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Contents lists available at SciVerse ScienceDirect

Maturitas

journa l h om epa ge: www.elsev ier .com/ locate /matur i tas

eview

an exercise-related improvements in immunity influence cancerrevention and prognosis in the elderly?

ustin B. Bigley ∗, Guillaume Spielmann, Emily C.P. LaVoy, Richard J. Simpsonaboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, 3855 Holman Street, Houston, TX 77204, USA

a r t i c l e i n f o

rticle history:eceived 6 June 2013ccepted 10 June 2013vailable online xxx

eywords:mmunosenescencegingancer

mmunitynnatedaptive

a b s t r a c t

Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occurin individuals aged 65 years or older. One factor that may contribute to this is immunosenescence –a canopy term that is used to describe age-related declines in the normal functioning of the immunesystem. There are multiple age-related deficits in both the innate and adaptive systems that may playa role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigenuptake and presentation by monocytes and dendritic cells, an increase in ‘inflammaging’, a decline inthe number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionallyexhausted senescent cells. There is consensus that habitual physical exercise can offer protection againstcertain types of cancer; however the evidence linking immunological mechanisms, exercise, and reducedcancer risk remain tentative. Multiple studies published over the last two decades suggest that exercisecan mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity.

The potential ameliorative effect of exercise on these mechanisms include evidence that physical activityis able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, andprevent senescent cell accumulation in the elderly. Here we discuss the role played by the immunesystem in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms.We also propose a pathway by which exercise-induced alterations in immunosenescence may decreasethe incidence of cancer and help improve prognosis in cancer patients.

© 2013 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. The immune system and cancer: elimination, equilibrium, and escape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Decreased cancer surveillance in the aging immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Prevention of age-related declines in immunity by exercise. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. The effects of exercise on cancer prevention and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Introduction relationship between cancer and aging is not fully understood,

Please cite this article in press as: Bigley AB, et al. Can exercise-related imin the elderly? Maturitas (2013), http://dx.doi.org/10.1016/j.maturitas.201

Cancer incidence increases with advancing age, which is a con-erning fact in most Western countries where life expectancys increasing and the elderly population is expanding [1]. The

∗ Corresponding author. Tel.: +1 713 743 1073; fax: +1 713 743 9860.E-mail address: abbigley@central.uh.edu (A.B. Bigley).

378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.maturitas.2013.06.010

although the natural passing of time may allow the accumula-tion of damage from free radicals, viruses, and carcinogens tocause mutated cellular proliferation that disrupts normal physi-ology and facilitates cancer development. Treatment options often

provements in immunity influence cancer prevention and prognosis3.06.010

entail some combination of surgery, radiation, and cytotoxic drugsalthough these are often limited by the incomplete eliminationof cancer cells causing recurrence, and by severe side-effects. Ascancer prevention is clearly the best option, it is important to

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nderstand how and why cancers develop in order to devise suit-ble therapeutic, pharmacologic, and/or holistic countermeasuresor both prevention and treatment, especially in the aged.

One factor that may contribute to the increased incidence ofancer in the elderly is immunosenescence – a canopy term that issed to describe age-related declines in the normal functioning ofhe immune system. Known consequences of immunosenescencenclude increased infection occurrence, poor vaccine responses,nd heightened levels of disease and mortality among the elderly2]. As the immune system also plays a role in cancer prevention,eclining immune function with age may contribute to loweredancer defenses and facilitate poorer prognosis. Recent evidencendicates that regular physical exercise may help prevent or possi-ly reverse many aspects of immunosenescence [3] and, in doing so,ay enhance cancer prevention and treatment in the elderly. Heree discuss the role played by the immune system in preventing and

ontrolling cancer, how aging may retard these anti-cancer mech-nisms, and how exercise appears to prevent age-related declinesn immunity. Finally, we review the literature showing an inverseelationship between cancer and physical activity, and propose

pathway by which exercise-induced alterations in immunose-escence may decrease the incidence of cancer and help improverognosis in cancer patients.

