bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒04‒18
fourteen papers selected by
Ayesh Seneviratne
University of Toronto
  1. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging.
  2. Healthy Aging-Nutrition Matters: Start Early and Screen Often.
  3. An aged bone marrow niche restrains rejuvenated hematopoietic stem cells.
  4. Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia.
  5. CRISPR base editor treats premature-aging syndrome.
  6. Editorial: Personalized Nutrition.
  7. Dietary Arthrospira platensis improves systemic antioxidant potential and changes plasma lipids without affecting related hepatic metabolic pathways in post-weaned piglets.
  8. Probiotics, Pre-biotics and Synbiotics in the Treatment of Pre-diabetes: A Systematic Review of Randomized Controlled Trials.
  9. Cancer genes and blood clots.
  10. The functional roles of TCA cycle metabolites in cancer.
  11. Early stem cell aging in the mature brain.
  12. SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases.
  13. Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure.
  14. Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome.
  1. Cell Stem Cell. 2021 Apr 07. pii: S1934-5909(21)00123-5. [Epub ahead of print]
    Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging.
    Kira Young, Elizabeth Eudy, Rebecca Bell, Matthew A Loberg, Tim Stearns, Devyani Sharma, Lars Velten, Simon Haas, Marie-Dominique Filippi, Jennifer J Trowbridge.
      Decline in hematopoietic stem cell (HSC) function with age underlies limited health span of our blood and immune systems. In order to preserve health into older age, it is necessary to understand the nature and timing of initiating events that cause HSC aging. By performing a cross-sectional study in mice, we discover that hallmarks of aging in HSCs and hematopoiesis begin to accumulate by middle age and that the bone marrow (BM) microenvironment at middle age induces and is indispensable for hematopoietic aging. Using unbiased approaches, we find that decreased levels of the longevity-associated molecule IGF1 in the local middle-aged BM microenvironment are a factor causing HSC aging. Direct stimulation of middle-aged HSCs with IGF1 rescues molecular and functional hallmarks of aging, including restored mitochondrial activity. Thus, although decline in IGF1 supports longevity, our work indicates that this also compromises HSC function and limits hematopoietic health span.
    Keywords:  IGF1; aging; healthspan; hematopoiesis; hematopoietic stem cell; lineage bias; metabolism; microenvironment; middle age; niche
    DOI:  https://doi.org/10.1016/j.stem.2021.03.017
  2. Adv Nutr. 2021 Apr 10. pii: nmab032. [Epub ahead of print]
    Healthy Aging-Nutrition Matters: Start Early and Screen Often.
    Susan B Roberts, Rachel E Silver, Sai Krupa Das, Roger A Fielding, Cheryl H Gilhooly, Paul F Jacques, Jennifer M Kelly, Joel B Mason, Nicola M McKeown, Meaghan A Reardon, Sheldon Rowan, Edward Saltzman, Barbara Shukitt-Hale, Caren E Smith, Allen A Taylor, Dayong Wu, Fang Fang Zhang, Karen Panetta, Sarah Booth.
      The amount of time spent in poor health at the end of life is increasing. This narrative review summarizes consistent evidence indicating that healthy dietary patterns and maintenance of a healthy weight in the years leading to old age are associated with broad prevention of all the archetypal diseases and impairments associated with aging including: noncommunicable diseases, sarcopenia, cognitive decline and dementia, osteoporosis, age-related macular degeneration, diabetic retinopathy, hearing loss, obstructive sleep apnea, urinary incontinence, and constipation. In addition, randomized clinical trials show that disease-specific nutrition interventions can attenuate progression-and in some cases effectively treat-many established aging-associated conditions. However, middle-aged and older adults are vulnerable to unhealthy dietary patterns, and typically consume diets with inadequate servings of healthy food groups and essential nutrients, along with an abundance of energy-dense but nutrient-weak foods that contribute to obesity. However, based on menu examples, diets that are nutrient-dense, plant-based, and with a moderately low glycemic load are better equipped to meet the nutritional needs of many older adults than current recommendations in US Dietary Guidelines. These summary findings indicate that healthy nutrition is more important for healthy aging than generally recognized. Improved public health messaging about nutrition and aging, combined with routine screening and medical referrals for age-related conditions that can be treated with a nutrition prescription, should form core components of a national nutrition roadmap to reduce the epidemic of unhealthy aging.
