bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒01‒31
38 papers selected by
Ayesh Seneviratne
University of Toronto

  1. Free Radic Biol Med. 2021 Jan 21. pii: S0891-5849(21)00051-4. [Epub ahead of print]
    Mohrin M.
      Hematopoietic stem cells (HSCs) are responsible for life-long production of blood and immune cells. HSC transplantation (HSCT) is the original cell therapy which can cure hematological disorders but also has the potential to treat other diseases if technical and safety barriers are overcome. To maintain homeostatic hematopoiesis or to restore hematopoiesis during transplantation HSCs must perform both self-renewal, replication of themselves, and differentiation, generation of mature blood and immune cells. These are just two of the cell fate choices HSCs have; the transitional phases where HSCs undergo these cell fate decisions are regulated by reduction-oxidation (redox) signaling, mitochondrial activity, and cellular metabolism. Recent studies revealed that mitochondria, a key source of redox signaling components, are central to HSC cell fate decisions. Here we highlight how mitochondria serve as hubs in HSCs to manage redox signaling and metabolism and thus guide HSC fate choices. We focus on how mitochondrial activity is modulated by their clearance, biogenesis, dynamics, distribution, and quality control in HSCs. We also note how modulating mitochondria in HSCs can help overcome technical barriers limiting further use of HSCT.
    Keywords:  Aging; Hematopoietic Stem Cells (HSCs); mitochondrial quality control; rejuvenation; transplantation
  2. Cell Signal. 2021 Jan 22. pii: S0898-6568(21)00017-6. [Epub ahead of print]80 109929
    D'Aprile C, Prioni S, Mauri L, Prinetti A, Grassi S.
      Spontaneous segregation of cholesterol and sphingolipids as a liquid-ordered phase leads to their clustering in selected membrane areas, the lipid rafts. These specialized membrane domains enriched in gangliosides, sphingomyelin, cholesterol and selected proteins involved in signal transduction, organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating cell homeostasis. Sphingosine 1-phosphate, an important biologically active mediator, is involved in several signal transduction processes regulating a plethora of cell functions and, not only several of its downstream effectors tend to localize in lipid rafts, some of the enzymes involved in its pathway, of receptors involved in its signalling and its transporters have been often found in these membrane microdomains. Considering this, in this review we address what is currently known regarding the relationship between sphingosine 1-phosphate metabolism and signalling and plasma membrane lipid rafts.
    Keywords:  Lipid rafts; S1P lyase; S1P phosphatases; Sphingosine 1-phosphate; Sphingosine 1-phosphate receptors; Sphingosine kinase
  3. Nat Commun. 2021 01 27. 12(1): 614
    Lita A, Pliss A, Kuzmin A, Yamasaki T, Zhang L, Dowdy T, Burks C, de Val N, Celiku O, Ruiz-Rodado V, Nicoli ER, Kruhlak M, Andresson T, Das S, Yang C, Schmitt R, Herold-Mende C, Gilbert MR, Prasad PN, Larion M.
      Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.
  4. JCI Insight. 2021 Jan 25. pii: 136083. [Epub ahead of print]6(2):
    Willmes DM, Daniels M, Kurzbach A, Lieske S, Bechmann N, Schumann T, Henke C, El-Agroudy NN, Da Costa Goncalves AC, Peitzsch M, Hofmann A, Kanczkowski W, Kräker K, Müller DN, Morawietz H, Deussen A, Wagner M, El-Armouche A, Helfand SL, Bornstein SR, de Cabo R, Bernier M, Eisenhofer G, Tank J, Jordan J, Birkenfeld AL.
      Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.
    Keywords:  Cardiovascular disease; Metabolism; Vascular Biology
  5. Mol Metab. 2021 Jan 20. pii: S2212-8778(21)00009-0. [Epub ahead of print] 101169
    Lemmer IL, Willemsen N, Hilal N, Bartelt A.
      BACKGROUND: The global rise of metabolic disorders, such as obesity, diabetes type 2 and cardiovascular disease, demands a thorough molecular understanding of the cellular mechanisms that govern health or disease. The endoplasmic reticulum (ER) is a key organelle for cellular function and metabolic adaptation and, therefore, disturbed ER function, "ER stress", is a key feature of metabolic disorders.SCOPE OF REVIEW: As ER stress remains an ill-defined phenomenon, this review provides a general guide to understanding the nature, aetiology and consequences of ER stress in metabolic disorders. We define ER stress by its type of stressor, which is driven by proteotoxicity, lipotoxicity, and/or glucotoxicity. We discuss the implications of ER stress in metabolic disorders by reviewing evidence implicating ER phenotypes and organelle communication, protein quality control, calcium homeostasis, lipid and carbohydrate metabolism, and inflammation as key mechanisms in the development of ER stress and metabolic dysfunction.
