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Ageing Research Reviews

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europhysiological and epigenetic effects of physical exercise onhe aging process

erla Kalimana,∗, Marcelina Párrizasa, Jaume F. Lalanzab,c, Antoni Caminsd,osa Maria Escorihuelac,∗, Mercè Pallàsd,∗

Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS) Villarroel 170, E-08036 Barcelona, SpainDeptartamento de Psicología Básica, Evolutiva y de la Educación, Facultad de Psicología, Universidad Autónoma de Barcelona, Bellaterra, SpainInstituto de Neurociencias, Departamento de Psiquiatría y Medicina Legal, Facultad de Medicina, Universidad Autónoma de Barcelona, Bellaterra, SpainUnidad de Farmacología y Farmacognósia, Facultad de Farmacia, Instituto de Biomedicina, Universidad de Barcelona y CIBERNED, Spain

r t i c l e i n f o

rticle history:eceived 7 February 2011eceived in revised form 29 April 2011ccepted 13 May 2011vailable online xxx

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a b s t r a c t

Aging is a gradual process during which molecular and cellular processes deteriorate progressively,often leading to such pathological conditions as vascular and metabolic disorders and cognitive decline.Although the mechanisms of aging are not yet fully understood, inflammation, oxidative damage, mito-chondrial dysfunction, functional alterations in specific neuronal circuits and a restricted degree ofapoptosis are involved. Physical exercise improves the efficiency of the capillary system and increasesthe oxygen supply to the brain, thus enhancing metabolic activity and oxygen intake in neurons, andincreases neurotrophin levels and resistance to stress. Regular exercise and an active lifestyle duringadulthood have been associated with reduced risk and protective effects for mild cognitive impairmentand Alzheimer’s disease. Similarly, studies in animal models show that physical activity has positive

ehaviorpigenetics

physiological and cognitive effects that correlate with changes in transcriptional profiles. According tonumerous studies, epigenetic events that include changes in DNA methylation patterns, histone modifica-tion and alterations in microRNA profiles seem to be a signature of aging. Hence, insight into the epigeneticmechanisms involved in the aging process and their modulation through lifestyle interventions such asphysical exercise might open new avenues for the development of preventive and therapeutic strategiesto treat aging-related diseases.

. The aging process

The accumulation of molecular and cellular damage through-ut life leads to a wide range of age-related pathological conditionsuch as vascular disorders, sarcopenia, osteoporosis, liver dysfunc-ion, and cognitive decline. Loss of protein and bone mass and aoncomitant increase in fat mass occur during aging, which resultsn a growing incidence of disorders such as inflammatory diseases,yslipidemia, atherosclerosis, obesity, insulin resistance and type

diabetes mellitus. In humans such disorders are risk factors forardiovascular disease or stroke in the later stages of life. In addi-ion, some of these factors, e.g. dyslipidemia, are associated withncreased incidence of neurodegenerative diseases characterized

Please cite this article in press as: Kaliman, P., et al., Neurophysiological anRes. Rev. (2011), doi:10.1016/j.arr.2011.05.002

y deterioration of neurons and glial cells, the core components ofhe nervous system and frequently lead to cognitive decline andenile dementia (Deary et al., 2009; McNeill et al., 2006). Remark-

∗ Corresponding authors.E-mail addresses: [email protected] (P. Kaliman),

[email protected] (R.M. Escorihuela), [email protected] (M. Pallàs).

568-1637/$ – see front matter © 2011 Elsevier B.V. All rights reserved.oi:10.1016/j.arr.2011.05.002

© 2011 Elsevier B.V. All rights reserved.

ably, two studies performed with 1624 Latino (Yaffe et al., 2007)and 2632 elders of African and Caucasian backgrounds (Yaffe et al.,2004) have reported that metabolic syndrome may be predictiveof cognitive decline in a 3- and 5-year follow-up, respectively.These data suggest that factors associated with a lifestyle thatreduces metabolic and cardiovascular risks might also diminishthe risk for developing cognitive decline or Alzheimer’s disease(AD).

Only a few decades ago, when life expectancy was shorter, neu-rodegenerative disorders were rarely manifested as the percentageof the population reaching ages commonly associated with centralnervous system damage, progressive loss of personal independenceand eventual disability, was much lower than nowadays. Therefore,understanding the mechanisms underlying aging-related alter-ations in brain structure and function has become critical for theidentification of new therapeutic targets and the development ofmultimodal health-care strategies that meet the needs of an aging

d epigenetic effects of physical exercise on the aging process. Ageing

population. In this context, here we explore recent findings thatgive insight into the molecular and neurophysiological mecha-nisms elicited by physical exercise from the perspective of the agingprocess.

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. Aging theories

While the mechanisms underlying aging remain to be eluci-ated, it is currently known that inflammatory processes, oxidativeamage, mitochondrial dysfunction and apoptosis are involvedCarter et al., 2007). Several non-mutually exclusive theories haveeen proposed to explain the aging process and based on experi-ental data, the following mechanisms, among others, have been

uggested.

