Review Article ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging … · 2019. 7. 30. · Review Article ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and

Review ArticleROS Cell Senescence and Novel Molecular Mechanisms inAging and Age-Related Diseases

Pierpaola Davalli1 Tijana Mitic2 Andrea Caporali3

Angela Lauriola1 and Domenico DrsquoArca14

1Department of Biomedical Metabolic and Neural Sciences University of Modena amp Reggio Emilia 41125 Modena Italy2Bristol Heart Institute University of Bristol Bristol BS2 8HW UK3UniversityBHF Centre for Cardiovascular Science The Queenrsquos Medical Research Institute 47 Little France CrescentEdinburgh EH16-4TJ UK4Istituto Nazionale di Biostrutture e Biosistemi 00136 Roma Italy

Correspondence should be addressed to Domenico DrsquoArca domenicodarcaunimoreit

Received 16 December 2015 Revised 2 April 2016 Accepted 6 April 2016

Academic Editor Michael Courtney

Copyright copy 2016 Pierpaola Davalli et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The aging process worsens the human body functions at multiple levels thus causing its gradual decrease to resist stress damageand disease Besides changes in gene expression and metabolic control the aging rate has been associated with the productionof high levels of Reactive Oxygen Species (ROS) andor Reactive Nitrosative Species (RNS) Specific increases of ROS level havebeen demonstrated as potentially critical for induction and maintenance of cell senescence process Causal connection betweenROS aging age-related pathologies and cell senescence is studied intensely Senescent cells have been proposed as a target forinterventions to delay the aging and its related diseases or to improve the diseases treatment Therapeutic interventions towardssenescent cells might allow restoring the health and curing the diseases that share basal processes rather than curing each disease inseparate and symptomatic way Here we review observations on ROS ability of inducing cell senescence through novel mechanismsthat underpin aging processes Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigeneticregulation of cell senescence and aging with the aim to individuate specific pathways which might promote healthy lifespan andimprove aging

1 Introduction

The reduced rate of birth and mortality is the motive of theolder population growth in western industrialized countrieswhere advanced age remains the fundamental risk factor formost chronic diseases and functional deficits As an exampleit is estimated that the individuals of age 65 and above in theUSA will reach 20 by 2030 while they constituted 124 in2004 [1] Human aging is developed from such an accumu-lation of physical environmental and social factors that thedefinition of themolecularmechanisms that trigger the agingmeans a difficult task Some theories associate various factorswith aging rate as changes of metabolic control [2] andgene expression patterns [3] and production of high levels ofReactive Oxygen Species (ROS) [4] Low ROS level has been

instead associated with lengthening of organismal lifespan[5] Current studies aim at deepening how cell senescenceprocess so far experimented in vitro may be extended to invivo studies Increasing evidence for causal role of cell senes-cence has been demonstrated in age-related dysfunctions andpathologies [6] Senescent cells proliferate in aging as a stressresponse primed by a number of ldquocountingmechanismsrdquo liketelomeres shortening DNA damage accumulation abnormaloncogenes activities metabolic alterations and excessiveROS generation [7] These mechanisms cause cell proliferat-ing arrest and generate features as constitutive production ofhigh ROS levels critical for the senescent phenotype mainte-nance Despite increasing modestly as a number the senes-cent cells are implicated in age-related diseases promotionthrough the restriction of the regenerative pool of the tissue

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 3565127 18 pageshttpdxdoiorg10115520163565127

2 Oxidative Medicine and Cellular Longevity

stem cells [8] Some observations indicate that senescent cellsdo not necessarily induce mechanisms that promote agingand can be efficiently removed from the human body [9]Thegeneral consensus on cellular damage accumulation as aginginitial event suggests that cell senescence process is a majorquestion regarding biological and clinical aging aspects [10]

Here we review evidences on novel molecular mech-anisms of the ldquoROS signalingrdquo during aging and relatedpathologies because they suggest a way of promoting healthylifespan and improve human aging

2 ROS Physioma Homeostasis

The ROS physioma is a family of highly reactive moleculeswhich includes free oxygen radicals like superoxide anion(O2

∙minus) hydroxyl radical (OH∙) and nonradical oxygenderivatives like the stable hydrogen peroxide (H

2O2) The

superoxide radicals react to form other ROS namely hydro-gen peroxides and hydroxyl radicals and interconvert withreactive nitrogen species (RNS) which generate effects simi-lar to ROS [11] The inefficient electron transfer in mitochon-drial respiratory chain is believed to be a main ROS sourceamong diverse possible enzymatic and nonenzymatic sources[12] Increased expression of catalase and peroxiredoxin-1 molecules are considered as OS markers The familycomprises seven transmembrane members namely Nox1ndash5 [13ndash15] and Duox1-2 [16] ROS are generated by oxygenmetabolism (ie cellular respiration) in all the cells thatutilize oxygen as inevitable consequence of aerobic lifeand may derive from exogenous metals recycling of redoxcompounds radiation chemotherapeutic agents carcino-gens (estrogenic molecules) and other dietary and environ-mental means Generally the ROS increasing levels causenonlinear cellular responses [17] A fine balance betweenoxidant-antioxidant mechanisms leads to continuous mod-ulation of ROS production location and inactivation inboth physiological and pathological conditions Endogenousantioxidants like the enzymes of catalase family glutathionegroup thioredoxin-related group and superoxide dismutase[18] together with exogenous antioxidant as reduced glu-tathione [19] carotenoids and vitamins C and E constitutethe indispensable ROS detoxifying system Neverthelessimbalance of redox homeostasis may occur usually in favorof oxidants so that ROS shift from physiological to poten-tially harmful levels named oxidative and nitrosative stress(OSNS) Increased expression of catalase and peroxiredoxin1 molecules are considered as OS markers [20ndash22]

21 ROSMeasurement Techniques ROS are so highly variableand freely diffusible molecules that the detection of ROS andantioxidants to obtain a picture of the cellular redox statusstill represents a challengeWe stress some specific points andsensitive methods that are subjected to continuous improve-ment Probes and antibodies have been developed to recog-nize oxidative damage by ROSRNS [23ndash25] The tools allowrevealing antioxidant enzymes [26] and a variety of oxidativeproducts as lipid peroxidation products protein carbonyls[27] oxidized DNA products [28] and nitrotyrosine [29]Combinations of diverse approaches will prove essential for

understanding ROS involvement in aging and age-relateddiseases [30] An innovative method simultaneously assessesglutathione hydrogen peroxide and superoxide levels ina single cell together with cell viability alterations thusallowing for defining both oxidant-antioxidant balance andcell death after the administration of a specific stimulus [31]A wide range of pathways and molecular mechanisms thatinvolve ROS suggests determining the redox state of thiols inROS targets which compose the ldquocellular oxidative interfacerdquo[32 33] ROS oxidize specific protein residues of cysteine intosulfenic acid reversibly This molecule functions as OSNSsensor within enzymes and transcriptional regulatory factorsand may allow priming the routes of the versatile ROS action[34ndash36]

22 ROS Functions The increasing comprehension of mech-anisms underlying the oxidant milieu of the cell showsROS as signaling molecules besides metabolic byproductsThey act in a myriad of pathways and networks mediatedby hormones which ranges from protein phosphorylationto transport systems for example ROS do not influencesingle steps of multistep processes rather they influenceall the steps at the same time by reacting with severalcompounds and taking part in several redox reactionsDepending on ROS concentration molecular species andsubcellular localization cell components and signaling path-ways are affected positively or negatively ROS levels arebelieved to be a ldquoredox biologyrdquo that regulates physiologicalfunctions including signal transduction gene expressionand proliferation ldquoRedox biologyrdquo rather than OS has beenproposed to underlie both physiological and pathologicalevents [37] Data in the literature on slow and constantROS increases have to be integrated with data on fast andstepwise ROS increases typical of signaling events whichdeliver messages among cellular compartments Questionsrelated to ROS dynamics and specificity as the effects of theirwaves of concentration on networks with other signalingpathways are investigated in single cells and across differentcells Proteins are the major target of ROSRNS signalingand undergo reversible or irreversible modifications of theirfunctions which result in cell death growth arrest andtransformation The modulation of the reversible oxida-tion of redox-sensitive proteins plays basic roles in sens-ing and transducing the oxygen signal Receptor-dependentor nondependent tyrosine kinases AMP-activated proteinkinases adaptor protein p66SHC and transcription factorsas FOXO (forkhead homeobox type O) Nrf2 (nuclear fac-tor E2-related factor 2) p53 (tumor suppressor 53) NF-120581B (nuclear factor kappa B) AP-1 (activator protein-1)HIF-1a (hypoxia inducible factor-1a) PPAR120574 (peroxisomeproliferator-activated receptor gamma) and 120573-cateninWntsignaling are listed in Table 1 [38ndash81] ROS mediate in vitroresponse towards intra- and extracellular conditions such asgrowth factors cytokines nutrients deprivation andhypoxiawhich regulate cell proliferation differentiation and apopto-sis besides being important cancer hallmarks [82] Intrinsicand extrinsic factors control ROS regulation on cellular self-renewal quiescence senescence and apoptosis during thein vivo tissues homeostasis and repair [83] and in ROS

Oxidative Medicine and Cellular Longevity 3

Table 1 Selected ROS sensitive proteins that are involved in cell signaling transduction mechanism Indicative examples of possible effectsand processes they promote after being directly andor indirectly modified by ROS (the references are indicated inside the square brackets)

ROS sensitive proteinsoxidative interface

(1) Effects of ROS sensitive proteins after beingredox modified

(2) Physiopathological processes in which ROSsensitive proteins are involved

Protein kinasesReceptornonreceptor tyrosinekinases(Src TRK AKT c-Abl MAPKCaMKII PKG ATM and Ask1)

(i) Interactions between kinases pathways [38 39](ii) Signal of ROS production feedback [40]

Control of cell cycle progression [56]Mitosis for anchorage-dependent cells [57]Cellular homeostasis [43 57]

AMP-activated protein kinases(AMPK) (i) Regulation of cell ROSredox balance [41 42]

Myocyte adaptation to energy requirement [42]Adipocyte differentiation [58]Lipid metabolism (ldquofatty liverrdquo) [59]Hyperglycemic damage [60]Cell fate (autophagy and apoptosis) [61]

Adaptor proteins

p66Shc (i) Signaling start in the aging process [43]Apoptosis [43] Prolonged life span [43 62]Cardiovascular diseases and obesity [63]Diabetic endothelial dysfunction [64]

Nuclear receptors

PPAR120574(i) Redox sensor function [43](ii) Regulation of genes that modulate ROSincreases [44]

Neurodegenerative diseases [65 66]Lipid dysfunction (fatty liver) [59]

Membrane receptors

Elements in Notch1 pathway (i) Notch signaling modulation in associationwith Wntbeta-catenin signal [45]

Cell fate control in vascular development [45]Biological clocks in embryonic development [67]

Transcription factor

p53 Modulation of cell redox balance(prooxidantantioxidant effects) [46ndash48]

Cell fate signaling [68]Autophagy and apoptosis [61 69]

Nrf2 Cell adaptation to ROS resistance [49 50]Apoptosis [70]Neurodegenerative diseases [71]Cardiovascular diseases [72]

FOXO3A Cell coordination in response to OS [51]

Metabolic adaptation to low nutrient intake [73]Cancer development [73]Diabetes [74]Atherosclerotic cardiovascular disease [75]

Components in 120573-cateninWntpathway

Regulation of Wnt signaling via nucleoredoxin[76]

Early embryonic development [76]Vascular development [45]

HIF-1a Cell adaption to oxygen tension modifications[52]

Cell proliferation angiogenesis [77]Cell transformation [78 79]

Components in JAKndashSTATpathway

(i) Cell adaption to OS [53](ii) Mediation of ROS mitogenic effect [53]

Stress response gene expression [51]Systemicpulmonary hypertension [80]

NF-120581B Regulation of redox-sensitive gene expression[54 55]

Rheumatoid arthritis dyslipidemiaatherosclerosis and insulin resistance [81]

induction of stem cells proliferation and differentiation ROSact as a rheostat which senses and translates environmentalcues in stem cells response thus balancing cellular output(function) with cellular input (nutrients cytokines) Thestem cells may undergo exhaustion depending on ROS levels[84] Mitochondrial ROS may activate an adaptive response(mitohormesis) which as defensive mechanism promoteshealth to extend the lifespan through diseases preventionand delay [5 85] ROS is integral in the development ofphysiopathologic events like mitochondrial death signaling[86] and autophagy [87] besides inflammation and infection[55 88] in which they impart immunological changes HighROS levels are generated by professional cells (lymphocytes

granulocytes and phagocytes) in defense against microbes[89 90] Differently any event which contributes to chronicOS or NS through its increased generation or defectivedetoxification dysregulates signaling networks alters lipidsand protein and nucleic acids and activates mechanisms toface the changes ROS overproduction hampers damagednuclear and mitochondrial DNA repair at multiple stepscontributing to cell genomic instability [91] ROS are rec-ognized as key modulators in processes that accumulateoxidized molecules chronically as diabetes cardiovasculardiseases atherosclerosis hypertension ischemia reperfusioninjury neurodegeneration and rheumatoid arthritis [17]Also ROS participate in cancer development through their


effects on cellular proliferation mutagenesis and apoptosisinhibition [56] The cross talk between ROS p53 and NF-120581Bplays crucial roles in tumorigenesis OS is allied with energymetabolism to stimulate the growth of cells transformed byoncogenes or tumor suppressors [92ndash94] The deregulatedROS productions in cancer cells and the consequent consti-tutive OS may cause the cellular invasive phenotype [57]

Although ROS functions remain difficult to investigatemultiple pharmacological investigations are in progress tomaintain ROS homeostasis through both OS decrease andantioxidant defense increase [95 96]