. The immune system and cancer: elimination,quilibrium, and escape

The evolution of cancer involves three critical phases: elimina-ion, equilibrium, and escape [4]. In the elimination phase, tumorells are deleted by effector cells of both the innate and adap-ive immune systems [5,6]. Natural killer (NK) cells are cytotoxicffectors of innate immunity that distinguish between healthynd malignant or virally-infected cells [7]. This process is tightlyegulated by inhibitory killer-cell immunoglobulin-like receptorsKIR) on NK-cells which ligate with human leukocyte antigensHLA) on healthy host cells [8]. When HLA becomes downregu-ated on transformed cells they are targeted for elimination byK-cells [9]. Tumor infiltration by antigen presenting cells, suchs dendritic cells (DCs) is required for the initiation of anti-tumordaptive immune responses [10] and is associated with prolongedatient survival and reduced metastasis in patients with many dif-erent carcinomas [11,12]. Once initiated, effector cells of adaptivemmunity play an important role in the elimination phase. Clonalxpansion of tumor-specific T-cells has been observed to accom-any spontaneously regressing melanoma lesions [13,14].

Unfortunately, such targeting of tumor cells leads to the selec-ion of cells with the least immunogenicity [15], resulting in aynamic equilibrium where tumor cells are contained, but not fullyradicated by the immune system [16]. During this phase of equi-ibrium, the growth of weakly immunogenic tumor cells is abatedy the immune system [17], but complete destruction of the tumor

s not achieved. Tumor cells decrease immunogenicity in severalays. Incomplete down-regulation of HLA expression by some

umor cells [18] prevents their killing by KIR-matched NK-cells [19].etastatic tumors evade detection by DCs by inducing apoptosis

f DCs and their precursors [20], leading to reduced DC numbersn malignant tumors [21]. This results in a marked reduction inlonal expansion of tumor-specific T-cells [22]. The importancef T-cells in maintaining the equilibrium phase has been shownn murine models, where depletion of T-cells leads to rapid andncontrolled tumor growth [23,24]. Clinical evidence also suggests

Please cite this article in press as: Bigley AB, et al. Can exercise-related imin the elderly? Maturitas (2013), http://dx.doi.org/10.1016/j.maturitas.201

critical role for adaptive immunity in the equilibrium phase inumans as several studies have shown that the presence of tumor-pecific T-cells is correlated with remission in leukemia patients25]. Similarly, the presence of tumor-infiltrating CD8+ T-cells and

PRESS xxx (2013) xxx– xxx

a high blood CD8+/CD4+ T-cell ratio have been shown to be asso-ciated with improved survival and prognosis in epithelial ovariancancer [26,27].

While the equilibrium phase represents a balance betweentumor cell division and clearance that may be long-lasting [28,29],it is often not permanent. As a result of selective honing of tumorimmunoevasive mechanisms [30], malignant cells escape con-tainment, resulting in uncontrolled tumor growth. In additionto mutations in cancerous cells leading to their evasion of theimmune system, normal functioning of the immune system maybe hijacked by tumor cells, leading to a favorable microenviron-ment for tumor growth [31]. For example, cancer is associatedwith disrupted infiltration of tumors by NK-cells [32], as well asa decreased cytotoxicity per NK-cell [33] due in part to overex-pression of inhibitory receptors [34] and decreased expression ofactivating receptors [35]. The tumor microenvironment also elicitsdownregulation of monocyte expression of tissue-homing recep-tors leading to impaired migration and adhesion [36], and candecrease monocyte anti-tumor cytotoxicity [37]. Certain tumors[38] are able to hijack macrophage function and switch theirphenotype from a pro-inflammatory state to an immunosup-pressive state [39]. Additionally, tumor-infiltrating macrophageshave been shown to support tumor growth by stimulating angio-genesis [40]. Multiple phenotypic and functional alterations areobserved in the DCs of cancer patients, including low expressionof co-stimulatory molecules [41] and inhibited antigen processing[42]. The tumor microenvironment also favors polarization of DCstoward a tolerogenic phenotype that stimulates the generation ofregulatory T-cells and myeloid-derived suppressor cells [43]. All ofthis impairs tumor-specific T-cell responses and encourages tumorescape [44].

