Ageing as a risk factor for neurodegenerative disease

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(10), P. 565 - 581

Published: Sept. 9, 2019

Language: Английский

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Cellular senescence in ageing: from mechanisms to therapeutic opportunities

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 22(2), P. 75 - 95

Published: Dec. 16, 2020

Language: Английский

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Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

EBioMedicine, Journal Year: 2019, Volume and Issue: 47, P. 446 - 456

Published: Sept. 1, 2019

Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing at etiological sites in multiple chronic diseases. Senolytics, including combination of Dasatinib Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks defend them against their own apoptotic environment. In first clinical trial senolytics, D Q improved physical function patients idiopathic pulmonary fibrosis (IPF), a fatal disease, but to date, no peer-reviewed study has directly demonstrated senolytics decrease humans.In an open label Phase 1 pilot study, we administered 3 days oral 100 mg 1000 subjects diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 2·3 kg/m2; eGFR:27·0 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, blood were collected before 11 after completing senolytic treatment. cell macrophage/Langerhans markers circulating SASP assayed.D reduced adipose tissue burden within days, decreases p16INK4A-and p21CIP1-expressing β-galactosidase activity, adipocyte progenitors limited replicative potential. macrophages, are attracted, anchored, activated crown-like structures decreased. Skin epidermal p16INK4A+ p21CIP1+ reduced, as factors, IL-1α, IL-6, MMPs-9 -12."Hit-and-run" treatment case have elimination half-lives <11 h, significantly humans. FUND: NIH Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, Mesenchymal Stem Cell Functionality Chronic Kidney Disease: Effect Senolytic Agents.

Language: Английский

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NAD+ metabolism and its roles in cellular processes during ageing

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 22(2), P. 119 - 141

Published: Dec. 22, 2020

Language: Английский

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Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(1), P. 131 - 142

Published: Jan. 1, 2020

Language: Английский

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Synergy between amyloid-β and tau in Alzheimer’s disease

Nature Neuroscience, Journal Year: 2020, Volume and Issue: 23(10), P. 1183 - 1193

Published: Aug. 10, 2020

Language: Английский

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Senolytic drugs: from discovery to translation

Journal of Internal Medicine, Journal Year: 2020, Volume and Issue: 288(5), P. 518 - 536

Published: July 20, 2020

Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using hypothesis-driven approach. SC accumulate with ageing at causal sites multiple chronic disorders, including diseases accounting for the bulk morbidity, mortality health expenditures. most deleterious resistant to apoptosis have up-regulation anti-apoptotic pathways which defend against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them survive, despite killing neighbouring cells. transiently disable these SCAPs, causing those tissue-destructive SASP. Because take weeks reaccumulate, senolytics can be administered intermittently - 'hit-and-run' In preclinical models, delay, prevent or alleviate frailty, cancers cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic skin disorders as well complications organ transplantation, radiation cancer treatment. As anticipated agents targeting fundamental mechanisms 'root cause' contributors potential uses protean, potentially alleviating over 40 conditions in studies, opening new route treating age-related dysfunction diseases. Early pilot trials suggest they decrease cells, reduce inflammation frailty humans. Clinical diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease, COVID-19, osteoarthritis, osteoporosis, eye bone marrow transplant childhood survivors underway beginning. Until such studies done, it is too early used outside clinical trials.

Language: Английский

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Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease

Cell, Journal Year: 2020, Volume and Issue: 182(4), P. 976 - 991.e19

Published: July 22, 2020

Language: Английский

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Cellular senescence and senolytics: the path to the clinic

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(8), P. 1556 - 1568

Published: Aug. 1, 2022

Language: Английский

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NAD+ in Brain Aging and Neurodegenerative Disorders

