Ageing, Age-related Diseases and Oxidative Str.pdf

Journal Pre-proofAgeing,Age-related Diseases and Oxidative Stress:What to Do Next?Jiao Luo,Kevin Mills,Saskia le Cessie,Raymond Noordam,Dianavan HeemstPII:S1568-1637(19)30174-6DOI:https:/doi.org/10.1016/j.arr.2019.100982Reference:ARR 100982To appear in:Ageing Research ReviewsReceived Date:7 June 2019Revised Date:4 October 2019Accepted Date:12 November 2019Please cite this article as:Luo J,Mills K,le Cessie S,Noordam R,van Heemst D,Ageing,Age-related Diseases and Oxidative Stress:What to Do Next?,Ageing Research Reviews(2019),doi:https:/doi.org/10.1016/j.arr.2019.100982This is a PDF file of an article that has undergone enhancements after acceptance,such asthe addition of a cover page and metadata,and formatting for readability,but it is not yet thedefinitive version of record.This version will undergo additional copyediting,typesetting andreview before it is published in its final form,but we are providing this version to give earlyvisibility of the article.Please note that,during the production process,errors may bediscovered which could affect the content,and all legal disclaimers that apply to the journalpertain.2019 Published by Elsevier.Ageing,Age-related Diseases and Oxidative Stress:What to Do Next?Jiao Luo 1,2,Kevin Mills 3,Saskia le Cessie 1,4,Raymond Noordam 2,Diana van Heemst 2 1 Department of Clinical Epidemiology,Leiden University Medical Center,Leiden,The Netherlands 2 Internal Medicine,section Gerontology and Geriatrics,Leiden University Medical Center,Leiden,The Netherlands 3 Biochemistry Research Group,Clinical&Molecular Genetics Unit,University College London Institute of Child Health,London,UK 4 Department of Medical Statistics and Bioinformatics,Leiden University Medical Center,Leiden,The Netherlands Corresponding author:Diana Van Heemst,E-mail:D.van_Heemstlumc.nl Highlights Damage caused by oxidative stress is an important hallmark of ageing Whereas experimental work shows clear antioxidant effects,clinical trials failed There is a lack of reliable markers of oxidative stress in large epidemiological studies Functional level,but not circulation level,of antioxidants could provide more insights Abstract Among other mechanisms,oxidative stress has been postulated to play an important role in the rate of ageing.Oxidative damage contributes to the hallmarks of ageing and essential components in pathological pathways which are thought to drive multiple age-related diseases.Nonetheless,results from studies testing the hypothesis of oxidative stress in ageing and diseases showed controversial results.While observational studies mainly found detrimental effects of high oxidative stress levels on disease status,randomized clinical trials examining the effect of antioxidant supplementation on disease status generally showed null effects.However,re-evaluations of these counterinitiative observations are required considering the lack of reliability and specificity of traditionally used biomarkers for measuring oxidative stress.To facilitate these re-evaluations,this review summarizes the basic knowledge of oxidative stress and the present findings regarding oxidative damage and Journal Pre-proofageing and age-related diseases.Meanwhile,two approaches are highlighted,namely proper participants selection,together with the development of reliable biomarkers.We propose that oxidized vitamin E metabolites may be used to accurately monitor individual functional antioxidant level,which might serve as promising key solutions for future elucidating the impact of oxidative stress on ageing and age-related diseases.Key words Ageing,Age-related diseases,Oxidative stress,Vitamin E metabolites Journal Pre-proof1.Introduction It has been widely acknowledged that life expectancy has increased over the past centuries as a specific result of improved medical care,vaccination and hygiene(Eggleston and Fuchs,2012;Rappuoli et al.,2014).The process of ageing is a dynamic,chronological process characterized by the gradual accumulation of damage to cells,progressive functional decline and increased susceptibility and vulnerability to diseases.In addition,ageing is closely connected to the onset and progression of multiple age-related diseases,such as cancer,type 2 diabetes mellitus,and cardiovascular and neurodegenerative diseases(Finkel et al.,2007;Samani and van der Harst,2008;Wyss-Coray,2016).The ageing process is postulated to originate from several basic molecular changes,better known as the hallmarks of ageing,which include four primary hallmarks,genomic instability,telomere attrition,epigenetic alterations,and loss of proteostasis,three antagonistic hallmarks,deregulated nutrient sensing,mitochondrial dysfunction,and cellular senescence,and two integrative hallmarks stem cell exhaustion,and altered intercellular communication(Lpez-Otn et al.,2013).These hallmarks contributing to the ageing process could be caused by oxidative damage.For example,telomeres are highly sensitive to