bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–09–03
twenty-one papers selected by
Ayesh Seneviratne, Western University
  1. An evolutionarily divergent mTOR powers up regeneration.
  2. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
  3. Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
  4. Lipids and the Hallmarks of Ageing: From Pathology to Interventions.
  5. Cost-effective Alzheimer's disease detection using plasma p-tau217-based risk stratification.
  6. Biomarkers of aging for the identification and evaluation of longevity interventions.
  7. Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment.
  8. Dietary change without caloric restriction maintains a youthful profile in ageing yeast.
  9. Hematopoiesis: a BETter understanding.
  10. Chronic inflammation can transform the fate of normal and mutant haematopoietic stem cells.
  11. Frailty-Guided Management of Cardiovascular Disease-From Clinical Trials to Clinical Practice.
  12. Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size.
  13. Linking cell cycle to hematopoietic stem cell fate decisions.
  14. Biomarkers of aging in frailty and age-associated disorders: state of the art and future perspective.
  15. Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review.
  16. The Inflamed Niche: A Double-Edged Sword in AML?
  17. Addressing the Complex Driving Needs of an Aging Population.
  18. Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study.
  19. Accelerated vascular aging in people with HIV: how can we slow down the clock?
  20. Enhancing reproducibility in human stem cell research.
  21. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
  1. Nat Aging. 2023 Aug 28.
    An evolutionarily divergent mTOR powers up regeneration.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00493-z
  2. Nat Aging. 2023 Aug 31.
    Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
    Mukul Girotra, Yi-Hsuan Chiang, Melanie Charmoy, Pierpaolo Ginefra, Helen Carrasco Hope, Charles Bataclan, Yi-Ru Yu, Frederica Schyrr, Fabien Franco, Hartmut Geiger, Stephane Cherix, Ping-Chih Ho, Olaia Naveiras, Johan Auwerx, Werner Held, Nicola Vannini.
      Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.
    DOI:  https://doi.org/10.1038/s43587-023-00473-3
  3. bioRxiv. 2023 Aug 19. pii: 2023.08.17.553736. [Epub ahead of print]
    Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
    Paul V Dellorusso, Melissa A Proven, Fernando J Calero-Nieto, Xiaonan Wang, Carl A Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W Swann, Theodore T Ho, Zhiyu Zhao, Sean C Bendall, Sean Morrison, Berthold Göttgens, Emmanuelle Passegué.
      Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction ( 1 ). Autophagy is central for the benefits associated with activation of longevity signaling programs ( 2 ), and for HSC function and response to nutrient stress ( 3,4 ). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional ( 4 ). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche ( 5 ). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.
    One-Sentence Summary: Autophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.
    DOI:  https://doi.org/10.1101/2023.08.17.553736
  4. Mech Ageing Dev. 2023 Aug 29. pii: S0047-6374(23)00084-2. [Epub ahead of print] 111858
    Lipids and the Hallmarks of Ageing: From Pathology to Interventions.
    Rohit Sharma, Bhawna Diwan.
      Lipids are critical structural and functional architects of cellular homeostasis. Change in systemic lipid profile is a clinical indicator of underlying metabolic pathologies, and emerging evidence is now defining novel roles of lipids in modulating organismal ageing. Characteristic alterations in lipid metabolism correlate with age, and impaired systemic lipid profile can also accelerate the development of ageing phenotype. The present work provides a comprehensive review of the extent of lipids as regulators of the modern hallmarks of ageing viz., cellular senescence, chronic inflammation, gut dysbiosis, telomere attrition, genome instability, proteostasis and autophagy, epigenetic alterations, and stem cells dysfunctions. Current evidence on the modulation of each of these hallmarks has been discussed with emphasis on inherent age-dependent deficiencies in lipid metabolism as well as exogenous lipid changes. There appears to be sufficient evidence to consider impaired lipid metabolism as key driver of the ageing process although much of knowledge is yet fragmented. Considering dietary lipids, the type and quantity of lipids in the diet is a significant, but often overlooked determinant that governs the effects of lipids on ageing. Further research using integrative approaches amidst the known aging hallmarks is highly desirable for understanding the therapeutics of lipids associated with ageing.
