ORIGINAL RESEARCHREVIEW

TheCoronary aging process artery diseaseand potential in women: interventions a review toon extendprevention, life expectancy pathophysiology, diagnosis, and treatment Author copy only Matteo Tosato1 Abstract: Aging is commonly defi ned as the accumulation of diverse deleterious changes Valentina Zamboni1 occurring in cells and tissues with advancing age that are responsible for the increased risk of Leila Fernandes Araujo Abstract: Despite numerous studies on women’s cardiac health throughout the past decade, the 1 disease and death. The major theories of aging are all specifi c of a particular cause of aging, pro- AlessandroAlexandre deFerrini Matos Soeiro number of female deaths caused by cardiovascular disease still rises and remains the leading cause 1,2 viding useful and important insights for the understanding of age-related physiological changes. Matteo Cesari of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular Juliano Lara Fernandes However, a global view of them is needed when debating of a process which is still obscure 1Department of Gerontology, disease, and more specifically coronary artery disease presentations in women, are different than Antônio Eduardo Pesaro in some of its aspects. In this context, the search for a single cause of aging has recently been Geriatrics and Physiatry; Catholic those in men. In addition, pathology and pathophysiology of the disease present significant UniversityCarlos V of SerranoSacred Heart, Jr Rome, replaced by the view of aging as an extremely complex, multifactorial process. Therefore, the gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the Italy; 2Department of Aging and different theories of aging should not be considered as mutually exclusive, but complementary GeriatricHeart Institute Research, (InCor), College University of female population. The reason for this disparity is all steps for female cardiovascular disease of São Paulo, School of Medicine, of others in the explanation of some or all the features of the normal aging process. To date, no Medicine, Institute on Aging, evaluation, treatment and prevention are not well elucidated; and an area for future research. This UniversityBrazil of Florida, Gainesville, FL, convincing evidence showing the administration of existing “anti-aging” remedies can slow aging review brings together the most recent studies published in the field of coronary artery disease USA or increase longevity in humans is available. Nevertheless, several studies on animal models in women and points out new directions for future investigation on some of the important issues. have shown that aging rates and life expectancy can be modifi ed. The present review provides Keywords: coronary artery disease, women, risk factors, prevention, diagnosis, treatment. an overlook of the most commonly accepted theories of aging, providing current evidence of those interventions aimed at modifying the aging process. Keywords:Introduction Aging, anti-aging medicine, caloric restriction, oxidative damage, infl ammation, physical exercise The first female-specific recommendations for preventive cardiology were published in 1999 (Mosca et al 1999). Even though research in the treatment of cardiovascular disease Introduction(CVD) had advanced in many areas, it remains the leading cause of death in women in Agingmost parts is commonly of the world. defi Studies ned as thehave accumulation shown that 500 of diversethousand deleterious women die changes of CVD occur- every ringyear inin cellsthe Unitedand tissues States, with somewhat advancing near age one that death are responsible every minute for the(American increased Heart risk ofAssociation disease and 2003). death Such (Harman index exceeds 2003). Thenot only observation the number that of most deaths of inthe men, animals but also living the innext a natural seven causesenvironment of death rarely in women becomes combined, senescent and (because more importantly, dying earlier coronary for predation, artery disease,disease (CAD) starvation, is believed or drought) to be the(Holliday major cause 2006) responsible suggests that for agingthese deathsis a phenomenon (American uniqueHeart Association to the human 2003). species Over (Hayfl a quarter ick of 2000b). a million In deathsother words, per year the are advancing attributed toknowl- CAD edgealone ofin hygienethe United and States biomedicine (Merz et has al led2004). us to Although discover already the aging high, process, these figuressomething are thatexpected was teleologicallyto rise even more not duringintended the for next us decades, to be experienced due to an increase (Hayfl ick of 2000b).diabetes Theand immediateobesity, as well consequence as the aging of ofthe the extended world population life expectancy (Merz iset represented al 2004). by the increas- ing Evennumber though of older women people have in adeveloped higher frequency countries, of an chest artefact pain/angina of human than civilization men, the (Hayflincidence ick 1998,of obstructive 2000a). CAD in the female population is lower when compared with menLife with expectancy similar symptoms is defi ned (Kenedy as the average et al 1982; total Diamond number et of al years 1983; that Merz a human et al 1999). expects In toaddition, live. Differently, it would appearlife span that is theyoung maximum women number with obstructive of years that CAD a human have cana worse live. Whileprognosis the humanafter acute life spanmyocardial has substantially infarction remained(AMI), whereas unchanged older for women the past in 100,000 similar yearscircumstances at ~125 years,often present life expectancy with larger has number sensibly of comorbidities increased (~27 that years adversely during influence the last Correspondence: Matteo Cesari century),the outcome, especially when compared in Western to men Countries (Coronado (Hayfl et alick 1997). 2000b). Women The withlengthening acute coronary of life Department of Gerontology, Geriatrics expectancysyndromes (ACS) is mainly are alsodue toless the likely elimination to receive of rapid most effective infectious diagnosis diseases and occurring treatment in and Physiatry; Catholic University of SacredCorrespondence: Heart; Largo Carlos F. Vito, V 1; Serrano 00186 Jr youth,than arebetter men hygiene, (Ayanian and the and adoption Epstein of antibiotics 1991; Maynard and vaccines. et al 1996; Pope Rome,Coronary Italy Care Unit, Av. Dr. Enéas et alBefore 2000). examining the hypothesized biological factors at the basis of the aging Carvalho Aguiar, 44 – sala 12 – bloco 2, Tel +39 06 3015 4341 process, it is crucial to underline that aging is not a disease. Based on this assump- FaxSão +39Paulo 06 -3051-911 SP - 05403-900, Brazil Regarding the North American population, the Women’s Ischemic Syndrome EmailTel +55 [email protected] 11 3069 5058 tion,Evaluation Hayfl ick (WISE) estimates study that workshop a potential (Hayes cure et of al the 2004; leading Maseri causes 2004; of Nabel death etin al old 2004; age Fax +55 11 3088 3809 Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

ClinicalVascular Interventions Health and in AgingRisk 2007:2(3)Management 401–412 2006:2(4) 465–475 401465 © 20072006 Dove Dove Medical Medical Press Press Limited. Limited. All rights All rightsreserved reserved Tosato et al REVIEW (ie, cardiovascular disease, stroke, cancer) would only lead intervention in the aging process has been achieved in any to a 15 year-increase in human life expectancy (Hayfl ick other life form in view of the absence of a generally accepted 2000b). Therefore, even in this hypothetical condition, we defi nition of aging and prec markers to measure its rate of will not become immortal, but we will only be able to expe- change (Hayfl ick 2004). Nevertheless, several studies on ani- rienceCoronary how death occurs in the absenceartery of disease. disease Because mal models in havewomen: shown that aging ratesa reviewand life expectancy aging is negatively associated with the ability to respond to can be modifi ed. stresson and positively prevention, related to the homeostatic pathophysiology, balance and diagnosis, and incidence of pathology, death remains the ultimate conse- Evolutionary theory of aging quencetreatment of aging (Kowald and Kirkwood 1996). Evolutionary theory indicates aging as the result from a decline Author copy only The notion that aging requires treatment is based on the in the force of natural selection. This theory was fi rst extensively belief that becoming old is undesirable. In the last decades, formulated in the Forties from the observation of patients with agingLeila has Fernandesreceived a negative Araujo connotationAbstract: and become Despite numerousHuntington’s studies on disease, women’s a cardiacdominant health lethal throughout mutation the past(Haldane decade, the synonymousAlexandre of deterioration, de Matos Soeiroapproachingnumber pathology, of female and deaths 1941). caused Itby was cardiovascular noted that, disease even if still subjects rises and affected remains by the this leading con- cause of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular death.Juliano If our societyLara wouldFernandes learn to value old age to the same dition should be strongly selected, the Huntington’s disease disease, and more specifically coronary artery disease presentations in women, are different than extentAntônio as presently Eduardo done for Pesaro youth, then the research aimed remained in the population. This lack of natural selection can those in men. In addition, pathology and pathophysiology of the disease present significant at slowing,Carlos stopping V Serrano or reversing Jr the aging process would be be explained by the late age of onset for the disease (30–40 gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the as unthinkableHeart Institute as the (InCor), intervention University on the developmentalfemale population. pro- Theyears) reason allowing for this disparity a carrier is to all reproduce steps for femalebefore cardiovasculardying. disease cessesof ofSão youth. Paulo, Instead, School of what Medicine, is desirable and demonstrably Even earlier than these observations, Darwin explained Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This attainable at all times in life, is the preventionreview or brings resolution together thethat most a natural recent selectionstudies published occurs in theorganisms field of coronary dying primarily artery disease of pathology (Hayfl ick 2004). in women and points outfrom new directionspredation for and future environmental investigation hazards on some and of the consequently important issues. The major theories of aging (eg, the freeKeywords: radical theorycoronary arteryevolving disease, a life women, span risk optimized factors, prevention, for their diagnosis,own particular treatment. (Harman 2003), the immunologic theory (Franceschi environment (Weinert and Timiras 2003). Supporting this et al 2000a), the infl ammation theory (Chung et al 2001), hypothesis is the evidence that animals living in a protected mitochondrial theory (Cadenas and DaviesIntroduction 2000)) are all environment (eg, a