3 ROS in Aging and Age-Related Diseases

Poor knowledge of basic processes in aging interferes withinterventions to prevent or delay age-related pathologieslike diabetes cardiovascular disorders neurodegenerativedisorders and cancer which consequently impact humanindependence general wellbeing and morbidity [97ndash99]Recently interest has been focused on stem cells becausetheir decline impairs tissues homeostasis maintenance lead-ing to the organism weakening and the age-related diseases[84] Agingmechanisms have been collected into two classesThe first class presents aging as genetically programmedby developmental processes like the cell senescence theneuroendocrine alterations and the immunological alter-ations The second class presents aging caused by randomdamage that is accumulation of somatic mutations and OSThe separation between the classes is no longer consideredclear because pathways involved in aging often share featureswith specific diseases [100] The genetic heredity contributesno more than 3 to aging while epigenetic processes andposttranslational processes imprint a significantly differentaging rate among diverse populations as well as amongdiverse anatomical sites of a single organism In the onsetof aging telomere erosion OS and cell senescence arecrucial events that originate from the disorganized homeosta-sis of cell metabolism For example mitochondria-nucleusinterplay [101] and alterations of mitochondrial homeostasisdrive age-dependent modifications [102 103] IneffectiveROS control on mitochondrial supercomplexes causes ROSsignaling alteration thus mediating cell stress responsestowards age-dependent damage [104] A progressive ROSscavengers decrease shifts aged cells towards a prooxidantstatus [105 106] In parallel all the suggested methods toprolong lifespan as caloric restriction and increased activityof SIRT1 share the OS reduction effect [107] It is knownthat chronic muscular exercise protects older persons fromdamage caused by OS and reinforces their defenses against itOn the other hand acute exercise increases ROS productionand damage from ROS [108] High levels of mitochondrialROS contribute to aging of genetically modified animals ina mechanistic way Superoxide dismutase-deficient animalsSOD1- [109] and SOD3-deficient animals [110] and p66SHC-deficient animals showmitochondrial dysfunctions that gen-erate oxidative damage and related phenotypes resemblingpremature aging features Similarly mice that overexpressmitochondrial catalase counteract oxidative damage and livelonger The incidence of age-related diseases and pathologies

in animal models after they have been submitted to disparatepatterns suggests that OS influences old age aspects signifi-cantly [111]The observations have been extended to humanseven if rate and distribution of mitochondrial mutations maydeviate from animalsThe conclusions regarding OS effect onaging in animals from mitochondrial genetic manipulationsare still conflicting SOD+minus mice have reduced ROS detox-ifying ability and high ROS level while they exhibit a quitenormal lifespan OS effect on wormsrsquo lifespan depends onwhere ROS are produced high mitochondrial or cytoplasmiclevels are associated with increased and decreased lifespanrespectively [109 112] It remains to define whether modelsrsquolongevity is entirely associated with response to OS becausetheir lifespan is not affected by modulation of the antioxidantdefense The complex genetic manipulation of the modelsmight weaken their support to the ldquoOS theory of agingrdquoInterventions to ROS lowering by both scavenging freeradicals and enhancing antioxidant defenses are widely pro-posed as an antiaging strategy However positive associationbetween supplementation with pharmacological or naturalcompounds and health beneficial effects has not been evi-denced Some antioxidants may be eventually useless or evenharmful [113 114] Moreover a number of ROS-independentmitochondrial dysfunctions appear so involved in aging thatdoubts arise that OS is the most concrete contributor to fuelaging [115] Based on the consideration that mitochondrialDNA (mtDNA) is a precise marker to detect total mitochon-drial OS methods have been developed to measure mtDNAreplication defects and the oxidative damage level simulta-neously The errors in mtDNA replication and repair whichaccumulate through clonal expansion in advanced age resultin amajor source ofmtDNAmutations rather than the errorsacquired through ROS-dependent vicious cycles [116] Sum-marizing ROS are involved in elderly lesions that concern (i)DNA insufficiency which is partly responsible for prematureaging and apoptosis [117] (ii) RNA involvement in the onsetof chronic-degenerative diseases [118] (iii) nuclear laminsthat participate in cell proliferation and longevity [119] Thevariations of speed and quality in the aging of each organismmay reflect the peculiar alterations that have been accumu-lated in DNA proteins and lipids [120] following the organ-ism exposition to chronic stressors Low ROS levels improvethe defense mechanisms by inducing adaptive responseswhich contributes to stress resistance and longevity whilehigh ROS levels induce insufficient adaptive responses whichmay contribute to aging onset and progression [121]

In conclusion accumulated mutations decreased mito-chondrial energy metabolism and increased OS may signifi-cantly contribute to the human aging and the related diseases

4 ROS-Dependent Epigenetic Modifications

Intra- and extracellular environments change hereditary cha-racters at the epigenetic level without altering genes sequence[122]The interplay between modified histones DNAmethy-lation regulator noncoding RNAs and other reversible pro-cesses constitutes the epigenetic machinery that regulatesgenes transcription and expression [123] The epigeneticmodulation provides the essential and flexible interface


between organism and environment which is essential for allthe cell functionsThe extent to which epigenome has shapedand might shape human populations over generations isinvestigated by an International Human Epigenome Con-sortium (httpwwwihec-epigenomesorg) Both long- andshort-acting stimuli lead to epigenetic effects that result in13 being long-term (heritable) or short-term (nonheritable)respectively These features suggest epigenetic modificationsas more attractive target for therapeutic interventions inhumans than genetic modification throughout the entirelife [124] ROS operate modifications on histone and DNAby acting in interconnected epigenetic phases during mito-chondrial and nuclear DNA regulation [125 126] A clin-ical example of ROS-dependent epigenetic modificationsis demonstrated in ldquononalcoholic fatty liverrdquo disease Thepathology represents themost common cause of chronic liverdisease in western countries and affects one-third of the pop-ulation Altered redox mechanisms mediate the link betweenincreased accumulation of triglycerides in hepatocytes andepigeneticmodifications that are recognized as crucial factorsin the pathophysiology of this disease [127] About the basicmechanisms of ROS action Afanasrsquoev proposes that ROSmight cause epigenetic activation and repression by actinglike nucleophilic compounds which accelerate and deceleratehydrolysis and esterification reactions The hypothesis sug-gests a ROS role different from free radicals because the lastmolecules cause an irreversible damage of the compoundswith which they react [128]

41 ROS-Induced DNA Methylation Usually condensedchromatin structure (heterochromatin) is associated withgenes repression by hypomethylation processes while openchromatin (eu-chromatin) is associated with genes activationby acetylation processes [129] The epigenetic marking mod-ulates the genes expression by altering the electrostatic natureand the protein binding affinity of chromatin DNAmethyla-tion causes gene silencing through inhibiting the transcrip-tional activators access to the target binding sites or throughactivating themethyl-binding protein domainsThe last func-tion interacts with histone deacetylases and promotes chro-matin condensation into transcriptionally repressive confor-mations Hypo- and hypermethylation stages occur consec-utively indicating how DNA methylation and the correlatemechanisms of DNA binding are complex ROS-dependentmodifications are related to DNA methylation and demethy-lation directly or indirectly The NF-120581B binding to DNAwhich is methylation dependent results in being alteredin SOD (CuZn)-deficient mice The observation associatesROS-dependent modifications with altered methylation pro-cesses although indirectly and suggests that modificationslinked to altered redoxmechanismsmay fit into cell signalingpathways [130] Also the oxidation of deoxy-guanine of CpGnucleotides to 8-hydroxy-21015840-deoxyguanosine (8-OHdG) isbelieved to be a surrogate marker of oxidative damage invarious human diseases [131] The 8-OHdG adducts interferewithDNA restriction nucleases andDNAmethyl transferases(DNMT) thus altering transcription factors binding to DNAand causing general DNA hypomethylation In vitro [132]and in vivo [133] studies demonstrate that ROS induce

general genome hypomethylation and specific DNA promot-ers hypomethylation via the DNMT upregulation and theDNMT complexes generationMoreover recent studies showthat aROS-mediated pathway causes repression of the proteinkinase C epsilon gene through its promotormethylationTheevents are important in heart hypoxia in utero which leadsto heightened heart vulnerability to ischemic injury later inpeoplersquos life [134]

42 ROS and DNA Methylation in Aging and Age-RelatedDiseases Starting from the observation that both defectivegenome and DNA repair processes promote phenotypes ofpremature aging the ldquoaging epigeneticsrdquo has been developedas emerging discipline which concerns genes and processesimpacting aging (Figure 1) [135] ROS effects on epigeneticmechanisms have been discussed as cause and consequenceof aging and age-related DNA modifications [128] Recentstudies demonstrate that global DNA hypomethylation isdeeply included in aging gene expression [136] and at thesame time cancer is the age-related disease that shows themost significant effects of ROS-dependent DNAmethylation[137] Tumor progression is induced by general hypomethy-lation of theDNA and hypermethylation of tumor suppressorgenes that lead to aberrant genes expression [138ndash140]Abnormal and selective DNA methylation may constitutea potential biomarker and a tool to assess therapeutictreatments at the same time The data on OS-mediatedalterations in DNA methylation which have been so farobtained motivate chemoprevention trials to reduce OS incancer diseases [141ndash143] In human aging the telomerasereverse transcriptase (hTERT) controls the mitochondrialfunction and the cellular metabolism besides the telomeresstructure The enzyme is regulated by DNA methylationVarious observations demonstrate that hTERT may confermajor sensitivity towards OS [144] and reduce ROS increasein aging and age-related diseases [145] Examples of bothROS levels and DNA methylation which seems to changewith age suggest that they are potentially linked [146 147]ROS-inducedmethylation at SOD2 gene promoter causes thedecreased expression of the gene which may be associatedwith the disruption of the cardiorespiratory homeostasis atypical problem of the old humans Treatments with DNAmethylation inhibitors in preclinical studies can preventthe hypoxic sensitivity that leads to the respiratory dysfunc-tion [148] Also both ROS-induced 8-OHdG and 5-methylcytosine generate abnormal GC regions in the DNA whichundergo further methylation and oxidation thus hamperingDNA repair enzymesThese regions have been demonstratedto hit gene expression and DNA susceptibility to damage inAlzheimerrsquos pathology [149]

In complex ROS are involved in DNAmethylation proc-esses in different conditions occurring in the human agingThe epigenetic machinery operates as OS sensor which con-tributes to the OS control and at the same time orches-trates the progressive homeostasis impairment which shapesthe cardiovascular respiratory and nervous systems of oldhuman beings [146] The ROS signaling in the DNA methy-lation during the aging process deserves to be more deeplystudied


Activating signalsCytokines

Growth factor (mitogens nutrients)Stress (hypoxia UV radiation

and chemotherapy)

Mitochondria

ROS

Membrane boundNADPH oxidases

ROS pool

ROS levels

+minus

Antioxidants and detoxicating enzymesSOD catalase glutathione

peroxiredoxinthioredoxin reductase and peroxidase

NADPH oxidase

Acceleratedaging

Cell death

Age-relateddiseases

ROS sensitive proteins(oxidative interface)

DamageNucleic acids lipids and proteins

Epigenetic machineryDNA methylation histone modification

and noncoding RNAs

Figure 1 Schematic representation of ROS signaling in physiological and pathological conditions Low andmedium ROS levels produced bymitochondria and NADPH oxidase activate cell ROS sensitive proteins and epigenetic machinery High ROS level causes nucleic acids lipidand proteins damage possibly involved in accelerated aging cell death and age-related diseases

5 ROS in Cell Senescence

The cell senescence has indicated the irreversible G1 growtharrest of normal primary cells which occurs after the cellshave accumulated time-dependent damage during extensiveculture passages (ldquoreplicative senescencerdquo) The cells resistapoptosis and face malignant progression through cytosta-sis thus causally contributing to cell senescence inductionand maintenance The senescent cells are able to diversifyconstantly like cancer cells but missing proliferation as adriver [7 9] Large and flat shape rich cytoplasmic andvacuolar granularity high levels of lysosomal 120573-galactosidaseactivity (SA-120573gal) p16 p21 macroH2A IL-6 phosphory-lated p38MAPK and ldquodouble-strand breaksrdquo are the mostcommon senescent cells features in in situ assays [9] Theexact mechanisms underlying the cell senescence onset andstabilization are still obscure OS mitochondrial deteriora-tion DNA damage oncogenes expression and loss of tumorsuppressor genes like PTEN RB1 NF1 and INPP4 caninduce cell senescence [9] ldquoReplicative senescencerdquo which is

provoked by endogenous stimuli is distinct from ldquostress-induced premature senescencerdquo which is provoked by exoge-nous stimuli The two processes share molecular and func-tional features although they are dependent or not ontelomeres status respectively Intrinsic and extrinsic eventscan induce either the cell senescence or the apoptosis processdepending on the level of the impairment of the cell home-ostasis [150] and the p53 activity [47]Themolecules secretedby senescent cells (secretoma) cooperate deeply to maintainthe tissues homeostasis through autocrine and paracrineactivities [151] by acting at multiple levels epigenome [152]gene expression protein processing and metabolic control[153] Moreover specific mitochondrial pathways contributeto priming the senescence process through the alteration ofthe mitochondrial redox state [6 151] The senescence secre-toma acts in physiological and pathological events as tissueremodeling during embryogenesis tissue repair in woundhealing and induction of aging as well as age-related diseasesof different organisms The secretoma develops beneficialeffects on carcinogenic DNA lesions of precancerous cells


by both preventing their uncontrolled cell proliferation andreacting with specific anticancer compounds [154] Howeverthe secretoma may provide indispensable cytokines for thecancer cells growth thus promoting tumorigenesis in definiteconditions which are partly related to the cellular meta-bolic state [155] Cause-effect relationships between cellularROS production and cell senescence have been investigatedthrough diverse pathways that comprise the following