Cell Metabolism, Journal Year: 2019, Volume and Issue: 30(4), P. 630 - 655

Published: Oct. 1, 2019

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are synaptic plasticity neuronal resistance. Here, we review emerging findings that reveal key roles for related metabolites the adaptation of neurons to wide range physiological stressors counteracting processes neurodegenerative diseases, such as those occurring Alzheimer's, Parkinson's, Huntington amyotrophic lateral sclerosis. Advances understanding molecular mechanisms NAD+-based resilience will lead novel approaches facilitating healthy brain aging treatment neurological disorders. Nicotinamide adenine dinucleotide (NAD+) fundamental molecule health disease, it central several bioenergetic functions. synthesized via three major pathways, including de novo biosynthesis, Preiss-Handler pathway, salvage pathway (Figure 1). While aspartate most photosynthetic eukaryotes, kynurenine only synthetic mammals. The starts with catabolism amino acid tryptophan converted two steps intermediate kynurenine, which can generate NAD+, kynurenic acid, or xanthurenic (Vécsei et al., 2013Vécsei L. Szalárdy Fülöp F. Toldi J. Kynurenines CNS: recent advances new questions.Nat. Rev. Drug Discov. 2013; 12: 64-82Crossref PubMed Scopus (263) Google Scholar). modulates functions synthesis neurotransmitters (glutamate acetylcholine) well regulates N-methyl-D-aspartate (NMDA) receptor activity free radical production exhibits "double-edged sword" effects on both neuroprotective (tryptophan, picolinic acid) neurotoxic intermediates, 3-hydroxykynurenine (3-HK) generates radicals, 3-hydroxyanthranilic (3-HAA), quinolinic (that induces glutamate excitotoxicity) an NMDA antagonist, agonist ambient levels these determined by different enzymes, preferentially localized microglia astrocytes, suggesting necessary glial cell-neuron communication (Schwarcz Pellicciari, 2002Schwarcz R. Pellicciari Manipulation kynurenines: targets, effects, clinical opportunities.J. Pharmacol. Exp. Ther. 2002; 303: 1-10Crossref (399) synthesize from pyridine bases. synthesizes nicotinic (NA) (NAAD). One important step constitutes nicotinamide mononucleotide adenylyltransferases (NMNATs), also pathways. Three mammalian NMNATs exist, NMNAT1–3, showing mice D. melanogaster models (Ali 2013Ali Y.O. Li-Kroeger Bellen H.J. Zhai R.G. Lu H.C. NMNATs, evolutionarily conserved maintenance factors.Trends Neurosci. 36: 632-640Abstract Full Text PDF (0) NMNAT1 NMNAT3 ubiquitously expressed, NMNAT2 enriched brain, adequate seem be essential axon development survival (Gilley 2019Gilley Mayer P.R. Yu G. Coleman M.P. Low compromise survival.Hum. Mol. Genet. 2019; 28: 448-458Crossref (4) recycling (NAM) (NMN) intracellular phosphoribosyltransferase (iNAMPT), followed conversion NMN into (Bogan Brenner, 2008Bogan K.L. Brenner C. Nicotinic nicotinamide, riboside: evaluation precursor vitamins human nutrition.Annu. Nutr. 2008; 115-130Crossref (269) Scholar, Verdin, 2015Verdin E. NAD(+) aging, metabolism, neurodegeneration.Science. 2015; 350: 1208-1213Crossref (234) Additionally, riboside (NR) integrates this NR kinase 1 (NRK1) NRK2 (Bieganowski 2004Bieganowski P. Discoveries nutrient NRK genes establish independent route fungi humans.Cell. 2004; 117: 495-502Abstract (315) Ratajczak 2016Ratajczak Joffraud M. Trammell S.A. Ras Canela N. Boutant Kulkarni S.S. Rodrigues Redpath Migaud M.E. al.NRK1 controls metabolism cells.Nat. Commun. 