bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–02–07
twenty-one papers selected by
Ayesh Seneviratne, University of Toronto
  1. The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.
  2. Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration.
  3. Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat.
  4. Principles of the Molecular and Cellular Mechanisms of Aging.
  5. Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes.
  6. Fruit Intake to Prevent and Control Hypertension and Diabetes.
  7. Concurrent inhibition of IDH and methyltransferase maximizes therapeutic efficacy in IDH mutant acute myeloid leukemia.
  8. RXR Negatively Regulates Ex Vivo Expansion of Human Cord Blood Hematopoietic Stem and Progenitor Cells.
  9. Cardiovascular Outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.
  10. Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle.
  11. A new era for research into aging.
  12. Therapeutic Strategies for Targeting IL-1 in Cancer.
  13. Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease.
  14. Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells.
  15. The cancer metabolic reprogramming and immune response.
  16. Bcl-xL as a Modulator of Senescence and Aging.
  17. Connecting vascular aging and frailty in Alzheimer's Disease.
  18. Mitochondrial metabolism is a key regulator of the fibro-inflammatory and adipogenic stromal subpopulations in white adipose tissue.
  19. Regulation of Cell Polarity and Tissue Architecture in Epidermal Aging and Cancer.
  20. Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study.
  21. NIH's 'precision nutrition' bet aims for individualized diets.
  1. J Diabetes Metab Disord. 2020 Dec;19(2): 1731-1775
    The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.
    Lakshmipathi Vadlakonda, Meera Indracanti, Suresh K Kalangi, B Meher Gayatri, Navya G Naidu, Aramati B M Reddy.
       Purpose: Re-examine the current metabolic models.
    Methods: Review of literature and gene networks.
    Results: Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.
    Keywords:  CD98; Fatty acids; Glutamine; Leucine; Mitochondrial pyruvate carrier proteins (MPC1&2); Tissue turnover; mTORC1
    DOI:  https://doi.org/10.1007/s40200-020-00566-5
  2. Front Neurosci. 2020 ;14 618395
    Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration.
    Yulia Komleva, Anatoly Chernykh, Olga Lopatina, Yana Gorina, Irina Lokteva, Alla Salmina, Maik Gollasch.
      Over the past decades, the human life span has dramatically increased, and therefore, a steady increase in diseases associated with age (such as Alzheimer's disease and Parkinson's disease) is expected. In these neurodegenerative diseases, there is a cognitive decline and memory loss, which accompany increased systemic inflammation, the inflamm-aging, and the insulin resistance. Despite numerous studies of age-related pathologies, data on the contribution of brain insulin resistance and innate immunity components to aging are insufficient. Recently, much research has been focused on the consequences of nutrients and adiposity- and nutrient-related signals in brain aging and cognitive decline. Moreover, given the role of metainflammation in neurodegeneration, lifestyle interventions such as calorie restriction may be an effective way to break the vicious cycle of metainflammation and have a role in social behavior. The various effects of calorie restriction on metainflammation, insulin resistance, and neurodegeneration have been described. Less attention has been paid to the social determinants of aging and the possible mechanism by which calorie restriction might influence social behavior. The purpose of this review is to discuss current knowledge in the interdisciplinary field of geroscience-immunosenescence, inflamm-aging, and metainflammation-which makes a significant contribution to aging. A substantial part of the review is devoted to frontiers in the brain insulin resistance in relation to neuroinflammation. In addition, we summarize new data on potential mechanisms of calorie restriction that influence as a lifestyle intervention on the social brain. This knowledge can be used to initiate successful aging and slow the onset of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; aging; anti-inflammatory strategies; calorie restriction; inflammasome; inflammation; insulin resistance; metaflammasome
    DOI:  https://doi.org/10.3389/fnins.2020.618395
  3. Cancers (Basel). 2021 Jan 26. pii: 474. [Epub ahead of print]13(3):
    Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat.
    Yuki Matsushita, Hayato Nakagawa, Kazuhiko Koike.