.1. Hayflick limit, telomeres and telomerase activity

The Hayflick limit was originally reported for human diploidbroblasts which can divide a finite number of times beforendergoing growth arrest and senescence (Hayflick, 1965). Mech-nistically, the Hayflick limit reflects telomere shortening duringach fibroblast replication. Telomerase is a ribonucleoprotein com-lex composed by the telomerase reverse transcriptase (TERT) andhe telomerase RNA component (TERC) that preserves chromo-ome stability by maintaining telomere length in proliferating cells.elomeres are sequences of nucleotides at the ends of chromo-omes that protect their integrity, and they are shortened with eachuccessive cell division. This shortening is due to the cell’s inabilityo replicate telomeres properly, and it ultimately leads to cellularamage and senescence (Blackburn, 2000).

Continued cell division in the absence of telomerase has beenhown to activate p53, which mediates growth arrest, senescencend apoptosis in stem and progenitor cells, and probably also inighly proliferative organs (Lee et al., 1998; Maser and DePinho,002). It has been recently proposed that telomere dysfunction

eads to premature tissue degeneration, chromosomal aberrationsnd neoplastic lesions (Donate and Blasco, 2011). However, theimple model that establishes a direct relationship between shorterelomeres and organism age can be misleading due to the pres-nce of active or readily activatable telomerase in many adult cellsChan and Blackburn, 2004). Although neurons do not generallyxhibit significant turnover, recent studies point to a role for telo-erase in the brain. Notably, psychiatric disorders such as major

epression, bipolar disorder and schizophrenia, which have beenssociated with decreased telomere length in peripheral tissues,o not seem to coexist with changes in telomere length in grayatter or brain cortex (Zhang et al., 2010; Teyssier et al., 2010).owever, TERT is constitutively expressed in the olfactory bulb and

he hippocampus, both of which exhibit stem cell-based adult neu-ogenesis (Gould, 2007), and its activity seems to be required forhe modulation of normal brain functions independently of telom-re lengthening (Lee et al., 2010). Moreover, telomeres shortenith age in neural stem cells of the subependymal zone whichrimarily produce olfactory bulb interneurons and neurogenesisnd neuronal differentiation and neuritogenesis are impaired inelomerase-deficient mice (Ferrón et al., 2009).

.2. Neuro-endocrine theory

This is based on the decline of the neuro-endocrine system, aomplex network that controls the secretion of several hormones,ostly through the hypothalamus. Aging reduces the ability of

he hypothalamus to regulate hormone secretion, which is con-omitant to reduced sensitivity to hormone action at the cellularevel (Dilman et al., 1986). It has been proposed that the declinen hypothalamus function is due to increased levels of cortisol,

hich is one of the few hormones that increases with age (Ferrari


nd Magri, 2008). The activity of the neuro-secretory cells of theypothalamus is modulated by other brain areas such as pre-

rontal cortex, amygdala and hippocampus that are interconnectedith hypothalamic nuclei. The hippocampus is especially sensi-

PRESSReviews xxx (2011) xxx– xxx

tive to age-related neurodegeneration and may be involved in theloss of hormonal modulation associated with aging (Stranahanet al., 2008). The neuro-endocrine theory of aging has been pro-posed to explain, at least in part, the pathogenesis of a clusterof age-associated disorders such as cardio-metabolic alterations,menopause, vascular cognitive impairment, late onset depres-sion, immune defense impairment, and breast and prostate cancer(Oxenkrug, 2010).

2.3. Free radical theory

This comprehensive theory was first proposed by Harman(1956). It involves free radicals, which are molecules with unpairedelectrons that confer high reactivity and the capacity to damageother molecules. Free radicals originate as a result of the energyproduction within the body, mitochondria being their main source.Free radicals can, however, be stabilized by free-radical scavengers,or antioxidants and living beings have antioxidant systems toprotect the organism against the continuous production of freeradicals, such as superoxide dismutase (SOD) (Melov et al., 2000;Finkel and Holbrook, 2000). Cellular oxidative damage is indis-criminate; there is evidence for the oxidative modification of DNA,protein, and lipid molecules (Mehlhorn, 2003). Free radicals attackthe structure of cell membranes, which then create metabolic wasteproducts. Such toxic accumulations interfere with cell communica-tion, disturb DNA, RNA and protein synthesis, lower energy levelsand generally impede vital chemical processes

2.4. Membrane theory

Cellular membranes become less lipidic during the aging pro-cess, thus impairing electrochemical processes and hindering thecellular function (Yeo and Park, 2002). In some cases, aging leadsto a membrane accumulation of toxins such as lipofuscin depositsin the brain, heart, lungs and skin and interestingly, it has beenreported that AD patients have much higher levels of lipofuscindeposits in the brain than healthy controls (Horie et al., 1997)

2.5. Mitochondrial decline theory

During aging, antioxidant defenses decline and therefore thepresence of free radicals eventually leads to a loss of mitochon-drial efficiency and a decrease in ATP production. Indeed, increasesin oxidative stress lead to accumulation of mitochondrial DNAdamage over the lifetime of an individual. Consequently, the func-tionality of the electron transport chain enzyme complexes thatproduce ATP and are in part encoded by mitochondrial DNAdecreases dramatically, gradually producing a cellular energy crisis(Linnane et al., 1998)

