve brain health and reduce pathological progression, addressing limitations and future directions for application and development.
    Keywords:  Aging; cellular senescence; neurodegeneration; senolytics
    DOI:  https://doi.org/10.1016/j.arr.2023.102141
  14. Acta Haematol. 2023 Nov 30.
    Geriatric assessment in Acute Myeloid Leukemia (AML).
    Justin D Woods, Heidi D Klepin.
      Background Acute myeloid leukemia (AML) is a heterogenous disease that affects mostly older adults with varying baseline health and functional status. Treatment options have expanded for older adults ranging from less intensive chronic therapies to intensive induction strategies with curative intent. Despite this, outcomes remain poor with advancing age due to underlying disease biology and variability in treatment tolerance. Reliance on chronologic age alone, however, increases risks of both over- and under-treatment. Strategies to better characterize fitness in the context of therapy are needed to optimize decision-making and enhance clinical trial design. Summary Geriatric assessment (GA) is a series of validated tools that evaluate multiple health and functional domains of an older adult including physical function, comorbidities, cognition, nutrition, psychological health, and social support. While studies of GA in AML remain limited, current evidence shows that it is feasible to perform GA among older adults starting therapy for AML. GA measures including those assessing physical function, cognition, and mood are associated with mortality and toxicity in both the intensive and less intensive treatment settings. Key Messages In this review, we discuss the existing evidence to support use of GA in AML and highlight implications for clinical practice and future research.
    DOI:  https://doi.org/10.1159/000535500
  15. Front Public Health. 2023 ;11 1303223
    Editorial: Sarcopenia and frailty: the role of physical activity for better aging.
    Ricardo Aurélio Carvalho Sampaio, Priscila Yukari Sewo Sampaio, Luciane Portas Capelo, Marco Carlos Uchida, Hidenori Arai.
      
    Keywords:  aging; body composition; disability; muscle strength; physical function; public health
    DOI:  https://doi.org/10.3389/fpubh.2023.1303223
  16. Front Physiol. 2023 ;14 1263420
    Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.
    Ashley L Reed, Wayne Mitchell, Andrei T Alexandrescu, Nathan N Alder.
      Most mitochondrial proteins are targeted to the organelle by N-terminal mitochondrial targeting sequences (MTSs, or "presequences") that are recognized by the import machinery and subsequently cleaved to yield the mature protein. MTSs do not have conserved amino acid compositions, but share common physicochemical properties, including the ability to form amphipathic α-helical structures enriched with basic and hydrophobic residues on alternating faces. The lack of strict sequence conservation implies that some polypeptides can be mistargeted to mitochondria, especially under cellular stress. The pathogenic accumulation of proteins within mitochondria is implicated in many aging-related neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases. Mechanistically, these diseases may originate in part from mitochondrial interactions with amyloid-β precursor protein (APP) or its cleavage product amyloid-β (Aβ), α-synuclein (α-syn), and mutant forms of huntingtin (mHtt), respectively, that are mediated in part through their associations with the mitochondrial protein import machinery. Emerging evidence suggests that these amyloidogenic proteins may present cryptic targeting signals that act as MTS mimetics and can be recognized by mitochondrial import receptors and transported into different mitochondrial compartments. Accumulation of these mistargeted proteins could overwhelm the import machinery and its associated quality control mechanisms, thereby contributing to neurological disease progression. Alternatively, the uptake of amyloidogenic proteins into mitochondria may be part of a protein quality control mechanism for clearance of cytotoxic proteins. Here we review the pathomechanisms of these diseases as they relate to mitochondrial protein import and effects on mitochondrial function, what features of APP/Aβ, α-syn and mHtt make them suitable substrates for the import machinery, and how this information can be leveraged for the development of therapeutic interventions.
    Keywords:  amyloids; cryptic targeting; mitochondria; neurodegeneration; protein import; targeting signals
    DOI:  https://doi.org/10.3389/fphys.2023.1263420
  17. Glob Med Genet. 2023 Dec;10(4): 339-344
    The Epigenetic Regulation of Quiescent in Stem Cells.
    Mehran Radak, Hossein Fallahi.
      This review article discusses the epigenetic regulation of quiescent stem cells. Quiescent stem cells are a rare population of stem cells that remain in a state of cell cycle arrest until activated to proliferate and differentiate. The molecular signature of quiescent stem cells is characterized by unique epigenetic modifications, including histone modifications and deoxyribonucleic acid (DNA) methylation. These modifications play critical roles in regulating stem cell behavior, including maintenance of quiescence, proliferation, and differentiation. The article specifically focuses on the role of histone modifications and DNA methylation in quiescent stem cells, and how these modifications can be dynamically regulated by environmental cues. The future perspectives of quiescent stem cell research are also discussed, including their potential for tissue repair and regeneration, their role in aging and age-related diseases, and their implications for cancer research. Overall, this review provides a comprehensive overview of the epigenetic regulation of quiescent stem cells and highlights the potential of this research for the development of new therapies in regenerative medicine, aging research, and cancer biology.
    Keywords:  DNA methylation; environmental cues; epigenetic regulation; histone modifications; molecular signature; quiescent stem cells; tissue repair
    DOI:  https://doi.org/10.1055/s-0043-1777072
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