(i) Mitochondrial DNA (mtDNA) Damage ROS contributeto cellular senescence onset and progression by damagingmtDNA directly or in synergy with modifications of thetelomerase reverse transcriptase (TERT) enzyme and thep53 and Ras pathways activity [9] Also ROS productionby serial signaling through GADD45-MAPK14 (p38MAPK)-GRB2-TGFBR2-TGFb is both necessary and sufficient for thestability of growth arrest during the establishment of thesenescent phenotype [156]

(ii) Signaling Pathways via Ras p53 p21 and p16 The path-ways generate ROS which act as signalingmolecules withoutcausing oxidative DNA damage ROS result as a tightly regu-lated signaling process for the induction of the cell senescence[157]

(iii) Autophagy High ROS levels mediate p53 activation thatinduces autophagy inhibition This event generates mito-chondrial dysfunction which in turn generates cell senes-cence The autophagy inhibition causes the senescent cellsto aggregate oxidized proteins and protein carbonyls withproducts of lipid peroxidation and protein glycation into thelipofuscin [158]

(iv)miR-210 andmiR-494The induction of thesemicroRNAsby ROS generates mitochondrial dysfunction and autophagyinhibition [159]

The (iii) and (iv) pathways generate vicious loop cyclesin ROS production Autophagy inhibition causes lipofuscinaccumulation which activates further autophagy impairmentand ROS production consequently All the factors (i) (ii)(iii) and (iv) may add to DNA damage and dysfunctions ofbothmitochondria and cell metabolism homeostasis [159] Invitro and preclinical experiments show that ROS decreasinginterventions influence cell senescence progression via theslowdown of telomere shortening and the extension of thecell lifespan Replicative telomere exhaustion DNA damageand OS prime the cell senescence by sharing the activationof the ldquoDNA Damage Responserdquo ATM or ATR kinases ofthese signaling pathways cause p53 stabilization and tran-scriptional activation of the p53 target p21 [9] p53 triggerscell cycle arrest by upregulating p21 which inhibits the cellcycle regulator cyclin-dependent kinases Cdk4 and Cdk2[159] Whereas high OS levels induce the prosenescencefunction of p53 the mild OS levels that are induced by thephysical exercise in humans have a positive effect on cell andmitochondrial homeostasis p53 exerts a dual effect on cellsenescence because of its ability to both decrease and increasethe cellular OS level [160] In parallel to ldquoDNA Damage

Responserdquo the mitochondrial p38-MAPK replenishes theshort-lived DNA damage foci via a ROS feedback loop andinduces the senescent secretoma [161]

The occurrence of the ROS role in cell senescence onsetand maintenance might be relevant for therapeutic interven-tions which aim to modulate ROS levels in cancer cells aswell as in aging processes [156] Human kidney dysfunctionsexemplify progressive stages of ROS-induced cell senescenceROS act like a sensor in regulating the oxygen-dependentgene expression of the kidney and play a leading role inthe inflammatory processes to which the organ is especiallysensitive [162] In conclusion the ROS signaling has high-lighted key factors for the cell senescence induction andmaintenance which are the object of intensive investigations

51 Cell Senescence in Aging and Age-Related Diseases (ROSEffect) The ldquoreplicative cell senescencerdquo is considered anaging hallmark on the basis of two motives (1) the senes-cent cells accumulate in organismal tissues by rate andproportion which parallel the age advancement (2) thesenescent cells accelerate the age-related decrease of tissueregeneration through the depletion of stem and progenitorscells [8 97]While the sequence of proliferative arrest (senes-cence) recruitment of immune phagocytic cells (clearance)and promotion of tissue renewal (regeneration) results inbeing beneficial upon a damaged tissue for instance thesequence is inefficiently completed in aging tissues causingsenescent cells to undergo chronic accumulation [163] Alsoa delicate balance exists between cell senescence positiveeffects on tumor suppression and negative effects on agingrelated processes [164] The transcription factor and tumorsuppressor p53 are involved in DNA repair and cellular stressresponse as well as cellular cycle control In addition p53modulates both the cell senescence and the aging processthrough the coordination of specific cellular pathways [165166] It is not clear whether p53 mechanisms in cell senes-cence and aging are common [160] An increased senescencesecretoma causes detrimental effects over the years andcontributes to the typical disruption of aged tissues [8 167168] Senescent cells endowed with the semiselective markerof senescence p16 drive age-related pathologies which aredelayed or prevented by the selective elimination of thesenescent cells [169] A partial list of suggested markers ofcell senescence in human tissues both aged and affectedby age-related pathologies is reported in Table 2 [170ndash197]Lungs show a typical example of cell senescence associatedwith the progressive age-related organ dysfunction The OSgenerated by the potent cigarette oxidants is a key elementin the pathogenesis of the pulmonary emphysema inducedby the chronic smokingThe fibroblasts that provide essentialsupport and matrix for lung integrity show reduced prolifer-ation rate and increased SA-120573gal activity in patients affectedby pulmonary emphysema These senescent fibroblasts con-tribute to the lung disease by affecting the tissue homeostasisAlso senescent features of the endothelial cells in chronicsmokers associate with premature vessels atherosclerosis Inpatients with severe coronary artery disease OS acceleratesthe senescence of endothelial cells which is related to riskfactors for cardiovascular disease [198] A further example


Table 2 Clinical examples of senescence-associated biomarkers detected in organs and tissues of patients affected by age-related diseases

Organtissue Senescence-associated biomarkers Clinical referencesCardiovascular diseasesAged vascular tissues Telomeres length SA-120573Gal p16 and p21 [170 171]AtherosclerosisSystolic heart failureMalignant tumorsLung cancer Telomeres length SA-120573gal [172 173]

Breast cancer SA-120573gal p21 p16 DEP1 NTAL EBP50 STX4 VAMP3ARMX3 B2MG LANCL1 VPS26A and PLD3 [174 175]

Neuroblastoma SA-120573gal [176]Astrocytoma SA-120573gal [177]Mesothelioma SA-120573gal p21 [178]Melanoma SA-120573gal p16 and p21 [179]Prostate cancer SA-120573gal Glb1 and HP1g [154 180]Liver cancer Telomeres length SA-120573gal [181]Colorectal cancer Short telomeres [182]FibrosisIdiopathic pulmonary fibrosis Telomeres length IGFBP5 and SA-120573gal [183 184]Cystic fibrosis Telomere length p16 [185]Liver fibrosis Telomere length IGFBP-5 SA-120573-gal and p21 [183 186]Renal fibrosis p16 [187 188]Neurological disordersAlzheimerrsquos disease SA-120573-gal [189 190]Other diseasesChronic obstructive pulmonary disease Telomere length p16 p21 and SA-120573gal [191 192]Pulmonary hypertension p16 p21 [192 193]Emphysema Telomere length IGFBP-3 IGFBP-rP1 p16INK4a and p21 [194 195]Benign prostatic hyperplasia SA-120573gal [196 197]

of aging dysfunction related to cell senescence is shown bythe scaffolding protein Caveolin 1 (Cav1) which controlsmolecular signaling in caveolar membranes Cav1 promotescellular senescence in age-related pathologies by mediatingp53 activation with EGF modulation focal adhesion andsmall Rho GTPase-dependent signaling The upregulationof the Cav1 promoter by high ROS levels contributes toexplaining how OS promotes cell senescence effects in agingand age-related diseases [198] In addition the interplaybetween different conditions of mitochondrial homeostasisand ROS-dependent signaling pathways contributes to agingprocess through the cell senescence induction and stabi-lization [199] Yet ROS-independent signaling pathways linkdysfunctions in mitochondria and aging through the cellsenescence process [6 151] As a new approach preclinicaland clinical studies demonstrate the therapeutic effects ofthe aging inhibitor rapamycin whose signaling pathway isinvolved in cellular senescence [160 200]

In conclusion cell senescence reduces the age-relatedtumor development and contributes to human aging sug-gesting that aging might be switched for tumorigenesis [201202] ROS may modulate tumor suppression process whichis induced by the senescence thus participating in anticancer

mechanisms although ROS may act as tumor promoters indefinite conditions [48] With the cell senescence and agingcontrolled by cells and cellular environment the possibilityis suggested that the two processes may be subjected tointerventional therapies [203 204]

52 Epigenetic Mechanism in Cell Senescence (ROS Involve-ment) The epigenetic control of acute and chronic cellularsenescence allows for the two processes that are involved invarious conditions that lead to the cells longevity preventingcell death and tumorigenesis [205] The abrogation of tumorsuppressor pathways as p53 and p16Rb bypasses the cellsenescence thus leading to the tumorigenic phenotypesacquiring [206] The mechanisms that balance the tran-scriptional state of the chromatin are not fully understoodSome regulative changes involve the histone proteins thatcoordinate the DNA accessibility through transcription fac-tors besides the DNA replication and repair The PolycombRepressor Complex 2 (PRC2) initiates and preserves specifichistone methylations thus acting as an epigenetic mark thatmediates targeted genes [207] The repression of the histoneactivity by the Polycomb Group (PcG) proteins causes genesilencing but it can be countered by specific demethylases


which erases the methyl mark [208] The upregulation ofmany PRC target genes leads to global epigenetic changes[209ndash211] Specific transcription factors [212] as well aslong noncoding RNAs [213] are involved in the recruitmentperformed by PRC PRC2 takes a crucial part in silencing thelocus of p16 the marker that is upregulated during cell senes-cence [212] The reversal of chromatin epigenetic pattern viadeacetylation demethylation and dephosphorylation is sig-nificantly involved in underscoring both flexible anddynamicnature of histone modifications [214] The histone demethy-lases JMJD3 produce diverse outputs of biological functiondepending on the action of their transcriptional complexesDifferent expression of these demethylases which havetumor suppressor activities during the ldquostress-induced senes-cencerdquo [215 216] is reflected into cellular phenotype changesand variations associated with cellular senescence [217] TheJMJD3 gene is located near the p53 tumor suppressor genethat is a genomic area that is frequently lost in variousmalig-nancies The SIRT1 histone deacetylase (SIRT1) is a knownregulator of age-related diseases that regulates the senescencesecretoma components by silencing their promoter regionsepigenetically SIRT1 plays a pivotal role in stress modulationalso through p53 deacetylation acting against aging and age-related diseases As indicated above the high ROS levelsactivate p53 which in turn activates p53-mediated apoptosisand cell senescence Moreover SIRT1 regulates the ROS-dependent FOXO factors which are responsible for cellgrowth proliferation and longevity The characteristic ROSincrease during aging may be responsible for the decreasedSIRT1 activity which facilitates the senescent-like phenotypeSIRT1 causes oxidant effects as well as antioxidant effects byacting on epigeneticmodifications which include acetylationand deacetylation (see references in [128 146]) Experimentson cell senescence induction show different molecular mech-anisms in acute versus chronic senescent cells A betterknowledge of the order in which epigenetics mechanismschange during the cell senescence progression from initialtowards full senescence is believed to be vital for findingtherapies against age-related disorders [9]

521 Noncoding RNA Latest genomics tools and sequenc-ing approaches have helped unravel large chromosomesstretches which were previously deemed not transcribed[218 219] These sequence regions contain noncoding RNA(ncRNA) which is known as long lncRNAs and shortncRNAs Among short ncRNAs the microRNAs (miRNAs)have emerged as being able to control the gene expressioneither by blocking targeted mRNA translation or by mRNAdegrading [220 221] Recently ncRNA role is gaining moreimportance in age-associated dysfunctions as cardiovascu-lar diseases [222 223] The senescence-associated lncRNAsare differentially expressed in proliferating and senescentfibroblasts as assessed by RNA sequencing [224ndash226] Tox-icological studies associate increased ROS production withincreased expression of a set of 115 lncRNAs which signifi-cantly affect p53 signaling pathway [227] A mitochondrial-transcribed lncRNA is induced in aorta and endothelial cellsaging during the ldquoreplicative vascular senescencerdquo which ispartly responsible for age-associated cardiovascular diseases

but not in the ldquostress-induced premature senescencerdquo by ROS[228]

522 microRNA (miRNA miR) Normal cellular develop-ment and homeostasis are under the control of miRNAsthroughout the entire life [229] since miRNAs regulatethe gene expression in biological processes as proliferationdevelopment differentiation and apoptosis Yet several miR-NAs families control cell senescence at multiple levels byregulating the autophagy process and the gene expressioninvolved in ATP and ROS production Some miRNAs mayinduce ROS production that generates a self-sustaining ROSvicious cycle [159] miRNAs constitute a connection betweenaging cell senescence and cancer The miRNAs dysregula-tion causes the activation of pathways they normally repressThe event may activate aberrant pathways and also agingmechanism in young individuals [222] Although currentstudies are monitoring miRNA tissues and systemic alter-ations instead of miRNA changes through lifespan andmetabolic modifications several profiles of miRNA expres-sion demonstrate changes during the aging As an examplemiR-29 which targets the genes of type IV collagen andmaintains the structure of the extracellular matrix increasesin elderly mice thus causing collagen decreasing a tissuesbasement membranes weakening [230] Only few miRNAshave been directly linked to age-related changes in cellularand organ functions whereas many miRNAs have beendirectly connected with disease states It is unclear if themodifications of miRNA profiles are mostly involved inpathological changes onset or if they mark the senescenceend which leads to the organ aging and dysfunction Alteredexpression in miRNA activity has been observed in elderlypeople as in the case of miR-34a which belongs to a familywith conserved functions in controlling aging and age-relateddiseases [203 231 232] miR-34a targets ROS scavengerenzymes inducing OS [159] The miR-34a upregulation oroverexpression has been associated with cell proliferationinhibition subsequent cell senescence induction and pre-mature death in both endothelial progenitor and maturecells miR-34a causes memory function impairment when itis upregulated in aged mice and in models for Alzheimerrsquosdisease (AD) while miR-34a targeting restores the memoryfunction [233] Also the miR-34 mutation of the loss-of-function delays the age-related decline markedly thusresulting in extended lifespan and increased resistance to theheat and the OS The human miR-34a is downregulated inParkinsonrsquos disease brain while it is upregulated in AD brains[234] and in plasma of Huntingtonrsquos disease patients [235]