As already mentioned, all the current molecular aging theoriesare compatible with each other, as they have common features. Theprevailing aging theories involve processes located at the nuclearand mitochondrial compartments. While simple reasoning mightindicates that telomere dysfunction mainly affects highly prolif-erative cells, whereas mitochondrial failure also has a deleteriousimpact on quiescent tissues such as the brain, a molecular linkthat seems to unify the telomere and the mitochondria age-relateddysfunction has recently been described. Sahin et al. (2011) showthat transgenic mice with progressive telomere dysfunction alsopresent altered mitochondrial function due to decreased activityof the mitochondrial master regulators peroxisome proliferator-


activated receptor gamma, coactivator 1 alpha and beta (PGC-1�and PGC-1�). The connection between these two compartmen-tally separated processes seems to be triggered by p53 activationin response to telomere dysfunction. Eventually, decreased PGC-

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function may lead to oxidative stress with damaging effects onitochondrial DNA, cell membranes and cell function.

. Aging and epigenetics

Gene expression is determined not only by the DNA primaryequence, but also by a large number of modifications at thehromatin level. Indeed, there are layers of molecular informa-ion accumulating above the DNA level [epigenetics means abovehe genome] that regulate gene expression in a stable, durablend potentially reversible manner, without modifying the primaryequence. Epigenetics is acquiring a central role in the medicine ofhe twenty-first century, as it represents a bridge to understand theelationships between the individual genetic background, environ-ent, lifestyle, disease and aging.Epigenetic mechanisms include covalent modification of his-

ones, DNA methylation as well as the synthesis of non-codingNAs. Among the latter, microRNAs are considered to be crucial

n the aging process for their putative role in the manifestation ofarious pathologies (Crepaldi and Riccio, 2009). Indeed, epigenomelterations are currently regarded as part of aging and aging-relatedathological phenotypes. A general DNA demethylation patternelated to aging has been observed in most tissues from vertebratesWilson et al., 1987). In mitotically active tissues this phenomenonould reflect a deficiency in the maintenance of the remethylationachinery, which occurs during DNA replication. The global loss of

-methylcytosine during aging might enable the expression of sev-ral genes and silenced retrotransposons, thus increasing genomicnstability. Tra et al. (2002) compared 2000 loci in human T lym-hocytes obtained from newborn, middle-aged and elderly people,nd found that more than 29 loci (approximately 1%) changed theirethylation pattern during aging. In a recent study, DNA methy-

ation changes during development, maturation and aging werenalyzed in human cerebral cortex from subjects whose age rangedrom 17 weeks of gestation to 104 years old. The study included tis-ues from two groups of subjects who had suffered severe mentaliseases, AD and schizophrenia (Siegmund et al., 2007). A progres-ive increase in methylation levels throughout life was found in 8f the 50 loci analyzed, and a rapid increase within the first fewears after birth was observed in 16 loci.

Apart from DNA methylation, histone modifications also regu-ate gene expression, either favoring it or repressing it. As has beeneported for DNA methylation, deregulation of histone modifica-ion patterns has been observed with age. Thus, in yeast acetylationf histone H4 at lysine 16 (H3K16), a mark of gene activity, increasesith age, resulting in spurious gene expression (Dang et al., 2009).

n Caenorhabditis elegans, deficiencies in members of the ASH-2omplex, such as the H3K4 methyltransferase SET-2, increase lifepan by reducing general levels of H3K4 trimethylation, also aarker of gene activation (Greer et al., 2010). In Drosophila, on

he other hand, mutations in components of the Polycomb repres-ive complex PRC2, such as histone H3K27 methyltransferase E(Z)r its histone-binding partner ESC increase longevity by reducingrimethylation levels at H3K27, a marker of transcriptional silenc-ng. Accordingly, mutations in the antagonistic trithorax proteinsncreased H3K27 trimethylation and life span (Siebold et al., 2010).

In summary, changes in the epigenome seem to be a signaturef aging, according to numerous studies that analyze DNA methy-ation, histone modifications and miRNA expression. However,lthough such epigenetic features could be related to cognitiveecline and other aging-related symptoms and diseases, their func-


ional relevance remains poorly characterized, except in the casef several forms of cancer (Kulis and Esteller, 2010). In this con-ext, insight into the epigenetic mechanisms involved in the agingrocess may provide new tools for the development of diagnostic,

PRESSReviews xxx (2011) xxx– xxx 3

preventive and therapeutic strategies to treat aging-related condi-tions.