oxidative damage and their repair capacity is less well than other parts of the chromosome(von Zglinicki,2000;von Zglinicki,2002).Hence,oxidative damage may result in telomere attrition that accelerates ageing and increases the risk of age-related diseases(Blackburn et al.,2015).The concept of oxidative stress was introduced in 1985 and updated later(Sies,1985;Sies,2015;Sies et al.,2017).Oxidative stress refers to“an imbalance between the generation of oxidants and their elimination systems,i.e.antioxidants,in favor of oxidants,leading to disruption of redox signaling and control and/or molecular damage”(Sies et al.,2017).Conceptually,the level of oxidative stress ranges from physiological level for redox signaling to toxic level of molecular or organelle damage(Figure 1).Redox signaling is essential for host defense as well as in a diverse array of signaling pathways(Holmstrm and Finkel,2014;Schieber and Chandel,2014).Other damages caused by non-physiological high oxidative stress leads to a wide range of phenotypic changes,including altered gene expression,arrested cell proliferation and cell growth,and cellular senescence(Burdon,1995;Hensley et al.,2000;Kreuz and Fischle,2016).Antioxidants may act as scavengers of oxidants to maintain the biological redox steady states.Therefore,since the oxidative stress theory was proposed(Harman,1972),antioxidants were postulated to potentially play a protective role in ageing and age-related diseases.Considering the premise that adverse health consequences caused by oxidative stress can be counteracted by antioxidants,a comprehensive body of studies aiming to examine the beneficial effects of antioxidants on diseases have been carried out in the past three decades.However,results were often disappointing and counterintuitive.The most appealing and well-known example is vitamin E,a well elucidated chain-breaking antioxidant.Although lower disease risks in individuals with higher vitamin E concentration have been found in many observational studies(Bostick et al.,1993;Li et al.,2012;Mayer-Davis et al.,2002;Rimm et al.,1993;Stampfer et al.,1993;Wright et al.,2006),as well as Journal Pre-proofprotective properties of vitamin E in animal experiments(Banks et al.,2010;Muller et al.,2007),most clinical trials examining vitamin E supplementation failed to demonstrate any advantageous effects on the prevention or treatment of various age-related diseases(Bjelakovic et al.,2007;Farina et al.,2017;Klein et al.,2011;Miller et al.,2005;Myung et al.,2013;Wang et al.,2014).Along with these conflicting evidences,it seems like the controversy about the oxidative stress theory in ageing and age-related diseases has never stopped(Figure 2).In addition,over the past 30 years,fluctuations in the use of antioxidant supplements were also observed,for example in the US(Figure 3)(Kantor et al.,2016;Kim et al.,2014).The percentage of individuals using antioxidant supplements gradually increased from 1980s and peaked in 1990s.Of note,specifically the use of vitamin E supplements steeply dropped in the early 21st century,where after decline turned to be stabilized.However,these observations neither imply that any consensus about the effect of antioxidants on diseases has been reached,nor that the oxidative stress theory has been refuted.Conversely,the annual publication count of antioxidant articles steadily increased since the 1990s,and more than 30,000 papers have been published in 2018 alone about this research topic(Yeung et al.,2019).So far,oxidative damages are thought to play a pivotal role in the pathological processes implicated in ageing and age-related diseases and the underlying biochemical mechanisms have been clarified in detail(Cui et al.,2012;Lpez-Otn et al.,2013).However,there are still several questions unsettled such as the existing paradox regarding the preventive and therapeutic role of antioxidants(such as vitamin E),the lack of stable and representative biomarkers of oxidative stress,and whether oxidative stress is causally associated with ageing and age-related disease in the general population setting.Therefore,this review is organized as such to provide an overview of the chemical processes involved in oxidative stress and an update on the available evidences about associations with ageing and age-related diseases.In the last part of the review,antioxidants,especially the controversial role of vitamin E will be addressed,together with novel insights and directions for future research.2.Generation of Reactive Oxygen Species(ROS)and health roles 2.1 Endogenous generation of ROS According to the“free radical theory”that was proposed in the 1950s and revised in the 1970s,damages induced by free radicals are the main cause of ageing and a shorter lifespan(Cadenas and Davies,2000;Harman,1956,1972).Reactive oxygen species(ROS)are highly reactive molecules,primarily including typical free radicals that contain at least one unpaired electron(superoxide O2-,hydroxyl radical OH)and hydrogen