    MAJOR CONCLUSIONS: In mammalian biology, ER is a phenotypically and functionally diverse platform for nutrient sensing, which is critical for cell-type specific metabolic control by e.g. hepatocytes, adipocytes, muscle cells, and neurons. In these cells, ER stress is a distinct, transient state of functional imbalance, which is usually resolved by the activation of adaptive programs such as the unfolded protein response (UPR), ER-associated protein degradation (ERAD), or autophagy. However, challenges to proteostasis also impact lipid and glucose metabolism and vice versa. In the ER, both sensing and adaptive measures are integrated and failure of the ER to adapt leads to aberrant metabolism, organelle dysfunction, insulin resistance, and inflammation. In conclusion, the ER is intricately linked to a wide spectrum of cellular functions and is a critical component in maintaining and restoring metabolic health.
    Keywords:  ERAD; NFE2L1; Obesity; UPR; UPS; autophagy; calcium homeostasis; diabetes; endoplasmic reticulum; glucotoxicity; inflammation; lipid metabolism; lipotoxicity; proteostasis; proteotoxicity
  6. Aging Cell. 2021 Jan 28. e13312
    Tobin SW, Alibhai FJ, Wlodarek L, Yeganeh A, Millar S, Wu J, Li SH, Weisel RD, Li RK.
      Recruited immune cells play a critical role in muscle repair, in part by interacting with local stem cell populations to regulate muscle regeneration. How aging affects their communication during myogenesis is unclear. Here, we investigate how aging impacts the cellular function of these two cell types after muscle injury during normal aging or after immune rejuvenation using a young to old (Y-O) or old to old (O-O) bone marrow (BM) transplant model. We found that skeletal muscle from old mice (20 months) exhibited elevated basal inflammation and possessed fewer satellite cells compared with young mice (3 months). After cardiotoxin muscle injury (CTX), old mice exhibited a blunted inflammatory response compared with young mice and enhanced M2 macrophage recruitment and IL-10 expression. Temporal immune and cytokine responses of old mice were partially restored to a young phenotype following reconstitution with young cells (Y-O chimeras). Improved immune responses in Y-O chimeras were associated with greater satellite cell proliferation compared with O-O chimeras. To identify how immune cell aging affects myoblast function, conditioned media (CM) from activated young or old macrophages was applied to cultured C2C12 myoblasts. CM from young macrophages inhibited myogenesis while CM from old macrophages reduced proliferation. These functional differences coincided with age-related differences in macrophage cytokine expression. Together, this study examines the infiltration and proliferation of immune cells and satellite cells after injury in the context of aging and, using BM chimeras, demonstrates that young immune cells retain cell autonomy in an old host to increase satellite cell proliferation.
    Keywords:  aging; bone marrow transplant; inflammation; myogenesis; satellite cells
  7. Nat Commun. 2021 01 27. 12(1): 608
    Renders S, Svendsen AF, Panten J, Rama N, Maryanovich M, Sommerkamp P, Ladel L, Redavid AR, Gibert B, Lazare S, Ducarouge B, Schönberger K, Narr A, Tourbez M, Dethmers-Ausema B, Zwart E, Hotz-Wagenblatt A, Zhang D, Korn C, Zeisberger P, Przybylla A, Sohn M, Mendez-Ferrer S, Heikenwälder M, Brune M, Klimmeck D, Bystrykh L, Frenette PS, Mehlen P, de Haan G, Cabezas-Wallscheid N, Trumpp A.
      Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential associated to dormancy. Here we identify the cell surface receptor neogenin-1 as specifically expressed in dormant HSCs. Loss of neogenin-1 initially leads to increased HSC expansion but subsequently to loss of self-renewal and premature exhaustion in vivo. Its ligand netrin-1 induces Egr1 expression and maintains quiescence and function of cultured HSCs in a Neo1 dependent manner. Produced by arteriolar endothelial and periarteriolar stromal cells, conditional netrin-1 deletion in the bone marrow niche reduces HSC numbers, quiescence and self-renewal, while overexpression increases quiescence in vivo. Ageing associated bone marrow remodelling leads to the decline of netrin-1 expression in niches and a compensatory but reversible upregulation of neogenin-1 on HSCs. Our study suggests that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1 function. Decline of netrin-1 production during ageing leads to the gradual decrease of Neo1 mediated HSC self-renewal.
  8. J Clin Invest. 2021 Jan 25. pii: 144734. [Epub ahead of print]
    Falck-Jones S, Vangeti S, Yu M, Falck-Jones R, Cagigi A, Badolati I, Österberg B, Lautenbach MJ, Ahlberg E, Lin A, Lepzien R, Szurgot I, Lenart K, Hellgren F, Maecker HT, Sälde J, Albert J, Johansson N, Bell M, Lore K, Färnert A, Smed-Sörensen A.
      The immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFNg production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.
    Keywords:  COVID-19; Immunology; Innate immunity
  9. Clin Chim Acta. 2021 Jan 21. pii: S0009-8981(21)00021-8. [Epub ahead of print]
    Lin Q, Zuo W, Liu Y, Wu K, Liu Q.