4. Lifestyle, exercise and aging

The World Health Organization has stressed the importance andpriority of an active lifestyle to fight sedentarism, which is consid-ered a risk factor for cardiovascular and metabolic diseases andfor premature mortality. It has been demonstrated that an activelifestyle and the regular practice of physical exercise can improvecardiovascular health (Kokkinos and Myers, 2010; Metkus et al.,2010; Bassuk and Manson, 2010; Möbius-Winkler et al., 2010),reduce the impact of risk factors affecting cardiometabolic andbrain health (Bianchi et al., 2008; Horton, 2009; Zanuso et al., 2010;Colberg, 2007; Saraceni and Broderick, 2007; Cotman et al., 2007),and provide beneficial effects at cognitive and psychological lev-els, including prevention and improvement of depressive statesand anxiety disorders, enhanced stress reduction, improved self-confidence and delayed cognitive decline in the elderly (van Praag,2009; Rolland et al., 2010; Erickson and Kramer, 2009; Deslandeset al., 2009). Physical activity seems to exert neurophysiologicaleffects by inducing changes in the transcriptional profiles of growthand neurotrophic factors such as VEGF, IGF-1 and BDNF that lead toimproved efficiency of the capillary system and trigger neuroplas-tic mechanisms in the brain (Dishman et al., 2006; Gomez-Pinilla,2008; Trejo et al., 2008; Carro et al., 2001). Although the precisemolecular pathways that sustain these processes are unknown,recent data have described the epigenetic impact of physical exer-cise in peripheral tissues and in the brain (see Sections 7 and 8).These changes might be involved in the mechanisms of cognitiveand stress resistance improvement associated with physical exer-cise (Fig. 1).

The epidemiological studies and clinical trials evaluating theeffects of exercise and physical activity in elderly healthy humans,and in elderly patients suffering dementia, mild cognitive impair-ment (MCI) or AD have been reviewed by Kramer et al. (2006) andRolland et al. (2010), respectively. A common conclusion is thatmore studies are needed to further characterize the amount, inten-sity, and types of exercise that produce the most robust effects inboth healthy and pathological conditions. Rolland et al. (2010) alsonoted that the specific aspects of exercise and physical activity thatprevent neurodegerative pathologies and age-related dementiahave not been accurately determined in randomized clinical trials(RCTs) yet. They also stressed the difficulties inherent to such trials,such as the impossibility of operating in double-blind conditions or,the unfeasibility of separating the effects of physical activity fromother benefits of an active lifestyle. More recently, Archer (2011)analyzed the putative mechanisms and factors underlying the maineffects of physical activity, which are neurogenesis, neurotrophicfactors, angiogenesis and improvement of depressive states, all ofwhich are involved in processes related with aging, AD and amnes-tic MCI (see also Lista and Sorrentino, 2010). Deslandes et al. (2009)summarized and reviewed the physical exercise interventions forelderly patients with major depressive disorder, AD and Parkinson’sdisease, and pointed out that the efficacy of the exercise interven-tion after the onset of the disease has not been reliably assessed.Thus, although consistent benefits of exercise have been reported,more specific studies addressing these issues are needed.

Table 1 lists the studies in elderly humans that report the effectsof exercise in the brain and in cognitive tasks, and it is orga-nized in three sections: interventional studies, studies based on


physical activity questionnaires (PAQ) and studies based on car-diorespiratory fitness (CRF). We have reviewed the literature usingthe PUBMED database using the search terms “exercise, physicalactivity, aging, and brain” combined with the term “human” (see

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Fig. 1. A model for the effect of exercise on molecular, neuroplastic and cognitive parameters. Physical activity has positive neurophysiological effects mediated by changesi F-1 anm se proe elated

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n the transcriptional profiles of growth and neurotrophic factors such as VEGF, IGechanisms in the brain. Although the precise molecular pathways that sustain the

xercise in peripheral tissues and in the brain. In mice such changes have been corr

upplementary Information for table references). We excluded caseeports and articles describing acute exercise interventions.

Interventional studies with exercise programs lasting from 12eeks to 10 months report consistent and significant results in

xecutive control performance and brain measurements. Thesetudies show significant improvements in the Wisconsin Card sort-ng test (Albinet et al., 2010), other tasks that evaluate executiveontrol, such as Stroop word-color conflict, task-switching or stopignal among others (Kramer et al., 1999; Smiley-Oyen et al., 2008);s well as increased gray and white matter volumes and greaterask-related activity in regions of the prefrontal and parietal cor-ices (Colcombe et al., 2004, 2006). A few studies evaluate thempact exercise on the evolution of neurodegenerative diseases.arson et al. (2006) observed a significantly reduced incidencef AD in individuals over 65 years of age who exercised a mini-um of 15 min, 3 times per week, compared with individuals of

he same age who exercised less than 3 times per week. Simi-arly, an interesting study by Baker et al. (2010), performed with6 men and 17 women (mean age, 70 years) with amnestic MCIlso revealed beneficial effects of the intervention exercise pro-ram (45–60 min/day, 4 days/week for 6 months), but the effectsere more significant for women than men. Thus, trained women

howed improved performance in tasks of executive control such aselective attention, search efficiency, processing speed and cogni-ive flexibility, whereas cognitive improvements in men were moreimited; gender differential effects have been also reported by otheruthors (Traustadottir et al., 2005; Komulainen et al., 2008), andy animal research studies (De Bono et al., 2006; Rezende et al.,006; Yamamoto et al., 2002; Navarro et al., 2004). Several stud-