zoo) live longer, potentially reaching specifi c of a particular cause of aging, providingThe first useful female-specific and their recommendations maximum life spansfor preventive (Holliday cardiology 2006). For were example, published in important insights for the understanding 1999of physiological (Mosca et al 1999).this Even theory though was researchconfi rmed in theby treatmentAustad in of a cardiovascular natural environ- disease changes occurring with aging. However, (CVD)a global had view advanced of mentin many by comparingareas, it remains mainland the leading opossums cause that of deathare subject in women to in them is needed when debating about a processmost which parts of is the still world. predation Studies haveto a shownpopulation that 500 of opossumsthousand women living dieon ofan CVDisland every obscure in some of its aspects (Holliday 2006).year In in this the context, United States,free of somewhat predators near (Austad one death1993). every The minuteevolutionary (American theory Heart the search for a single cause of aging (such asAssociation a single gene 2003). or Suchpredicts index thatexceeds the protectednot only the island number opossums of deaths would in men, have but had also the the decline of a body system) has recently beennext replaced seven causes by the of deaththe opportunity in women combined, to evolve anda longer more importantly,life span, if coronarybenefi cial artery view of aging as an extremely complex, multifactorialdisease (CAD) process is believed to their to be fi tness.the major Indeed, cause islandresponsible opossums for these did deaths live longer(American (Kowald and Kirkwood 1996; Weinert andHeart Timiras Association 2003). 2003).and Over aged a quartermore slowly of a million than deaths their permainland year are counterparts. attributed to CAD In fact, it is very likely that several processesalone simultaneously in the United StatesHowever, (Merz the et so-calledal 2004). Although“disposable already soma high, theory these of aging”figures are interact and operate at different levels of functionalexpected organiza- to rise even arguesmore during that the the somatic next decades, organism due isto effectivelyan increase maintained of diabetes and tion (Franceschi et al 2000b). Therefore, differentobesity, theories as well asof the onlyaging for of thereproductive world population success; (Merz afterwards et al 2004). it is disposable. aging should not be considered as mutually exclusive,Even thoughbut may women Therefore, have a thehigher somatic frequency maintenance of chest (in pain/angina other words than longev- men, the be complementary of others to explain someincidence or all the features of obstructive ity) CADhas a incost. the The female equilibrium population between is lower resources when compared invested with of the normal aging process (Weinert and Timirasmen with 2003). similar symptomsin longevity (Kenedy versus et al 1982;those forDiamond reproductive et al 1983; fi tness Merz determines et al 1999). In Throughout history, humans have alwaysaddition, dreamed ofit beingwould appearlife span that (Loisonyoung women et al 1999). with obstructiveThis antagonism CAD havebetween a worse able to cure aging and diseases, looking forprognosis the discovery after ofacute reproduction myocardial infarction and longevity (AMI), is whereas supported older by womenexperiments in similar a “fountain of youth”. This dream has nevercircumstances become reality often presentin which with the larger limitation number of comorbiditiesthe reproduction that adverselyby destroying influence because of the diffi cult understanding of thethe agingoutcome, process. when comparedgerm line to mencells (Coronado can extend et life al 1997). span in Women both Drosophila with acute coronary and Any intervention able to delay the developmentsyndromes of age-related (ACS) areCaenorhabditis also less likely to elegans receive. rapid effective diagnosis and treatment modifiCorrespondence: cations that are Carlos not consideredV Serrano Jr as diseasesthan areare indicated men (Ayanian and Epstein 1991; Maynard et al 1996; Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). withCarvalho the term Aguiar, “anti-aging 44 – sala medicine” 12 – bloco (Butler2, et al 2002). To Free radical theory of aging date,São we Paulo know - SP of - no05403-900, intervention Brazil that will slow,Regarding stop, theor NorthMore American than 300 theoriespopulation, have the been Women’s proposed Ischemic to explain Syndrome the Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; reverseFax the+55 aging11 3088 process 3809 in humans. It is also doubtful that aging process (Medvedev 1990), but none has yet been Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

402 Vascular Health and Risk Management 2006:2(4) Clinical465–475 Interventions in Aging 2007:2(3)465 © 2006 Dove Medical Press Limited. All rights reserved Aging process and interventions REVIEW generally accepted by gerontologists. Neverthelss, the free and catalase activity (Larsen 1993). The life span extension in radical theory of aging seems to be the one receiving the Caenorhabditis elegans models by using synthetic molecules widest acceptance as a plausible explanation of the primary that mimic catalase and/or superoxide dismutase demon- chemical reactions at the basis of the aging process (De La strates that antioxidant compounds may play an important FuenteCoronary 2002). artery diseaserole in in delaywomen: aging (Melov et ala 2000). review The free radical theory of aging was fi rst formulated in The free radical theory of aging is divided into several theon Fifties prevention, by Harman who hypothesized pathophysiology, a single common hypotheses focusing diagnosis, on the exclusive role ofand particular process, modifi able by genetic and environmental factors, organelles and types of damaged molecules in the aging intreatment which the accumulation of endogenous oxygen radi- process (Weinert and Timiras 2003). For example, it has Author copy only cals generated in cells could be responsible for the aging been hypothesized that mutations in mitochondrial DNA and death of all living beings (Harman 1957; Finkel and accelerate free radical damage by introducing altered en- HolbrookLeila Fernandes 2000). This Araujo theory was thenAbstract: revised Despite in 1972 numerous zyme studies components on women’s intocardiac the health electron throughout transport the past chain. decade, Faulty the (HarmanAlexandre 1972) de Matoswhen mitochondria Soeiro number were ofidentified female deaths as causedelectron by cardiovascular transport disease consequently still rises and results remains in the elevated leading causefree of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular responsibleJuliano Lara for Fernandesthe initiation of most of the free radical radical leakage and ultimately more mitochondrial DNA disease, and more specifically coronary artery disease presentations in women, are different than reactionsAntônio related Eduardo to the Pesaroaging process. It was also postulated mutation and exacerbated oxidant production. This “vi- those in men. In addition, pathology and pathophysiology of the disease present significant thatCarlos the lifeV Serrano span is determined Jr by the rate of free radical cious cycle” of mutation and oxidant production may then gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the damageHeart Institute to the (InCor),mitochondria. University female population. The reasoneventually for this disparity lead to is cellular/organ all steps for female failure, cardiovascular and senescence disease of SãoThe Paulo, increasing School age-relatedof Medicine, oxidative stress seems to be (Mandavilli et al 2002). Another hypothesis argues that Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This a consequence of the imbalance betweenreview the brings free together radical the mostfree recent radicals studies cause published aging in because the field ofof thecoronary accumulation artery disease of production and antioxidant defenses within women a higher and production points out newoxidized directions proteinsfor future investigationin cells. The on age-dependent some of the important reduction issues. of the former (Sastre et al 2000). Keywords: coronary arteryin disease, the capacity women, ofrisk degradation factors, prevention, of oxidized diagnosis, proteins treatment. may All organisms live in an environment that contains be responsible for the build-up of damaged, dysfunctional reactive oxygen species. Mitochondrial respiration, the molecules in the cell (Shringarpure and Davies 2002). basis of energy production in all eukaryotes,Introduction generates It has been suggested that oxidative damage may be an reactive oxygen species by leakingThe intermediates first female-specific from recommendationsimportant source for of preventivesomatic mutations cardiology at were the basispublished of the in the electron transport chain (Finkel and1999 Holbrook (Mosca et 2000).al 1999). Evenso-called though “somatic research mutationin the treatment theory of of cardiovascular aging”. This diseasetheory The universal nature of oxidative(CVD) free radicals,had advanced and in manyhypothesizes areas, it remains that the theaccumulation leading cause of ofgenetic death mutationsin women in possibly of the free radical theory ofmost aging, parts is of suggested the world. Studiessomatic have cells shown represents that 500 thousandthe specifi women c cause die of of senescenceCVD every by the presence of superoxide dismutaseyear in inthe all United aerobic States, (Beckman somewhat and near Ames one 1998).death every minute (American Heart organisms and responsible for scavengingAssociation superoxide 2003). Such indexThe exceeds identifi not cation only the of numberfree radical of deaths reactions in men, as butpromoters also the anions (Finkel and Holbrook 2000).next Moreover, seven causes cellular of death of in thewomen aging combined, process andimplies more that importantly, interventions coronary aimed artery at oxidative damage is indiscriminate.disease In fact, (CAD) oxidative is believed limiting to be the or major inhibiting cause themresponsible should for be these able todeaths reduce (American the rate modifications have been shown toHeart occur Association in of DNA, 2003). Overof formation a quarter ofof a aging million changes deaths perwith year a consequent are attributed reduction to CAD protein, and lipid molecules (Weinertalone and inTimiras the United 2003). States of (Merz the aging et al 2004).rate and Although disease alreadypathogenesis high, these(Harman figures 2003). are Elevated levels of both oxidant-damagedexpected to DNA rise even and more An during ideal the “golden next decades, triangle” due of tooxidative an increase balance, of diabetes in which and protein have been found in aged organismsobesity, as well(Beckman as the aging oxidants, of the world antioxidants population and (Merz biomolecules et al 2004). are placed at each and Ames 1998; Shringarpure and DaviesEven 2002). though women haveapex, a has higher been frequency described of (Carmeli