      Lipids in our body, which are mainly composed of fatty acids, triacylglycerides, sphingolipids, phospholipids, and cholesterol, play important roles at the cellular level. In addition to being energy sources and structural components of biological membranes, several types of lipids serve as signaling molecules or secondary messengers. Metabolic reprogramming has been recognized as a hallmark of cancer, but changes in lipid metabolism in cancer have received less attention compared to glucose or glutamine metabolism. However, recent innovations in mass spectrometry- and chromatography-based lipidomics technologies have increased our understanding of the role of lipids in cancer. Changes in lipid metabolism, so-called "lipid metabolic reprogramming", can affect cellular functions including the cell cycle, proliferation, growth, and differentiation, leading to carcinogenesis. Moreover, interactions between cancer cells and adjacent immune cells through altered lipid metabolism are known to support tumor growth and progression. Characterization of cancer-specific lipid metabolism can be used to identify novel metabolic targets for cancer treatment, and indeed, several clinical trials are currently underway. Thus, we discuss the latest findings on the roles of lipid metabolism in cancer biology and introduce current advances in lipidomics technologies, focusing on their applications in cancer research.
    Keywords:  cholesterol metabolism; fatty acid metabolism; lipid droplet metabolism; lipidomics; mass spectrometry; metabolic reprogramming; phospholipid metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13030474
  4. J Invest Dermatol. 2021 Jan 28. pii: S0022-202X(20)32364-2. [Epub ahead of print]
    Principles of the Molecular and Cellular Mechanisms of Aging.
    Paulo F L da Silva, Björn Schumacher.
      Aging can be defined as a state of progressive functional decline accompanied by an increase in mortality. Time-dependent accumulation of cellular damage, namely lesions and mutations in the DNA and misfolded proteins, impair organellar and cellular function. Ensuing cell fate alterations lead to the accumulation of dysfunctional cells and hamper homeostatic processes, thus limiting regenerative potential; trigger low-grade inflammation; and alter intercellular and intertissue communication. The accumulation of molecular damage together with modifications in the epigenetic landscape, dysregulation of gene expression, and altered endocrine communication, drive the aging process and establish age as the main risk factor for age-associated diseases and multimorbidity.
    DOI:  https://doi.org/10.1016/j.jid.2020.11.018
  5. Int J Mol Sci. 2021 Jan 28. pii: 1280. [Epub ahead of print]22(3):
    Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes.
    Caterina Bernacchioni, Veronica Ghini, Roberta Squecco, Eglantina Idrizaj, Rachele Garella, Elisa Puliti, Francesca Cencetti, Paola Bruni, Chiara Donati.
      Skeletal muscle atrophy is characterized by a decrease in muscle mass causing reduced agility, increased fatigability and higher risk of bone fractures. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), are strong inducers of skeletal muscle atrophy. The bioactive sphingolipid sphingosine 1-phoshate (S1P) plays an important role in skeletal muscle biology. S1P, generated by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK1/2), exerts most of its actions through its specific receptors, S1P1-5. Here, we provide experimental evidence that TNFα induces atrophy and autophagy in skeletal muscle C2C12 myotubes, modulating the expression of specific markers and both active and passive membrane electrophysiological properties. NMR-metabolomics provided a clear picture of the deep remodelling of skeletal muscle fibre metabolism induced by TNFα challenge. The cytokine is responsible for the modulation of S1P signalling axis, upregulating mRNA levels of S1P2 and S1P3 and downregulating those of SK2. TNFα increases the phosphorylated form of SK1, readout of its activation. Interestingly, pharmacological inhibition of SK1 and specific antagonism of S1P3 prevented the increase in autophagy markers and the changes in the electrophysiological properties of C2C12 myotubes without affecting metabolic remodelling induced by the cytokine, highlighting the involvement of S1P signalling axis on TNFα-induced atrophy in skeletal muscle.
    Keywords:  NMR metabolomics; autophagy; electrophysiological properties; skeletal muscle atrophy; sphingosine 1-phosphate; sphingosine 1-phosphate receptors; tumor necrosis factor alpha
    DOI:  https://doi.org/10.3390/ijms22031280
  6. Korean J Fam Med. 2021 Jan;42(1): 9-16
    Fruit Intake to Prevent and Control Hypertension and Diabetes.
    Hyun Ah Park.
      Fruits are considered healthy because of their high antioxidant, vitamin, mineral, fiber, and phytochemical contents. However, their high sugar content is a concern for glucose, lipid, and uric acid metabolism. We reviewed related articles published in the last 10 years and summarized evidence that relates fruit intake to the prevention and control of hypertension and diabetes mellitus. Clinicians should familiarize themselves with appropriate fruit intake to counsel at-risk patients on hypertension and diabetes.
    Keywords:  Blood Glucose; Blood Pressure; Diabetes Mellitus; Fruit; Hypertension
    DOI:  https://doi.org/10.4082/kjfm.20.0225
  7. Haematologica. 2021 Feb 01. 106(2): 324-326
    Concurrent inhibition of IDH and methyltransferase maximizes therapeutic efficacy in IDH mutant acute myeloid leukemia.