    Keywords:  age-related macular degeneration; aging; cognition; constipation; diabetic retinopathy; noncommunicable diseases; nutrition; obstructive sleep apnea; sarcopenia; urinary incontinence
    DOI:  https://doi.org/10.1093/advances/nmab032
  3. Stem Cells. 2021 Apr 13.
    An aged bone marrow niche restrains rejuvenated hematopoietic stem cells.
    Novella Guidi, Gina Marka, Vadim Sakk, Yi Zheng, Maria Carolina Florian, Hartmut Geiger.
      Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.
    Keywords:  Cdc42; aging; hematopoietic stem cell; niche; osteopontin; rejuvenation
    DOI:  https://doi.org/10.1002/stem.3372
  4. Front Oncol. 2021 ;11 654817
    Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia.
    Kristine Yttersian Sletta, Oriol Castells, Bjørn Tore Gjertsen.
      Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.
    Keywords:  acute myeloid leukemia; biomarkers; colony stimulating factor 1 receptor; signal transduction; targeted therapy; therapy development; tumor-stroma
    DOI:  https://doi.org/10.3389/fonc.2021.654817
  5. Signal Transduct Target Ther. 2021 Apr 16. 6(1): 158
    CRISPR base editor treats premature-aging syndrome.
    Ping Lin, Jianxin Jiang, Min Wu.
      
    DOI:  https://doi.org/10.1038/s41392-021-00576-6
  6. Front Nutr. 2021 ;8 669307
    Editorial: Personalized Nutrition.
    Ellen E Blaak, Helen M Roche, Lydia A Afman.
      
    Keywords:  childhood; microbiome; personalized nutrition; plant-based diets; precision-based nutrition; web-based intervention
    DOI:  https://doi.org/10.3389/fnut.2021.669307
  7. BMC Vet Res. 2021 Apr 13. 17(1): 158
    Dietary Arthrospira platensis improves systemic antioxidant potential and changes plasma lipids without affecting related hepatic metabolic pathways in post-weaned piglets.
    Marta Sofia Morgado Dos Santos Madeira, Paula Alexandra Antunes Brás Lopes, Cátia Falcão Martins, José Miguel Pestana Assunção, Cristina Maria Riscado Pereira Mateus Alfaia, Rui Manuel Amaro Pinto, José António Mestre Prates.
      BACKGROUND: The ability of a high level of dietary Arthrospira platensis, individually or in combination with two exogenous carbohydrate-degrading enzymes (lysozyme and Rovabio®), to improve systemic antioxidant potential and hepatic lipid metabolism was tested in piglets. Forty male post-weaned piglets, sons of Large White × Landrace sows crossed with Pietrain boars, were allocated into 4 groups (n = 10) and fed during 28 days one of the following diets: 1) a control basal diet (cereal and soybean meal); 2) a basal diet with 10% of A. platensis (AP); 3) the AP diet supplemented with 0.005% of Rovabio® (AP + R); 4) the AP diet supplemented with 0.01% of lysozyme (AP + L).RESULTS: Arthrospira platensis decreased BW gain of piglets, regardless the addition of feed enzymes. The majority of plasma metabolites were affected by diets. A. platensis increased total lipids, total cholesterol and LDL-cholesterol, without changing hepatic fatty acid content or modulating, in an expressive manner, the transcriptional profile of lipid sensitive mediators. The antioxidant potential in general, and total carotenoids in particular, were improved by the microalga, regardless lysozyme or Rovabio®.