chest pain/angina et al 2002). than In amen, normal the However, even if it is clear that theincidence age-related of obstructiveaccumu- CADsituation, in the a femalebalanced-equilibrium population is lower exists when among compared these three with lation of oxidative damage, it is not yetmen clear with whethersimilar symptoms this elements. (Kenedy Excess et al 1982; generation Diamond of etfree al 1983;radicals Merz may et overwhelmal 1999). In process contributes to aging in all organisms.addition, The it wouldincreased appear natural that young cellular women antioxidant with obstructivedefenses leading CAD to have lipid a peroxi- worse life span of transgenic fl ies expressing prognosissuperoxide after dismutase acute myocardialdation and infarction further contributing(AMI), whereas to muscle older women damage in (Bowles similar indicates that free radical-scavenging enzymescircumstances are suffi often cient present et with al 1991; larger Meydani number ofet comorbiditiesal 1993). that adversely influence to delay aging in Drosophila (Tower 2000).the outcome, Moreover, when fl comparedies toEven men if (Coronado antioxidant et supplementation al 1997). Women is with receiving acute coronarygrowing selected for increased longevity havesyndromes elevated (ACS) levels are of alsoattention less likely and to receiveis increasingly rapid effective adopted diagnosis in Western and countries,treatment superoxideCorrespondence: dismutase Carlos V andSerrano increased Jr resistancethan are to men oxidative (Ayanian supporting and Epstein evidence 1991; is still Maynard scarce and et equivocal. al 1996; In Pope fact, Coronary Care Unit, Av. Dr. Enéas et al 2000). stressCarvalho (Arking Aguiar, 44et al– sala2000). 12 – It bloco has also 2, been demonstrated that even if some epidemiological studies shown that dietary long-livedSão Paulo - mutantSP - 05403-900, worms areBrazil also resistantRegarding to oxidative the stress North supplementationAmerican population, with vitamin the Women’s E decreases Ischemic the risk Syndrome of cancer Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; andFax +55show 11 an 3088 age-dependent 3809 increase in superoxide dismutase and cardiovascular disease, such observations are not universal Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

Clinical Interventions in Aging 2007:2(3) Vascular Health and Risk Management 2006:2(4) 465–475 403465 © 2006 Dove Medical Press Limited. All rights reserved Tosato et al REVIEW (Butler et al 2002). The only capability of reducing oxidative It has been demonstrated by the Framingham Longevity damage through antioxidant supplementation is limited. McCall Study of Coronary Heart Disease that longevity is more and Frei (1999) stated that “except for supplemental vitamin E, strongly associated with age of maternal death than that of and possibly vitamin C, being able to signifi cantly lower paternal death, suggesting that mitochondrial DNA inheri- lipidCoronary oxidative damage in both smokersartery and nonsmokers, disease the tance mightin playwomen: an important role ina determining review longevity current evidence is insuffi cient to conclude that antioxidant (Brand et al 1992). Even if the matter is still controversial vitaminon supplementation prevention, materially reduces oxidativepathophysiology, damage (Ross et al 2001), several diagnosis, studies demonstrate that longevityand in humans”. Therefore, the longevity-extending potential of is associated with specifi c mitochondrial DNA polymor- antioxidanttreatment supplementation (in particular, vitamin E as the phisms (Ivanova et al 1998; Tanaka et al 1998; De Benedictis Author copy only most studied one) remains uncertain even in animal studies et al 1999). (Anisimov 2001). The only robust fi nding that a pharmaco- The mitochondrial theory of aging is often considered logicalLeila antioxidant Fernandes can extendAraujo longevity hasAbstract: been reported Despite numerousas an studiesextension on women’s and refi cardiac nement health of thethroughout free radical the past theory decade, the by MelovAlexandre and colleagues de Matos (2000) Soeiro in an animalnumber model of femalein dem- deaths(Harman caused by cardiovascular1972; Miquel disease et al still 1980). rises andMitochondrial remains the leading DNA cause of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular onstratingJuliano that Lara EUK-134, Fernandes a compound with both catalase and mutations accumulate progressively during life and are disease, and more specifically coronary artery disease presentations in women, are different than superoxideAntônio dismutase Eduardo activities, Pesaro signifi cantly extends longevity directly responsible for a measurable defi ciency in cellular those in men. In addition, pathology and pathophysiology of the disease present significant in nematodes.Carlos V Serrano Jr oxydative phosphorylation activity, leading to an enhanced gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the Heart Institute (InCor), University female population. Thereactive reason for oxygen this disparity species is all production. steps for female This cardiovascular latter results disease of São Paulo, School of Medicine, in an increased rate of mitochondrial DNA damage and MitochondrialBrazil theory of agingevaluation, treatment and prevention are not well elucidated; and an area for future research. This The age-related physiological decline seemsreview to be brings due to together the themutagenesis, most recent studiestriggering published the onset in the offield a of“vicious coronary cycle” artery diseaseof accumulation of defects in the several metabolicin women pathways. and points outexponentially new directions forincreasing future investigation oxidative on damage some of theand important dysfunc- issues. Looking for potential candidates to progressiveKeywords: accumu- coronary arterytion, whichdisease, ultimately women, risk culminates factors, prevention, in death. diagnosis,Supporting treatment. the lation of damage over a lifetime, it seems reasonable to primary importance of mitochondria in the aging process exclude RNA, proteins and other cellular macromolecules and in determining longevity, it has been documented that with a rapid turned over. For this mainIntroduction reason, studies several mutagenic chemicals and lipophilic carcinogens (eg, exploring mechanisms of aging have alwaysThe beenfirst female-specificfocused polycyclic recommendations aromatic forhydrocarbons) preventive cardiology tend to preferentially were published in on DNA. In mammalian cells, mitochondria1999 and (Mosca the nucleus et al 1999). damage Even mitochondrialthough research DNA in the (Wunderlich treatment of cardiovascularet al 1970; Allen disease are the only organelles possessing DNA. It(CVD) appears had obvious advanced andin many Coombs areas, 1980; it remains Niranjan the etleading al 1982; cause Rossi of deathet al 1988).in women It in that the physiological integrity of the cell ismost strongly parts of linked the world. can Studies then behave hypothesized shown that 500that thousand a life-long women exposure die of to CVD these every to the integrity of its genome. year in the United States,environmental somewhat toxins near mayone leaddeath to everya preferential minute accumulation(American Heart Even if mitochondrial DNA comprisesAssociation only 1%–3% 2003). of Suchof mitochondrialindex exceeds not DNA only damage the number and accelerateof deaths in aging. men, but also the genetic material in animal cells, its contributionnext seven to cellular causes of deathThe in superoxidewomen combined, anion radical and more (or superoxide)importantly, andcoronary hydro- artery physiology seems to be much greater thandisease what (CAD)expected is believed gen peroxide, to be the majorrespectively cause responsible the products for of these the univalent deaths (American and from its size alone. Mitochondrial DNA, inHeart close Association proximity 2003).bivalent Over areduction quarter of of a million oxygen, deaths are producedper year are during attributed normal to CAD to the sites of oxygen radical productionalone and unprotectedin the United Statesaerobic (Merz metabolism et al 2004). and constituteAlthough physiologicalalready high, theseintracellular figures are by the histones that are associated with expectednuclear DNA,to rise iseven metabolitesmore during (Cadenasthe next decades, and Davies due to2000). an increase Several of reactions diabetes and a sensitive target for oxygen radical attack.obesity, In fact, as well it has as the inaging biological of the world systems population contribute (Merz to etthe al steady 2004). state concen- been estimated that the level of oxydatively oxidizedEven though bases women trations have of a highersuperoxide frequency and hydrogenof chest pain/angina peroxyde, thanalthough men, the in mitochondrial DNA is 10- to 20-fold higherincidence than of that obstructive in mitochondria CAD in the seem female to bepopulation quantitatively is lower the when most compared important with nuclear DNA (Richter et al 1988; Ames 1989).men with Moreover, similar symptoms source (Kenedy (Cadenas et aland 1982; Davies Diamond 2000). et al 1983; Merz et al 1999). In mitochondrial DNA encodes polypeptidesaddition, of the electronit would appearAlthough that young mild women amounts with of obstructiveoxidative damage CAD have such a asworse transfer chain as well as components requiredprognosis for after their acute that myocardial experienced infarction during (AMI),exercise whereas training older(Davies women et al 1982)in similar synthesis. Therefore, any coding mutationscircumstances in mitochon- often presentmay actually with larger be the number stimulus of comorbidities for physiological that adversely mitochondrial influence drial DNA will affect the entire electronthe transfer outcome, chain, when comparedbiogenesis, to men more (Coronado severe, more et al 1997).extensive, Women or more with acuteprolonged coronary potentially altering both the assembly andsyndromes function (ACS)of the areoxidative also less likelydamage to isreceive clearly rapid toxic effective (Cadenas diagnosis and Davies and 2000). treatment productsCorrespondence: of numerous Carlos nuclear V Serrano genes Jr in thanelectron are transfer men (Ayanian and Epstein 1991; Maynard et al 1996; Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). chainCarvalho complexes. Aguiar, 44Finally, – sala 12defects – bloco in 2, the electron transfer Gene regulation theory of aging chainSão can Paulo have - SP pleiotropic - 05403-900, effectsBrazil because Regardingaffecting thethe NorthThe geneAmerican regulation population, theory theof agingWomen’s proposes Ischemic that senes-Syndrome Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; entireFax cellular +55 11 energetics3088 3809 (Alexeyev et al 2004). cence is the resulting of changes occurring in the gene Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