    Zhihong Zeng, Marina Konopleva.
      
    DOI:  https://doi.org/10.3324/haematol.2020.266809
  8. Stem Cell Rev Rep. 2021 Feb 01.
    RXR Negatively Regulates Ex Vivo Expansion of Human Cord Blood Hematopoietic Stem and Progenitor Cells.
    Yuting Jin, Jie Huang, Qin Wang, Jiefeng He, Yincheng Teng, Rongzhen Jiang, Hal E Broxmeyer, Bin Guo.
      Ex vivo expansion of human cord blood (CB) hematopoietic stem cells (HSCs) is one approach to overcome limited numbers of HSCs in single CB units. However, there is still no worldwide acceptable HSC ex vivo expansion system. A main reason is that we still have very limited knowldege regarding mechanisms underlying maintenance and expansion of CB HSCs. Here we report that retinoid X receptor (RXR) activity is of significance for CB HSC ex vivo expansion. RXR antagonist HX531 significantly promoted ex vivo expansion of CB HSCs and progenitor cells (HPCs). RXR agonist Bexarotene notably suppressed ex vivo expansion of CB HSCs. Activation of RXR by Bexarotene significantly blocked expansion of phenotypic HSCs and HPCs and expressed increased functional HPCs as assessed by colony formation induced by UM171 and SR1. In vivo transplantation experiments in immune-deficient mice demonstrated that HX531 expanded CB HSCs possess long-term reconstituting capacities, and Bexarotene treatment inhibited expansion of functional CB HSCs. RNA-seq analysis revealed that RXR regulates expression of FBP1 (a negative regulator of glucose metabolism) and many genes involved in differentation. ECAR analysis showed that HX531 significantly promoted glycolytic activity of CB CD34+ HSCs and HPCs. Our studies suggest that RXR is a negative regulator of ex vivo expansion of CB HSCs and HPCs.
    Keywords:  Cord blood; Ex vivo expansion; Hematopoietic stem and progenitor cells; Retinoid X receptor
    DOI:  https://doi.org/10.1007/s12015-021-10124-y
  9. Diabetes Metab Syndr. 2021 Jan 20. pii: S1871-4021(21)00008-4. [Epub ahead of print]15(1): 351-359
    Cardiovascular Outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.
    Awadhesh Kumar Singh, Ritu Singh.
       BACKGROUND AND AIMS: We conducted a systematic review and meta-analysis of all the randomized controlled trials (RCTs) with SGLT-2 inhibitors (SGLT-2i) in patients with known heart failure (HF) with or without type 2 diabetes (T2DM), that have studied the outcomes of cardiovascular (CV) death, hospitalization due to HF (HHF), and composite of CV death or HHF.
    METHODS: A systematic search in PubMed, Embase and Cochrane Library database were made up till November 20, 2020 using specific keywords. RCTs that qualified underwent a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio (HR) using both random- and fixed-effects model.
    RESULTS: This meta-analysis of 9 RCTs (N = 19,741) have found a significant 26% relative risk reduction in composite of CV death or HHF (HR 0.74; 95% CI, 0.69-0.79; p < 0.001) with SGLT-2i in patients with HF. The meta-analysis of 8 RCTs (N = 16,460) also showed a significant reduction in CV death (HR 0.86; 95% CI, 0.78-0.95; p = 0.003) and HHF (HR 0.68; 95% CI, 0.62-0.74; p < 0.001) outcomes with SGLT-2i in patients with HF. Subgroup analysis stratified on baseline ejection fraction (EF) showed a similar benefit in the composite of CV death or HHF in patients with HF with reduced EF (HFrEF) or preserved EF (HFpEF).
    CONCLUSIONS: SGLT-2i significantly reduces the composite of CV death or HHF, CV death, and HHF in patients with HF. Although subgroup analysis suggested an insignificant Pheterogenity for these outcomes irrespective of the types of HF, however, reduction in both CV death and HHF were more pronounced in patients with HFrEF.
    Keywords:  Cardiovascular death; Heart failure hospitalization; Meta-analysis; SGLT-2 inhibitors; Systematic review; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.dsx.2021.01.006
  10. Sci Adv. 2021 01;pii: eabd6322. [Epub ahead of print]7(1):
    Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle.