    CONCLUSIONS: Summing up, A. platensis, individually and combined with feed enzymes, impacts negatively on piglets' growth but improves the systemic antioxidant potential and changes plasma lipids with a minor modulation on related hepatic metabolic pathways.
    Keywords:  Antioxidant potential; Arthrospira platensis; Enzymes; Hepatic lipid metabolism; Piglets
    DOI:  https://doi.org/10.1186/s12917-021-02869-y
  8. Front Public Health. 2021 ;9 645035
    Probiotics, Pre-biotics and Synbiotics in the Treatment of Pre-diabetes: A Systematic Review of Randomized Controlled Trials.
    Xian Wang, Jiao Yang, Xianliang Qiu, Qing Wen, Min Liu, Dongqi Zhou, Qiu Chen.
      Objectives: This study aimed to review the data from randomized controlled trials (RCTs) and identify evidence for microbiota's role and use of probiotics, pre-biotics, or synbiotics in pre-diabetes. Methods: RCTs of pro-, pre-, synbiotics for the treatment of pre-diabetes population will be summarized. We searched for EMBASE, MEDLINE, Web of Science, Cochrane Central, Clinical Trials (ClinicalTrials.gov) from inception to February 2021. Results: The gut microbiota influences host metabolic disorders via the modulation of metabolites, including short-chain fatty acids (SCFAs), the endotoxin lipopolysaccharides (LPS), bile acids (BA) and trimethylamine N-oxide (TMAO), as well as mediating the interaction between the gastrointestinal system and other organs. Due to the limited sources of studies, inconsistent outcomes between included studies. Probiotics can decrease glycated hemoglobin (HbA1c) and have the potential to improve post-load glucose levels. The supplementation of probiotics can suppress the rise of blood cholesterol, but the improvement cannot be verified. Pre-biotics are failed to show an evident improvement in glycemic control, but their use caused the changes in the composition of gut microbiota. A combination of probiotics and pre-biotics in the synbiotics supplementation is more effective than probiotics alone in glycemic control. Conclusion: In the current studies using probiotics, pre-biotics or synbiotics for the treatment of pre-diabetes, the benefits of modulating the abundance of gut microbiota were partially demonstrated. However, there is insufficient evidence to show significant benefits on glucose metabolism, lipid metabolism and body composition.
    Keywords:  gut microbiota; pre-biotics; pre-diabetes; probiotics; synbiotics
    DOI:  https://doi.org/10.3389/fpubh.2021.645035
  9. Blood. 2021 Apr 15. 137(15): 1996-1997
    Cancer genes and blood clots.
    Janusz Rak.
      
    DOI:  https://doi.org/10.1182/blood.2020009967
  10. Oncogene. 2021 Apr 16.
    The functional roles of TCA cycle metabolites in cancer.
    Joseph Eniafe, Shuai Jiang.
      The tricarboxylic acid cycle (TCA cycle) has been known for decades as a hub for generating cellular energy and precursors for biosynthetic pathways. Several cancers harbor mutations that affect the integrity of this cycle, mostly at the levels of isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH). This results in dysregulation in the production of TCA cycle metabolites and is probably implicated in cancer initiation. By modulating cellular activities, including metabolism and signaling, TCA cycle intermediates are able to impact the processes of cancer development and progression. In this review, we discuss the functional roles of the TCA cycle intermediates in suppressing or promoting the progression of cancers. A further understanding of TCA metabolites' roles and molecular mechanisms in oncogenesis would prompt developing novel metabolite-based cancer therapy in the future.
    DOI:  https://doi.org/10.1038/s41388-020-01639-8
  11. Cell Stem Cell. 2021 Apr 07. pii: S1934-5909(21)00124-7. [Epub ahead of print]
    Early stem cell aging in the mature brain.
    Albina Ibrayeva, Maxwell Bay, Elbert Pu, David J Jörg, Lei Peng, Heechul Jun, Naibo Zhang, Daniel Aaron, Congrui Lin, Galen Resler, Axel Hidalgo, Mi-Hyeon Jang, Benjamin D Simons, Michael A Bonaguidi.
      Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to promote tissue function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term NSCs (ST-NSCs) and long-term NSCs (LT-NSCs). ST-NSCs divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months but are pushed out of homeostasis by lengthening quiescence. Single-cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC aging factor. Treatment with the Abl inhibitor imatinib increased NSC activation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable and adaptable to cellular aging.
    Keywords:  Abl; Imatinib; adult neurogenesis; aging; bioinformatics; cell fate; clonal analysis; hippocampus; intervention; proliferation; quiescence; single cell RNA-seq; stem cell
    DOI:  https://doi.org/10.1016/j.stem.2021.03.018
  12. Endocrinology. 2021 Apr 15. pii: bqab079. [Epub ahead of print]
    SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases.
    Caroline W S Hoong, Marvin W J Chua.
      SGLT2 inhibitors induce glycosuria, reduce insulin levels, promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF-1, and modulate the closely-linked HIF-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favour a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signalling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors such as PCG-1α, TFAM and NRF2 that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared to other calorie restriction mimetics such as metformin, rapamycin, resveratrol and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of ageing-related diseases, due to its regulation of multiple longevity pathways that closely resemble that achieved by calorie restriction, and their established efficacy in reduction in cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-ageing therapeutics.
    Keywords:  SGLT2 inhibitors; ageing; calorie restriction; cellular senescence; longevity
    DOI:  https://doi.org/10.1210/endocr/bqab079
  13. Clin Sci (Lond). 2021 Apr 16. 135(7): 991-1007
    Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure.
    Leanne Mooney, Carl S Goodyear, Tamir Chandra, Kristina Kirschner, Mhairi Copland, Mark C Petrie, Ninian N Lang.
      Ageing is a major risk factor for the development of cardiovascular disease (CVD) and cancer. Whilst the cumulative effect of exposure to conventional cardiovascular risk factors is important, recent evidence highlights clonal haematopoiesis of indeterminant potential (CHIP) as a further key risk factor. CHIP reflects the accumulation of somatic, potentially pro-leukaemic gene mutations within haematopoietic stem cells over time. The most common mutations associated with CHIP and CVD occur in genes that also play central roles in the regulation of inflammation. While CHIP carriers have a low risk of haematological malignant transformation (<1% per year), their relative risk of mortality is increased by 40% and this reflects an excess of cardiovascular events. Evidence linking CHIP, inflammation and atherosclerotic disease has recently become better defined. However, there is a paucity of information about the role of CHIP in the development and progression of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). While systemic inflammation plays a role in the pathophysiology of both heart failure with reduced and preserved ejection fraction (EF), it may be of greater relevance in the pathophysiology of HFpEF, which is also strongly associated with ageing. This review describes CHIP and its pathogenetic links with ageing, inflammation and CVD, while providing insight into its putative role in HFpEF.
    Keywords:  ageing; atherosclerosis; cardiovascular disease; clonal haematopoiesis of indeterminate potential; heart failure
    DOI:  https://doi.org/10.1042/CS20200306
  14. Sci Rep. 2021 Apr 12. 11(1): 7911
    Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome.
    Fahim Ebrahimi, Sandrine Andrea Urwyler, Matthias Johannes Betz, Emanuel Remigius Christ, Philipp Schuetz, Beat Mueller, Marc Yves Donath, Mirjam Christ-Crain.
      Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1β expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44-66), 26% were female and median BMI was 37 kg/m2 (IQR 34-39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by - 200 pg/mL (95%CI - 334 to - 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: - 8.8 pg/mL (95%CI - 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI - 236 to - 113; p < 0.001). Anti-inflammatory treatment with both, IL-1 antagonism and corticosteroids reduced FGF21 levels at short-term in individuals with the metabolic syndrome.Trial registration: ClinicalTrials.gov Identifiers NCT02672592 and NCT00757276.
    DOI:  https://doi.org/10.1038/s41598-021-87207-w
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