    Keywords:  Ageing; Cellular senescence; Diet; Hallmarks; Inflammation; Lipidome; Lipids
    DOI:  https://doi.org/10.1016/j.mad.2023.111858
  5. Nat Aging. 2023 Aug 31.
    Cost-effective Alzheimer's disease detection using plasma p-tau217-based risk stratification.
      
    DOI:  https://doi.org/10.1038/s43587-023-00485-z
  6. Cell. 2023 Aug 31. pii: S0092-8674(23)00857-7. [Epub ahead of print]186(18): 3758-3775
    Biomarkers of aging for the identification and evaluation of longevity interventions.
    Biomarkers of Aging Consortium
      With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.
    DOI:  https://doi.org/10.1016/j.cell.2023.08.003
  7. Cell Mol Immunol. 2023 Aug 30.
    Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment.
    Weinian Liao, Chaonan Liu, Ke Yang, Jun Chen, Yiding Wu, Shuzhen Zhang, Kuan Yu, Lisha Wang, Li Ran, Mo Chen, Fang Chen, Yang Xu, Song Wang, Fengchao Wang, Qian Zhang, Jinghong Zhao, Lilin Ye, Changhong Du, Junping Wang.
      Although DNA mutation drives stem cell aging, how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood. Here, using a mouse model of irradiation-induced premature aging and middle-aged mice, we show that DNA mutation accumulation in hematopoietic stem cells (HSCs) during aging upregulates their surface expression of major histocompatibility complex class II (MHCII). MHCII upregulation increases the chance for recognition by bone marrow (BM)-resident regulatory T cells (Tregs), resulting in their clonal expansion and accumulation in the HSC niche. On the basis of the establishment of connexin 43 (Cx43)-mediated gap junctions, BM Tregs transfer cyclic adenosine monophosphate (cAMP) to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A (PKA) signaling. Importantly, targeting the HSC-Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs. These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.
    Keywords:  Aging; Hematopoietic stem cell; regulatory T cell
    DOI:  https://doi.org/10.1038/s41423-023-01072-3
  8. PLoS Biol. 2023 Aug;21(8): e3002245
    Dietary change without caloric restriction maintains a youthful profile in ageing yeast.
    Dorottya Horkai, Hanane Hadj-Moussa, Alex J Whale, Jonathan Houseley.
      Caloric restriction increases lifespan and improves ageing health, but it is unknown whether these outcomes can be separated or achieved through less severe interventions. Here, we show that an unrestricted galactose diet in early life minimises change during replicative ageing in budding yeast, irrespective of diet later in life. Average mother cell division rate is comparable between glucose and galactose diets, and lifespan is shorter on galactose, but markers of senescence and the progressive dysregulation of gene expression observed on glucose are minimal on galactose, showing that these are not intrinsic aspects of replicative ageing but rather associated processes. Respiration on galactose is critical for minimising hallmarks of ageing, and forced respiration during ageing on glucose by overexpression of the mitochondrial biogenesis factor Hap4 also has the same effect though only in a fraction of cells. This fraction maintains Hap4 activity to advanced age with low senescence and a youthful gene expression profile, whereas other cells in the same population lose Hap4 activity, undergo dramatic dysregulation of gene expression and accumulate fragments of chromosome XII (ChrXIIr), which are tightly associated with senescence. Our findings support the existence of two separable ageing trajectories in yeast. We propose that a complete shift to the healthy ageing mode can be achieved in wild-type cells through dietary change in early life without caloric restriction.
    DOI:  https://doi.org/10.1371/journal.pbio.3002245
  9. EMBO Rep. 2023 Aug 31. e57927
    Hematopoiesis: a BETter understanding.
    Nirmalya Dasgupta, Peter D Adams.
      Epigenetic modifications are known to be crucial for hematopoietic stem cell (HSC) differentiation, with the BET family member BRD4 playing a vital role in this as an epigenetic reader. In this issue of EMBO reports, Yang et al (2023) demonstrate that the absence of BRD4 leads to senescence in HSCs and hematopoietic progenitor cells (HPCs), affecting the expression of crucial genes involved in myeloid and erythroid development. These data suggest that BRD4 has a protective role in preserving histone tails, thereby sustaining normal HSC/HPC functions.