    Alexandre Prola, Jordan Blondelle, Aymeline Vandestienne, Jérôme Piquereau, Raphaël G P Denis, Stéphane Guyot, Hadrien Chauvin, Arnaud Mourier, Marie Maurer, Céline Henry, Nahed Khadhraoui, Cindy Gallerne, Thibaut Molinié, Guillaume Courtin, Laurent Guillaud, Mélanie Gressette, Audrey Solgadi, Florent Dumont, Julien Castel, Julien Ternacle, Jean Demarquoy, Alexandra Malgoyre, Nathalie Koulmann, Geneviève Derumeaux, Marie-France Giraud, Frédéric Joubert, Vladimir Veksler, Serge Luquet, Frédéric Relaix, Laurent Tiret, Fanny Pilot-Storck.
      Unbalanced energy partitioning participates in the rise of obesity, a major public health concern in many countries. Increasing basal energy expenditure has been proposed as a strategy to fight obesity yet raises efficiency and safety concerns. Here, we show that mice deficient for a muscle-specific enzyme of very-long-chain fatty acid synthesis display increased basal energy expenditure and protection against high-fat diet-induced obesity. Mechanistically, muscle-specific modulation of the very-long-chain fatty acid pathway was associated with a reduced content of the inner mitochondrial membrane phospholipid cardiolipin and a blunted coupling efficiency between the respiratory chain and adenosine 5'-triphosphate (ATP) synthase, which was restored by cardiolipin enrichment. Our study reveals that selective increase of lipid oxidative capacities in skeletal muscle, through the cardiolipin-dependent lowering of mitochondrial ATP production, provides an effective option against obesity at the whole-body level.
    DOI:  https://doi.org/10.1126/sciadv.abd6322
  11. Elife. 2021 Jan 28. pii: e65286. [Epub ahead of print]10
    A new era for research into aging.
    Matt Kaeberlein, Jessica K Tyler.
      eLife is publishing a special issue on aging, geroscience and longevity to mark the rapid progress made in this field over the past decade, both in terms of mechanistic understanding and translational approaches that are poised to have clinical impact on age-related diseases.
    Keywords:  aging; cell biology; geroscience; longevity; medicine
    DOI:  https://doi.org/10.7554/eLife.65286
  12. Cancers (Basel). 2021 Jan 26. pii: 477. [Epub ahead of print]13(3):
    Therapeutic Strategies for Targeting IL-1 in Cancer.
    Adrian Gottschlich, Stefan Endres, Sebastian Kobold.
      Since its discovery, interleukin-1 has been extensively studied in a wide range of medical fields. Besides carrying out vital physiological functions, it has been implicated with a pivotal role in the progression and spreading of different cancer entities. During the last years, several clinical trials have been conducted, shedding light on the role of IL-1 blocking agents for the treatment of cancer. Additionally, recent developments in the field of immuno-oncology have implicated IL-1-induced signaling cascades as a major driver of severe chimeric antigen receptor T cell-associated toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity. In this review, we summarize current clinical trials investigating the role of IL-1 blockade in cancer treatment and elaborate the proposed mechanism of these innovative treatment approaches. Additionally, we highlight cutting-edge developments utilizing IL-1 blocking agents to enhance the safety and efficacy of adoptive T cell therapy.
    Keywords:  CAR; IL-1-blockade; adoptive T cell therapy; cancer; chimeric antigen receptor T cells; clinical trials; immunotherapy
    DOI:  https://doi.org/10.3390/cancers13030477
  13. Blood. 2021 Feb 02. pii: blood.2020008720. [Epub ahead of print]
    Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease.
    Yun Zhang, Lichong Shen, Katja Dreissigacker, Honglin Zhu, Thuong Trinh-Minh, Xianyi Meng, Cuong Tran-Manh, Clara Dees, Alexandru-Emil Matei, Chih-Wei Chen, Markus Ditschkowski, Stefan Krauss, Julia Winkler, Daniel Wolff, Mirjana Ziemer, Andreas Beilhack, Sigrid Karrer, Wolfgang Herr, Andreas Mackensen, Georg Schett, Bernd Michael Spriewald, Jörg H W Distler.