Several miRNA families are modulated by ROS inthe development of mitochondria-mediated cell senescencewhich are indirectly or directly implicated in humanpathologies Little is known about the roles of ROS-modulated miRNAs in cell function The molecular mecha-nisms that control neuronal response to OS have been deeplystudied in different strains of senescence accelerated micebased on the consideration that OS plays a critical role in ADetiology and pathogenesis OS upregulates a group of miR-NAs (miR-329 miR-193b miR-20a miR-296 andmiR-130b)which is associated with affecting 83 target genes Among the


genes mitogen-activated protein kinase signaling pathwayhas been suggested to play a role in pathogenesis of neurode-generative diseases [233] OS effects on vascular homeostasisincluding angiogenesis in physiological processes and age-related diseases are largely studied in human umbilicalvein endothelial cells (HUVECs) considering that miRNAsmodulate endothelial cells response to OS ROS induce theexpression of miR-200 family members (miR-200c miR-141 miR-200a miR-200b and miR-429) which determinesapoptosis and cell senescence both in HUVEC cells and ina model of hind limb ischemia which shows OS-mediatedmechanism [236] The miR-200 family plays a causative rolein the vascular diabetic inflammatory phenotype in a diabeticmodel and in the human vasculopathy disease suggestingthat miR-200 inhibition might represent a therapeutic targetto prevent OS negative effects on cell function and survival[146] Also miR-200 family has been extensively studied inepithelial-to-mesenchymal transition of cancer cells [236]Lately miR-760 and miR-186 upregulation has been asso-ciated with replicative senescence in human lung fibroblastcellsThese miRNAs cooperate to induce senescence throughthe ROS-p53-p21Cip1WAF1 pathway which depends on theROS generated by the downregulation of the protein kinase2 (CK2120572) A better understanding of the mechanisms of CK2regulation might provide new therapeutic options to restorethe function of lungs in aged people An example of theincreasing evidence thatmiRNAs are critically involved in theposttranscriptional regulation of cell functions including theROS signaling modulation is underlined in Figure 2

6 Conclusion and Future Perspectives

The multifactorial and inexorable phenomenon of agingworsens the human functions at multiple levels causing agradual reduced ability to resist stress damage and illnessHealthy aging appears to be an ideal healthcare priority thatentails a better understanding of aging with the aim ofslowing down the process and preventing or even treatingits related pathologies [200] Indeed genetic insights com-bined with findings from animal and cellular models haveadvanced our understanding of pathways that lead to age-related features highlighting possible interventional targets[2ndash5] The cellular senescence process is considered an aginghallmark because it drives the cells through longevity byhampering tumorigenesis and cell death and is involved inmany age-related diseases [97 205 206] The cell senescenceis a feature that characterizes somatic cells except for mosttumor cells and certain stem cells [6ndash10] The senescent cellsproduce a specific secretoma that cause beneficial effectsthrough its autocrine and paracrine mechanisms When thesenescent cell program is inefficiently developed as it occursduring the aging the secretoma causes detrimental effects[151ndash153 167 168 199] In the recent years evidence has beenaccumulating that ROS which include H

2O2 superoxide

anion and hydroxyl radicals generated from both intrinsicand extrinsic events inhibit cell growth and induce cell deathand senescence in a context-dependent manner [157 236]Through the understanding of the ROS role as signalingmolecules in a myriad of signaling pathways ROS levels are

no longer considered as mere metabolic byproducts but arebelieved to be a ldquoredox biologyrdquo that regulates physiologicalfunctions including signal transduction gene expressionand proliferation [37] Firstly it has been evidenced that theDNA damage caused by ROS acting as mutating agents con-tributes to the induction and maintenance of the cell senes-cence process [9 156] More recently particular attention hasbeen focused on the ROS involvement as signaling moleculesin cell senescence induction without causing DNA damageSignaling pathways via Ras p53 p21 and p16 have beendefined to generate ROS which may act as tightly regulatedprocess contributing to the cell senescence induction [20 157158] Cause-effect relationships between cell ROS productionand cell senescence have been investigated through diversepathways that include the field of mitochondrial DNA andautophagy inhibition and the effects of the microRNAs miR-210 and miR-494 in various mitochondrial processes [159]These pathways highlight ROS contribution to prime cellsenescence at diverse levels among which epigenetic levelis attracting more and more attention in studies aimed atthe senescence control [227 233 236] Indeed the epigeneticmodulation provides the essential and flexible interfacebetween the organisms and the environment which resultsin being essential for all the cell functions [122 123 129]throughout the lifespan [135ndash137] A major breakthrough inthe last decades has been the understanding that epigeneticscontribute to human diseases development

In parallel the ldquoOS theory of agingrdquo remains the mostdocumented mechanistic hypothesis of aging although itdoes not necessarily imply ROS imbalance as the earliesttrigger or the main cause of aging [98ndash103] TherapeuticROS modulation is suggested as relevant in aging and relatedevents [95 96 114] Also the senescent cells have beenidentified as a novel potential therapeutic target in the agingand age-related diseases [169 171] Further research is neededto define when and where cell senescence results in beingfavorable or unfavorable to organismal health Both pro-and antisenescent therapies can be equally helpful whenthey are opportunely modulated and balanced Prosenescenttherapies contribute to minimize damage in the cancerdisease and in the active tissue repair by limiting proliferationand fibrosis respectively while antisenescent therapies mayhelp to eliminate accumulated senescent cells and to recovertissue function The current research points to a doubleobjective to define the changes about the redox-sensitive cellpathways and to define the OS role in linking environmentalfactors with epigenetic modifications

Particular emphasis is addressed to novel mechanism ofROS and epigenetics in cell senescence and aging [160 165166] The histone demethylases network is often synergizingwith the action of histone deacetylases histone methyltransferases and various nuclear transcriptional complexesthus ensuring that the chromatinic environment is correctfor the cell [128 146] Preclinical and clinical examplesof ROS-dependent epigenetic modifications [125ndash127 130ndash134 138] extend their effects to aging [135 136] and age-related diseases [137 142ndash144 146ndash149] particularly towardscancer disease [139ndash141 145] Among the noncoding RNAsmiRNAs families provide a broad silencing activity of mRNA


Oxidative stress

ROS

Antioxidants

p53

DNA damage

Mitochondrial dysfunctionApoptosis

Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus

SIRT1 (metabolicoxidative balance)PNUT (DNA protection)

Beneficial effect(i) Developmental senescence(ii) Tumor suppression(iii) Wound healing(iv) Liver fibrosis(v) Cardiac fibrosis

Detrimental effect(i) Age-related phenotypes(ii) Tumor promotion(iii) Obesity and diabetes(iv) Atherosclerosis(v) Other cell senescence

related diseases

Figure 2 ROS-mediated senescence Besides causing DNA damage and mitochondria dysfunction OS activates p53 that in turn inducesprooxidant genes and imbalances antioxidant genes induction The set of alterations caused by ROS lead to induction of cell senescencewhich in turn can develop both positive and negative effects miR34a expression increases with aging in many tissues downregulating SIRT1protein activity (a longevity promoting factor) and PNUT protein (a DNA protecting factor which prevents telomere attrition and is involvedin tissues repairs)

targets in a sequence dependent fashion that modulatesthe stress response [159] Accumulating evidences show thatstressors including ROS potentially alter the function ofmiRNA-processing in aging organisms which renders thecells even more prone to stress linking aging and cancerSeveral miRNAs families induce ROS level increase in agingor target factors involved in the ROS signaling In additionROS increase highly correlates with a specific miRNA dys-regulation which mediates the cross talk between p53 NF-120581B p65 and ROS All these events have been associated withcell senescence [203 231 232] At the same time certainlyseveral miRNAs families are modulated by ROS in the devel-opment of mitochondria-mediated cell senescence whichare indirectly or directly implicated in human pathologies[159 233 236] Because epigenome is so tightly regulated andcomplex understanding individual modifications and theirnetwork of interaction offers the potential to design drugsthat are very effective therapies against a number of diseases[124 203ndash205 219ndash222] More reliable OS biomarkers as wellas OS related epigenetic mechanisms have emerged over thelast years as potentially useful tools to design therapeuticapproaches aimed at modulating in vivo enhanced OS

Abbreviations

AP-1 Activator protein-1DDR DNA Damage ResponseFOXO3a Forkead homeobox type OHIF-1a Hypoxia inducible factor-1ahTERT Human telomerase reverse transcriptasemiRNA miR MicroRNAJAKSTAT Janus kinasesignal transducers and

activators of transcriptionNox NADPH oxidasesNF-120581B Nuclear factor kappa BNS Nitrosative stressNrf2-ARE NF-E2-related factor 2 binding to the

antioxidant responsive elementsp53 Tumor suppressor p53OS Oxidative stressPPAR120574 Peroxisome proliferator-activated receptor

gammaRNS Reactive Nitrosative SpeciesROS Reactive Oxygen SpeciesSA-120573gal Senescence-associated 120573-galactosidaseSOD Superoxide dismutase


Competing Interests

The authors declare that they have no competing interests

Acknowledgments

The authors sincerely apologize to colleagues whose workthey could not include due to space limitations

References

[1] C AWerner ldquoThe older population 2010rdquo httpswwwcensusgovprodcen2010briefsc2010br-09pdf

[2] D B Lynch ldquoThe role of the microbiota in ageing current stateand perspectivesrdquo WIREs Systems Biology and Medicine vol 7pp 131ndash138 2015

[3] A H Shadyab and A Z LaCroix ldquoGenetic factors associatedwith longevity a review of recent findingsrdquo Ageing ResearchReviews vol 19 pp 1ndash7 2015

[4] P V Sergiev O A Dontsova and G V Berezkin ldquoTheories ofaging an ever-evolving fieldrdquo Acta Naturae vol 7 no 1 pp 9ndash18 2015

[5] M Ristow and S Schmeisser ldquoExtending life span by increasingoxidative stressrdquo Free Radical Biology and Medicine vol 51 no2 pp 327ndash336 2011

[6] C Correia-Melo and J F Passos ldquoMitochondria are they causalplayers in cellular senescencerdquo Biochimica et Biophysica ActamdashBioenergetics vol 1847 no 11 pp 1373ndash1379 2015

[7] T Kuilman C Michaloglou W J Mooi and D S Peeper ldquoTheessence of senescencerdquo Genes amp Development vol 24 no 22pp 2463ndash2479 2010

[8] J Campisi and L Robert ldquoCell senescence role in aging andage-related diseasesrdquo Interdisciplinary Topics in Gerontologyvol 39 pp 45ndash61 2014

[9] J M Van Deursen ldquoThe role of senescent cells in ageingrdquoNature vol 509 no 7501 pp 439ndash446 2014

[10] C B Newgard and N E Sharpless ldquoComing of age moleculardrivers of aging and therapeutic opportunitiesrdquo The Journal ofClinical Investigation vol 123 no 3 pp 946ndash950 2013

[11] D G Hirst and T Robson ldquoNitric oxide physiology and path-ologyrdquoMethods in Molecular Biology vol 704 pp 1ndash13 2011

[12] C L Quinlan I V Perevoshchikova M Hey-Mogensen A LOrr and M D Brand ldquoSites of reactive oxygen species genera-tion by mitochondria oxidizing different substratesrdquo RedoxBiology vol 1 no 1 pp 304ndash312 2013

[13] M Fransen M Nordgren B Wang and O Apanasets ldquoRole ofperoxisomes in ROSRNS-metabolism implications for humandiseaserdquo Biochimica et Biophysica ActamdashMolecular Basis of Dis-ease vol 1822 no 9 pp 1363ndash1373 2012

[14] J D Lambeth and A S Neish ldquoNox enzymes and new thinkingon reactive oxygen a double-edged sword revisitedrdquo AnnualReview of Pathology Mechanisms of Disease vol 9 pp 119ndash1452014

[15] M V Chuong Nguyen B Lardy M-H Paclet et al ldquoNADPHoxidases Nox new isoenzymes familyrdquoMedecineSciences vol31 no 1 pp 43ndash52 2015

[16] X De Deken B Corvilain J E Dumont and F Miot ldquoRolesof DUOX-mediated hydrogen peroxide in metabolism hostdefense and signalingrdquo Antioxidants and Redox Signaling vol20 no 17 pp 2776ndash2793 2014

[17] A Phaniendra D B Jestadi and L Periyasamy ldquoFree radicalsproperties sources targets and their implication in variousdiseasesrdquo Indian Journal of Clinical Biochemistry vol 30 no 1pp 11ndash26 2015

[18] G Bresciani I B da Cruz and X Gonzalez-Gallego ldquoMan-ganese superoxide dismutase and oxidative stress modulationrdquoJournal of AdvancedClinical Chemistry vol 68 pp 87ndash130 2015

[19] A Pompella and A Corti ldquoEditorial the changing faces ofglutathione a cellular protagonistrdquo Frontiers in Pharmacologyvol 6 article 98 2015

[20] B Halliwell ldquoFree radicals and antioxidants updating a per-sonal viewrdquo Nutrition Reviews vol 70 no 5 pp 257ndash265 2012

[21] A Rahal A Kumar V Singh et al ldquoOxidative stress prooxi-dants and antioxidants the interplayrdquo BioMed Research Inter-national vol 2014 Article ID 761264 19 pages 2014

[22] E Ginter V Simko and V Panakova ldquoAntioxidants in healthand diseaserdquoBratislavaMedical Journal vol 115 no 10 pp 603ndash606 2014