2016; 7: 13103Crossref (82) Despite NAMPT being relatively highly expressed brown adipocyte, liver, kidney tissues compared tissue mice, studies have supported role iNAMPT (Stein Imai, 2014Stein L.R. Imai S. Specific ablation Nampt adult neural stem cells recapitulates their functional defects during aging.EMBO 2014; 33: 1321-1340PubMed Stein Wozniak D.F. Dearborn J.T. Kubota Apte R.S. Izumi Y. Zorumski C.F. Expression hippocampal cortical excitatory critical cognitive function.J. 34: 5800-5815Crossref Zhang 2010Zhang W. Xie Wang T. Bi Li H. L.Q. Ye S.Q. Ding Neuronal protective PBEF mouse model cerebral ischemia.J. Cereb. Blood Flow Metab. 2010; 30: 1962-1971Crossref (62) Experimental evidence suggests blood NA NAM able cross plasma membrane, while cannot taken up directly but needs smaller uncharged molecules enter (Hara 2007Hara Yamada K. Shibata Osago Hashimoto Tsuchiya Elevation NAD involvement cells.J. Biol. Chem. 2007; 282: 24574-24582Crossref (104) Extracellularly, digested membrane-bound CD38 CD157, further metabolized extracellular (eNAMPT); however, CD73 ways been proposed. First, converts CD73, presumptive nucleoside transporter (Fletcher 2017Fletcher Doig C.L. Oakey L.A. Callingham Da Silva Xavier Garten A. Elhassan Y.S. al.Nicotinamide kinases display redundancy mediating skeletal muscle cells.Mol. 2017; 6: 819-832Crossref (11) Grozio 2013Grozio Sociali Sturla Caffa I. Soncini Salis Raffaelli De Flora Nencioni Bruzzone protein source precursors sustained biosynthesis FK866-treated tumor 288: 25938-25949Crossref (55) Nikiforov 2011Nikiforov Dölle Niere Ziegler Pathways subcellular compartmentation cells: entry generation.J. 2011; 286: 21767-21778Crossref (154) 2016Sociali Raffaghello Magnone Zamporlini Emionite Bianchi Vigliarolo Nahimana al.Antitumor effect combined inhibition ovarian cancer model.Oncotarget. 2968-2984Crossref (16) Second, may metabolize NMN, not NR, NAM, membrane (Camacho-Pereira 2016Camacho-Pereira Tarragó M.G. Chini C.C.S. Nin V. Escande Warner G.M. Puranik A.S. Schoon R.A. Reid J.M. Galina al.CD38 dictates age-related decline dysfunction through SIRT3-dependent mechanism.Cell 23: 1127-1139Abstract (112) Sauve 1998Sauve A.A. Munshi Lee Schramm V.L. reaction mechanism CD38. A single responsible cyclization, hydrolysis, base-exchange chemistries.Biochemistry. 1998; 37: 13239-13249Crossref (83) Third, has reported (Grozio 2019Grozio Mills K.F. Yoshino Tokizane Lei Cunningham Sasaki al.Slc12a8 transporter.Nat. 1: 47-57Crossref (88) 2011Yoshino Yoon M.J. mononucleotide, intermediate, treats pathophysiology diet- age-induced diabetes mice.Cell 14: 528-536Abstract (442) newly transporter, Slc12a8, regulated murine small intestine, Slc12a8 deficiency abrogates uptake vitro vivo These pathways detailed Figure 1. Studies humans indicate supplementation dramatically upregulates NAAD, unknown metabolic possibilities NAAD and/or (NAMN) (Trammell 2016aTrammell Schmidt M.S. Weidemann B.J. Jaksch Dellinger R.W. Z. Abel E.D. uniquely orally bioavailable humans.Nat. 12948Crossref (131) Thus, although intensively characterized long time, there remaining determined. vital redox cofactor ATP production, substrate at least four families healthspan longevity (Fang 2017Fang E.F. Lautrup Hou Y.J. Demarest T.G. Croteau D.L. Mattson Bohr V.A. aging: translational implications.Trends Med. 899-916Abstract Gomes 2013Gomes A.P. Price N.L. Ling A.J. Moslehi J.J. Montgomery M.K. Rajman White J.P. Teodoro J.S. Wrann C.D. Hubbard B.P. al.Declining pseudohypoxic state disrupting nuclear-mitochondrial aging.Cell. 155: 1624-1638Abstract (529) plays glycolysis citric (TCA) cycle, its ability accept hydride equivalents, forming NADH (Krebs, 1970Krebs H.A. Rate control tricarboxylic cycle.Adv. Enzyme Regul. 