peroxides(H2O2),and have been considered the main source of endogenous oxidative stress damage(Liochev,2013).It is widely accepted that the bulk of ROS are generated by the mitochondrial electron transport chain during normal oxidative respiration in addition to numerous intracellular pathways(Figure 4).It is estimated that about 1-2%of the daily overall oxygen molecules consumed are reduced into O2-Journal Pre-proofwith the leak of electrons(Turrens,2003).This process occurs mainly in two discrete complexes of mitochondrial electron transport chain in the matrix side of inner mitochondrial membrane,notably complex I(NADH-ubiquinone oxidoreductase)and complex III(ubiquinone-cytochrome c reductase)(Finkel and Holbrook,2000).Iron-sulphur centers are thought as the most likely site of ROS production in complex I(Andreyev et al.,2005).Complex III,also known as the Q cycle,which refers to a set of ubiquinone oxidation reactions,is responsible for the robust production of superoxide,the precursor of other ROS,by non-enzymatic transfer of electrons to molecular oxygen.Once generated,superoxide could be catalyzed by superoxide dismutase(SOD)into H2O2,which is unstable and membrane-diffusible peroxide.Subsequently,in the presence of transition cation with reduced form(Fe2+or Cu+,referred to as the Fenton reaction)or myeloid peroxide(MPO)(Castagna et al.,2008),H2O2 further dismutates to OH,the extremely unstable and most reactive ion among all ROS.In summary,the main process of ROS generation in mitochondria could be schematically presented as O2 O2-H2O2 OH.Hydroxyl radicals may lead to detrimental damages to macromolecules owing to its chemical properties(Halliwell,1989).Moreover,its formation relies on the presence of a reduced form transition cation,mainly iron generated from the hemoglobin heme group during hemolysis.Hence any component which can stabilize heme iron within hemoglobin could prevent oxidative damage caused by hydroxyl radicals.In recent years,haptoglobin(Hp),an abundant,acute-phase inflammatory glycoprotein,which is predominantly synthesized in the liver and is regulated by cytokines,has been indicated to have an important role in the prevention of the generation of hydroxyl radicals by virtue of its ability to bind hemoglobin with high affinity and stability,thus preventing the release of heme iron from hemolysis into the circulation(Andersen et al.,2017),as shown in Figure 4.The Hp gene basically contains two common alleles,namely Hp1 and Hp2,with homozygous(1-1 or 2-2)and heterozygous(2-1)genotypes.In parallel with the theoretical evidence,both haptoglobin concentration and genotype,specifically Hp2-2,are associated with various age-related diseases,such as cancer,cardiovascular disease,etc.(Levy et al.,2010).However,the underlying mechanisms related to the pathophysiology of these diseases still remain to be demonstrated.2.2 Complex role of ROS in health maintenance and diseases The role of ROS in the body is rather complex,and the influences on health vary largely along with changing ROS levels.ROS levels,as a reflection of oxidative stress,are modulated by oxidant generation and their elimination,and are linked to many pathophysiological processes.Within physiological levels,ROS are in a biological redox steady state(Sies et al.,2017)and facilitate the maintenance of cellular homeostasis and function.However,ROS levels would go toward either side beyond dynamic balance(pathological states).Thus ROS levels have both beneficial and damaging aspects,as put forward in the concept of mitohormesis(Ristow and Schmeisser,2014),Consequently,both(too)low and(too)high levels of ROS will have adverse health effects,as illustrated in Figure 1.Journal Pre-proof2.2.1 Physiological levels:beneficial health effects ROS may act as second messengers owing to the characteristics of having an intricate system for synthesis and removal as well as reversible signaling effects.Both superoxide and hydrogen peroxide could be potential messengers to regulate reduction-oxidation-dependent signaling mechanisms,while hydrogen peroxide has higher advantage in signaling capacity given its stability and membrane permeability.The major mechanism underlying most redox-dependent signaling has been considered as the reversible modulation of cysteine thiol groups(thiolate anion to sulfenic form Cys-SOH)regulated by hydrogen peroxide(Holmstrm and Finkel,2014;Reczek and Chandel,2015).Within physiological levels(Range II in Figure 1),ROS can promote host defense mechanisms such as for the optimal activity for macrophages against bacteria,as well as in signaling pathways,such as toll-like receptors initiated pathways,Mitogen-Activated Protein Kinase(MAPK)signaling pathways,NF-?B signaling pathway and Keap1-Nrf2-ARE signaling pathway(Hekimi et al.,2011;Holmstrm and Finkel,2014;Schieber and Chandel,2014;Zhang et al.,2016).Therefore,ROS levels within the physiological range are critical signaling molecules for many redox-dependent signaling processes including