[23] MAbo RMinakami KMiyano et al ldquoVisualization of phago-somal hydrogen peroxide production by a novel fluorescentprobe that is localized via SNAP-tag labelingrdquoAnalytical Chem-istry vol 86 no 12 pp 5983ndash5990 2014

[24] D Kim G Kim S-J Nam J Yin and J Yoon ldquoVisualizationof endogenous and exogenous hydrogen peroxide using alysosome-targetable fluorescent proberdquo Scientific Reports vol 5article 8488 2015

[25] X Zhou Y Kwon G Kim J-H Ryu and J Yoon ldquoA ratiometricfluorescent probe based on a coumarin-hemicyanine scaffoldfor sensitive and selective detection of endogenous peroxyni-triterdquo Biosensors and Bioelectronics vol 64 pp 285ndash291 2015

[26] G Y Liou and P Storz ldquoDetecting reactive oxygen speciesby immunohistochemistryrdquo in Stress Responses vol 1292 ofMethods in Molecular Biology pp 97ndash104 Springer 2015

[27] E Cabiscol J Tamarit and J Ros ldquoProtein carbonylation pro-teomics specificity and relevance to agingrdquo Mass SpectrometryReviews vol 33 no 1 pp 21ndash48 2014

[28] H E Poulsen L L Nadal K Broedbaek P E Nielsen andA Weimann ldquoDetection and interpretation of 8-oxodG and 8-oxoGua in urine plasma and cerebrospinal fluidrdquo Biochimica etBiophysica Acta (BBA)mdashGeneral Subjects vol 1840 no 2 pp801ndash808 2014

[29] D A Butterfield L Gu F Di Domenico and R A S RobinsonldquoMass spectrometry and redox proteomics applications indiseaserdquoMass Spectrometry Reviews vol 33 no 4 pp 277ndash3012014

[30] L M Fan and J-M Li ldquoEvaluation of methods of detectingcell reactive oxygen species production for drug screening andcell cycle studiesrdquo Journal of Pharmacological and ToxicologicalMethods vol 70 no 1 pp 40ndash47 2014

[31] A Cossarizza R Ferraresi L Troiano et al ldquoSimultaneous ana-lysis of reactive oxygen species and reduced glutathione contentin living cells by polychromatic flow cytometryrdquo Nature Proto-cols vol 4 no 12 pp 1790ndash1797 2009

[32] H Miki and Y Funato ldquoRegulation of intracellular signallingthrough cysteine oxidation by reactive oxygen speciesrdquo Journalof Biochemistry vol 151 no 3 pp 255ndash261 2012

[33] D W Bak and E Weerapana ldquoCysteine-mediated redox sig-nalling in the mitochondriardquo Molecular BioSystems vol 11 no3 pp 678ndash697 2015

[34] C C Winterbourn and M B Hampton ldquoThiol chemistry andspecificity in redox signalingrdquo Free Radical Biology and Medi-cine vol 45 no 5 pp 549ndash561 2008


[35] T Finkel ldquoFrom sulfenylation to sulfhydration what a thiolateneeds to toleraterdquo Science Signaling vol 5 no 215 article pe102012

[36] T H Truong and K S Carroll ldquoRedox regulation of proteinkinasesrdquoCritical Reviews in Biochemistry andMolecular Biologyvol 48 no 4 pp 332ndash356 2013

[37] M Schieber and N S Chandel ldquoROS function in redox signal-ing and oxidative stressrdquo Current Biology vol 24 no 10 ppR453ndashR462 2014

[38] J Korbecki I Baranowska-Bosiacka I Gutowska and DChlubek ldquoThe effect of reactive oxygen species on the synthesisof prostanoids from arachidonic acidrdquo Journal of Physiology andPharmacology vol 64 no 4 pp 409ndash421 2013

[39] A Corcoran and T G Cotter ldquoRedox regulation of protein kin-asesrdquo FEBS Journal vol 280 no 9 pp 1944ndash1965 2013

[40] G A Knock and J P T Ward ldquoRedox regulation of proteinkinases as a modulator of vascular functionrdquo Antioxidants ampRedox Signaling vol 15 no 6 pp 1531ndash1547 2011

[41] J W Zmijewski S Banerjee H Bae A Friggeri E RLazarowski and E Abraham ldquoExposure to hydrogen peroxideinduces oxidation and activation of AMP-activated proteinkinaserdquoThe Journal of Biological Chemistry vol 285 no 43 pp33154ndash33164 2010

[42] S Wang P Song and M-H Zou ldquoAMP-activated proteinkinase stress responses and cardiovascular diseasesrdquo ClinicalScience vol 122 no 12 pp 555ndash573 2012

[43] P D Ray B-W Huang and Y Tsuji ldquoReactive oxygen species(ROS) homeostasis and redox regulation in cellular signalingrdquoCellular Signalling vol 24 no 5 pp 981ndash990 2012

[44] A F Chen D-D Chen A Daiber et al ldquoFree radical biology ofthe cardiovascular systemrdquo Clinical Science vol 123 no 2 pp73ndash91 2012

[45] C Caliceti P Nigro P Rizzo and R Ferrari ldquoROS Notch andWnt signaling pathways crosstalk between three major regula-tors of cardiovascular biologyrdquo BioMed Research Internationalvol 2014 Article ID 318714 8 pages 2014

[46] B Liu Y Chen and D K St Clair ldquoROS and p53 a versatilepartnershiprdquo Free Radical Biology ampMedicine vol 44 no 8 pp1529ndash1535 2008

[47] A V Budanov ldquoThe role of tumor suppressor p53 in the antiox-idant defense and metabolismrdquo in Mutant p53 and MDM2in Cancer vol 85 of Subcellular Biochemistry pp 337ndash358Springer Berlin Germany 2014

[48] B Vurusaner G Poli and H Basaga ldquoTumor suppressor genesand ROS complex networks of interactionsrdquo Free Radical Bio-logy and Medicine vol 52 no 1 pp 7ndash18 2012

[49] L E Tebay H Robertson S T Durant et al ldquoMechanisms ofactivatio nof the transcription factor Nrf2 by redox stressorsnutrient cues and energy status and the pathways throughwhich it attenuates degenerative diseaserdquo Free Radical Biologyamp Medicine B vol 88 pp 108ndash146 2015

[50] P Storz ldquoForkhead homeobox type O transcription factorsin the responses to oxidative stressrdquo Antioxidants and RedoxSignaling vol 14 no 4 pp 593ndash605 2011

[51] T Kietzmann and A Gorlach ldquoReactive oxygen species in thecontrol of hypoxia-inducible factor-mediated gene expressionrdquoSeminars in Cell amp Developmental Biology vol 16 no 4-5 pp474ndash478 2005

[52] N RMadamanchi andM S Runge ldquoRedox signaling in cardio-vascular health and diseaserdquo Free Radical Biology andMedicinevol 61 pp 473ndash501 2013

[53] M J Morgan and Z-G Liu ldquoCrosstalk of reactive oxygenspecies and NF-120581B signalingrdquo Cell Research vol 21 no 1 pp103ndash115 2011

[54] H-J KHawkes T C Karlenius andK F Tonissen ldquoRegulationof the human thioredoxin gene promoter and its key sub-strates a study of functional and putative regulatory elementsrdquoBiochimica et Biophysica Acta (BBA)mdashGeneral Subjects vol1840 no 1 pp 303ndash314 2014

[55] N Bakunina C M Pariante and P A Zunszain ldquoImmunemechanisms linked to depression via oxidative stress andneuroprogressionrdquo Immunology vol 144 no 3 pp 365ndash3732015

[56] E H Verbon J A Post and J Boonstra ldquoThe influence of react-ive oxygen species on cell cycle progression in mammaliancellsrdquo Gene vol 511 no 1 pp 1ndash6 2012

[57] P Chiarugi ldquoFrom anchorage dependent proliferation to sur-vival lessons from redox signallingrdquo IUBMB Life vol 60 no 5pp 301ndash307 2008

[58] G Liu E Chan M Higuchi G Dusting and F Jiang ldquoRedoxmechanisms in regulation of adipocyte differentiation beyonda general stress responserdquo Cells vol 1 no 4 pp 976ndash993 2012

[59] G Serviddio F Bellanti and G Vendemiale ldquoFree radicalbiology for medicine learning from nonalcoholic fatty liverdiseaserdquo Free Radical Biology andMedicine vol 65 pp 952ndash9682013

[60] E Araki and T Nishikawa ldquoOxidative stress a cause and thera-peutic target of diabetic complicationsrdquo Journal of DiabetesInvestigation vol 1 no 3 pp 90ndash96 2010

[61] V O Kaminskyy and B Zhivotovsky ldquoFree radicals in crosstalk between autophagy and apoptosisrdquo Antioxidants amp RedoxSignaling vol 21 no 1 pp 86ndash102 2014

[62] E Migliaccio M Giorgio and P G Pelicci ldquoApoptosis andaging role of p66Shc redox proteinrdquo Antioxidants amp RedoxSignaling vol 8 no 3-4 pp 600ndash608 2006

[63] EDeMarchi F Baldassari A BononiMRWieckowski andPPinton ldquoOxidative stress in cardiovascular diseases and obesityrole of p66Shc and protein kinase Crdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 564961 11 pages 2013

[64] A Magenta S Greco M C Capogrossi C Gaetano and FMartelli ldquoNitric oxide oxidative stress and p66Shc interplayin diabetic endothelial dysfunctionrdquo BioMed Research Interna-tional vol 2014 Article ID 193095 16 pages 2014

[65] S Aleshin M Strokin M Sergeeva and G Reiser ldquoPerox-isome proliferator-activated receptor (PPAR)120573120575 a possiblenexus of PPAR120572- and PPAR120574-dependent molecular pathwaysin neurodegenerative diseases review and novel hypothesesrdquoNeurochemistry International vol 63 no 4 pp 322ndash330 2013

[66] A Popa-Wagner S Mitran S Sivanesan E Chang and A-MBuga ldquoROS and brain diseases the good the bad and the uglyrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID963520 14 pages 2013

[67] S Ventre A Indrieri C Fracassi et al ldquoMetabolic regulation ofthe ultradian oscillatorHes1 by reactive oxygen speciesrdquo Journalof Molecular Biology vol 427 no 10 pp 1887ndash1902 2015

[68] A Maillet and S Pervaiz ldquoRedox regulation of p53 redoxeffectors regulated by p53 a subtle balancerdquo Antioxidants ampRedox Signaling vol 16 no 11 pp 1285ndash1294 2012

[69] R Elkholi and J E Chipuk ldquoHow do I kill thee Let me countthe ways P53 regulates PARP-1 dependent necrosisrdquo BioEssaysvol 36 no 1 pp 46ndash51 2014


[70] J Trujillo L F Granados-Castro C Zazueta A C Anderica-Romero Y I Chirino and J Pedraza-Chaverrı ldquoMitochondriaas a target in the therapeutic properties of curcuminrdquoArchiv derPharmazie vol 347 no 12 pp 873ndash884 2014

[71] S Kovac P R Angelova K M Holmstrom Y Zhang A TDinkova-Kostova and A Y Abramov ldquoNrf2 regulates ROSproduction by mitochondria and NADPH oxidaserdquo Biochimicaet Biophysica Acta (BBA)mdashGeneral Subjects vol 1850 no 4 pp794ndash801 2015

[72] S Ichihara ldquoThe pathological roles of environmental and redoxstresses in cardiovascular diseasesrdquo Environmental Health andPreventive Medicine vol 18 no 3 pp 177ndash184 2013

[73] L-O Klotz C Sanchez-Ramos I Prieto-Arroyo P UrbanekH Steinbrenner and M Monsalve ldquoRedox regulation of FoxOtranscription factorsrdquo Redox Biology vol 6 pp 51ndash72 2015

[74] B Ponugoti G Dong and D T Graves ldquoRole of forkhead tran-scription factors in diabetes-induced oxidative stressrdquo Experi-mental Diabetes Research vol 2012 Article ID 939751 7 pages2012

[75] J Tanaka L Qiang A S Banks et al ldquoFoxo1 links hyper-glycemia to LDLoxidation and endothelial nitric oxide synthasedysfunction in vascular endothelial cellsrdquo Diabetes vol 58 no10 pp 2344ndash2354 2009

[76] Y Funato and H Miki ldquoRedox regulation of Wnt signalling vianucleoredoxinrdquo Free Radical Research vol 44 no 4 pp 379ndash388 2010

[77] S Movafagh S Crook and K Vo ldquoRegulation of hypoxia-inducible Factor-1a by reactive oxygen species new develop-ments in an old debaterdquo Journal of Cellular Biochemistry vol116 no 5 pp 696ndash703 2015

[78] S Cannito E Novo A Compagnone et al ldquoRedoxmechanismsswitch on hypoxia- dependent epithelial-mesenchymal transi-tion in cancer cellsrdquo Carcinogenesis vol 29 no 12 pp 2267ndash2278 2008

[79] J E Klaunig L M Kamendulis and B A Hocevar ldquoOxidativestress and oxidative damage in carcinogenesisrdquo ToxicologicPathology vol 38 no 1 pp 96ndash109 2010

[80] L Zuo B A Rose W J Roberts F He and A K Banes-Berceli ldquoMolecular characterization of reactive oxygen speciesin systemicand pulmonary hypertensionrdquo American Journal ofHypertension vol 27 no 5 pp 643ndash650 2014

[81] Y Lavrovsky B Chatterjee R A Clark and A K Roy ldquoRoleof redox-regulated transcription factors in inflammation agingand age-related diseasesrdquo Experimental Gerontology vol 35 no5 pp 521ndash532 2000

[82] S Coso I Harrison C B Harrison et al ldquoNADPH oxidasesas regulators of tumor angiogenesis current and emergingconceptsrdquo Antioxidants and Redox Signaling vol 16 no 11 pp1229ndash1247 2012