      Nicotinamide adenine dinucleotide (NAD) plays pivotal roles in controlling many biochemical processes. 'NAD' refers to the chemical backbone irrespective of charge, whereas 'NAD+' and 'NADH' refers to oxidized and reduced forms, respectively. NAD+/NADH ratio is essential for maintaining cellular reduction-oxidation (redox) homeostasis and for modulating energy metabolism. As a sensing or consuming enzyme of the poly (ADP-ribose) polymerase 1 (PARP1), the cyclic ADP-ribose (cADPR) synthases (CD38 and CD157), and sirtuin protein deacetylases (sirtuins, SIRTs), NAD+ participates in several key processes in cardiovascular disease. For example, NAD+ protects against metabolic syndrome, heart failure, ischemia-reperfusion (IR) injury, arrhythmia and hypertension. Accordingly, the subsequent loss of NAD+ in aging or during stress results in altered metabolic status and potentially increased disease susceptibility. Therefore, it is essential to maintain NAD+ or reduce loss in the heart. This review focuses on the involvement of NAD+ in the pathogenesis of cardiovascular disease and explores the effects of NAD+ boosting strategies in cardiovascular health.
    Keywords:  NAD(+); NADH; SIRTs; biological processes; cardiovascular disease
  10. Biogerontology. 2021 Jan 27.
    Li Z, Zhang Z, Ren Y, Wang Y, Fang J, Yue H, Ma S, Guan F.
      Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.
    Keywords:  Age‐related diseases; Aging; Anti‐aging drugs; Hallmarks of aging
  11. Trends Mol Med. 2021 Jan 23. pii: S1471-4914(21)00001-0. [Epub ahead of print]
    Lothstein KE, Gause WC.
      Helminths are an emerging source of therapeutics for dysregulated inflammatory diseases. Excretory/secretory (ES) molecules, released during infection, are responsible for many of these immunomodulatory effects and are likely to have evolved as a means for parasite survival in the host. While the mechanisms of action of these molecules have not been fully defined, evidence demonstrates that they target various pathways in the immune response, ranging from initiation to effector cell modulation. These molecules are applied in controlling specific effector mechanisms of type 1 and type 2 immune responses. Recently, studies have further focused on their therapeutic potential in specific disease models. Here we review recent findings on ES molecule modulation of immune functions, specifically highlighting their clinical implications for future use in inflammatory disease therapeutics.
    Keywords:  Tregs; excretory/secretory; helminths; inflammatory diseases; therapeutics; type 2 immune response
  12. Pharmaceuticals (Basel). 2021 Jan 27. pii: 93. [Epub ahead of print]14(2):
    Kittimongkolsuk P, Roxo M, Li H, Chuchawankul S, Wink M, Tencomnao T.
      The tiger milk mushroom, Lignosus rhinocerus (LR), exhibits antioxidant properties, as shown in a few in vitro experiments. The aim of this research was to study whether three LR extracts exhibit antioxidant activities in Caenorhabditis elegans. In wild-type N2 nematodes, we determined the survival rate under oxidative stress caused by increased intracellular ROS concentrations. Transgenic strains, including TJ356, TJ375, CF1553, CL2166, and LD1, were used to detect the expression of DAF-16, HSP-16.2, SOD-3, GST-4, and SKN-1, respectively. Lifespan, lipofuscin, and pharyngeal pumping rates were assessed. Three LR extracts (ethanol, and cold and hot water) protected the worms from oxidative stress and decreased intracellular ROS. The extracts exhibited antioxidant properties through the DAF-16/FOXO pathway, leading to SOD-3 and HSP-16.2 modification. However, the expression of SKN-1 and GST-4 was not changed. All the extracts extended the lifespan. They also reduced lipofuscin (a marker for aging) and influenced the pharyngeal pumping rate (another marker for aging). The extracts did not cause dietary restriction. This novel study provides evidence of the functional antioxidant and anti-aging properties of LR. Further studies must confirm that they are suitable for use as antioxidant supplements.
    Keywords:  Caenorhabditis elegans; DAF-16; Lignosus rhinocerus; aging; antioxidants; tiger milk mushroom
  13. Trends Mol Med. 2021 Feb;pii: S1471-4914(20)30334-8. [Epub ahead of print]27(2): 93-96
  14. Pharmaceutics. 2021 Jan 20. pii: E129. [Epub ahead of print]13(2):
    Kopustinskiene DM, Bernatoniene J.
      Melatonin, an endogenously synthesized indolamine, is a powerful antioxidant exerting beneficial action in many pathological conditions. Melatonin protects from oxidative stress in ischemic/reperfusion injury, neurodegenerative diseases, and aging, decreases inflammation, modulates the immune system, inhibits proliferation, counteracts the Warburg effect, and promotes apoptosis in various cancer models. Melatonin stimulates antioxidant enzymes in the cells, protects mitochondrial membrane phospholipids, especially cardiolipin, from oxidation thus preserving integrity of the membranes, affects mitochondrial membrane potential, stimulates activity of respiratory chain enzymes, and decreases the opening of mitochondrial permeability transition pore and cytochrome c release. This review will focus on the molecular mechanisms of melatonin effects in the cells during normal and pathological conditions and possible melatonin clinical applications.