      Chronic graft-versus-host disease (cGvHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGvHD remain poorly understood and targeted therapies are not well established for clinical use. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGvHD (sclGvHD). WNT signaling was activated in human sclGvHD with increased nuclear accumulation of the transcription factor β-catenin and WNT-biased gene expression signature in lesional skin. Treatment with highly selective tankryase inhibitor G007-LK, CK1α agonist pyrvinium or LRP6 inhibitor salinomycin, abrogated the activation of WNT signaling and protected against experimental cGvHD, without significant impact on graft-versus-leukemia effect (GvL). Treatment with G007-LK, pyrvinium or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d)→BALB/c (H-2d) and in the LP/J (H-2b)→C57BL/6 (H-2b) model of sclGvHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect, inflammation-dependent effects in sclGvHD. Our findings may have direct translational potential, as pyrvinium is in clinical use and tankyrase inhibitors are in clinical trials for other implications.
    DOI:  https://doi.org/10.1182/blood.2020008720
  14. Aging Cell. 2021 Feb 01. e13316
    Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells.
    Dingxi Zhou, Mariana Borsa, Anna Katharina Simon.
      The ageing of the global population brings about unprecedented challenges. Chronic age-related diseases in an increasing number of people represent an enormous burden for health and social care. The immune system deteriorates during ageing and contributes to many of these age-associated diseases due to its pivotal role in pathogen clearance, tissue homeostasis and maintenance. Moreover, in order to develop treatments for COVID-19, we urgently need to acquire more knowledge about the aged immune system, as older adults are disproportionally and more severely affected. Changes with age lead to impaired responses to infections, malignancies and vaccination, and are accompanied by chronic, low-degree inflammation, which together is termed immunosenescence. However, the molecular and cellular mechanisms that underlie immunosenescence, termed immune cell senescence, are mostly unknown. Cellular senescence, characterised by an irreversible cell cycle arrest, is thought to be the cause of tissue and organismal ageing. Thus, better understanding of cellular senescence in immune populations at single-cell level may provide us with insight into how immune cell senescence develops over the life time of an individual. In this review, we will briefly introduce the phenotypic characterisation of aged innate and adaptive immune cells, which also contributes to overall immunosenescence, including subsets and function. Next, we will focus on the different hallmarks of cellular senescence and cellular ageing, and the detection techniques most suitable for immune cells. Applying these techniques will deepen our understanding of immune cell senescence and to discover potential druggable pathways, which can be modulated to reverse immune ageing.
    Keywords:  ageing markers; immunosenescence; methods
    DOI:  https://doi.org/10.1111/acel.13316
  15. Mol Cancer. 2021 Feb 05. 20(1): 28
    The cancer metabolic reprogramming and immune response.
    Longzheng Xia, Linda Oyang, Jinguan Lin, Shiming Tan, Yaqian Han, Nayiyuan Wu, Pin Yi, Lu Tang, Qing Pan, Shan Rao, Jiaxin Liang, Yanyan Tang, Min Su, Xia Luo, Yiqing Yang, Yingrui Shi, Hui Wang, Yujuan Zhou, Qianjin Liao.
      The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.
    Keywords:  Immune checkpoint…; Immunity; Metabolic reprogramming; Oxysterols; TIL; TME
    DOI:  https://doi.org/10.1186/s12943-021-01316-8
  16. Int J Mol Sci. 2021 Feb 03. pii: 1527. [Epub ahead of print]22(4):
    Bcl-xL as a Modulator of Senescence and Aging.
    Cristina Mas-Bargues, Consuelo Borrás, Jose Viña.
      Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.
    Keywords:  Bcl-xL; aging; apoptosis; centenarians; immunosenescence; senescence; senolytics
    DOI:  https://doi.org/10.3390/ijms22041527
  17. Mech Ageing Dev. 2021 Feb 01. pii: S0047-6374(21)00016-6. [Epub ahead of print] 111444
    Connecting vascular aging and frailty in Alzheimer's Disease.
    Jacopo Sabbatinelli, Deborah Ramini, Angelica Giuliani, Rina Recchioni, Liana Spazzafumo, Fabiola Olivieri.
      Aging plays an important role in the etiology of the most common age-related diseases (ARDs), including Alzheimer's disease (AD). The increasing number of AD patients and the lack of disease-modifying drugs warranted intensive research to tackle the pathophysiological mechanisms underpinning AD development. Vascular aging/dysfunction is a common feature of almost all ARDs, including cardiovascular (CV) diseases, diabetes and AD. To this regard, interventions aimed at modifying CV outcomes are under extensive investigation for their pleiotropic role in ameliorating and slowing down cognitive impairment in middle-life and elderly individuals. Evidence from observational and clinical studies confirm the notion that the earlier the interventions are conducted, the most favorable are the effects on cognitive function. Therefore, epidemiological research should focus on the early detection of deviations from a healthy cognitive aging trajectory, through the stratification of adult individuals according to the rate of aging. Here, we review the interplay between vascular and cognitive dysfunctions associated with aging, to disentangle the complex mechanisms underpinning the development and progression of neurodegenerative disorders, with a specific focus on AD.