[83] M Maryanovich and A Gross ldquoA ROS rheostat for cell fateregulationrdquo Trends in Cell Biology vol 23 no 3 pp 129ndash1342013

[84] R Liang and S Ghaffari ldquoStem cells redox signaling and stemcell agingrdquo Antioxidants amp Redox Signaling vol 20 no 12 pp1902ndash1916 2014

[85] M Scheibye-Knudsen E F Fang D L Croteau D M Wilsonand V A Bohr ldquoProtecting the mitochondrial powerhouserdquoTrends in Cell Biology vol 25 no 3 pp 158ndash170 2015

[86] S J Dixon and B R Stockwell ldquoThe role of iron and reactiveoxygen species in cell deathrdquo Nature Chemical Biology vol 10no 1 pp 9ndash17 2014

[87] G Filomeni D De Zio and F Cecconi ldquoOxidative stress andautophagy the clash between damage and metabolic needsrdquoCell Death and Differentiation vol 22 no 3 pp 377ndash388 2015

[88] Y Lei K Wang L Deng Y Chen E C Nice and C HuangldquoRedox regulation of inflammation old elements a new storyrdquoMedicinal Research Reviews vol 35 no 2 pp 306ndash340 2015

[89] J M Abais M Xia Y Zhang K M Boini and P-L LildquoRedox regulation of NLRP3 inflammasomes ROS as trigger oreffectorrdquo Antioxidants and Redox Signaling vol 22 no 13 pp1111ndash1129 2015

[90] J Cachat C Deffert S Hugues and K-H Krause ldquoPhagocyteNADPH oxidase and specific immunityrdquo Clinical Science vol128 no 10 pp 635ndash648 2015

[91] U Weyemi and C Dupuy ldquoThe emerging role of ROS-generatingNADPHoxidaseNOX4 inDNA-damage responsesrdquoMutation ResearchReviews inMutation Research vol 751 no 2pp 77ndash81 2012

[92] S W Kang S Lee and E K Lee ldquoROS and energy metabolismin cancer cells alliance for fast growthrdquo Archives of PharmacalResearch vol 38 no 3 pp 338ndash345 2015

[93] W-S Wu ldquoThe signaling mechanism of ROS in tumor progres-sionrdquoCancer andMetastasis Reviews vol 25 no 4 pp 695ndash7052006

[94] S Reuter S C Gupta M M Chaturvedi and B B AggarwalldquoOxidative stress inflammation and cancer how are theylinkedrdquo Free Radical Biology and Medicine vol 49 no 11 pp1603ndash1616 2010

[95] P Davalli F Rizzi A Caporali et al ldquoAnticancer activity ofgreen tea polyphenols in prostate glandrdquo Oxidative Medicineand Cellular Longevity vol 2012 Article ID 984219 18 pages2012

[96] M Assuncao and J P Andrade ldquoProtective action of green teacatechins in neuronal mitochondria during agingrdquo Frontiers inBioscience vol 20 no 2 pp 247ndash262 2015

[97] C Lopez-Otın M A Blasco L Partridge M Serrano and GKroemer ldquoThe hallmarks of agingrdquoCell vol 153 no 6 pp 1194ndash1217 2013

[98] C C Benz and C Yau ldquoAgeing oxidative stress and cancerparadigms in parallaxrdquoNature Reviews Cancer vol 8 no 11 pp875ndash879 2008

[99] F Bonomini L F Rodella and R Rezzani ldquoMetabolic syn-drome aging and involvement of oxidative stressrdquo Aging andDisease vol 6 no 2 pp 109ndash120 2015

[100] J EMartin andM T Sheaff ldquoThe pathology of ageing conceptsand mechanismsrdquo The Journal of Pathology vol 211 no 2 pp111ndash113 2007

[101] A K Biala R Dhingra and L A Kirshenbaum ldquoMitochondrialdynamics orchestrating the journey to advanced agerdquo Journal ofMolecular and Cellular Cardiology vol 83 pp 37ndash43 2015

[102] A Bratic and N-G Larsson ldquoThe role of mitochondria inagingrdquo The Journal of Clinical Investigation vol 123 no 3 pp951ndash957 2013

[103] H P Indo H-C Yen I Nakanishi et al ldquoA mitochondrialsuperoxide theory for oxidative stress diseases and agingrdquo Jour-nal of Clinical Biochemistry and Nutrition vol 56 no 1 pp 1ndash72015

[104] M L Genova and G Lenaz ldquoThe interplay between respiratorysupercomplexes and ros in agingrdquoAntioxidants amp Redox Signal-ing vol 23 no 3 pp 208ndash238 2015

[105] G Barja ldquoThe mitochondrial free radical theory of agingrdquoProgress in Molecular Biology and Translational Science vol 127pp 1ndash27 2014


[106] G Lopez-Lluch C Santos-Ocana J A Sanchez-Alcazar et alldquoMitochondrial responsibility in ageing process innocent sus-pect or guiltyrdquo Biogerontology vol 16 no 5 pp 599ndash620 2015

[107] L Fontana and L Partridge ldquoPromoting health and longevitythrough diet from model organisms to humansrdquo Cell vol 161no 1 pp 106ndash118 2015

[108] M A Bouzid E Filaire A McCall and C Fabre ldquoRadical oxy-gen species exercise and aging an updaterdquo SportsMedicine vol45 no 9 pp 1245ndash1261 2015

[109] Y Zhang Y Ikeno W Qi et al ldquoMice deficient in bothMn superoxide dismutase and glutathione peroxidase-1 haveincreased oxidative damage and a greater incidence of pathol-ogy but no reduction in longevityrdquoThe Journals of GerontologySeries A Biological Sciences andMedical Sciences vol 64 no 12pp 1212ndash1220 2009

[110] M J Kwon K Y Lee H-W Lee J-H Kim and T-Y KimldquoSOD3 variant R213G altered SOD3 function leading to ROSmediated inflammation and damage in multiple organs ofpremature aging micerdquo Antioxidants amp Redox Signaling vol 23no 12 pp 985ndash999 2015

[111] Y H Edrey and A B Salmon ldquoRevisiting an age-old questionregarding oxidative stressrdquo Free Radical Biology and Medicinevol 71 pp 368ndash378 2014

[112] C E Schaar D J Dues K K Spielbauer et al ldquoMitochondrialand cytoplasmic ROS have opposing effects on lifespanrdquo PLoSGenetics vol 1 no 2 Article ID e1004972 2015

[113] G M Cunningham M G Roman L C Flores et al ldquoTheparadoxical role of thioredoxin on oxidative stress and agingrdquoArchives of Biochemistry and Biophysics vol 576 pp 32ndash382015

[114] G Bjelakovic D Nikolova and C Gluud ldquoAntioxidant supple-ments and mortalityrdquo Current Opinion in Clinical Nutrition andMetabolic Care vol 17 no 1 pp 40ndash44 2014

[115] M Breitenbach M Rinnerthaler J Hartl et al ldquoMitochondriain ageing there is metabolism beyond the ROSrdquo FEMS YeastResearch vol 14 no 1 pp 198ndash212 2014

[116] M Lagouge and N-G Larsson ldquoThe role of mitochondrialDNAmutations and free radicals in disease and ageingrdquo Journalof Internal Medicine vol 273 no 6 pp 529ndash543 2013

[117] C Bertram and R Hass ldquoCellular responses to reactive oxygenspecies-induced DNA damage and agingrdquo Biological Chemistryvol 389 no 3 pp 211ndash220 2008

[118] C Fimognari ldquoRole of oxidative RNA damage in chronic-degenerative diseasesrdquo Oxidative Medicine and Cellular Lon-gevity vol 2015 Article ID 358713 8 pages 2015

[119] T Shimi and R D Goldman ldquoNuclear lamins and oxidativestress in cell proliferation and longevityrdquo Advances in Experi-mental Medicine and Biology vol 773 pp 415ndash430 2014

[120] M Rinnerthaler J Bischof M K Streubel A Trost and KRichter ldquoOxidative stress in aging human skinrdquo Biomoleculesvol 5 no 2 pp 545ndash589 2015

[121] L-J Yan ldquoPositive oxidative stress in aging and aging-relateddisease tolerancerdquo Redox Biology vol 2 pp 165ndash169 2014

[122] M Szyf ldquoNongenetic inheritance and transgenerational epige-neticsrdquo Trends in Molecular Medicine vol 21 no 2 pp 134ndash1442015

[123] B Jin Y Li and K D Robertson ldquoDNA methylation superioror subordinate in the epigenetic hierarchyrdquo Genes amp Cancervol 2 no 6 pp 607ndash617 2011

[124] C A Hamm and F F Costa ldquoEpigenomes as therapeutictargetsrdquo Pharmacology and Therapeutics vol 151 pp 72ndash862015

[125] P DrsquoAquila D Bellizzi and G Passarino ldquoMitochondria inhealth aging and diseases the epigenetic perspectiverdquo Bioger-ontology vol 16 no 5 pp 569ndash585 2015

[126] D T Shaughnessy KMcAllister LWorth et al ldquoMitochondriaenergetics epigenetics and cellular responses to stressrdquo Envi-ronmental Health Perspectives vol 122 no 12 pp 1271ndash12782015

[127] C PodriniM Borghesan A Greco V Pazienza GMazzoccoliand M Vinciguerra ldquoRedox homeostasis and epigenetics innon-alcoholic fatty liver disease (NAFLD)rdquo Current Pharma-ceutical Design vol 19 no 15 pp 2737ndash2746 2013

[128] I Afanasrsquoev ldquoNew nucleophilic mechanisms of ros-dependentepigenetic modifications comparison of aging and cancerrdquoAging vol 5 no 1 pp 52ndash62 2014

[129] H Tamaru ldquoConfining euchromatinheterochromatin terri-tory Jumonji crosses the linerdquo Genes amp Development vol 24no 14 pp 1465ndash1478 2010

[130] A Siomek D Gackowski A Szpila et al ldquoEpigenetic modi-fications and NF-120581B pathway activity in CuZn-SOD-deficientmicerdquoMolecular and Cellular Biochemistry vol 397 no 1-2 pp187ndash194 2014

[131] L J Kroese and P G Scheffer ldquo8-hydroxy-2rsquo-deoxyguanosineand cardiovascular disease a systematic reviewrdquo CurrentAtherosclerosis Reports vol 16 no 11 p 452 2014

[132] W Wongpaiboonwattana P Tosukhowong T DissayabutraA Mutirangura and C Boonla ldquoOxidative stress induceshypomethylation of LINE-1 and hypermethylation of theRUNX3 promoter in a bladder cancer cell linerdquo Asian PacificJournal of Cancer Prevention vol 14 no 6 pp 3773ndash3778 2013

[133] Y Wang W Wu C Yao et al ldquoElevated tissue Cr levelsincreased plasma oxidative markers and global hypomethyla-tion of blood DNA in male Sprague-Dawley rats exposed topotassium dichromate indrinking waterrdquo Environmental Toxi-cology 2015

[134] A J Patterson D Xiao F Xiong B Dixon and L ZhangldquoHypoxia-derived oxidative stress mediates epigenetic repres-sion of PKC120576 gene in foetal rat heartsrdquoCardiovascular Researchvol 93 no 2 pp 302ndash310 2012

[135] D Ben-Avraham RHMuzumdar andGAtzmon ldquoEpigeneticgenome-wide association methylation in aging and longevityrdquoEpigenomics vol 4 no 5 pp 503ndash509 2012

[136] M Zampieri F Ciccarone R Calabrese C Franceschi ABurkle and P Caiafa ldquoReconfiguration of DNAmethylation inagingrdquoMechanisms of Ageing and Development vol 151 pp 60ndash70 2015

[137] S D van Otterdijk J C Mathers and G Strathdee ldquoDo age-related changes in DNAmethylation play a role in the develop-ment of age-related diseasesrdquo Biochemical Society Transactionsvol 41 no 3 pp 803ndash807 2013

[138] J Y Min S-O Lim and G Jung ldquoDownregulation of catalaseby reactive oxygen species via hypermethylation of CpG islandII on the catalase promoterrdquo FEBS Letters vol 584 no 11 pp2427ndash2432 2010

[139] Q Wu and X Ni ldquoROS-mediated DNA methylation patternalterations in carcinogenesisrdquo Current Drug Targets vol 16 no1 pp 13ndash19 2015

[140] D Ziech R Franco A Pappa andM I Panayiotidis ldquoReactiveOxygen Species (ROS)mdashinduced genetic and epigenetic alter-ations in human carcinogenesisrdquoMutationResearch vol 711 no1-2 pp 167ndash173 2011


[141] M Venza M Visalli C Beninati G V De Gaetano D Teti andI Venza ldquoCellular mechanisms of oxidative stress and actionin melanomardquo Oxidative Medicine and Cellular Longevity vol2015 Article ID 481782 11 pages 2015

[142] S L Archer G Marsboom G H Kim et al ldquoEpigenetic atten-uation of mitochondrial superoxide dismutase 2 in pulmonaryarterial hypertension a basis for excessive cell proliferation anda new therapeutic targetrdquo Circulation vol 121 no 24 pp 2661ndash2671 2010

[143] V Iacobazzi A Castegna V Infantino and G Andria ldquoMito-chondrial DNA methylation as a next-generation biomarkerand diagnostic toolrdquo Molecular Genetics and Metabolism vol110 no 1-2 pp 25ndash34 2013

[144] J H Santos J N Meyer M Skorvaga L A Annab and BVan Houten ldquoMitochondrial hTERT exacerbates free-radical-mediatedmtDNAdamagerdquoAging Cell vol 3 no 6 pp 399ndash4112004

[145] I R Indran M P Hande and S Pervaiz ldquohTERT overexpres-sion alleviates intracellular ROS production improves mito-chondrial function and inhibits ROS-mediated apoptosis incancer cellsrdquo Cancer Research vol 71 no 1 pp 266ndash276 2011