3. Decreased cancer surveillance in the aging immunesystem

Many of the immunosuppressive effects of aging are similarto those observed in cancer patients, and are associated with theescape of malignant cells from immune control and the devel-opment of cancer [45]. Much like cancer, aging is associatedwith decreased NK-cell function [46], and cancer and aging areboth associated with a decline in NK-cell expression of activat-ing receptors [46] and an increase in inhibitory KIR expression[47]. Aging also alters monocyte, macrophage, and DC functionin a number of ways that facilitate tumor progression. Increasesin pro-inflammatory monocytes lead to elevated levels of localand circulating pro-inflammatory cytokines, which contribute to“inflammaging” [48]. DCs also exhibit amplified baseline NF�Bactivation and thus amplified unstimulated production of pro-inflammatory cytokines and increased reactivity to self-antigens[49]. This chronic, low-grade inflammation resulting from theaging process creates a tumor-promoting environment and isassociated with increased cancer risk [48]. Furthermore, aging isassociated with decreased antigen presentation by monocytes andmacrophages [50], and decreased antigen presentation and migra-tory capacity of DCs [51], resulting in decreased cytotoxic T-cellresponses to emergent tumors [52].

Maintenance of equilibrium requires vigorous T-cell responsesto contain a constantly evolving pool of potentially malignant cells[53]. Unfortunately, aging is associated with an accumulation offunctionally exhausted and suppressor CD8+ T-cells that are inca-pable of undergoing clonal expansion [54] and interfere with the

provements in immunity influence cancer prevention and prognosis3.06.010

immune response to tumors [55]. Increases in the proportion ofsenescent CD8+ T-cells are associated with increases in the inci-dence of both solid tumors [56] and blood borne malignancies[57]. One reason senescent cells may lack a sufficient anti-tumor

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esponse is their co-expression of KLRG1 and CD57 [58]. Stud-es have shown that up-regulation of E-cadherins [59], laminin-160], and selectins [61,62] by tumor cells enhance their aggressive-ess and facilitate their escape from immunologic-containment.-selectin is a natural ligand for KLRG1 [63], while selectins andaminin-1 are natural ligands for CD57 [64]. Upon ligation withLRG1, E-cadherins inhibit the activation of CTLs [59] and although

n vivo data demonstrating an inhibitory effect of CD57 interac-ions with selectins and laminin-1 are still to be documented,xpression of CD57 on T-cells has been correlated with reducedctivation upon antigenic challenge [65]. Consequently, the accu-ulation of KLRG1+/CD57+ T-cells likely reduces tumor cell killing

nd promotes their escape from the equilibrium phase. Senes-ent T-cells also lose expression of the co-stimulatory markersD28 and CD27 [58], further contributing to the reduced responseo antigenic challenges. T-cells with senescent phenotypes haveeen observed to also have immune suppressor activities in can-er patients [66]. Elderly cancer patients, who will have a greaterumber of senescent T-cells than younger patients, may thereforelso have a greater number of suppressor cells and consequentlyay be at greater risk for tumor cell escape from the equilibrium

hase. In addition to the requirement for strong effector responsesnd clonal expansion to prevent escape of tumor cells, a T-cell poolith rich TCR diversity is required to respond to all of the novelutations that premalignant cells undergo in an effort to escape

mmunological containment [67,68]. Thus, the marked age-driveneductions in TCR diversity in both the CD4+ and CD8+ T-cell sub-ets [69] are likely to contribute to the increased incidence of cancerith advancing age.

There is evidence to suggest that cancer itself may drivemmunosenescence. The hypoxic environment found inside of allumors is associated with profound effects on T-cell differentiation,nd favor the generation of CD4+ regulatory T-cells and senescentD8+/CD28− T-cells [70,71]. CD4+ and CD8+ T-cells taken fromealthy donors become senescent when cultured with tumor cellsnd show suppressor functions against responding T-cells [66].ancer progression is associated with an increased proportion ofD8+/PD1+ T-cells, a phenotype that is associated with both func-ional exhaustion and replicative senescence [72]. Thus, it is clearhat immunosenescence contributes to the development of can-er and in turn cancer further exacerbates the development ofmmunosenescence (Fig. 1).