404 Vascular Health and Risk Management 2006:2(4) Clinical465–475 Interventions in Aging 2007:2(3)465 © 2006 Dove Medical Press Limited. All rights reserved Aging process and interventions REVIEW expression (Kanungo 1975; Weinert and Timiras 2003). from the tissue or an increased proportion of dysfunctional Although it is clear that many genes show changes in cells. expression with age, it is unlikely that selection could act The recent isolation of nearly totipotent cells, such as on genes that promote senescence directly (Weinert and human embryonic stem cells, offers a great range of potential TimirasCoronary 2003). To date, evidence artery in this fi eld disease remains con- opportunities. in women: These cells express a telomerasereview and appear to troversial, and aging should be more safely considered as a maintain an immortal phenotype even after extended culture stochasticon prevention, process, rather than a programmed pathophysiology, mechanism in vitro. Cells and tissuesdiagnosis, derived from such andcultures may directly governed by genes. At least 15 different genetic provide the unique advantage of possessing a large replicative manipulationstreatment inducing life extension in organisms such capacity and broad differentiation potential. Author copy only as yeast, fruit fl ies, nematodes, and mice have been dem- However, it is important to note that formidable hurdles onstrated (Butler et al 2002). However, it is still unknown are yet to be overcome. Cells derived from established human howLeila the Fernandes proteins coded Araujo by these genesAbstract: are acting Despite in numerous the embryonic studies on women’s stem cell cardiac lines health will throughout probably thenot past prove decade, to thebe regulationAlexandre of delongevity. Matos OnSoeiro the othernumber hand, of other female studies deaths causedimmunologically by cardiovascular compatible disease still riseswith and most remains patients. the leading This causemay of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular performedJuliano Lara using Fernandes animal models have suggested that genes be resolved by immunosuppressive therapy, genetic modi- disease, and more specifically coronary artery disease presentations in women, are different than supposedAntônio toEduardo be involved Pesaro in aging are not able to reverse or fi cation of the cells to reduce immunogenicity, or possibly those in men. In addition, pathology and pathophysiology of the disease present significant arrestCarlos the V inexorable Serrano expressionJr of the molecular disorder the creation of a chimeric immune system in the patient to gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the thatHeart is Institutethe hallmark (InCor), of agingUniversity (Hayfl ickfemale 2004). population. The reasoninduce for this tolerance. disparity The is allrecent steps discovery for female of cardiovascular cell reprogramming disease of SãoIt mayPaulo, be School that the of Medicine,genome is necessary to govern bio- through nuclear transfer offers a path to the reprogramming Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This logical development and maintenance,review but unnecessarybrings together to the mostof a recent patient’s studies cell, published thereby in thereverting field of coronaryit to an artery autologous disease cause the animal’s aging. Because genesin women do not and drivepoints theout newembryonic directions for stem future cell. investigation The ethics on of some the ofembryonic the important stem issues. cell aging process, an understanding of Keywords:the human coronary genome, artery technology disease, women, and therisk usefactors, of nuclearprevention, transfer diagnosis, in medicine treatment. is even beyond what is known today, will not provide insights currently a matter of intense debate. Finally, it remains to into a process that is random and thermodynamically driven be seen whether such new tissue (even if it were autologous) (Hayfl ick 2004). Recently, an insulin-likeIntroduction signaling pathway would be adequately vascularized and subsequently function regulating life span in worms, fl ies, andThe mice first has female-specific been identi- recommendationsappropriately in thefor patient.preventive cardiology were published in fi ed (Tatar et al 2003). Life span extension1999 (Moscaresults fromet al 1999). the Even though research in the treatment of cardiovascular disease activation of a conserved transcription(CVD) factor hadin response advanced to in manyTelomere areas, it remains theory the leading of causeaging of death in women in a reduction in insulin-like signaling, mostsuggesting parts of that the world.gene StudiesThe cellular have shown senescence that 500 theory thousand of womenaging was die formulatedof CVD every in expression can regulate life span. year in the United States,1965 somewhat when cellnear senescenceone death everywas describedminute (American as the process Heart Studies of human centenaries andAssociation their relatives 2003). have Such indexoccurring exceeds in normalnot only human the number cells ofin deathsculture in and men, characterized but also the identifi ed a signifi cant genetic aspect ofnext the sevenability causes to survive of death by in awomen limited combined, number of and cell more divisions importantly, (Hayfl ickcoronary 1965). artery This to exceptional ages. By identifying a locusdisease on (CAD) chromosome is believed limit to be inthe “replicative major cause capacity” responsible occurs for these after deaths a characteristic (American 4 that may contain gene(s) promotingHeart longevity Association (Puca et2003). al Overnumber a quarter of cell of adivisions million deaths and results per year in are terminally attributed arrested to CAD 2001), it has recently been supported thealone theory in the of Uniteda genetic States cells (Merz with et alaltered 2004). physiology Although (Campisialready high, 2003). these figures are component for exceptional longevity.expected to rise even more duringTelomeres the next are decades, specialized due to DNA an increase sequences of diabetes located and at If it will be confi rmed that changesobesity, in gene as wellexpression as the aging the of ends the world of eukariotic population chromosomes. (Merz et al 2004). In humans, telomeres can modulate the aging process, a majorEven step thoughforward women the haveare composed a higher frequency by repeated of sequenceschest pain/angina TTAGGG than reiterated men, the understanding of aging will be completedincidence and of a obstructive starting CADin tandem in the femalefor up populationto 15 kilobases is lower at when birth compared (Ahmed withand point for the development of interventionsmen aimed with similar at delaying symptoms Tollefsbol (Kenedy et2001). al 1982; Telomeres Diamond etare al synthesized1983; Merz et by al 1999).telomer- In aging provided. addition, it would appearase, that a ribonucleoproteinyoung women with reverse obstructive transcriptase CAD have enzyme a worse that Gene manipulations possible in laboratoryprognosis animals after appearacute myocardialmaintains infarction the lengths (AMI), of chromosomes whereas older (Lingner women et in al similar1997). to have limited potential for direct applicationcircumstances in humans, often present Telomere with larger sequences number of stabilize comorbidities chromosomal that adversely ends influenceby bind- although they do provide insight intothe important outcome, biological when compared ing toto men proteins (Coronado that preventet al 1997). them Women from with being acute recognized coronary factors in longevity determination in modelsyndromes systems. (ACS) In con- are alsoas less double-stranded likely to receive breaks rapid effective by repair diagnosis enzymes and (de treatment Lange trast,Correspondence: the potential Carlos of Vcell Serrano replacement Jr than therapy are in men reversing (Ayanian 1992). and The Epstein attrition 1991; of chromosomal Maynard ettermini, al 1996; caused Pope by Coronary Care Unit, Av. Dr. Enéas et al 2000). someCarvalho of Aguiar,the adverse 44 – sala effects 12 – ofbloco aging 2, appears to be substantial. loss of telomerase, can lead to breaks and subsequent AgingSão Paulo is accompanied- SP - 05403-900, by someBrazil loss of tissueRegarding function, thewhich North translocation,American population, fusion, or the rearrangement Women’s Ischemic within these Syndrome DNA Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; isFax at +55 least 11 partially 3088 3809 due to either the age-related loss of cells regions (de Lange 1992). Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

Clinical Interventions in Aging 2007:2(3) Vascular Health and Risk Management 2006:2(4) 465–475 405465 © 2006 Dove Medical Press Limited. All rights reserved Tosato et al REVIEW The telomerase enzyme, which stabilize chromosomal Supporting the hypothesized relationship between termini by adding telomere repeats to the ends of chro- telomeres and aging, it has been demonstrated that some mosomes using a dedicated RNA template (Greider and telomere dysfunctions are involved in the premature aging Blackburn 1989; Artandi 2006), is of considerable interest characteristic of progerias. For example, the DNA helicase to gerontologists.Coronary Its expression artery is thought to be diseasenecessary protein, in that iswomen: mutant in the Werner’s a syndrome,review is required for cellular immortalization (Rhyu 1995), and its absence for the effi cient replication and stability of telomeres. There- mayon constitute prevention, a fundamental basis for cellular pathophysiology, aging (Harley fore, by extension, as itdiagnosis, happens in the premature and aging, et al 1990; Ahmed and Tollefsbol 2001; Artandi 2006). telomeres might be, at least partially, responsible for the Immortaltreatment cells in general have a stable telomere length normal human aging (Artandi 2006). Author copy only and mortal cells have telomeres that shorten with each cell The human telomerase reverse transcriptase (hTERT), division, thus establishing a link between the presence of the active component of telomerase, has been identifi ed and telomerase,Leila Fernandes chromosomal Araujo stability, and the Abstract:mortality of Despite cells. numerouscloned studies and its on messenger women’s cardiac RNA health is undetectable throughout thein differenti- past decade, the In fact,Alexandre specialized de immortal Matos cellSoeiro types (suchnumber as stem of female cells, deaths ated caused cells by cardiovascularthat do not expressdisease still telomerase, rises and remains but is the abundant leading cause of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular germJuliano cells, and Lara T lymphocytes) Fernandes express telomerase and will in undifferentiated cells expressing telomerase (Meyerson disease, and more specifically coronary artery disease presentations in women, are different than eitherAntônio maintain Eduardotelomere length Pesaro or delay telomere attrition. et al 1997). Although post-transcriptional mechanisms those in men. In addition, pathology and pathophysiology of the disease present significant Additionally,Carlos V telomerase Serrano isJr up-regulated in 85% to 95% of may modify hTERT activity (Liu et al 1999), the expres- gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the