1970; 8: 335-353Crossref Wallace, 2012Wallace D.C. Mitochondria cancer.Nat. Cancer. 2012; 685-698Crossref (853) one electron donors oxidative phosphorylation (OXPHOS) mitochondria, providing electrons transport chain (ETC) ratio NAD+/NADH various reactions compartments, increased influence homeostasis changes (Ying, 2008Ying NADP+/NADPH death: regulation biological consequences.Antioxid. Redox Signal. 10: 179-206Crossref (649) functions, antioxidation generation stress, calcium death In addition NAD+-consuming proteins, catabolize NAM. They class III histone deacetylases sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), ADP ribosyl-cyclases (CD38/CD157), NADase sterile alpha TIR motif-containing (SARM1) mammals, seven SIRTs, regulate large number survival, rejuvenation, cancer, (Chalkiadaki Guarente, 2015Chalkiadaki Guarente multifaceted 15: 608-624Crossref (150) SIRTs spectrum disease 2000Imai Armstrong C.M. Kaeberlein Transcriptional silencing Sir2 NAD-dependent deacetylase.Nature. 2000; 403: 795-800Crossref (2280) For example, SIRT1 consumes glycolysis, gluconeogenesis, balance between biogenesis mitophagy responses exercise metabolic/excitatory challenges (Bonkowski Sinclair, 2016Bonkowski Sinclair D.A. Slowing ageing design: rise sirtuin-activating compounds.Nat. Cell 17: 679-690Crossref Cheng 2016Cheng Yang Zhou Maharana Peng Liu Wan Marosi Misiak al.Mitochondrial SIRT3 mediates challenges.Cell 128-142Abstract (98) Fang, 2019Fang Mitophagy inhibit Alzheimer disease.Autophagy. 1112-1114Crossref (2) Furthermore, shown promote neurite outgrowth development, regulating dendritic arborization, long-term potentiation learning, memory (Gao 2010Gao W.Y. Mao Y.W. Gräff Guan Pan Mak Kim Su S.C. Tsai L.H. miR-134.Nature. 466: 1105-1109Crossref (585) Among 17 PARPs, them capable adding multiple ADP-ribose units (poly[ADP-ribosyl]ation) PARylation; they PARP1, PARP2, PARP5a (tankyrase 1), PARP5b 2) (Leung, 2017Leung A.K.L. PARPs.Curr. 27: R1256-R1258Abstract Rouleau 2010Rouleau Patel Hendzel Kaufmann S.H. Poirier G.G. PARP inhibition: PARP1 beyond.Nat. 293-301Crossref (813) supports transfers first moiety lysine, arginine, glutamate, aspartate, serine residues acceptor protein, preceding ones, thereby poly(ADP-ribose) (PAR) chains (Bonfiglio 2017Bonfiglio Fontana Q. Colby Gibbs-Seymour Atanassov Bartlett Zaja Ahel Matic Serine ADP-ribosylation depends HPF1.Mol. Cell. 940: 932-940Abstract Daniels 2014Daniels Ong S.E. Leung A.K. Phosphoproteomic approach characterize mono- poly(ADP-ribosyl)ation sites Proteome Res. 13: 3510-3522Crossref (74) majority PARylation executed participates processes, DNA repair, DNA/RNA response. PAR serving signaling scaffolding element 2016bFang Scheibye-Knudsen Chua Nuclear damage signalling mitochondria ageing.Nat. 308-321Crossref Leung, Scholar), e.g., stabilization repair forks, catalytic single-strand breaks, bulky lesions, double-strand breaks (DSBs) (Ray Chaudhuri Nussenzweig, 2017Ray Nussenzweig chromatin remodelling.Nat. 18: 610-621Crossref (33) However, excessive activation trigger