    Keywords:  Alzheimer’s disease; cardiovascular diseases; endothelial dysfunction; frailty; vascular aging
    DOI:  https://doi.org/10.1016/j.mad.2021.111444
  18. Cell Stem Cell. 2021 Feb 01. pii: S1934-5909(21)00002-3. [Epub ahead of print]
    Mitochondrial metabolism is a key regulator of the fibro-inflammatory and adipogenic stromal subpopulations in white adipose tissue.
    Nolwenn Joffin, Vivian A Paschoal, Christy M Gliniak, Clair Crewe, Abdallah Elnwasany, Luke I Szweda, Qianbin Zhang, Chelsea Hepler, Christine M Kusminski, Ruth Gordillo, Da Young Oh, Rana K Gupta, Philipp E Scherer.
      The adipose tissue stroma is a rich source of molecularly distinct stem and progenitor cell populations with diverse functions in metabolic regulation, adipogenesis, and inflammation. The ontology of these populations and the mechanisms that govern their behaviors in response to stimuli, such as overfeeding, however, are unclear. Here, we show that the developmental fates and functional properties of adipose platelet-derived growth factor receptor beta (PDGFRβ)+ progenitor subpopulations are tightly regulated by mitochondrial metabolism. Reducing the mitochondrial β-oxidative capacity of PDGFRβ+ cells via inducible expression of MitoNEET drives a pro-inflammatory phenotype in adipose progenitors and alters lineage commitment. Furthermore, disrupting mitochondrial function in PDGFRβ+ cells rapidly induces alterations in immune cell composition in lean mice and impacts expansion of adipose tissue in diet-induced obesity. The adverse effects on adipose tissue remodeling can be reversed by restoring mitochondrial activity in progenitors, suggesting therapeutic potential for targeting energy metabolism in these cells.
    Keywords:  adipocyte; adipogenesis; inflammation; metabolism; mitochondria; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2021.01.002
  19. J Invest Dermatol. 2021 Jan 30. pii: S0022-202X(20)32410-6. [Epub ahead of print]
    Regulation of Cell Polarity and Tissue Architecture in Epidermal Aging and Cancer.
    Oana D Persa, Janis Koester, Carien M Niessen.
      The mammalian skin is essential to protect the organism from external damage while at the same time enabling communication with the environment. Aging compromises skin function and regeneration, which is further exacerbated by external influences, such as UVR from the sun. Aging and UVR are also major risk factors contributing to the development of skin cancer. Whereas aging research traditionally has focused on the role of DNA damage and metabolic and stress pathways, less is known about how aging affects tissue architecture and cell dynamics in skin homeostasis and regeneration and whether changes in these processes promote skin cancer. This review highlights how key regulators of cell polarity and adhesion affect epidermal mechanics, tissue architecture, and stem cell dynamics in skin aging and cancer.
    DOI:  https://doi.org/10.1016/j.jid.2020.12.012
  20. Age Ageing. 2021 Feb 05. pii: afab026. [Epub ahead of print]
    Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study.
    Geriatric Medicine Research Collaborative
       INTRODUCTION: Increased mortality has been demonstrated in older adults with COVID-19, but the effect of frailty has been unclear.
    METHODS: This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty, and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation, and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS), and delirium on risk of increased care requirements on discharge, adjusting for the same variables.
    RESULTS: Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, IQR 54-83; 55.2% male). The risk of death increased independently with increasing age (>80 vs 18-49: HR 3.57, CI 2.54-5.02), frailty (CFS 8 vs 1-3: HR 3.03, CI 2.29-4.00) inflammation, renal disease, cardiovascular disease, and cancer, but not delirium. Age, frailty (CFS 7 vs 1-3: OR 7.00, CI 5.27-9.32), delirium, dementia, and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9.
    CONCLUSIONS: Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.
    Keywords:  covid-19; delirium; frailty; mortality; transitions of care
    DOI:  https://doi.org/10.1093/ageing/afab026
  21. Science. 2021 Feb 05. 371(6529): 552
    NIH's 'precision nutrition' bet aims for individualized diets.
    Jocelyn Kaiser.
      
    DOI:  https://doi.org/10.1126/science.371.6529.552
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