cancerHeart cells, Institute which (InCor), show noUniversity net loss of averagefemale population. telomere Thesion reason of forhTERT this disparity correlates is all directly steps for with female telomerase cardiovascular activity disease length,of São suggesting Paulo, School that telomereof Medicine, stability may be required and substantial evidence indicates that hTERT activity is Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This for cells to escape replicative senescence andreview to bringsproliferate together thecontrolled most recent primarily studies atpublished the level in ofthe transcription field of coronary (Cong artery et diseaseal indefi nitely (Shay and Wright 1996; Artandiin women 2006). and points out1999; new directions Wick et foral future1999). investigation The telomerase on some promoter of the important must be issues. In actively dividing differentiated cells,Keywords: with each coronary cell artery“ON” disease, in cells women, that can risk proliferate factors, prevention, indefi nitely, diagnosis, but “OFF” treatment. in division, a small amount of DNA is necessarily lost at each cells with limited proliferative lifespan. Unfortunately, little chromosome end, resulting in ever-shorter telomeres and is still known about the switching mechanism that controls altered telomere structure, eventually leadingIntroduction to the cessa- telomerase expression, leading to its down-regulation and tion of cellular proliferation (Blackburn 2000;The firstWeinert female-specific and subsequent recommendations cellular mortality for preventive in somatic cardiology cells. were published in Timiras 2003). This progressive shortening1999 of (Mosca telomeres et al 1999). EvenMoreover, though even research if studies in the treatment of telomere of cardiovascular shortening and disease starts soon after conception, when cells begin(CVD) widespread had advanced telomerasein many areas, show it remains great promise the leading in helping cause of to death elucidate in women the in differentiation. Although in some of thesemost cells parts telomerase of the world. underlying Studies have basis shown of cellular that 500 aging,thousand it iswomen not yet die clear of CVD how every is inactivated before birth, in others some telomeraseyear in the activity United States,this knowledge somewhat wouldnear one enhance death ourevery understanding minute (American of aging Heart can be detected after birth (Ulaner and GiudiceAssociation 1997; Ahmed 2003). Suchof indexthe individual. exceeds not In only fact, the itnumber is possible of deaths the in presence men, but alsoof the and Tollefsbol 2001). Thus, telomere shorteningnext seven and the causes loss of deathsome intissues women in combined, which proliferative and more importantly, failure contributes coronary toartery of telomerase in normal somatic cells havedisease been implicated (CAD) is believed the declining to be the majorphysiology cause responsibleassociated forwith these aging, deaths but (American those as a potential molecular clock triggering cellularHeart Association senescence 2003).tissues Over have a quarter not ofbeen a million unequivocally deaths per yearidentifi are attributeded. Only toup CAD (Harley et al 1990), loss of proliferative capacity,alone in theand Unitedage- Statesto 70% (Merz of immortalized et al 2004). Although human somaticalready high,cell lines these (Bryan figures are related pathologies (Campisi 1997; Fosselexpected 1998). to rise even etmore al 1997) during and the about next 90%decades, of human due to canceran increase cell lines of diabetes (Shay and The fi nding that most of the cells expressingobesity, telomerase, as well as the andaging Gazdar of the world 1997) population have demonstrated (Merz et al in2004). vitro telomerase instead of undergoing cellular aging, maintainEven a youthful though women activity, have suggestinga higher frequency that factors of chest other pain/angina than telomerase than men, are the state and proliferate indefi nitely has openedincidence new fi elds of of obstructive re- involved CAD inin cellthe femalereplication population and senescence. is lower whenMoreover, compared many with search for a potential “anti-aging” interventionmen (Bodnarwith similar et al symptoms telomerase-negative (Kenedy et al 1982; immortalized Diamond et cell al 1983; lines Merz can maintainet al 1999). In 1998; Vaziri and Benchimol 1998). Cellsaddition, that have it wouldbeen appeartheir telomere that young lengths women (Bryan with et obstructiveal 1995). On CAD the other have hand, a worse supplied with an exogenous source of telomeraseprognosis maintain after acute hybrids myocardial of telomerase-negative infarction (AMI), whereas and telomerase-positive older women in similar a youthful state and proliferate indefi nitelycircumstances (Bodnar et often al presentcells havewith largerfailed number to become of comorbidities immortal, sothat that adversely it is likely influence 1998). These “rejuvenated” cells are not onlythe outcome,immortal, when but comparedthat telomerase to men (Coronado enzyme alone et al 1997). is insuffi Women cient withto prevent acute coronary cell they have also shown reversal of senescentsyndromes characteristics (ACS) aresenescence also less likely (Bryan to receive et al 1995). rapid effective diagnosis and treatment (suchCorrespondence: as increased Carlosfragility V Serrano and subepidermalJr than areblistering) men (AyanianAlthough and Epsteinstudies to 1991;this point Maynard indicate etthat al telomerase 1996; Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). (FunkCarvalho et al 2000). Aguiar, Thus,44 – sala the 12 biological – bloco 2, and potential medical may be intimately involved in cellular senescence and consequencesSão Paulo - ofSP telomerase- 05403-900, expressionBrazil appearRegarding to be highly the Northholds American great promise, population, our understanding the Women’s of theseIschemic age-related Syndrome Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; signifiFax cant. +55 11 3088 3809 mechanisms is still at the beginning. The amount of Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

406 Vascular Health and Risk Management 2006:2(4) Clinical465–475 Interventions in Aging 2007:2(3)465 © 2006 Dove Medical Press Limited. All rights reserved Aging process and interventions REVIEW currently available evidence for claiming that preventing heat shock proteins (Franceschi 1989; Franceschi et al 2000b). telomere shortening would infl uence any aspect of aging These mechanisms function to limit the negative effects of a is still insuffi cient. variety of physical, chemical, and biological stressors. The effi ciency of the network is genetically controlled and differs InCoronaryfl ammation hypothesis artery of diseaseaging among in specieswomen: and individuals, a explaining review in this way the Even if the involvement of the infl ammatory process in observed differences in life span. severalon (sub)clinicalprevention, conditions (eg, atherosclerosis, pathophysiology, diabetes, In the network diagnosis,theory of aging, the immune and system dementia) is well-demonstrated, the importance of infl am- represents the most powerful mechanism to face stressors mationtreatment in the aging process was recognized only recently (Franceschi et al 2000a). In particular, Franceschi identifi ed Author copy only (McGeer and McGeer 1999; Chung et al 2001). Nevertheless, the macrophage as the primary modulator of the vicious cycle infl ammation is growingly considered as a cornerstone of the existing between innate immunity, infl ammation and stress. mechanismsLeila Fernandes underlying Araujo the aging process,Abstract: so to evenDespite gener- numerousThe studies macrophage on women’s activation cardiac health due to throughout chronic stress the past may decade, provide the ateAlexandre the neologism de Matos“infl amm-aging” Soeiro (Franceschinumber of femaleet al 2000a). deaths causeda potential by cardiovascular explanation disease to stillthe risessubclinical and remains chronic the leading infl amma- cause of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular InflJuliano ammation Lara is Fernandes a complex host’s normal defense reaction tory status characterizing older persons and, at the same time, disease, and more specifically coronary artery disease presentations in women, are different than toAntônio physiological Eduardo and nonphysiologicalPesaro stressors. Acute as a possible feature of the aging process. Lymphocytes are also those in men. In addition, pathology and pathophysiology of the disease present significant wellCarlos as chronic V Serrano infl ammatory Jr responses are constituted by affected by the continuous age-related antigenic stress, result- gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the sequentialHeart Institute phases, (InCor), controlled University by humoralfemale and cellular population. stimula: The reasoning for in athis chronic disparity stimulation is all steps responsible for female cardiovascularfor the expansion disease of 1)of Sãointracellular Paulo, School activation; of Medicine, 2) proinfl ammatory cells in the memory cells, the decrease (even exhaustion) of naïve cells, Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This tissues; 3) increase of vascular permeability;review brings 4) damaging together the mostand recentthe shrinkage studies published of the T-cell in the repertoire.field of coronary artery disease of tissues and cell death (Huerre and Gounonin women 1996; and points Chung out new directionsSupporting for future this investigation hypothesis on and some the of importancethe important ofissues. the et al 2001). Keywords: coronary arteryimmune disease, systemwomen, in risk determining factors, prevention, the senescence diagnosis, is the treatment. evidence An individual threshold of the capability to cope with of the high incidence of tumors and greater susceptibility stress has been hypothesized. If the age-related infl amma- to infections from pathogens shown by the older persons. tion (or infl amm-aging) trespasses thisIntroduction level, the transition It has been suggested that aged subjects maintaining their between successful and unsuccesful agingThe occurs. first female-specific Epidemio- recommendationsimmune functions for at preventive an exceptionally cardiology high were level published are more in logic data support the hypothesis that the1999 period (Mosca of life et duringal 1999). Evenlikely though to have research a long in life the spantreatment (Wayne of cardiovascular et al 1990; Pawelek disease unsuccessful aging (disability) is maximal(CVD) inhad the advanced elderly, in manyet al areas,1999). it remains the leading cause of death in women in and minimal in young people and centenariansmost parts (Franceschiof the world. StudiesAs have noted shown above, that theories500 thousand of aging women often die ofoverlap CVD everyeach et al 2000a). year in the United States,other, somewhat suggesting near oneinteractions death every across minute different (American systems Heart and Even when debating about infl ammationAssociation and