es use a questionnaire (Physical Activity Questionnaire, PAQ) tocore the mean level of hours spent on different activities over aeek (stair-walking, gardening, sporting activities, etc.) and their

pecific metabolic equivalent conversion (MET in kcal). These stud-es reveal some interesting and consistent quantitative data thateed to be confirmed in RCTs to further determine their preventivend clinical impact. Some of the effects reported in these studiesre: (i) a negative association between cognitive decline and a fre-uency of exercise ≥3 times/week for at least 30 min/session (Lytlet al., 2004), (ii) walking less than 0.25 miles/day doubled the riskf dementia when compared with walking more than 2 miles/dayAbbott et al., 2004) or (iii) in women more than 4 h exercise/week,educes the risk of cognitive impairment by 88% compared with lessctive subjects (Sumic et al., 2007). In addition, some self-reportedpidemiological studies reveal more benefits for women than for


en, suggesting again that the mechanisms underlying physicalctivity may differ between the sexes, and need to be furtherharacterized. Table 1 also lists studies based on cardiorespira-ory fitness (CRF: oxygen consumption in ml), usually measured

d BDNF that lead to improved efficiency of the capillary system and neuroplasticcesses are unknown, recent data have described the epigenetic impact of physical

with cognitive enhancement and increased stress resistance.

by a maximal treadmill or cycle ergometer exercise tests, wherethe individuals run or cycle until they reach their maximal power;the test is terminated by volitional exhaustion reported by the par-ticipant or by the physician for medical reasons. However, sincethe maximal exercise tests can be strongly influenced by subjec-tive and motivational parameters, the lactate step test measuringthe walking speed conducted aerobically, independently of motiva-tion, is used alternatively in some studies (Flöel et al., 2010). Morerecently, an increasing amount of evidence supports a causal linkbetween the integrity of the vascular system and brain health andbetween the vascular disease risk factors and brain degenerationand dementia (Kalaria, 2010). Indeed, cerebral blood flow velocitydeclines with aging, and it has been found to be increased as a resultof aerobic fitness (Ainslie et al., 2008). This is consistent with thechanges in the cerebrovasculature reported in high-activity healthyelderly volunteers, in terms of lower vessel tortuosity values andan increase in the number of small-caliber vessels, compared withlow-activity healthy elderly subjects (Bullitt et al., 2009).

5. Exercise in rodents

Tables 2 and 3 list reports showing positive, negative orabsence of neurophysiological effects of wheel running and tread-mill exercise in healthy aged rats (Table 2) and in wild typemice and transgenic mouse models for neurodegenerative diseases(Table 3) (see Supplementary Information for table references).We have reviewed the literature using the PUBMED databaseusing the search terms “exercise, physical activity, aging, andbrain” combined with the terms “rat” (Table 2) or “mouse”(Table 3). Studies performed with aged animals, transgenic mod-els of neurodegeneration or aging-induced models have beenincluded.

The methods most frequently used to study physical exercisein rodents are the running wheel and the treadmill. In the runningwheel model, the animal is usually housed in a cage containinga free-access wheel, allowing the subject to run voluntarily. Thismodel has consistently shown beneficial effects on cognitive per-formance in aged healthy animals and has helped to unveil some ofthe underlying mechanisms responsible for these outcomes, suchas neurogenesis, synaptogenesis, angiogenesis and modulation ofneurotrophic factors (Neeper et al., 1995; Nithianantharajah andHannan, 2009; Kempermann et al., 2010; Fabel et al., 2003) as wellas protection against oxidative stress and inflammatory processesassociated with aging (Boveris and Navarro, 2008). However, a dis-


advantage of the voluntary wheel running model is that the animalshave to be individually housed to measure the amount, frequencyand intensity of the exercise performed by each subject and, iso-lation per se can affect behavior and many other neurobiological

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Table 1Neurophysiological effects of physical exercise in elderly humans.

Age/sex/condition Model Observations References

65–78 y/B/H (n = 24) Aerobic or stretching:1 h/d, 3 d/w, 12 w

Aerobic training improved working memory andcardiovascular function

Albinet et al. (2010)

55–85 y/B/MCI (n = 33) High intensity aerobic orstretching: 45–60 min/d,4 d/w, 6 m

Aerobic training induced sex-specific improvements oncognition

Baker et al. (2010)

58–77 y/B/H CRF (n = 41); aerobic orstretching (n = 29)40–45 min/d; 3 d/w; 6 m

Increases in cardiovascular fitness associated withimproved functioning of the brain attentional networkduring a cognitively challenging task.