. Prevention of age-related declines in immunity byxercise

Multiple studies published over the last two decades suggesthat exercise can mitigate the deleterious effects of age on immuneunction, thus increasing anti-cancer immunity [73]. Habitual aer-bic and resistance exercise have both shown promise as a meansf increasing NK-cell cytotoxicity in the elderly. Elderly womenith relatively high aerobic capacity have higher NK-cell cyto-

oxic activity (NKCA) than their less-fit counterparts [74]. Exercisencreases the number and function of monocytes and macrophages,ncluding their anti-tumor cytotoxicity and production of cytokineshat inhibit tumor growth [75]. Additionally, [76] reported that

12-week training program consisting of aerobic and resistancexercise resulted in a decreased proportion of pro-inflammatoryonocytes in blood and reduced LPS-stimulated production of

ro-inflammatory cytokines. A similar 12-week training programas found to increase the antigen-presenting capacity of mono-

Please cite this article in press as: Bigley AB, et al. Can exercise-related imin the elderly? Maturitas (2013), http://dx.doi.org/10.1016/j.maturitas.201

ytes [77]. Collectively, these data suggest that exercise is ableo inhibit the development of a tumor-promoting environmenty combating “inflammaging”, while also enhancing the cyto-oxic, antigen-presenting, and tumor-suppressive functions of

PRESS xxx (2013) xxx– xxx 3

monocytes and macrophages. A 6-month program of Tai Chiexercises in middle-aged and elderly women reported a markedincrease in the frequency of dendritic cells with concomitantincreases in the frequency of IL-4 and IFN-� expressing T-cells, thussuggesting improved T-cell priming and antigen presentation [78].Further support for this idea comes from rat models where fiveweeks of endurance training was found to enhance DC-inducedleukocyte activation through increased IL-12 production and MHCClass II expression [79].

Physical exercise may also improve adaptive immunity in theelderly. We have shown that increasing scores of aerobic fitnessare associated with increased proportions of naïve CD8+ T-cellsand decreased proportions of senescent/exhausted CD4+ and CD8+T-cells [80]. Remarkably, the increase in senescent CD8+ T-cellswith age was eliminated when adjusted for fitness scores, indi-cating that decreasing fitness may be a stronger determinant ofimmunosenescence than increasing age. It has been hypothesizedthat the altered composition of naïve, memory, and senescent T-cellsubsets in the physically fit is due to preferential apoptosis of theexhausted/senescent cell population as a response to regular boutsof acute exercise [81]. Thus, repeated bouts of exercise could leadto continual deletion of senescent T-cells and creation of “immunespace” for naive T-cells that can respond to ever-evolving tumorsand maintain equilibrium. Regular physical activity is associatedwith superior T-cell proliferative responses [74] and production ofTh1 and Th2 cytokines by T-cells in the elderly [82,83]. Exercisetraining interventions in previously sedentary elderly individualshave been shown to enhance T-cell proliferative capacity [84,85]as well as humoral and cell-mediated responses to vaccination[86,87]. From this data, it seems clear that exercise has the potentialto both prevent and reverse some of the deleterious effects of agingon immunity in a manner conducive to improved cancer preventionand prognosis (Fig. 2).

5. The effects of exercise on cancer prevention andprognosis

There is a consensus that habitual exercise can offer protec-tion against certain types of cancer; however the evidence linkingimmunological mechanisms, exercise, and reduced cancer riskremain tentative [88]. Multiple studies have correlated frequentbouts of aerobic exercise with a reduced risk of cancer, especiallycolorectal, breast, and prostate cancer [89]. One meta-analysisreported that high levels of physical activity may be able to reduceall-cause cancer rates by 46% [90]. Moreover, it was reported that12-months of aerobic exercise in middle-aged and elderly mendecreased colon crypt cell proliferation, a precursor to colon cancer[91]. Exercise may exert this protective effect through preven-tion of visceral fat accumulation and the resulting inflammation,as the association between cancers and chronic inflammation iswell established [92]. The anti-inflammatory effect of exercise mayalso help reduce cancer-risk in the elderly, possibly by ameliorating‘inflammaging’.