its 2003). relation- Such indexmechanisms. exceeds not In only this the context number it of should deaths bein men,considered but also the ship with aging, it is important to underlinenext seven how this causes mecha- of deathassociation in women combined, between theand immunemore importantly, cell functions coronary (such artery as nism is associated with others at the basisdisease of different (CAD) theories is believed those to be theinvolved major causein the responsible cytotoxic foractivity these deathsand particularly (American of aging. In fact, the close relationship betweenHeart Association infl ammation 2003). Overin phagocytes a quarter of asa million regards deaths their per microbicidal year are attributed activity) to CAD and and oxidative damage is well-known inalone literature in the (Cesari United et Statesal the (Merz reactive et al 2004).oxygen Although species already generation. high, theseThe figuresexcessive are 2005). In fact, reactive oxygen speciesexpected and reactive to rise nitrogen even more amount during ofthe reactive next decades, oxygen due species to an notincrease counteracted of diabetes by andthe species are heavily implicated in the inflobesity, ammatory as well processes. as the aging antioxidant of the world defenses population can (Merz become et al a 2004). potential source of tis- The overproduction or uncontrolled releaseEven of reactivethough womenspe- havesue damage a higher (De frequency La Fuente of chest2002). pain/angina Moreover, than antioxidants men, the cies is a major causative factor in tissueincidence infl ammation. of obstructive CADmaintain in the the female integrity population and function is lower ofwhen membrane compared lipids, with men with similar symptomscellular (Kenedy proteins, et al 1982; and Diamond nucleic etacids al 1983; and Merzthe control et al 1999). of sig- In Immune theory of agingaddition, it would appearnal that transduction young women of gene with expression obstructive in CAD immune have cells. a worse Not In 1989, Franceschi proposed the immuneprognosis theory afterof aging, acute or myocardialsurprisingly, infarction immune (AMI), system whereas cells olderusually women contain in similarhigher network theory of aging (Franceschi 1989;circumstances Franceschi often et presental concentrations with larger number of antioxidants of comorbidities than thatdo other adversely cells influence (Knight 2000a), in which suggested that aging isthe indirectly outcome, controlled when compared 2000), to men given (Coronado the high et alpercentage 1997). Women of polyunsatured with acute coronary fatty by a network of cellular and molecularsyndromes defense mechanisms. (ACS) are alsoacids less likely in their to receiveplasma rapid membranes. effective Thus,diagnosis the andimmune treatment cell TheCorrespondence: major parts Carlos of the V network Serrano areJr constitutedthan are by DNAmen repair (Ayanian functions and Epstein are strongly 1991; influenced Maynard byet theal 1996;antioxidant/ Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). enzymes,Carvalho Aguiar, activation 44 – sala of poly12 – (ADP-ribosyl)bloco 2, polymerase, enzy- oxidant balance and, therefore, the antioxidant levels maticSão Paulo and - nonenzymaticSP - 05403-900, antioxidant Brazil systemsRegarding (eg, superoxide the North playAmerican a pivotal population, role in maintainingthe Women’s immune Ischemic cells Syndrome I) in a Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; dismutase,Fax +55 11 3088catalase, 3809 glutathione peroxidase), production of reduced environment and II) in protecting them from Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

Clinical Interventions in Aging 2007:2(3) Vascular Health and Risk Management 2006:2(4) 465–475 407465 © 2006 Dove Medical Press Limited. All rights reserved Tosato et al REVIEW oxidative stress, so to preserve their adequate function- (eg, production and secretion of hypophysiotropic hormones ing (Knight 2000). stimulating/inhibiting hormone release from the hypophysis). In response to hypothalamic signals, the hypophysis produces Neuroendocrine theory of aging and secrets several hormones acting in the regulation of many It isCoronary generally accepted a bidirectional artery communication disease important in functions women: of the body. This a regulation review is controlled between the nervous and the immune systems (Besedovsky by the release of hormones (eg, growth hormone, oxytocin, and Delon Rey 1996).prevention, With aging not only a functionalpathophysiology, decline vasopressin) or by the stimulationdiagnosis, of peripheral endocrineand in the immune and nervous systems occurs, but also an glands (eg, adrenal cortex, thyroid, gonads). impairedtreatment relationship between these two regulatory systems Major hormones of the adrenal medulla are the catecola- Author copy only can become evident, with the resulting loss of homeostasis mines epinephrine and norepinephrine, functioning as neu- and higher risk of death (Fabris 1991; De La Fuente 2002). rotransmitters for the sympathetic division of the autonomic TheLeila neuroendocrine Fernandes theoryAraujo proposes thatAbstract: aging is Despite due to numerousnervous studies system on women’s and rapidly cardiac responding health throughout to any the external past decade, or the changesAlexandre in neural de and Matos endocrine Soeiro functionsnumber that are of female crucial deaths internal caused by stress cardiovascular through circulatory disease still andrises metabolic and remains adjustments the leading cause of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular for:1)Juliano coordination Lara andFernandes responsiveness of different systems (Weinert and Timiras 2003). With aging, a reduction in disease, and more specifically coronary artery disease presentations in women, are different than to theAntônio external environment;Eduardo Pesaro 2) programming physiological sympathetic responsiveness is characterized by: 1) a lower those in men. In addition, pathology and pathophysiology of the disease present significant responsesCarlos to environmental V Serrano Jrstimuli; and 3) the maintenance of number of catecholamine receptors in peripheral target tis- gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the an optimalHeart Institute functional (InCor), status University for reproductionfemale and population. survival. Thesues; reason 2) for a declinethis disparity of heat is allshock steps proteins for female that cardiovascular increase stress disease Theseof São changes,Paulo, School not onlyof Medicine, selectively affect neurons and resistance; and 3) a decreased capability of catecholamines Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This hormones regulating evolutionarily signifi cantreview functions brings togethersuch theto inducemost recent heat studies shock publishedproteins. in the field of coronary artery disease as reproduction, growth, and development,in womenbut also and infl points u- out newThe directions hormones for future of the investigation adrenal cortex on some are of glucocorticoids the important issues. ence the regulation of survival through adaptationKeywords: to stress.coronary artery(responsible disease, forwomen, the regulation risk factors, of prevention, lipid, protein, diagnosis, and carbo-treatment. Thus, the life span, regulated by “biological clocks”, would hydrate metabolism), mineralcorticoids (regulating water undergo a continuum of sequential stages driven by nervous and electrolytes), and sex hormones. Among the latter is and endocrine signals. Alterations of the biologicalIntroduction clock (eg, dehydroepiandrosterone, which has shown to decrease with reduced responsiveness to the stimuli regulatingThe first the female-specific clock, aging. recommendations for preventive cardiology were published in excessive or insuffi cient coordination of responses)1999 (Mosca would et al 1999). Even Dehydroepiandrosterone though research in the replacementtreatment of cardiovasculartherapy has been disease disrupt the clock and the corresponding adjustments(CVD) had (Finkel advanced advocatedin many areas, in humans, it remains despite the leading unconvincing cause of results death (Daynesin women in 1976; Timiras 1978; Weinert and Timiras most2003). parts of the world.and Studies Araneo have 1992). shown Glucocorticoids, that 500 thousand as womenwell as dieother of steroidCVD every An important component of this theoryyear indicates in the United the States,hormones, somewhat are regulated near one by death positive every and minute negative (American feedbacks Heart hypothalamo-pituitary-adrenal (HPA) axisAssociation as the primary 2003). Suchbetween index exceedsthe target not hormones only the number and their of centraldeaths incontrol men, butby thealso the regulator, a sort of pacemaker signaling thenext onset seven and causes ter- of deathhypophysis in women and combined,hypothalamus. and more With importantly, aging and in coronary response artery mination of each stage of life. The HPA diseaseaxis controls (CAD) the is believed to chronic to be the stress, major not cause only responsible feedback formechanisms these deaths may (American be physiological adjustments aimed at the Heartpreservation Association and 2003).altered, Over but a quarter also glucocorticoids of a million deaths themselves per year are become attributed toxic to to CAD maintenance of an internal homeostasis despitealone thein thecontinu- United Statesneural (Merz cells, et thus al 2004).disrupting Although feedback already control high, and these hormonal figures are ing changes in the environment (Weinert andexpected Timiras to 2003). rise even cyclicitymore during (Sapolsky the next et decades, al 1986; dueSapolsky to an increase1992; Weinert of diabetes and and During life span, chronic exposure to severeobesity, and as multiple well as the Timirasaging of 2003).the world population (Merz et al 2004). physical, biological, or emotional stressors mayEven exhaust though or women Thehave circulating a higher frequency levels of growthof chest hormone, pain/angina testosterone, than men, the weaken this capacity to adapt and to the so-calledincidence “disease of obstructive estrogen, CAD in dehydroepiandrosterone, the female population is lower and otherwhen comparedhormones with of adaptation” and death (Selye 1976; Weinertmen with and similarTimiras symptoms decrease (Kenedy with etage. al 1982; Although Diamond some et alhormone 1983; Merz replacement et al 1999). In 2003). Aging should then be considered addition,as the result it would of a appearstrategies that haveyoung been women shown with in clinical obstructive trials toCAD modify have some a worse decrease ability to survive stress, suggestingprognosis once more after the acute of myocardial physiological infarction attributes (AMI), associated whereas with older aging, women negative in similar close relationship between stress and longevity.circumstances often presentside effects with larger occur number frequently of comorbidities with those interventions that adversely shown influence The integration of responses to environmentalthe outcome, stimuli when comparedto have tosome men benefi (Coronado t, such et as al growth1997). Women hormone. with acute coronary seems to be carried out by hypothalamus fromsyndromes information (ACS) are alsoAlthough less likely the to receiveepidemiological rapid effective data diagnosis are overwhelm- and treatment derivedCorrespondence: in various Carloscerebral V Serrano structures. Jr Thethan hypothalamus are men (Ayanianingly positive and Epstein regarding 1991; some Maynardhealth benefi et ts al of 1996;estrogen Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). itselfCarvalho regulates: Aguiar, 1) 44nervous – sala 12 functions – bloco 2, (eg, sympathetic and replacement therapy, a recent study has raised a concern parasympatheticSão Paulo - SP visceral - 05403-900, functions), Brazil 2) behaviorsRegarding (eg, sexual the Northabout American ovarian cancer population, after long-term the Women’s use. It Ischemichas been shownSyndrome Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; and eatingFax +55 behavior, 11 3088 3809rage, fear), and 3) endocrine functions that melatonin supplementation increases the mean life Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