Colcombe et al. (2004)

60–79 y/B/H (n = 59) Aerobic or stretching:1 h/d, 3 d/w, 6 w

Aerobic training increased brain volume (gray and whitematter)

Colcombe et al. (2006)

60–80 y/F/H (n = 45) Aerobic: 40–50 min/d,3 d/w, 4 m

Improved cognitive scores Kara et al. (2005)

60–75 y/B/H (n = 124) Aerobic or stretching: 6 m Aerobic training showed substantial improvements inperformance on tasks requiring executive control

Kramer et al. (1999)

65–79 y/B/H (n = 57) Aerobic or stretching: 10 m Aerobic exercise induced beneficial effects on theperformance of executive control-dependent tasks.Changes in aerobic fitness were found unrelated toneurocognitive function

Smiley-Oyen et al.(2008)

71–93 y/M/H (n = 2257) PAQ Walking distance/day negatively correlated with risk ofdementia

Abbott et al. (2004)

60–80 y/B/H (n = 14) PAQ Aerobic activity in elderly subjects was associated withlower vessel tortuosity values and increased number ofsmall-caliber vessels in the brain

Bullitt et al. (2009)

50–78 y/B/H (n = 75) PAQ; CRF Physical activity, but not cardiovascular fitness, wasassociated with better memory encoding and cerebral graymatter density in preforntal and cingulate cortex

Flöel et al. (2010)

65 y mean/B/H (n = 1740) PAQ The incidence rate of dementia was lower for those whoexercised 3 or more times/week

Larson et al. (2006)

>65 y/B/H (n = 1146) PAQ High exercise level at baseline was protective againstcognitive decline in a 2-year follow up

Lytle et al. (2004)

65–79 y/B/H at midlife(n = 1449)

PAQ Leisure-time physical activity at midlife at least twice aweek correlated with decreased dementia or AD in afollow up of 21 y

Rovio et al. (2005)

72.1 y mean/B/H (n = 31),MCI (n = 23), AD (n = 21)

PAQ Physical activity at midlife associated with larger totalbrain volume and frontal lobe gray but not white matter inlate-life

Rovio et al. (2010)

88.5 y mean/B/H (n = 66) PAQ Physical activity in women (>4 h/week) reduced theincidence of CI

Sumic et al. (2007)

70-81 y/F/H (n = 16466) PAQ Physical activity including walking associates with bettercognitive function and less cognitive decline (follow up:1.8 y mean)

Weuve et al. (2004)

66.5 y mean/M/H athletes(n = 10), sedentarycontrols (11)

CRF Long-term exercise decreased event-related mentalreaction time and increased V02max, testosterone andgrowth hormone

Ari et al. (2004)

20–35 y (n = 40) and60–75 y (n = 39),respectively/B/H

CRF Improved memory but not executive function with fitness.Association decreased between the ages of 60 and 75 y

Bunce et al. (2006)

>70 y/B/H (n = 64), earlystage AD (n = 57)

CRF In healthy subjects, fitness was associated with betterglobal cognitive performance. In AD cardiorespiratoryfitness associated with reduced brain atrophy

Burns et al. (2008)

20–31 y (n = 30), 50–62 y(n = 30)/M/H

CRF High aerobic fitness was associated with shorterevent-related potentials latencies, stronger centralinhibition, better cognitive performance and better visualsensitivity.

Dustman et al. (1990)

57–78 y/B/H (n = 1349) CRF The number of chronic diseases inversely correlated withV02max in men and women

Hakola et al. (2010)

27.9 y mean (n = 10) and66.5 y mean (n = 26)/F/H

CRF High aerobic fitness in elderly women attenuated the HPAaxis reactivity to psychological stress associated with aging

Traustadottir et al.(2005)

A F: femD hours

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bbreviations: PAQ: physical activity questionnaires; CRF: cardiorespiratory fitness;isease; MCI: mild cognitive impairment; n: number of subjects; min: minutes; h:

arameters (Stranahan et al., 2006; Leasure and Decker, 2009). Aecond disadvantage of this model is the variability in the amountnd intensity of the exercise performed by the animals on the wheelssociated with individual and sex differences, as well as the exer-ise fluctuations from one day to another (De Bono et al., 2006).hus, although voluntary wheel running is used consistently totudy the effects and mechanisms of exercise, these factors must


e bourn in mind when drawing conclusions about the amount,requency and duration of the interventions.

The forced treadmill is an alternative way to evaluate theffects of physical activity in rodents. The animals do not need

ales; M: males; B: females and males; H: mentally healthy subjects; AD: Alzheimer; d: days; w: weeks; m: months; y: years.

to be isolated in their home-cages and the exercise sessions areprogrammed and administered at a certain intensity, frequencyand duration, in such a way that all animals receive the sameamount of training. However, this model has the disadvantageof the stress inherent to a forced situation. In some studies,rodents are stimulated to run by tapping on their backs or byusing specific protocols involving a gradual adaptation to a run-


ning schedule. In other studies electrified wire loops are placedat the end of the belt in order to force the animal to stay andrun on the belt to avoid an electric shock. Thus, the effects offorced exercise in the treadmill must be interpreted carefully since

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Table 2Neurophysiological effects of physical exercise in aging rats.

Sex/age/condition Exercise/duration Observations References

M/23 m/H TM/7 w/8 m/m (15 min/d,5 d/w)

Exercise improved spatial learning, but not modified BDNF/NGF levelsin the basal forebrain.