    Keywords:  antioxidant; cardiolipin; cardioprotection; melatonin; mitochondria; neuroprotection; tumor suppression
  15. Aging (Albany NY). 2021 Jan 20. 12
    Huang S, You S, Qian J, Dai C, Shen S, Wang J, Huang W, Liang G, Wu G.
      Vascular remodeling is a pertinent target for cardiovascular therapy. Vascular smooth muscle cell (VSMC) dysfunction plays a key role in vascular remodeling. Myeloid differentiation 2 (MD2), a cofactor of toll-like receptor 4 (TLR4), is involved in atherosclerotic progress and cardiac remodeling via activation of chronic inflammation. In this study, we explored the role of MD2 in vascular remodeling using an Ang II-induced mouse model and cultured human aortic VSMCs. MD2 deficiency suppressed Ang II-induced vascular fibrosis and phenotypic switching of VSMCs without affecting blood pressure in mice. Mechanistically, MD2 deficiency prevented Ang II-induced expression of inflammatory cytokines and oxidative stress in mice and cultured VSMCs. Furthermore, MD2 deficiency reversed Ang II-activated MAPK signaling and Ang II-downregulated SIRT1 expression. Taken together, MD2 plays a significant role in Ang II-induced vascular oxidative stress, inflammation, and remodeling, indicating that MD2 is a potential therapeutic target for the treatment of vascular remodeling-related cardiovascular diseases.
    Keywords:  MD2; VSMCs; inflammation; oxidative stress; vascular remodeling
  16. Trends Cancer. 2021 Jan 25. pii: S2405-8033(20)30341-1. [Epub ahead of print]
    Ferguson LP, Diaz E, Reya T.
      Despite gains in knowledge of the intrinsic signals governing cancer progression, effective clinical management of cancer remains a challenge. Drug resistance and relapse, pose the greatest barriers to cancer care, and are often driven by the co-option of stem cell programs by subpopulations of aggressive cancer cells. Here, we focus on the role of the microenvironment in the acquisition and/or maintenance of stem cell states in cancer in the context of resistance and metastasis. We further discuss the role of cancer stem cells in immune evasion through the course of metastasis, dormancy, and relapse. Understanding the niche in which cancer stem cells live and the signals that sustain them may lead to new strategies that target them by disrupting microenvironmental support.
    Keywords:  Cancer; Metastasis; Stem cell; Therapy resistance; Tumor microenvironment
  17. Nat Commun. 2021 Jan 29. 12(1): 692
    Relaix F, Bencze M, Borok MJ, Der Vartanian A, Gattazzo F, Mademtzoglou D, Perez-Diaz S, Prola A, Reyes-Fernandez PC, Rotini A, Taglietti .
      Skeletal muscle has remarkable regeneration capabilities, mainly due to its resident muscle stem cells (MuSCs). In this review, we introduce recently developed technologies and the mechanistic insights they provide to the understanding of MuSC biology, including the re-definition of quiescence and Galert states. Additionally, we present recent studies that link MuSC function with cellular heterogeneity, highlighting the complex regulation of self-renewal in regeneration, muscle disorders and aging. Finally, we discuss MuSC metabolism and its role, as well as the multifaceted regulation of MuSCs by their niche. The presented conceptual advances in the MuSC field impact on our general understanding of stem cells and their therapeutic use in regenerative medicine.
  18. Clin Nutr ESPEN. 2021 Feb;pii: S2405-4577(20)31092-5. [Epub ahead of print]41 13-22
    Hey P, Gow P, Testro AG, Apostolov R, Chapman B, Sinclair M.
      BACKGROUND AND AIMS: Sarcopenia, defined as loss of muscle mass, strength and function, is associated with adverse clinical outcomes in patients with cirrhosis. Despite improved understanding of the multifaceted pathogenesis, there are few established therapies to treat or prevent muscle loss in this population. This narrative review examines the available literature investigating the role of nutraceuticals for the prevention or treatment of muscle wasting in chronic liver disease.METHODS: A comprehensive search or Medline and PubMED databases was conducted. Reference lists were screened to identify additional articles.
    RESULTS: A number of nutritional supplements and vitamins target the specific metabolic derangements that contribute to sarcopenia in cirrhosis including altered amino acid metabolism, hyperammonaemia and inflammation. Branched chain amino acid (BCAA) supplementation has proposed anabolic effects through dual pathways of enhanced ammonia clearance and stimulation of muscle protein synthesis. l-carnitine also has multimodal effects on muscle and shows promise as a therapy for muscle loss through anti-inflammatory, antioxidant and ammonia lowering properties. Other nutraceuticals including l-ornithine l-aspartate, omega-3 polyunsaturated fatty acids and zinc and vitamin D supplementation, may similarly have positive effects on muscle homeostasis, however further evidence to support their use in cirrhotic populations is required.