408 Vascular Health and Risk Management 2006:2(4) Clinical465–475 Interventions in Aging 2007:2(3)465 © 2006 Dove Medical Press Limited. All rights reserved Aging process and interventions REVIEW expectancy of mice by approximately 5%, but in association The evidence from both nematodes and fruit flies with an increase in spontaneous tumor incidence. suggests that decreased activity of the insulin-like signaling In order to adequately address hormone decline pathway is associated with increased life expectancy, rather occurring with aging, it is crucial the understanding of than the reverse. Thus, further research is needed before theCoronary complex hormonal cascade,artery an intricate disease interplay the in GH supplementationwomen: in humansa review encouraged by many between signals, pathways, and production and delivery “antiaging” clinicians can be considered either safe or useful systems.on prevention, pathophysiology,for long-term intervention. diagnosis, and Estrogen replacement therapy represents a special case oftreatment hormone replacement therapy and deserves particular Neuroendocrine-immuno theory Author copy only attention because of its long clinical history and apparent of aging record of success in increasing quality of life in postmeno- In the hierarchy of multisystem regulation throughout the pausalLeila Fernandeswomen. Estrogen Araujo is particularlyAbstract: recommended Despite numerous for sequential studies on women’sstages of cardiac life, therehealth isthroughout a signifi thecant past role decade, for thethe number of female deaths caused by cardiovascular disease still rises and remains the leading cause theAlexandre prevention de of Matososteoporosis, Soeiro but it has been suggested it interaction and integration of the neuroendocrine and immune of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular mayJuliano reduce Lara the riskFernandes of dementia and cardiovascular disease. systems. Such interaction occurs through 1) neuropeptides disease, and more specifically coronary artery disease presentations in women, are different than ItAntônio has been estimatedEduardo that Pesaro favorable changes in plasma lipids and cytokines present in the immune system mediating both those in men. In addition, pathology and pathophysiology of the disease present significant mayCarlos account V Serrano for approximately Jr 25% of the cardioprotective gender differences, which leadsintraimmune to difficulties communication concerning diagnosis, and treatmentbetween and the outcome neuroendo- of the effectHeart Instituteof estrogen. (InCor), University female population. The reasoncrine for andthis disparityimmune issystems, all steps 2)for severalfemale cardiovascularhormones from disease the of SãoThe Paulo, conclusion School ofthat Medicine, estrogen protects postmenopausal posterior (vasopressin) and anterior (thyroid-stimulating Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This women against cardiovascular diseasereview is now brings being together ques- the mosthormone, recent studiesprolactin, published adrenocorticotropic in the field of coronary hormone, artery growth disease tioned, based mainly on experiments inexamining women and secondary points out newhormone) directions forhypophysis, future investigation and 3) reciprocal on some of action the important of cytokines issues. prevention in women with preexistingKeywords: heart disease. coronary arteryon disease, neuroendocrine women, risk functions. factors, prevention, diagnosis, treatment. Estrogen replacement therapy has been called the fi rst Besides of neuroendocrine interactions, the immune true anti-aging therapy. However, no results have yet been system must control and eliminate foreign organisms and reported of randomized studies that compareIntroduction effects of this substances in the host body while at the same time recogniz- therapy with placebos, beginning at theThe menopausal first female-specific transi- recommendationsing, and therefore for sparing preventive from cardiology destruction, were the published molecules in tion, in women with no known preexisting1999 (Mosca coronary et al heart 1999). Evenfrom though oneself. research In most in theolder treatment persons, of immunosenescencecardiovascular disease is disease or dementia. (CVD) had advanced in manycharacterized areas, it remains by a decreased the leading resistance cause toof infectious death in women diseases, in It has been demonstrated that circulatingmost parts of levels the world. of Studiesa decreased have shown protection that 500 against thousand cancer, women and die ofan CVD increased every growth hormone drop with increasingyear age.in the It Unitedhas also States, failure somewhat to recognize near one self death (leading every to minuteconsequent (American autoimmune Heart been shown that GH replacement in Associationadults with 2003). pituitary Such indexpathology) exceeds (Franceschi not only the et number al 2000b). of deaths Both thein men, neuroendocrine but also the disease and GH defi ciency has benefinext cial seven effects causes on body of death and in womenimmune combined, systems areand characterized more importantly, by a coronaryhigh degree artery of composition, reducing fat and increasingdisease lean (CAD) body is mass, believed plasticity to be the majorand are cause able responsible to modify for their these functioning deaths (American accord- muscle strength, and bone mass. RudmanHeart Associationand colleagues 2003). Overing toa quarter demand. of aPlasticity million deaths is most per effi year cient are attributedat early ages, to CAD but investigated whether GH injections alonein older in the men United would States persists (Merz etat aladvanced 2004). Although age. already high, these figures are restore muscle mass typical of youngerexpected men. toThey rise foundeven more duringTo describe the next the decades, theoretical due totrajectories an increase of of the diabetes aging pro-and that insulin growth factor (IGF)-1obesity, levels asdid well rise as theand aging cess, of the Rowe world and population Kahn (1987) (Merz described et al 2004). three curves: the fi rst that lean body mass increased while fatEven mass though decreased, women havecharacterized a higher byfrequency disease andof chest disability; pain/angina the second, than known men, the as suggesting that GH injections did reverseincidence the ofchanges obstructive in CAD“usual in aging”, the female characterized population by is absencelower when of overt compared pathology with body composition that were due to agemen and with decondition- similar symptomsbut (Kenedy presence et al of 1982; some Diamond decline etin alfunction; 1983; Merz and et the al 1999).last, the In ing. Recent data obtained with mice addition,suggest that it would lifelong appear so-called that young “successful women aging”,with obstructive with little CADor no havephysiological a worse overproduction of GH reduces longevityprognosis in mice, after whereas acute myocardialloss and infarctionno pathology. (AMI), Mechanisms whereas older of successful women inaging similar are underproduction or an inability to respondcircumstances to GH increases often present based with on:larger 1) number persistence of comorbidities of normal function that adversely and plasticity, influence it. Transgenic mice overexpressingthe GH outcome, exhibit when severe compared 2) compensatory to men (Coronado responses et al 1997). to restore Women normal with acute function, coronary 3) kidney lesions and increased incidencesyndromes of neoplasms, (ACS) andare alsointerventions less likely to receiveto replace rapid defi effective cient functions, diagnosis 4) and changing treatment of overproductionCorrespondence: Carlos of GH V inSerrano adult Jr humansthan leads are to amen condition (Ayanian health and outcome Epstein by 1991;modifying Maynard risk profi et les,al 5)1996; prevention Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). knownCarvalho as Aguiar, acromegaly, 44 – sala 12 which – bloco is characterized2, by excessive of disease, and 6) strengthening of social interactions and growthSão Paulo of - SPcertain - 05403-900, organs Brazil and tissues, butRegarding also premature the North supportAmerican (Rowe population, and Kahn the 1998). Women’s It has Ischemicbeen postulated Syndrome that Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; heartFax +55 and 11 lung3088 failure.3809 a successful example of this “functional remodeling” may be Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