[146] C Cencioni F Spallotta F Martelli et al ldquoOxidative stressand epigenetic regulation in ageing and age-related diseasesrdquoInternational Journal of Molecular Sciences vol 14 no 9 pp17643ndash17663 2013

[147] F J Rang and J Boonstra ldquoCauses and consequences of age-related changes in DNA methylation a role for ROSrdquo Biologyvol 3 no 2 pp 403ndash425 2014

[148] J Nanduri VMakarenko V D Reddy et al ldquoEpigenetic regula-tion of hypoxic sensing disrupts cardiorespiratory homeostasisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 7 pp 2515ndash2520 2012

[149] N H Zawia D K Lahiri and F Cardozo-Pelaez ldquoEpigeneticsoxidative stress and Alzheimer diseaserdquo Free Radical Biologyand Medicine vol 46 no 9 pp 1241ndash1249 2009

[150] A Lechel A Satyanarayana Z Ju et al ldquoThe cellular level oftelomere dysfunction determines induction of senescence orapoptosis in vivordquo EMBO Reports vol 6 no 3 pp 275ndash2812005

[151] D V Ziegler C D Wiley and M C Velarde ldquoMitochondrialeffectors of cellular senescence beyond the free radical theoryof agingrdquo Aging Cell vol 14 no 1 pp 1ndash7 2015

[152] Y Y Sanders H Liu X Zhang et al ldquoHistone modificationsin senescence-associated resistance to apoptosis by oxidativestressrdquo Redox Biology vol 1 no 1 pp 8ndash16 2013

[153] K Tominaga ldquoThe emerging role of senescent cells in tissuehomeostasis and pathophysiologyrdquo Pathobiology of Aging ampAge-Related Diseases vol 5 Article ID 27743 2015

[154] J Wagner N Damaschke B Yang et al ldquoOverexpression ofthe novel senescencemarker 120573-galactosidase (GLB1) in prostatecancer predicts reduced PSA recurrencerdquo PLoSONE vol 10 no4 Article ID e0124366 2015

[155] R-M Laberge Y Sun A V Orjalo et al ldquoMTOR regulates thepro-tumorigenic senescence-associated secretory phenotype bypromoting IL1A translationrdquo Nature Cell Biology vol 17 no 8pp 1049ndash1061 2015

[156] J F Passos G Nelson C Wang et al ldquoFeedback between p21and reactive oxygen production is necessary for cell senes-cencerdquoMolecular Systems Biology vol 6 article 347 2010

[157] C Lawless D Jurk C S Gillespie et al ldquoA stochastic stepmodel of replicative senescence explains ROS production rate

in ageing cell populationsrdquo PLoS ONE vol 7 no 2 Article IDe32117 2012

[158] E K Ahmed A Rogowska-Wrzesinska P Roepstorff A-LBulteau and B Friguet ldquoProtein modification and replicativesenescence of WI-38 human embryonic fibroblastsrdquo Aging Cellvol 9 no 2 pp 252ndash272 2010

[159] A Lauri G Pompilio and M C Capogrossi ldquoThe mito-chondrial genome in aging and senescencerdquo Ageing ResearchReviews vol 18 pp 1ndash15 2014

[160] A Vigneron and K H Vousden ldquop53 ROS and senescence inthe control of agingrdquo Aging vol 2 no 8 pp 471ndash474 2010

[161] A Freund C K Patil and J Campisi ldquop38MAPK is a novelDNA damage response independent regulator of the senes-cence-associated secretory phenotyperdquoThe EMBO Journal vol30 no 8 pp 1536ndash1548 2011

[162] M Geiszt J B Kopp P Varnai and T L Leto ldquoIdentificationof Renox an NAD(P)H oxidase in kidneyrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 97 no 14 pp 8010ndash8014 2000

[163] D J Baker T Wijshake T Tchkonia et al ldquoClearance of p16Ink4a-positive senescent cells delays ageing-associated disor-dersrdquo Nature vol 479 no 7372 pp 232ndash236 2011

[164] J-P Coppe P-Y Desprez A Krtolica and J Campisi ldquoThesenescence-associated secretory phenotype the dark side oftumor suppressionrdquo Annual Review of Pathology Mechanismsof Disease vol 5 pp 99ndash118 2010

[165] Z Feng M Lin and R Wu ldquoThe regulation of aging andlongevity a new and complex role of p53rdquo Genes amp Cancer vol2 no 4 pp 443ndash452 2011

[166] A Rufini P Tucci I Celardo and G Melino ldquoSenescence andaging the critical roles of p53rdquo Oncogene vol 32 no 43 pp5129ndash5143 2013

[167] J C Jeyapalan and J M Sedivy ldquoCellular senescence and org-anismal agingrdquo Mechanisms of Ageing and Development vol129 no 7-8 pp 467ndash474 2008

[168] H-O Byun Y-K Lee J-M Kim and G Yoon ldquoFrom cellsenescence to age-related diseases differential mechanisms ofaction of senescence-associated secretory phenotypesrdquo BMBReports vol 48 no 10 pp 549ndash558 2015

[169] R M Naylor D J Baker and J M van Deursen ldquoSenescentcells a novel therapeutic target for aging and age-related dis-easesrdquoClinical Pharmacology andTherapeutics vol 93 no 1 pp105ndash116 2013

[170] L M Holdt K Sass G Gabel H Bergert J Thieryand D Teupser ldquoExpression of Chr9p21 genes CDKN2B(p15INK4b) CDKN2A (p16INK4a p14ARF) and MTAP inhuman atherosclerotic plaquerdquo Atherosclerosis vol 214 no 2pp 264ndash270 2011

[171] J C Wang and M Bennett ldquoAging and atherosclerosis mecha-nisms functional consequences and potential therapeutics forcellular senescencerdquo Circulation Research vol 111 no 2 pp245ndash259 2012

[172] R S Roberson S J Kussick E Vallieres S-Y J Chen and D YWu ldquoEscape from therapy-induced accelerated cellular senes-cence in p53-null lung cancer cells and in human lung cancersrdquoCancer Research vol 65 no 7 pp 2795ndash2803 2005

[173] T Fernandez-Marcelo A Gomez I Pascua et al ldquoTelomerelength and telomerase activity in non-small cell lung cancerprognosis clinical usefulness of a specific telomere statusrdquoJournal of Experimental and Clinical Cancer Research vol 34no 1 article 78 2015


[174] CThangavel J L Dean A Ertel et al ldquoTherapeutically activat-ing RB reestablishing cell cycle control in endocrine therapy-resistant breast cancerrdquo Endocrine-Related Cancer vol 18 no 3pp 333ndash345 2011

[175] M Althubiti L Lezina S Carrera et al ldquoCharacterization ofnovel markers of senescence and their prognostic potential incancerrdquo Cell Death and Disease vol 5 no 11 Article ID e15282014

[176] J A Rader M R Russell L S Hart et al ldquoDual CDK4CDK6inhibition induces cell-cycle arrest and senescence in neurob-lastomardquoClinical Cancer Research vol 19 no 22 pp 6173ndash61822013

[177] A Tsugu K Sakai P B Dirks et al ldquoExpression of p57(KIP2)potently blocks the growth of human astrocytomas and inducescell senescencerdquoTheAmerican Journal of Pathology vol 157 no3 pp 919ndash932 2000

[178] R Sidi G Pasello I Opitz et al ldquoInduction of senescencemarkers after neo-adjuvant chemotherapy of malignant pleu-ral mesothelioma and association with clinical outcome anexploratory analysisrdquo European Journal of Cancer vol 47 no2 pp 326ndash332 2011

[179] V C Gray-Schopfer S C Cheong H Chong et al ldquoCellularsenescence in naevi and immortalisation in melanoma a rolefor p16rdquo British Journal of Cancer vol 95 no 4 pp 496ndash5052006

[180] J A Ewald J A Desotelle D R Church et al ldquoAndrogendeprivation induces senescence characteristics in prostate can-cer cells in vitro and in vivordquo The Prostate vol 73 no 4 pp337ndash345 2013

[181] V Paradis N Youssef D Dargere et al ldquoReplicative senescencein normal liver chronic hepatitis C and hepatocellular carcino-masrdquo Human Pathology vol 32 no 3 pp 327ndash332 2001

[182] T Fernndez-Marcelo A Morn C de Juan et al ldquoDifferentialexpression of senescence and cell death factors in non-smallcell lung and colorectal tumors showing telomere attritionrdquoOncology vol 82 no 3 pp 153ndash164 2012

[183] G J Allan J Beattie and D J Flint ldquoEpithelial injury inducesan innate repair mechanism linked to cellular senescence andfibrosis involving IGF-binding protein-5rdquo Journal of Endo-crinology vol 199 no 2 pp 155ndash164 2008

[184] H Yanai A Shteinberg Z Porat et al ldquoCellular senescence-likefeatures of lung fibroblasts derived from idiopathic pulmonaryfibrosis patientsrdquo Aging vol 7 no 9 pp 664ndash672 2015

[185] B M Fischer J K Wong S Degan et al ldquoIncreased expressionof senescence markers in cystic fibrosis airwaysrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 304 no 6 pp L394ndashL400 2013

[186] P M Tachtatzis A Marshall A Aravinthan et al ldquoChronichepatitis B virus infection the relation between hepatitis Bantigen expression telomere length senescence inflammationand fibrosisrdquo PLoS ONE vol 10 no 5 Article ID e0127511 2015

[187] D Portilla ldquoApoptosis fibrosis and senescencerdquo Nephron-Clinical Practice vol 127 no 1ndash4 pp 65ndash69 2014

[188] M Naesens ldquoReplicative senescence in kidney aging renal dis-ease and renal transplantationrdquo Discovery Medicine vol 11 no56 pp 65ndash75 2011

[189] R Bhat E P Crowe A Bitto et al ldquoAstrocyte senescence asa component of Alzheimerrsquos diseaserdquo PLoS ONE vol 7 no 9Article ID e45069 2012

[190] A Salminen J Ojala K Kaarniranta A Haapasalo MHiltunen and H A Soininen ldquoAstrocytes in the aging brain

express characteristics of senescence-associated secretory phe-notyperdquo European Journal of Neuroscience vol 34 no 1 pp 3ndash11 2011

[191] J Birch R K Anderson C Correia-Melo et al ldquoDNAdamage response at telomeres contributes to lung ageing andchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 309no 10 pp L1124ndashL1137 2015

[192] S Adnot V Amsellem L Boyer et al ldquoTelomere dysfunctionand cell senescence in chronic lung diseases therapeutic poten-tialrdquo Pharmacology ampTherapeutics vol 153 pp 125ndash134 2015

[193] H Noureddine G Gary-Bobo M Alifano et al ldquoPulmonaryartery smooth muscle cell senescence is a pathogenic mech-anism for pulmonary hypertension in chronic lung diseaserdquoCirculation Research vol 109 no 5 pp 543ndash553 2011

[194] T Tsuji K Aoshiba and A Nagai ldquoAlveolar cell senescencein patients with pulmonary emphysemardquo American Journal ofRespiratory and Critical Care Medicine vol 174 no 8 pp 886ndash893 2006

[195] J K Alder N Guo F Kembou et al ldquoTelomere length is adeterminant of emphysema susceptibilityrdquo American Journal ofRespiratory and Critical Care Medicine vol 184 no 8 pp 904ndash912 2011

[196] J Choi I Shendrik M Peacocke et al ldquoExpression of senes-cence-associated beta-galactosidase in enlarged prostates frommen with benign prostatic hyperplasiardquo Urology vol 56 no 1pp 160ndash166 2000

[197] P Castro C Xia L Gomez D J Lamb and M IttmannldquoInterleukin-8 expression is increased in senescent prostaticepithelial cells and promotes the development of benign pro-static hyperplasiardquo Prostate vol 60 no 2 pp 153ndash159 2004

[198] H Zou E Stoppani D Volonte and F Galbiati ldquoCaveolin-1 cellular senescence and age-related diseasesrdquo Mechanisms ofAgeing and Development vol 132 no 11-12 pp 533ndash542 2011

[199] D Munoz-Espın and M Serrano ldquoCellular senescence fromphysiology to pathologyrdquo Nature Reviews Molecular Cell Biol-ogy vol 15 no 7 pp 482ndash496 2014

[200] M V Blagosklonny ldquoProspective treatment of age-related dis-eases by slowing down agingrdquoThe American Journal of Pathol-ogy vol 181 no 4 pp 1142ndash1146 2012

[201] M Collado and M Serrano ldquoSenescence in tumours evidencefrom mice and humansrdquo Nature Reviews Cancer vol 10 no 1pp 51ndash57 2010

[202] A S L Chan S N Mowla P Arora and P S Jat ldquoTumoursuppressors and cellular senescencerdquo IUBMB Life vol 66 no12 pp 812ndash822 2014

[203] I Badiola F Santaolalla P Garcia-Gallastegui S-D R Ana FUnda and G Ibarretxe ldquoBiomolecular bases of the senescenceprocess and cancer A new approach to oncological treatmentlinked to ageingrdquo Ageing Research Reviews B vol 23 pp 125ndash138 2015

[204] P Yaswen K L MacKenzie W N Keith et al ldquoTherapeutic tar-geting of replicative immortalityrdquo Seminars in Cancer Biologyvol 35 pp S104ndashS128 2015

[205] G Taormina and M G Mirisola ldquoLongevity epigenetic andbiomolecular aspectsrdquo Biomolecular Concepts vol 6 no 2 pp105ndash117 2015

[206] HA Cruickshanks TMcBryanDMNelson et al ldquoSenescentcells harbour features of the cancer epigenomerdquo Nature CellBiology vol 15 no 12 pp 1495ndash1506 2013


[207] R Cao L Wang H Wang et al ldquoRole of histone H3 lysine 27methylation in polycomb-group silencingrdquo Science vol 298 no5595 pp 1039ndash1043 2002