death, termed parthanatos, formation triggers release apoptosis-inducing factor (AIF) cytosolic side outer membrane. AIF then translocated nucleus activate macrophage migration inhibitory (MIF, nuclease), finally results MIF-dependent chromatinolysis (Wang 2011Wang N.S. Haince J.F. Kang David K.K. Andrabi Dawson T.M. Poly(ADP-ribose) binding polymerase-1-dependent (parthanatos).Sci. 4: ra20Crossref (198) 2016Wang An Umanah G.K. Park Nambiar Eacker S.M. B. Bao Harraz M.M. Chang al.A nuclease induced polymerase-1.Science. 354Crossref (65) 2002Yu S.W. Poitras M.F. Coombs Bowers W.J. Federoff Mediation factor.Science. 297: 259-263Crossref (1386) Notably, depletion PAR-dependent hexokinase activity, resulting dysfunctional likely (Andrabi 2014Andrabi Stevens Karuppagounder Gagné polymerase-dependent energy occurs glycolysis.Proc. Natl. Acad. Sci. USA. 111: 10209-10214Crossref (128) Fouquerel 2014Fouquerel Goellner E.M. Barbi Moura Feinstein Wheeler Romero al.ARTD1/PARP1 negatively inhibiting depletion.Cell Rep. 1819-1831Abstract loss, hyperactivation PARP1-induced induce loss accelerated 2016aFang Kassahun Shamanna Kalyanasundaram Bollineni R.C. Wilson M.A. al.NAD(+) replenishment improves lifespan ataxia telangiectasia repair.Cell 24: 566-581Abstract view detrimental endogenous exogenous excitotoxicity, ischemia-reperfusion injury, inflammation-induced (Yu Scholar) targeting provide therapeutic strategies diseases. catalyzes Ca2+-responsive messenger cyclic (cADPR) use immunity, inflammation, even social behaviors (Jin 2007Jin H.X. Hirai Torashima Nagai Lopatina O. Shnayder N.A. Noda Seike behaviour oxytocin secretion.Nature. 446: 41-45Crossref (395) type II form (i.e., C-terminal) (with domain facing cytosol) (Liu 2017Liu Zhao W.H. Y.N. Z.Y. Fang S.L. Cytosolic interaction CIB1 levels.Proc. 2008Liu Graeff Kriksunov I.A. Lam Hao Conformational closure site (dagger) (double dagger).Biochemistry. 47: 13966-13973Crossref age-dependent increase CD38, contribute impaired function lymphocyte differentiation antigen, (Mizuguchi 1995Mizuguchi Otsuka Sato Ishii Kon Nishina Katada Ikeda localization antigen brain.Brain 1995; 697: 235-240Crossref (57) knockout show significant protection against ischemic (Long 2017Long J.H. Klimova Fowler Loane D.J. Kristian despite high level poly-ADP-ribosylation.Neurochem. 42: 283-293Crossref (1) SARM1 recognized cleaves ADPR, cADPR domain. It non-brain tissues, liver (Essuman 2017Essuman Summers D.W. X. DiAntonio Milbrandt toll/interleukin-1 possesses intrinsic cleavage promotes pathological axonal degeneration.Neuron. 93: 1334-1343Abstract (18) An, 2018Pan Z.G. X.S. deletion restrains NAFLD fat diet (HFD) reducing lipid accumulation.Biochem. Biophys. 2018; 498: 416-423Crossref (7) cyclase glycohydrolase activities, estimated Michaelis constant (Km) 24 μM, similar other known NAD+-consumers (PARP1, 50–97 μM; SIRT1, 94–96 15–25 μM) (Cantó 2015Cantó Menzies K.J. Auwerx homeostasis: balancing act nucleus.Cell 22: 31-53Abstract degeneration therefore potential target intervention holds signal, clear. SIRTS, CD38/CD157, compete each consume NAD+; thus, enzyme impair activities enzymes. interrelationships reviewed recently equilibrium synthesis, consumption, cytoplasm, nucleus, Golgi apparatus. Two expression subcellular-specific NAD+-synthetic transporters metabolites. convert NAD+. include

Language: Английский

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