    CONCLUSION: Nutraceuticals offer a promising and likely safe adjunct to standard care for sarcopenia in cirrhosis. While there is most evidence to support the use of BCAA and l-carnitine supplementation, further well-designed clinical trials are needed to elucidate their efficacy as a therapy for muscle loss in this population.
    Keywords:  Cirrhosis; Nutrition; Sarcopenia; Therapy
  19. Cancer Discov. 2021 Jan 26. pii: candisc.1375.2020. [Epub ahead of print]
    Duy C, Li M, Teater M, Meydan C, Garrett-Bakelman FE, Lee TC, Chin CR, Durmaz C, Kawabata KC, Dhimolea E, Mitsiades CS, Doehner H, D'Andrea RJ, Becker MW, Paietta EM, Mason CE, Carroll M, Melnick AM.
      Acute myeloid leukemia (AML) patients frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA-seq suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential.
  20. J Gerontol A Biol Sci Med Sci. 2021 Jan 25. pii: glab024. [Epub ahead of print]
    Baran SW, Lim MA, Do JP, Stolyar P, Rabe MD, Schaevitz LR, Cadena SM.
      To understand the growing needs of an aging human population, there is demand for scalable and reproducible approaches to study animal models of aging and to test novel therapeutic interventions. We investigated the sensitivity and utility of a continuous monitoring platform and its digital biomarkers (motion, breathing rate, and wheel running) to evaluate behavioral and physiological differences between "young" (12 weeks) and "old" (23 months) male C57BL/6J mice with or without running wheels in the home cage. Compared to young mice, old mice showed marked reductions in motion and breathing rate, as well as altered circadian rhythms. Mice without running wheels possessed lower breathing rates compared to their counterparts with running wheels. Digital biomarkers showed age-dependent changes in response to routine procedures (cage changes and blood sampling) and alterations in subjects that unexpectedly reached endpoint. Continuous collection of digital biomarkers in the home cage can enhance current approaches by providing unbiased longitudinal monitoring for large-scale aging studies.
    Keywords:  3Rs; Behavior; Breathing rate; Endpoint detection; Rodent
  21. Diabetologia. 2021 Jan 26.
    Burgess S, Malik R, Liu B, Mason AM, Georgakis MK, Dichgans M, Gill D.
      AIMS/HYPOTHESIS: Our aim was to investigate the relationship between average blood glucose levels and incident CHD in individuals without diabetes mellitus.METHODS: To investigate average blood glucose levels, we studied HbA1c as predicted by 40 variants previously shown to be associated with both type 2 diabetes and HbA1c. Linear and non-linear Mendelian randomisation analyses were performed to investigate associations with incident CHD risk in 324,830 European ancestry individuals from the UK Biobank without diabetes mellitus.
    RESULTS: Every one mmol/mol increase in genetically proxied HbA1c was associated with an 11% higher CHD risk (HR 1.11, 95% CI 1.05, 1.18). The dose-response curve increased at all levels of HbA1c, and there was no evidence favouring a non-linear relationship over a linear one.
    CONCLUSIONS/INTERPRETATIONS: In individuals without diabetes mellitus, lowering average blood glucose levels may reduce CHD risk in a dose-dependent way.
    Keywords:  Average blood glucose levels; CHD; Mendelian randomisation
  22. Trends Mol Med. 2021 Jan 21. pii: S1471-4914(20)30329-4. [Epub ahead of print]
    Dan J, Memczak S, Izpisua Belmonte JC.
      Genome editing holds great promise for treating a range of human genetic diseases. While emerging clustered regularly interspaced short-palindromic repeats (CRISPR) technologies allow editing of the nuclear genome, it is still not possible to precisely manipulate mitochondrial DNA (mtDNA). Here, we summarize past developments and recent advances in nuclear and mitochondrial genome editing.
    Keywords:  gene therapy; genome editing; mitochondria; translational medicine
  23. Front Physiol. 2020 ;11 571416
    Bajaj V, Gadi N, Spihlman AP, Wu SC, Choi CH, Moulton VR.