    DOI:  https://doi.org/10.15252/embr.202357927
  10. Exp Hematol. 2023 Aug 28. pii: S0301-472X(23)01697-1. [Epub ahead of print]
    Chronic inflammation can transform the fate of normal and mutant haematopoietic stem cells.
    Jingjing Li, Camille Malouf, Linde A Miles, Mara B Willis, Eric M Pietras, Katherine Y King.
      Chronic inflammation, while subtle, puts the body in a constant state of alert and is associated with a number of diseases, including cancer and cardiovascular diseases. It leads hematopoietic cells to produce and release pro-inflammatory cytokines, which trigger specific signalling pathways in hematopoietic stem cells (HSCs) that cause changes in proliferation, differentiation, and migration. This response is essential when HSCs are needed to produce specific blood cells to eliminate an intruder, such as a pathogenic virus, but mutant HSCs can use these pro-inflammatory signals to their advantage and accelerate the development of haematological disease or malignancy. Understanding this complex process is vital in monitoring and controlling disease progression in patients. In the 2023 Winter International Society for Experimental Hematology (ISEH) webinar, Dr. Eric Pietras (University of Colorado Anschutz Medical Campus, USA) and Dr. Katherine Y. King (Baylor College of Medicine, USA) gave a presentation on this topic, which is summarized in this review article.
    DOI:  https://doi.org/10.1016/j.exphem.2023.08.008
  11. JAMA Cardiol. 2023 Aug 30.
    Frailty-Guided Management of Cardiovascular Disease-From Clinical Trials to Clinical Practice.
    Dae Hyun Kim, Lily Zhong, Michael W Rich.
      
    DOI:  https://doi.org/10.1001/jamacardio.2023.1634
  12. JACC Heart Fail. 2023 Aug 21. pii: S2213-1779(23)00509-7. [Epub ahead of print]
    Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size.
    Maurits A Sikking, Sophie L V M Stroeks, Michiel T H M Henkens, Anne G Raafs, Benjamin Cossins, Rosanne C van Deuren, Marlies Steehouwer, Niels P Riksen, Arthur van den Wijngaard, Han G Brunner, Alexander Hoischen, Job A J Verdonschot, Stephane R B Heymans.
       BACKGROUND: Clonal hematopoiesis (CH) gives rise to mutated leukocyte clones that induce cardiovascular inflammation, and thereby impact the disease course in atherosclerosis and ischemic heart failure. Clonal hematopoiesis of indeterminate potential (CHIP) refers to a variant allele frequency (VAF; a marker for clone size) in blood of ≥2%. The impact of CH clones -including small clone sizes (VAF<0.5%)- in non-ischemic dilated cardiomyopathy (DCM) remains largely undetermined.
    OBJECTIVES: To establish the prognostic impact of CH in DCM including small clones.
    METHODS: CH is determined using an ultrasensitive single-molecule Molecular Inversion Probe technique that allows detection of clones down to a VAF of 0.01%. Cardiac death and all-cause mortality were analyzed using receiver operating characteristic curve-optimized VAF cut-off values.
    RESULTS: Five hundred twenty DCM patients have been included. One hundred and nine patients (21%) had CH driver mutations, of which 45 had a VAF of ≥2% and 31 <0.5%. The median follow-up duration is 6.5 years [interquartile range 4.7-9.7]. DCM patients with CH have a higher risk of cardiac death (HR 2.33 using a VAF cut-off of 0.36%, 95% confidence interval 1.24-4.40) and all-cause mortality (HR 1.72 using a VAF cut-off of 0.06%, 95% confidence interval 1.10-2.69), independent of age, sex, left ventricle ejection fraction and New York Heart Association classification.
    CONCLUSION: CH predicts cardiac death and all-cause mortality in DCM patients with an optimal threshold for clone size of 0.36% and 0.06%, respectively. Therefore, CH is prognostically relevant independent of clone size in patients with DCM.