Habitual exercise may also enhance survival in cancer patients.Breast cancer patients who engage in moderate physical activityhave improved survival and reduced cancer recurrence comparedto sedentary patients [93]; similar results have been found withcolorectal cancer patients [94]. This protection may arise fromreduced tumor escape, as exercise has been shown to limit therisk of metastasis in mice [95]. The time required for malignantcells to escape the equilibrium phase is influenced by multiple fac-

provements in immunity influence cancer prevention and prognosis3.06.010

tors, including age and lifestyle. CD8+ T-cell activity is importantin the control of tumor outgrowth observed during the equilibriumphase [23], which is in turn known to be detrimentally affectedby both chronological aging and by sustained sedentary behavior

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Fig. 1. Aging and cancer. Chronological aging is associated with profound changes in metabolism and immunity that facilitate cancer development. Latent viral infectionsare known to be more prevalent in the elderly, some of which are able to directly induce tumorigenesis. The chronic systemic inflammation, enhanced oxidative stress, andtissue hypoxia seen in the aged encourage tumor development and outgrowth. Cellular changes associated with aging, such as the accumulation of senescent, suppressor,and exhausted T-cells and the concomitant reduction in innate immunity can accelerate immune evasion by tumors.

F yle chi emenR ersed

[tlnctwi

ig. 2. The impact of lifestyle on the age-associated increase in cancer risk. Lifestn cancer susceptibility. A sedentary lifestyle is associated with many distinct decrecent evidence suggests that many of these deleterious effects of aging can be rev

79,96]. While the exact mechanisms by which T-cells maintainumor cells in the equilibrium phase remain to be unraveled, it isikely that any disturbance in T-cell function, as seen in immunose-escence, will promote tumor cell escape from immunological

Please cite this article in press as: Bigley AB, et al. Can exercise-related imin the elderly? Maturitas (2013), http://dx.doi.org/10.1016/j.maturitas.201

ontainment. It is likely that the reduced risk of acquiring cer-ain cancers and the improved prognosis that has been associatedith regular exercise is at least partially due to the amelioration of

mmunosenescence.

oices lead to divergent immunological aging pathways with resultant differencests in innate and adaptive immunity that facilitate tumor development in the aged.through habitual aerobic exercise. NK, natural killer; TCR, T-cell receptor.

6. Conclusions

It must be noted that the case implicating immune dysfunc-tion in the increased incidence of cancer in the aged is largely

provements in immunity influence cancer prevention and prognosis3.06.010

circumstantial, as no direct causal link has yet been establishedin humans. However, the association between aging and cancer isclear: more than 60% of new cancers and more than 70% of can-cer deaths occur in individuals that are more than 65 years old [1].

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nterestingly this association exists in spite of decreased de novoarcinogenesis in the very elderly when compared to younger indi-iduals [45], which has led to the idea that a decline in anti-tumormmunity is responsible for the increased incidence of cancer in theged. There are multiple age-related deficits in both the innate anddaptive immune systems that may play a role in the increased inci-ence of cancer with age, such as decreased NK-cell cytotoxicity,ecreased antigen-presentation by monocytes and dendritic cells,n increase in “inflammaging”, a decline in the number of naïve-cells able to respond to evolving tumor cells, and an increasen functionally exhausted senescent cells. The potential amelio-ative effect of exercise on these mechanisms is supported byvidence that physical activity is able to stimulate greater NK-ell activity, enhance antigen-presentation, reduce inflammation,nd clear senescent cells in the elderly. However, more prospec-ive, mechanism-probing research studies are required to establishausative links between cancer, exercise, and immunosenescence.

ontributors

Austin Bigley conceived the idea of the review, performed theiterature review, and organized the manuscript. Dr. Guillaumepielmann, Emily C.P. LaVoy, and Dr. Richard J. Simpson all con-ributed to the writing of the manuscript and provided expertommentary throughout the writing process.

ompeting interest

The authors declare no conflict of interest.

rovenance and peer review

Commissioned and externally peer reviewed.

unding

No external funding sources were utilized for this work.

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