      The novel coronavirus severe acute respiratory syndrome coronavirus 2 causing the Coronavirus disease (COVID-19) pandemic has ravaged the world with over 72 million total cases and over 1.6 million deaths worldwide as of early December 2020. An overwhelming preponderance of cases and deaths is observed within the elderly population, and especially in those with pre-existing conditions and comorbidities. Aging causes numerous biological changes in the immune system, which are linked to age-related illnesses and susceptibility to infectious diseases. Age-related changes influence the host immune response and therefore not only weaken the ability to fight respiratory infections but also to mount effective responses to vaccines. Immunosenescence and inflamm-aging are considered key features of the aging immune system wherein accumulation of senescent immune cells contribute to its decline and simultaneously increased inflammatory phenotypes cause immune dysfunction. Age-related quantitative and qualitative changes in the immune system affect cells and soluble mediators of both the innate and adaptive immune responses within lymphoid and non-lymphoid peripheral tissues. These changes determine not only the susceptibility to infections, but also disease progression and clinical outcomes thereafter. Furthermore, the response to therapeutics and the immune response to vaccines are influenced by age-related changes within the immune system. Therefore, better understanding of the pathophysiology of aging and the immune response will not only help understand age-related diseases but also guide targeted management strategies for deadly infectious diseases like COVID-19.
    Keywords:  COVID-19; SARS-CoV; aging; coronavirus; immune response; immunity; infection
  24. J Hypertens. 2021 Jan 25.
    Ribó-Coll M, Lassale C, Sacanella E, Ros E, Toledo E, Sorlí JV, Babio N, Lapetra J, Gómez-Gracia E, Alonso-Gómez ÁM, Fiol M, Serra-Majem L, Pinto X, Castañer O, Díez-Espino J, González JI, Becerra-Tomás N, Cofán M, Díaz-López A, Estruch R, Hernáez Á.
      OBJECTIVE: To examine in older individuals at high cardiovascular risk whether following a Mediterranean diet decreased the necessity of antihypertensive drugs and modulated their associated cardiovascular risk.METHODS: In the PREvención con DIeta MEDiterránea study, we assessed whether volunteers randomly allocated to an intervention with a Mediterranean diet enriched with extra-virgin olive oil or nuts (relative to a low-fat control diet) disclosed differences in the risk of: initiating antihypertensive medication in nonusers at baseline (n = 2188); and escalating therapy in participants using one, two, or three drugs at baseline (n = 2361, n = 1579, and n = 554, respectively). We also assessed whether allocation to Mediterranean diet modified the association between antihypertensive drug use and incident cardiovascular events.
    RESULTS: Participants allocated to Mediterranean diet interventions were associated with lower risk of initiating antihypertensive therapy [5-year incidence rates: 47.1% in the control diet, 43.0% in MedDiets; hazard ratio = 0.84, 95% CI (0.74--0.97), in a model adjusted for age, sex, and recruitment site]. Volunteers using two drugs at baseline in the Mediterranean diet intervention enriched with extra-virgin olive oil decreased their risk of therapy escalation [5-year incidence rates: 22.9% in the control diet, 20.1% in the MedDiet; hazard ratio = 0.77, 95% CI (0.60--0.99)]. Allocation to Mediterranean diet interventions attenuated the association between antihypertensive therapy at baseline and incidence of major adverse cardiovascular events (P interaction = 0.003).
    CONCLUSION: In an older population at high cardiovascular risk, following a Mediterranean diet reduced the risk of initiating or escalating antihypertensive medication and attenuated cardiovascular risk in antihypertensive drug users.
  25. Sci Rep. 2021 Jan 25. 11(1): 2157
    Subramanian V, Rodemoyer B, Shastri V, Rasmussen LJ, Desler C, Schmidt KH.
      Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.
  26. JCI Insight. 2021 Jan 25. pii: 145207. [Epub ahead of print]6(2):
    Ferrere G, Tidjani Alou M, Liu P, Goubet AG, Fidelle M, Kepp O, Durand S, Iebba V, Fluckiger A, Daillère R, Thelemaque C, Grajeda-Iglesias C, Alves Costa Silva C, Aprahamian F, Lefevre D, Zhao L, Ryffel B, Colomba E, Arnedos M, Drubay D, Rauber C, Raoult D, Asnicar F, Spector T, Segata N, Derosa L, Kroemer G, Zitvogel L.
      Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
    Keywords:  Cancer; Immunotherapy; Metabolism; Mouse models; Oncology
  27. Science. 2021 Jan 29. 371(6528): 462-463
    Becker F, Rudolph KL.
  28. J Nutr Health Aging. 2021 ;25(2): 141-145
    Edelman LS, Drost J, Moone RP, Owens K, Towsley GL, Tucker-Roghi G, Morley JE.
    Keywords:  Age-Friendly health system; elderly; long term care
  29. Aging (Albany NY). 2021 Jan 28.
    Connors J, Haddad E, Petrovas C.
    Keywords:  T-follicular helper cells; adjuvants; aging; germinal center; vaccines
  30. Int J Oncol. 2020 Sep 22.
    Yan A, Jia Z, Qiao C, Wang M, Ding X.