    Keywords:  clonal hematopoiesis; dilated cardiomyopathy; heart failure
    DOI:  https://doi.org/10.1016/j.jchf.2023.06.037
  13. Front Cell Dev Biol. 2023 ;11 1231735
    Linking cell cycle to hematopoietic stem cell fate decisions.
    Sydney Treichel, Marie-Dominique Filippi.
      Hematopoietic stem cells (HSCs) have the properties to self-renew and/or differentiate into any blood cell lineages. In order to balance the maintenance of the stem cell pool with supporting mature blood cell production, the fate decisions to self-renew or to commit to differentiation must be tightly controlled, as dysregulation of this process can lead to bone marrow failure or leukemogenesis. The contribution of the cell cycle to cell fate decisions has been well established in numerous types of stem cells, including pluripotent stem cells. Cell cycle length is an integral component of hematopoietic stem cell fate. Hematopoietic stem cells must remain quiescent to prevent premature replicative exhaustion. Yet, hematopoietic stem cells must be activated into cycle in order to produce daughter cells that will either retain stem cell properties or commit to differentiation. How the cell cycle contributes to hematopoietic stem cell fate decisions is emerging from recent studies. Hematopoietic stem cell functions can be stratified based on cell cycle kinetics and divisional history, suggesting a link between Hematopoietic stem cells activity and cell cycle length. Hematopoietic stem cell fate decisions are also regulated by asymmetric cell divisions and recent studies have implicated metabolic and organelle activity in regulating hematopoietic stem cell fate. In this review, we discuss the current understanding of the mechanisms underlying hematopoietic stem cell fate decisions and how they are linked to the cell cycle.
    Keywords:  asymmetric division; cell cycle; differentiation; fate decision; hematopoietic stem cells
    DOI:  https://doi.org/10.3389/fcell.2023.1231735
  14. Ageing Res Rev. 2023 Aug 28. pii: S1568-1637(23)00203-9. [Epub ahead of print] 102044
    Biomarkers of aging in frailty and age-associated disorders: state of the art and future perspective.
    Stefano Salvioli, Maria Sofia Basile, Leonardo Bencivenga, Sara Carrino, Maria Conte, Sarah Damanti, Rebecca De Lorenzo, Eleonora Fiorenzato, Alessandro Gialluisi, Assunta Ingannato, Angelo Antonini, Nicola Baldini, Miriam Capri, Simone Cenci, Licia Iacoviello, Benedetta Nacmias, Fabiola Olivieri, Giuseppe Rengo, Patrizia Rovere Querini, Fabrizia Lattanzio.
      According to the Geroscience concept that organismal aging and age-associated diseases share the same basic molecular mechanisms, the identification of biomarkers of age that can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) age is becoming of paramount importance. These people will be in fact at higher (or lower) risk for many different age-associated diseases, including cardiovascular diseases, neurodegeneration, cancer, etc. In turn, patients suffering from these diseases are biologically older than healthy age-matched individuals. Many biomarkers that correlate with age have been described so far. The aim of the present review is to discuss the usefulness of some of these biomarkers (especially soluble, circulating ones) in order to identify frail patients, possibly before the appearance of clinical symptoms, as well as patients at risk for age-associated diseases. An overview of selected biomarkers will be discussed in this regard, in particular we will focus on biomarkers related to metabolic stress response, inflammation, and cell death (in particular in neurodegeneration), all phenomena connected to inflammaging (chronic, low-grade, age-associated inflammation). In the second part of the review, next-generation markers such as extracellular vesicles and their cargos, epigenetic markers and gut microbiota composition, will be discussed. Since recent progresses in omics techniques have allowed an exponential increase in the production of laboratory data also in the field of biomarkers of age, making it difficult to extract biological meaning from the huge mass of available data, Artificial Intelligence (AI) approaches will be discussed as an increasingly important strategy for extracting knowledge from raw data and providing practitioners with actionable information to treat patients.
    Keywords:  Artificial Intelligence; Biomarkers of aging; frailty; inflammaging; multimorbidity
    DOI:  https://doi.org/10.1016/j.arr.2023.102044
  15. Cureus. 2023 Jul;15(7): e42550
    Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review.