Albeck et al. (2006)

ns/1, 6, 12 and 18 m/H WR/4 w Exercise decreased brain lactate. Anitha et al. (1997)M/1.5 m (aged induced) TM/8 w/19 m/m

(50 min/d, 5 d/w)Exercise increased NGF levels and reduced apoptosis viaphosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway.

Chae et al. (2009)

M/5–23 m/H WR or TM/72 w/20 m/m,40 min/d, 5 d/w

WR and TM modified hippocampal signaling protein levels fromseveral cascades related with membrane organization, cytoskeleton,endocytosis, neuronal growth, apoptosis, learning and neurogenesisamong others.

Chen et al. (2007)

M/11 and 18 m/H WR/94 or 12 w Exercise (94 w) reduced DNA and lipid oxidation in the cerebellum;exercise (12 w) only reduced lipid oxidation.

Cui et al. (2009)

M/8, 12 and 22 m/H Swim training(5–30 min/day) + v.E/12 w

Exercise increased antioxidant enzymes activity in the hippocampusand cerebral cortex, grater effects if combined with vitamin Esupplementation.

Devi et al. (2004)

F/22 m/H TM/3 w/(30 min/d) Exercise increased brain microvessels and the mRNA expression ofangiogenesis markers.

Ding et al. (2006)

ns/3, 12 and 25 m/H TM/18 w/30 min Exercise enhanced spatial learning, changed hippocampal high-affinitycholine uptake and upregulated muscarinic receptor density. Theeffects were not observed in parietal or frontal cortex.

Fordyce and Farrar(1991)

ns/3 and 10–27 m/H TM/ns Exercise compensated the age-related decline in hippocampalmuscarinic receptor density.

Fordyce et al. (1991)

M/11, 3 and 22 m/H WR or Swim/0.5 or 2 w Exercise and/or antidepressant treatment increased hippocampalBDNF mRNA.

Garza et al. (2004)

M/4 and 14 m/H WR or swim(60–90 min)/9 w

Exercise upregulated antioxidant mechanisms including antioxidativeand repair-degradation enzymes.

Goto et al. (2007)

M/5–23 m/H TM/72 w/20 m/m2 × 20 min

Exercise increased the number and the volume of the Purkinje cells ofthe cerebellum.

Larsen et al. (2000)

M/5, 24 m/H TM/6 w/8 m/m 30 min/d,5 d/w)

Exercise increased short-term and spatial memories, enhancedneurogenesis and suppressed apoptosis in the dentate gyrus.

Kim et al. (2010)

M/5–23 m/H WR orTM/72 w/20 m/m/2 × 20 min

WR and TM differently altered hippocampal mitochondrial activityand metabolic proteins.

Kirchner et al. (2008)

M/13–15 m/H TM/32 w/16.7 m/m60 min

Exercise and manipulation increased hippocampal plasticity andgrowth factor expression, and improved spatial learning.

O’Callaghan et al.(2009)

M/14 m/H Swim/6 + 3 w (60 min/d,5 d/w)

Exercise improved short and long memories, and attenuated theaged-associated increase of oxidative damaged proteins.

Radak et al. (2001)

M/3–4, 10–12 and 23–24 m/H TM/10 w/15 m/m(60 min/d, 5 d/w)

Exercise reversed the age-associated decline of flunitrazepam bindingsites and the increased sensitivity of flunitrazepam binding by GABA.

Jalilian Tehrani et al.(1995)

M/6, 24 m/H WR/1 w (60 min/d) Exercise increased tyrosine hydroxylase mRNA in substantia nigra. Tümer et al. (2001)M/5, 25 m/H TM/9 w/18 m/m Exercise increased Tyrosine hydroxylase mRNA TH immunoreactivity

and TH activity in the hypothalamus of old animals, but not in young.Tümer et al. (1997)

M/14 and 24 m/H TM/4 w/17 m/m(30 min/d)

Exercise increased the density of nigral microvessels and VEGF mRNAexpression in the rat substantia nigra.

Villar-Cheda et al.(2009)

M/ns TM/10 w Exercise did not increase brain-reactive antibody formation and didnot improve spatial memory.

Barnes et al. (1991)

M/24 m/H WR/12 or 84 w WR alone did not affect the mRNA expression of Tyrosine hydroxylasein the adrenal medulla and hypothalamus.

Erdös et al. (2007)

M/18 m/H WR or TM/1 w (20 m/m,40 min/d)

Exercise did not counteract the aged-related deficit observed in spatialmemory.

Hansalik et al. (2006)

M/30 m/H TM/4 w (20–40 min/d) Exercise did not prevent the age-associated loss in muscle strengthand did not improved spatial memory. No exercise effects on SIRT1activity were detected in the cerebellum.

Marton et al. (2010)

M/5–23 m/H WR or TM/72 w Housing and social interactions had more influence on BDNF thanise.