Clinical Interventions in Aging 2007:2(3) Vascular Health and Risk Management 2006:2(4) 465–475 409465 © 2006 Dove Medical Press Limited. All rights reserved Tosato et al REVIEW mediated by neuroendocrine and immune systems (Mobbs assessed over the time spent inside the biosphere (ie, while et al 2001). crew members experienced caloric restriction) as well as 18 months after exiting the biosphere and returning to their Caloric restriction normal diets. The physiological modifi cations experienced A singleCoronary chapter in this review isartery deserved by caloric disease restric- by the Biospherein women: 2 participants were a similar review to those found in tion, the only nongenetic intervention that has consistently caloric restricted rodents and nonhuman primates: decline in shownon to slow prevention, the intrinsic rate of aging in mammalspathophysiology, (Dirks metabolic rate, body temperature, diagnosis, and systolic and anddiastolic and Leeuwenburgh 2006). It is defi ned by the reduction in blood pressure, and reductions in blood glucose, insulin, and calorictreatment intake while maintaining essential nutrient require- thyroid hormone levels. Author copy only ments. Traditionally, experimental mammalian models of It has been shown that the Okinawan population is caloric restriction reduce caloric intake by ~40% of the characterized by reduced morbidity and mortality, and the adlibitumLeila dietFernandes throughout Araujo the lifespan of Abstract:the animal. Despite This numerousgreatest studies percentage on women’s of centenarians cardiac health in throughout the world the lives past in decade, this the reductionAlexandre has resulted de Matos in a 30%–40% Soeiro increasenumber in ofmaximum female deaths island. caused Itby has cardiovascular been hypothesized disease still that rises the and long remains disability-free the leading cause of death in women in most areas of the world. Novel studies have demonstrated that cardiovascular lifespanJuliano (Weindruch Lara Fernandes et al 1986). life expectancy of this population might be due to the diet, disease, and more specifically coronary artery disease presentations in women, are different than HowAntônio is caloric Eduardo restriction Pesaro able to increase lifespan? It is based on vegetables, grains, soy, fruits, fi sh and seaweed, and those in men. In addition, pathology and pathophysiology of the disease present significant likelyCarlos that this V interventionSerrano Jr can obtain benefi cial effects by characterized by a low caloric intake (~20% less than the rest gender differences, which leads to difficulties concerning diagnosis, treatment and outcome of the actingHeart at various Institute levels (InCor), of function University and involvingfemale population. a number Theof reason Japan for and this ~40% disparity less is than all stepsUnited for States). female cardiovascularIt is noteworthy disease of molecularof São Paulo, cellular, School ofand Medicine, systemic changes. Not only that this diet is very similar to the caloric restriction interven- Brazil evaluation, treatment and prevention are not well elucidated; and an area for future research. This is longevity increased, but also metabolicreview (eg, brings increased together thetions most designed recent studies for experiments published in in the animal field of models. coronary artery disease tissue sensitivity to insulin), neuroendocrinein women and immuneand points out newDespite directions of thefor futureabundant investigation data showing on some health of the benefi important ts and issues. (eg, increased defenses against stress, infections,Keywords: cancer), coronary arterythe reduction disease, women,of the aging risk factors, rate by prevention, use of a caloric diagnosis, restriction treatment. and collagen responses (eg, reduction of cross-linking) are intervention in mammalian animal models, it is likely that signifi cantly enhanced (Mobbs et al 2001). It is noteworthy these benefi cial effects will be lost in the translation to human that such functional changes might also Introductionbe modulated by models (Dirks and Leeuwenburgh 2006). Consequently, the changes in gene expression profi le. CaloricThe restriction first female-specific may previous recommendations great expectations for preventive about long-term cardiology caloric were publishedrestric- in promote longevity by a metabolic reprogramming1999 (Mosca with et al a 1999).tion Even in humans though as research the new in “fountain the treatment of youth” of cardiovascular have recently disease transcriptional shift (perhaps triggered by insulin)(CVD) hadtoward advanced 1) beenin many resized. areas, it remains the leading cause of death in women in reduced energy metabolism, and 2) increasedmost biosynthesisparts of the world. Studies have shown that 500 thousand women die of CVD every and turnover of proteins. It has also been demonstratedyear in the United that States,Conclusion somewhat near one death every minute (American Heart caloric restriction markedly infl uences theAssociation expression 2003). of SuchIt has index been exceeds argued not that only more the number than half of deathsof the inbudget men, butof thealso the pathological phenotypes in rodent species selectivelynext seven bredcauses as of deathUS National in women Institute combined, on andAging more is importantly,spent on Alzheimer’s coronary artery models of human pathology (Weinert and diseaseTimiras (CAD) 2003). is believeddisease to be(Hayfl the major ick 2000a). cause responsible Nevertheless, for thesethe elimination deaths (American of Even if the short-term effects in humansHeart are Association promising 2003).this Over clinical a quarter condition of a millionwill have deaths only per a minimal year are impact attributed on lifeto CAD (Walford et al 1999; Weyer et al 2000; Fontanaalone inet althe 2004), United Statesexpectancy (Merz andet al will 2004). not helpAlthough the advancing already high, of our these knowledge figures are long-term studies are not surprisingly diffi expectedcult to conduct to rise ineven ofmore fundamental during the biologynext decades, of aging. due toGreater an increase attention of diabetes has to and humans. The lack of data from human modelsobesity, is mainly as well due as the beaging given of the to aworld rarely population posed question: (Merz et why al 2004). are old cells more to the diffi culties of adhering to this rigorousEven intervention though women vulnerable have a higherto disease frequency than young of chest cells? pain/angina The answer than to men, this the and the length of the human life span. incidence of obstructiveissue CAD will in not the only female advance population our fundamental is lower when knowledge compared of with The most famous reports about the effectsmen with of similar caloric symptoms aging, (Kenedy but also et promote al 1982; Diamondthe understanding et al 1983; Merzof age-related et al 1999). In restriction on humans’ health were obtainedaddition, from it would the appeardiseases that (Hayfl young ick women 2000a). with obstructive CAD have a worse Biosphere 2 experiments. Biosphere 2 is a prognosisclosed ecological after acute myocardialSeveral and infarction important (AMI), step whereas forward older the understandingwomen in similar space located in the deserts of Arizona. In 1991,circumstances eight individ- often presentof the withaging larger process number have of beencomorbidities done, so that that adversely it is no moreinfluence uals entered the biosphere for a two-year periodthe outcome, to study when the comparedan obscure to men issue (Coronado of biology et al(Holliday 1997). Women 2006). with Nevertheless, acute coronary effects from living in a closed system. Becausesyndromes of unexpected (ACS) arefurther also less studies likely areto receive still needed rapid effectiveand numerous diagnosis cues and solved. treatment technicalCorrespondence: problems, Carlos the access V Serrano to foodJr wasthan limited are formen the (AyanianIn particular, and Epsteinit is important 1991; to Maynardclarify to whichet al extent 1996; and Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). entireCarvalho duration Aguiar, of the44 –study, sala 12 so – thatbloco the 2, actual caloric intake at which price the aging process can be limited or reversed. of theSão participants Paulo - SP - was05403-900, approximately Brazil 30% lowerRegarding than what the NorthIn pursuing American a solution population, to these the issues, Women’s we should Ischemic keep Syndrome clear Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; expected.Fax +55 Physiological 11 3088 3809 and biochemical measurements were in mind what Hayfl ick wrote in a Nature commentary: “If Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

410 Vascular Health and Risk Management 2006:2(4) Clinical465–475 Interventions in Aging 2007:2(3)465 © 2006 Dove Medical Press Limited. All rights reserved Aging process and interventions REVIEW the main goal of our biomedical research enterprises is to Cong YS, Wen J, Bacchetti S. 1999. The human telomerase catalytic subunit resolve causes of death, then every old person becomes a hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet, 8:137–42. testimony to those successes. Biogerontologists have an Davies KJ, Quintanilha A, Brooks GA, et al. 1982. Free radicals and obligation to emphasize that the goal of research on ageing tissue damage produced by exercise. Biochem Biophys Res Comm, Coronary artery disease in107:1292–9. women: a review is not to increase human longevity regardless of the conse- Daynes RA, Araneo BA. 1992. Prevention and reversal of some age- quences, but to increase active longevity free from disability associated changes in immunologic responses by supplemental andon functional prevention, dependence” (Hayfl ick 2000b).pathophysiology, dehydroepiandrosterone diagnosis, sulfate therapy. Aging: Immunology,and and Infectious Disease, 3:135–53. De Benedictis G, Rose G, Carrieri G, et al. 1999. Mitochondrial DNA treatment inherited variants are associated with successful aging and longevity

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Telomeres, telomerase, and immortality. J Natl Cancer 72:946–53. Inst, 87:884–94. Heart Association 2003).Wick Over M, Zubov a quarter D, Hagen of a million G. 1999. deaths Genomic per organization year are attributed and promoter to CAD Richter C, Park JW, Ames BN. 1988. Normal oxidativealone damage in to the mitochon- United Statescharacterization (Merz et al 2004).of the gene Although encoding already the human high, telomerase these figuresreverse are drial and nuclear DNA is extensive. Proc Natl Acadexpected Sci, 85:6465–7. to rise even moretranscriptase during the (hTERT). next decades, Gene, 232:97–106. due to an increase of diabetes and Ross OA, McCormack R, Curran MD, et al. 2001. Mitochondrial DNA Wunderlich V, Schutt M, Bottger M, et al. 1970. Preferential alkylation polymorphism: its role in longevity of the Irishobesity, population. as well Exp as the agingof mitochondrialof the world deoxyribonucleicpopulation (Merz acid et by al N-methyl-N-nitrosourea.2004). Gerontol, 36:1161–78. Even though women Biochemhave a Jhigher, 118:99–109. frequency of chest pain/angina than men, the Rossi SC, Gorman N, Wetterhahn KE. 1988. Mitochondrial reduction of the carcinogen chromate: formation of chromium(V).incidence Chem of obstructive Res CAD in the female population is lower when compared with Toxicol, 1:101–7. men with similar symptoms (Kenedy et al 1982; Diamond et al 1983; Merz et al 1999). In addition, it would appear that young women with obstructive CAD have a worse prognosis after acute myocardial infarction (AMI), whereas older women in similar circumstances often present with larger number of comorbidities that adversely influence the outcome, when compared to men (Coronado et al 1997). Women with acute coronary syndromes (ACS) are also less likely to receive rapid effective diagnosis and treatment Correspondence: Carlos V Serrano Jr than are men (Ayanian and Epstein 1991; Maynard et al 1996; Pope Coronary Care Unit, Av. Dr. Enéas et al 2000). Carvalho Aguiar, 44 – sala 12 – bloco 2, São Paulo - SP - 05403-900, Brazil Regarding the North American population, the Women’s Ischemic Syndrome Tel +55 11 3069 5058 Evaluation (WISE) study workshop (Hayes et al 2004; Maseri 2004; Nabel et al 2004; Fax +55 11 3088 3809 Email [email protected] Pepine et al 2004; Shaw et al 2004; Waters et al 2004) from the National Heart, Lung and

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