      Cancer represents a severe challenge to healthcare systems and individuals worldwide. The development of multiple drug resistance is a major issue regarding cancer therapy, which can result in the progression of disease. Cholesterol is a major constituent of cell membranes and participates in the regulation of several cellular processes, such as cell growth, proliferation, differentiation, survival and apoptosis. Numerous studies have provided correlative support for a role of cholesterol in cancer development and drug resistance. In the present review, recent insights into the regulation of cholesterol metabolism, the association between cholesterol and the efficacy of antitumor agents in preclinical studies, as well as the possible mechanisms through which cholesterol influences drug resistance, are summarized. Furthermore, the clinical relevance of cholesterol to the development of cancer, as well as strategies targeting cholesterol for therapeutic intervention are detailed. Collectively, studies on various types of cancer have suggested that increased cholesterol levels promote resistance to chemotherapeutic drugs in cancer through a variety of mechanisms, and that the depletion of cholesterol using statins significantly enhances the sensitivity of the therapeutic agents. However, additional studies are required to enhance the current understanding of the involvement of cholesterol in the development of drug‑resistant cancer.
  31. Cells. 2021 Jan 21. pii: 208. [Epub ahead of print]10(2):
    Demirci D, Dayanc B, Mazi FA, Senturk S.
      Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of normal physiology with tumor suppressive functions. In the last few decades, novel cancer treatment strategies exploiting pro-senescence therapies have attracted considerable interest. Recent insight, however, suggests that therapy-induced senescence (TIS) elicits cell-autonomous and non-cell-autonomous implications that potentially entail detrimental consequences, reflecting the Jekyll and Hyde nature of cancer cell senescence. In essence, the undesirable manifestations that generally culminate in inflammation, cancer stemness, senescence reversal, therapy resistance, and disease recurrence are dictated by the persistent accumulation of senescent cells and the SASP. Thus, mitigating these pro-tumorigenic effects by eliminating these cells or inhibiting their SASP production holds great promise for developing innovative therapeutic strategies. In this review, we describe the fundamental aspects and dynamics of cancer cell senescence and summarize the comprehensive research on the adverse outcomes of TIS. Furthermore, we underline the rationale and motivation of emerging senotherapeutic modalities surrounding the removal of senescent cells and the SASP to help maximize the overall efficacy of cancer therapies.
    Keywords:  SASP; cancer; cellular senescence; senolytic; senostatic; therapy-induced senescence
  32. Cancer Lett. 2021 Jan 20. pii: S0304-3835(21)00026-4. [Epub ahead of print]503 11-18
    Lam C, Low JY, Tran PT, Wang H.
      The hexosamine biosynthetic pathway (HBP) is a glucose metabolism pathway that results in the synthesis of a nucleotide sugar UDP-GlcNAc, which is subsequently used for the post-translational modification (O-GlcNAcylation) of intracellular proteins that regulate nutrient sensing and stress response. The HBP is carried out by a series of enzymes, many of which have been extensively implicated in cancer pathophysiology. Increasing evidence suggests that elevated activation of the HBP may act as a cancer biomarker. Inhibition of HBP enzymes could suppress tumor cell growth, modulate the immune response, reduce resistance, and sensitize tumor cells to conventional cancer therapy. Therefore, targeting the HBP may serve as a novel strategy for treating cancer patients. Here, we review the current findings on the significance of HBP enzymes in various cancers and discuss future approaches for exploiting HBP inhibition for cancer treatment.
    Keywords:  Biomarkers; Cancer signaling; Glucosamine; Glucose; Glycosylation; Immune system; O-GlcNAcylation; Sugar; UDP-GlcNAc
  33. Sheng Wu Gong Cheng Xue Bao. 2021 Jan 25. 37(1): 40-52
    Chen X, Sun C, Liu C, Wu J.
      In recent years, long non-coding RNA (lncRNA) has been proved to be involved in the regulation of biological processes at various levels, attracting research interests in life science. LncRNA possesses the unique capability and exert discrete effects on transcription, translation and post-translational modification of the target genes through interacting with DNA, RNA and protein. Current studies have revealed that lncRNA plays an important role in hepatic metabolism via diverse pathways. This review focuses on the function of lncRNA and its relationship with hepatic energy metabolism and the correlated diseases, to elucidate the underlying mechanisms and prospects of lncRNA researches.
    Keywords:  glucose metabolism; lipid metabolism; liver; lncRNA
  34. Aging (Albany NY). 2021 Jan 27.
    Stotesbury C, Sigal LJ.
    Keywords:  aging; dendritic cells; inflammatory monocytes; innate immunity; natural killer cells; viral infection
  35. Cochrane Database Syst Rev. 2021 Jan 29. 1 CD013496
    Allaf M, Elghazaly H, Mohamed OG, Fareen MFK, Zaman S, Salmasi AM, Tsilidis K, Dehghan A.
      BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. Lifestyle changes are at the forefront of preventing the disease. This includes advice such as increasing physical activity and having a healthy balanced diet to reduce risk factors. Intermittent fasting (IF) is a popular dietary plan involving restricting caloric intake to certain days in the week such as alternate day fasting and periodic fasting, and restricting intake to a number of hours in a given day, otherwise known as time-restricted feeding. IF is being researched for its benefits and many randomised controlled trials have looked at its benefits in preventing CVD.OBJECTIVES: To determine the role of IF in preventing and reducing the risk of CVD in people with or without prior documented CVD.