[208] P A C Cloos J Christensen K Agger and K Helin ldquoErasingthe methyl mark histone demethylases at the center of cellulardifferentiation and diseaserdquo Genes amp Development vol 22 no9 pp 1115ndash1140 2008

[209] M De Cecco S W Criscione E J Peckham et al ldquoGenomes ofreplicatively senescent cells undergo global epigenetic changesleading to gene silencing and activation of transposable ele-mentsrdquo Aging Cell vol 12 no 2 pp 247ndash256 2013

[210] A Scelfo A Piunti and D Pasini ldquoThe controversial role ofthe Polycomb group proteins in transcription and cancer howmuch do we not understand Polycomb proteinsrdquo The FEBSJournal vol 282 no 9 pp 1703ndash1722 2015

[211] D Pasini P A C Cloos J Walfridsson et al ldquoJARID2 regulatesbinding of the Polycomb repressive complex 2 to target genes inES cellsrdquo Nature vol 464 no 7286 pp 306ndash310 2010

[212] N Martin S Raguz G Dharmalingam and J Gil ldquoCo-regula-tion of senescence-associated genes by oncogenic homeoboxproteins and polycomb repressive complexesrdquoCell Cycle vol 12no 14 pp 2194ndash2199 2013

[213] P K Puvvula R D Desetty P Pineau et al ldquoLong noncodingRNA PANDA and scaffold-attachment-factor SAFA controlsenescence entry and exitrdquo Nature Communications vol 5article 5323 2014

[214] R J Klose E M Kallin and Y Zhang ldquoJmjC-domain-contain-ing proteins and histone demethylationrdquoNature Reviews Genet-ics vol 7 no 9 pp 715ndash727 2006

[215] K Agger P A C Cloos L Rudkjaeligr et al ldquoThe H3K27me3demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senes-cencerdquoGenes ampDevelopment vol 23 no 10 pp 1171ndash1176 2009

[216] M Barradas E Anderton J C Acosta et al ldquoHistone demethy-lase JMJD3 contributes to epigenetic control of INK4aARF byoncogenic RASrdquoGenes amp Development vol 23 no 10 pp 1177ndash1182 2009

[217] P M Perrigue M E Silva C D Warden et al ldquoThe histonedemethylase Jumonji coordinates cellular senescence includingsecretion of neural stem cell-attracting cytokinesrdquo MolecularCancer Research vol 13 no 4 pp 636ndash650 2015

[218] S Djebali C A Davis AMerkel et al ldquoLandscape of transcrip-tion in human cellsrdquoNature vol 489 no 7414 pp 101ndash108 2012

[219] J T Y Kung D Colognori and J T Lee ldquoLong noncodingRNAs past present and futurerdquo Genetics vol 193 no 3 pp651ndash669 2013

[220] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[221] S Dimmeler and P Nicotera ldquoMicroRNAs in age-related dis-easesrdquo EMBO Molecular Medicine vol 5 no 2 pp 180ndash1902013

[222] S Greco M Gorospe and F Martelli ldquoNoncoding RNA inage-related cardiovascular diseasesrdquo Journal of Molecular andCellular Cardiology vol 83 pp 142ndash155 2015

[223] L Li and H Y Chang ldquoPhysiological roles of long noncodingRNAs insight from knockout micerdquo Trends in Cell Biology vol24 no 10 pp 594ndash602 2014

[224] K Abdelmohsen A PandaM-J Kang et al ldquoSenescence-asso-ciated lncRNAs senescence-associated long noncoding RNAsrdquoAging Cell vol 12 no 5 pp 890ndash900 2013

[225] V Tripathi Z Shen A Chakraborty et al ldquoLong noncodingRNA MALAT1 controls cell cycle progression by regulatingthe expression of oncogenic transcription factor B-MYBrdquo PLoSGenetics vol 9 no 3 Article ID e1003368 2013

[226] K Abdelmohsen A C Panda M Kang et al ldquo7SL RNArepresses p53 translation by competingwithHuRrdquoNucleic AcidsResearch vol 42 no 15 pp 10099ndash10111 2014

[227] J Nie C Peng W Pei et al ldquoA novel role of long non-codingRNAs in response to X-ray irradiationrdquo Toxicology In Vitro vol30 no 1 pp 536ndash544 2015

[228] V Bianchessi I Badi M Bertolotti et al ldquoThe mitochondriallncRNA ASncmtRNA-2 is induced in aging and replicativesenescence in Endothelial Cellsrdquo Journal of Molecular andCellular Cardiology vol 81 pp 62ndash70 2015

[229] J J Cassidy A R Jha D M Posadas et al ldquoMiR-9a minimizesthe phenotypic impact of genomic diversity by buffering atranscription factorrdquo Cell vol 155 no 7 pp 1556ndash1567 2013

[230] M Takahashi A Eda T Fukushima and H Hohjoh ldquoReduc-tion of type IV collagen by upregulated miR-29 in normalelderly mouse and klotho-deficient senescence-model mouserdquoPloS ONE vol 7 no 11 Article ID e48974 2012

[231] M Kato X Chen S Inukai H Zhao and F J Slack ldquoAge-associated changes in expression of small noncoding RNAsincluding microRNAs in C elegansrdquo RNA vol 17 no 10 pp1804ndash1820 2011

[232] N Liu M Landreh K Cao et al ldquoThe microRNA miR-34 modulates ageing and neurodegeneration in DrosophilardquoNature vol 482 no 7386 pp 519ndash523 2012

[233] R ZhangQ Zhang J Niu et al ldquoScreening ofmicroRNAs asso-ciated with Alzheimerrsquos disease using oxidative stress cell modeland different strains of senescence accelerated micerdquo Jour-nal of the Neurological Sciences vol 338 no 1-2 pp 57ndash64 2014

[234] E Minones-Moyano S Porta G Escaramıs et al ldquoMicroRNAprofiling of Parkinsonrsquos disease brains identifies early downreg-ulation of miR-34bc which modulate mitochondrial functionrdquoHuman Molecular Genetics vol 20 no 15 pp 3067ndash3078 2011

[235] P M Gaughwin M Ciesla N Lahiri S J Tabrizi P BrundinandM Bjorkqvist ldquoHsa-miR-34b is a plasma-stable microRNAthat is elevated in pre-manifest Huntingtonrsquos diseaserdquo HumanMolecular Genetics vol 20 no 11 Article ID ddr111 pp 2225ndash2237 2011

[236] A Magenta C Cencioni P Fasanaro et al ldquomiR-200c is upreg-ulated by oxidative stress and induces endothelial cell apoptosisand senescence via ZEB1 inhibitionrdquo Cell Death and Differenti-ation vol 18 no 10 pp 1628ndash1639 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


stem cells [8] Some observations indicate that senescent cellsdo not necessarily induce mechanisms that promote agingand can be efficiently removed from the human body [9]Thegeneral consensus on cellular damage accumulation as aginginitial event suggests that cell senescence process is a majorquestion regarding biological and clinical aging aspects [10]

Here we review evidences on novel molecular mech-anisms of the ldquoROS signalingrdquo during aging and relatedpathologies because they suggest a way of promoting healthylifespan and improve human aging

2 ROS Physioma Homeostasis

The ROS physioma is a family of highly reactive moleculeswhich includes free oxygen radicals like superoxide anion(O2

∙minus) hydroxyl radical (OH∙) and nonradical oxygenderivatives like the stable hydrogen peroxide (H

2O2) The

superoxide radicals react to form other ROS namely hydro-gen peroxides and hydroxyl radicals and interconvert withreactive nitrogen species (RNS) which generate effects simi-lar to ROS [11] The inefficient electron transfer in mitochon-drial respiratory chain is believed to be a main ROS sourceamong diverse possible enzymatic and nonenzymatic sources[12] Increased expression of catalase and peroxiredoxin-1 molecules are considered as OS markers The familycomprises seven transmembrane members namely Nox1ndash5 [13ndash15] and Duox1-2 [16] ROS are generated by oxygenmetabolism (ie cellular respiration) in all the cells thatutilize oxygen as inevitable consequence of aerobic lifeand may derive from exogenous metals recycling of redoxcompounds radiation chemotherapeutic agents carcino-gens (estrogenic molecules) and other dietary and environ-mental means Generally the ROS increasing levels causenonlinear cellular responses [17] A fine balance betweenoxidant-antioxidant mechanisms leads to continuous mod-ulation of ROS production location and inactivation inboth physiological and pathological conditions Endogenousantioxidants like the enzymes of catalase family glutathionegroup thioredoxin-related group and superoxide dismutase[18] together with exogenous antioxidant as reduced glu-tathione [19] carotenoids and vitamins C and E constitutethe indispensable ROS detoxifying system Neverthelessimbalance of redox homeostasis may occur usually in favorof oxidants so that ROS shift from physiological to poten-tially harmful levels named oxidative and nitrosative stress(OSNS) Increased expression of catalase and peroxiredoxin1 molecules are considered as OS markers [20ndash22]

21 ROSMeasurement Techniques ROS are so highly variableand freely diffusible molecules that the detection of ROS andantioxidants to obtain a picture of the cellular redox statusstill represents a challengeWe stress some specific points andsensitive methods that are subjected to continuous improve-ment Probes and antibodies have been developed to recog-nize oxidative damage by ROSRNS [23ndash25] The tools allowrevealing antioxidant enzymes [26] and a variety of oxidativeproducts as lipid peroxidation products protein carbonyls[27] oxidized DNA products [28] and nitrotyrosine [29]Combinations of diverse approaches will prove essential for

understanding ROS involvement in aging and age-relateddiseases [30] An innovative method simultaneously assessesglutathione hydrogen peroxide and superoxide levels ina single cell together with cell viability alterations thusallowing for defining both oxidant-antioxidant balance andcell death after the administration of a specific stimulus [31]A wide range of pathways and molecular mechanisms thatinvolve ROS suggests determining the redox state of thiols inROS targets which compose the ldquocellular oxidative interfacerdquo[32 33] ROS oxidize specific protein residues of cysteine intosulfenic acid reversibly This molecule functions as OSNSsensor within enzymes and transcriptional regulatory factorsand may allow priming the routes of the versatile ROS action[34ndash36]

22 ROS Functions The increasing comprehension of mech-anisms underlying the oxidant milieu of the cell showsROS as signaling molecules besides metabolic byproductsThey act in a myriad of pathways and networks mediatedby hormones which ranges from protein phosphorylationto transport systems for example ROS do not influencesingle steps of multistep processes rather they influenceall the steps at the same time by reacting with severalcompounds and taking part in several redox reactionsDepending on ROS concentration molecular species andsubcellular localization cell components and signaling path-ways are affected positively or negatively ROS levels arebelieved to be a ldquoredox biologyrdquo that regulates physiologicalfunctions including signal transduction gene expressionand proliferation ldquoRedox biologyrdquo rather than OS has beenproposed to underlie both physiological and pathologicalevents [37] Data in the literature on slow and constantROS increases have to be integrated with data on fast andstepwise ROS increases typical of signaling events whichdeliver messages among cellular compartments Questionsrelated to ROS dynamics and specificity as the effects of theirwaves of concentration on networks with other signalingpathways are investigated in single cells and across differentcells Proteins are the major target of ROSRNS signalingand undergo reversible or irreversible modifications of theirfunctions which result in cell death growth arrest andtransformation The modulation of the reversible oxida-tion of redox-sensitive proteins plays basic roles in sens-ing and transducing the oxygen signal Receptor-dependentor nondependent tyrosine kinases AMP-activated proteinkinases adaptor protein p66SHC and transcription factorsas FOXO (forkhead homeobox type O) Nrf2 (nuclear fac-tor E2-related factor 2) p53 (tumor suppressor 53) NF-120581B (nuclear factor kappa B) AP-1 (activator protein-1)HIF-1a (hypoxia inducible factor-1a) PPAR120574 (peroxisomeproliferator-activated receptor gamma) and 120573-cateninWntsignaling are listed in Table 1 [38ndash81] ROS mediate in vitroresponse towards intra- and extracellular conditions such asgrowth factors cytokines nutrients deprivation andhypoxiawhich regulate cell proliferation differentiation and apopto-sis besides being important cancer hallmarks [82] Intrinsicand extrinsic factors control ROS regulation on cellular self-renewal quiescence senescence and apoptosis during thein vivo tissues homeostasis and repair [83] and in ROS











Adaptor proteins


Nuclear receptors



Membrane receptors







































and chemotherapy)

Mitochondria

ROS


ROS pool

ROS levels

+minus



NADPH oxidase

Acceleratedaging

Cell death

Age-relateddiseases




and noncoding RNAs


































2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























Adaptor proteins


Nuclear receptors



Membrane receptors







































and chemotherapy)

Mitochondria

ROS


ROS pool

ROS levels

+minus



NADPH oxidase

Acceleratedaging

Cell death

Age-relateddiseases




and noncoding RNAs


































2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































and chemotherapy)

Mitochondria

ROS


ROS pool

ROS levels

+minus



NADPH oxidase

Acceleratedaging

Cell death

Age-relateddiseases




and noncoding RNAs


































2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























and chemotherapy)

Mitochondria

ROS


ROS pool

ROS levels

+minus



NADPH oxidase

Acceleratedaging

Cell death

Age-relateddiseases




and noncoding RNAs


































2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















and chemotherapy)

Mitochondria

ROS


ROS pool

ROS levels

+minus



NADPH oxidase

Acceleratedaging

Cell death

Age-relateddiseases




and noncoding RNAs


































2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















2O2 superoxide






Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Oxidative stress

ROS

Antioxidants

p53

DNA damage


Age

miR34a

Aging

Prooxidant genes

Antioxidant genes

Senescence

+minus




related diseases



Abbreviations






Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Competing Interests


Acknowledgments


References


























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging … · 2019. 7. 30. · Review Article ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and