    Breanne Kothe, Sarah Klein, Stephanie N Petrosky.
      The aging of an organism is hallmarked by systemic loss of functional tissue, resulting in increased fragility and eventual development of age-related neurodegenerative, musculoskeletal, cardiovascular, and neoplastic diseases. Growing scientific evidence points to mitochondrial dysfunction as a key contributor in the aging process and subsequent development of age-related pathologies. Under normal physiologic conditions, the body removes dysfunctional mitochondria via an autophagic process known as mitophagy. Urolithin A (UA), a metabolite produced when gut microflora digests the polyphenol compounds ellagitannin and ellagic acid, is a known inducer of mitophagy via several identified mechanisms of action. The primary objective of this scoping review is to identify and summarize the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases. A computer-assisted literature review was performed using PubMed and EMBASE for primary source research articles examining UA supplementation and aging-related pathologies. A total of 293 articles were initially identified from a database search, and 15 articles remained for inclusion in this review, based on predetermined criteria. Analysis of the 15 identified publications demonstrated that UA holds potential as a dietary intervention for slowing the progression of aging and preventing the development of age-related disease. This review also illustrates the potential role that mitochondrial health and inflammation play in the progression of age-related pathology. Identifying the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases will help further the focus of research on treatments that may improve the longevity and quality of life in patients at risk for these comorbidities.
    Keywords:  age-related disease; aging; cholangiocarcinoma; colorectal cancer; neoplastic disease; neurodegenerative disease; osteoporosis; photo-aging; sarcopenia; urolithin a
    DOI:  https://doi.org/10.7759/cureus.42550
  16. Blood Cancer Discov. 2023 Sep 01. 4(5): 349-351
    The Inflamed Niche: A Double-Edged Sword in AML?
    Livia E Lisi-Vega, Simón Méndez-Ferrer.
       SUMMARY: Although inflammation has long been recognized as a hallmark of many cancers, including acute myeloid leukemia (AML), how it affects individual cells of the tumor microenvironment and their interaction with normal and neoplastic cells is incompletely understood. A comprehensive single-cell transcriptomic analysis of human bone marrow from patients with AML and healthy individuals identified skewing of stem cell and stromal cell populations in AML toward proinflammatory states associated with reduced risk of relapse, paralleling previous findings in mouse models and suggesting that inflamed bone marrow mesenchymal stromal cells might be a double-edged sword in AML by hampering normal hematopoiesis (while AML cells appear comparatively more resilient) but also rendering AML cells more susceptible to chemotherapy or immune attack. See related article by Chen et al., p. 394 (7) .
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0125
  17. JAMA. 2023 Sep 01.
    Addressing the Complex Driving Needs of an Aging Population.
    David Brian Carr, Ganesh Muneshwar Babulal.
      
    DOI:  https://doi.org/10.1001/jama.2023.16093
  18. Leuk Res. 2023 Aug 22. pii: S0145-2126(23)00638-0. [Epub ahead of print]133 107373
    Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study.
    Fernando De la Garza-Salazar, Perla Rocío Colunga-Pedraza, David Gómez-Almaguer, Valeria Abigail García-Zárate, Andrés Gómez-De León.
      Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1-21, itraconazole 100 mg twice daily from days 1-21, and azacytidine 100 mg subcutaneously, once daily from days 1-7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25-73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.
    Keywords:  Acute myeloid leukemia; CYP inhibition; Low-dose; Outpatient induction; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2023.107373
  19. AIDS. 2023 Oct 01. 37(12): N11
    Accelerated vascular aging in people with HIV: how can we slow down the clock?
    Iulia Filip.
      
    DOI:  https://doi.org/10.1097/QAD.0000000000003640
  20. Nat Cell Biol. 2023 Aug 30.
    Enhancing reproducibility in human stem cell research.
    Stylianos Lefkopoulos.
      
    DOI:  https://doi.org/10.1038/s41556-023-01218-5
  21. Nat Metab. 2023 Aug 31.
    A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
    Undiagnosed Diseases Network
      In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00873-0
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