    SEARCH METHODS: We conducted our search on 12 December 2019; we searched CENTRAL, MEDLINE and Embase. We also searched three trials registers and searched the reference lists of included papers. Systematic reviews were also viewed for additional studies. There was no language restriction applied.
    SELECTION CRITERIA: We included randomised controlled trials comparing IF to ad libitum feeding (eating at any time with no specific caloric restriction) or continuous energy restriction (CER). Participants had to be over the age of 18 and included those with and without cardiometabolic risk factors. Intermittent fasting was categorised into alternate-day fasting, modified alternate-day fasting, periodic fasting and time-restricted feeding.
    DATA COLLECTION AND ANALYSIS: Five review authors independently selected studies for inclusion and extraction. Primary outcomes included all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, and heart failure. Secondary outcomes include the absolute change in body weight, and glucose. Furthermore, side effects such as headaches and changes to the quality of life were also noted. For continuous data, pooled mean differences (MD) (with 95% confidence intervals (CIs)) were calculated. We contacted trial authors to obtain missing data. We used GRADE to assess the certainty of the evidence.  MAIN RESULTS: Our search yielded 39,165 records after the removal of duplicates. From this, 26 studies met our criteria, and 18 were included in the pooled analysis. The 18 studies included 1125 participants and observed outcomes ranging from four weeks to six months. No studies included data on all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, and heart failure at any point during follow-up. Of quantitatively analysed data, seven studies compared IF with ab libitum feeding, eight studies compared IF with CER, and three studies compared IF with both ad libitum feeding and CER. Outcomes were reported at short term (≤ 3 months) and medium term (> 3 months to 12 months) follow-up. Body weight was reduced with IF compared to ad libitum feeding in the short term (MD -2.88 kg, 95% CI -3.96 to -1.80; 224 participants; 7 studies; low-certainty evidence). We are uncertain of the effect of IF when compared to CER in the short term (MD -0.88 kg, 95% CI -1.76 to 0.00; 719 participants; 10 studies; very low-certainty evidence) and there may be no effect in the medium term (MD -0.56 kg, 95% CI -1.68 to 0.56; 279 participants; 4 studies; low-certainty evidence). We are uncertain about the effect of IF on glucose when compared to ad libitum feeding in the short term (MD -0.03 mmol/L, 95% CI -0.26 to 0.19; 95 participants; 3 studies; very-low-certainty of evidence) and when compared to CER  in the short term: MD -0.02 mmol/L, 95% CI -0.16 to 0.12; 582 participants; 9 studies; very low-certainty; medium term: MD 0.01, 95% CI -0.10 to 0.11; 279 participants; 4 studies; low-certainty evidence). The changes in body weight and glucose were not deemed to be clinically significant. Four studies reported data on side effects, with some participants complaining of mild headaches. One study reported on the quality of life using the RAND SF-36 score. There was a modest increase in the physical component summary score.
    AUTHORS' CONCLUSIONS: Intermittent fasting was seen to be superior to ad libitum feeding in reducing weight. However, this was not clinically significant. There was no significant clinical difference between IF and CER in improving cardiometabolic risk factors to reduce the risk of CVD. Further research is needed to understand the safety and risk-benefit analysis of IF in specific patient groups (e.g. patients with diabetes or eating disorders) as well as the effect on longer-term outcomes such as all-cause mortality and myocardial infarction.
  36. Int J Environ Res Public Health. 2021 Jan 22. pii: 962. [Epub ahead of print]18(3):
    Sánchez-Izquierdo M, Fernández-Ballesteros R.
      The study of cognitive change across a life span, both in pathological and healthy samples, has been heavily influenced by developments in cognitive psychology as a theoretical paradigm, neuropsychology and other bio-medical fields; this alongside the increase in new longitudinal and cohort designs, complemented in the last decades by the evaluation of experimental interventions. Here, a review of aging databases was conducted, looking for the most relevant studies carried out on cognitive functioning in healthy older adults. The aim was to review not only longitudinal, cross-sectional or cohort studies, but also by intervention program evaluations. The most important studies, searching for long-term patterns of stability and change of cognitive measures across a life span and in old age, have shown a great range of inter-individual variability in cognitive functioning changes attributed to age. Furthermore, intellectual functioning in healthy individuals seems to decline rather late in life, if ever, as shown in longitudinal studies where age-related decline of cognitive functioning occurs later in life than indicated by cross-sectional studies. The longitudinal evidence and experimental trials have shown the benefits of aerobic physical exercise and an intellectually engaged lifestyle, suggesting that bio-psycho-socioenvironmental factors concurrently with age predict or determine both positive or negative change or stability in cognition in later life.
    Keywords:  cognitive aging; cognitive change; cognitive trajectories; healthy cognitive aging; intelligence across life span; well being