Strasser et al. (2006)

A zheimt eters

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physical exerc

bbreviations: F: females; M: males; B: females and males; H: healthy rats; AD: Alreadmill; WR: wheel running; EE: environmental enrichment; V: vitamin; m/m: m

hey may be influenced by the stress triggered by the trainingrocedure.

. Transcriptional effects of exercise

Changes in gene expression in response to exercise training haveeen explored but highly variable results are reported probably dueo differences in the type and intensity of exercise, previous train-ng status, age, gender, health conditions, target tissue and in someases even the type of microarray platform used, all of which com-licates the integration of the data. In rodents, there is extensiveibliography about the impact of exercise on gene expression in the


rain. In humans, although there are no data regarding the modula-ion of brain gene expression by physical training, results obtainedrom peripheral blood cells or skeletal muscle biopsies show signif-cant transcriptional changes induced by acute or chronic exercise

er Disease; min: minutes; h: hours; d: days; w: weeks; m: months; y: years; TM:/minutes; MWM: morris water maze; ns: not specified.

practice. It is important to note, however, that data from peripheraltissues in humans can be informative about the potential impactof exercise at the neurophysiological level, as cardiometabolic,inflammatory and immune factors are known to influence thedevelopment of neurodegeneration and cognitive impairment.

In rodents, gene expression in response to physical exerciseis particularly sensitive in the hippocampus, which plays a keyrole in learning, memory processes and stress response (Cotmanet al., 2007). The hippocampus is especially susceptible to dysfunc-tional and degenerative processes during aging and it is involvedin the regulation of mood and antidepressant responses (Mattsonand Magnus, 2006). In the rodent hippocampus, changes in the


expression of neurotrophic factor genes such as the vascular growthfactor (VGF) and BDNF as well as in several genes associated withneuronal plasticity, activity and structure have been reported inresponse to voluntary exercise on running wheels (Hunsberger

dx.doi.org/10.1016/j.arr.2011.05.002



P. Kaliman et al. / Ageing Research Reviews xxx (2011) xxx– xxx 7

Table 3Effects of physical exercise in mouse aging, neurophysiology and neurodegeneration.

Sex/age/condition Exercise/duration Observations References

M/2 and 24 m/H WR/1 w Exercise improved retention and increased the expression oflearning/memory related genes in the hippocampus

Adlard et al. (2011)

F/6, 12, 8 and 24 m/H WR/3 w Exercise restored the number of cultured periventricular neural stemcells and augmented regenerative capacity

Blackmore et al. (2009)

M/3–24 m/H WR/84 w (1 h/d) Exercise increased the expression of GAP-43 and synaptophysin in thehippocampal formation

Chen et al. (1998a)

M/3–13 and 24 m/H WR/40 or 84 w (1 h/d) Exercise increased cholinergic fibers in the hippocampus, motor andsomatosensory cortices

Chen et al. (1998b)

M/12, 24 and 3–9 m/H WR/2 w or 24 w Exercise reduced the age-dependent decline in hippocampalneurogenesis, but did not maintain the younger age levels

Kronenberg et al.(2006)

B/9–12 and 19.5 m/H TM/50 w (15 min/w) Moderate exercise increased lifespan, improved neuromuscularcoordination and exploratory cognitive activity and mitochondrialfunction. Effects were lost at 19.5 m of age

Navarro et al. (2004)

M/19 and 27–29 m/H WR/12 w Exercise increased survival rate and decreased heart and adrenal glandnorepinephrine content in aged animals

Samorajski et al. (1987)

M/2–4 m to 18–20 m/H WR/64 w Lifelong exercise upregulated synaptic plasticity and mitochondrialfunction genes and downregulated genes associated with oxidativestress and lipid metabolism

Stranahan et al. (2010)

ns/3 and 19 m/H WR/4 w Exercised improved acquisition and retention in the MWM andpartially reversed the age-associated decline in hippocampalneurogenesis.

van Praag et al. (2005)

M/2, 15 and 24 m/H WR/4 w Exercise increased BDNF mRNA expression after 1 week, but decreasedto sedentary levels after 2 weeks in aged animals

Adlard et al. (2005)

M/3 and 22 m/H WR/10.5 w In adult mice, exercise enhanced spatial pattern discrimination andthe performance was correlated with increased neurogenesis in thehippocampus

Creer et al. (2010)

M/24 m/H TM/4 w/8 m/m 45 min Exercise has detrimental effect on motor behavior in male micewithout improving cognitive parameters

Fabene et al. (2008)

F/6 and 18 m/AD WR/2 w Exercise and EE did not change the plaques load, but decreased thepathological variant of the A� molecule and increased neurogenesis inthe dentate gyrus of the APP23 mice

Mirochnic et al. (2009)

ns/10–12 m/AD WR/6 w Exercise improved spatial learning in the transgenic APOE �4 mice,and increased synaptic plasticity markers in hippocampus

Nichol et al. (2009)

ns/16–18 m/AD WR/3 w Exercise decreased the pro-inflamatory response associated with AD Nichol et al. (2008)ns/16–18 m/AD WR/3 w Exercise improved reference and working memory in the radial-arm

water mazeNichol et al. (2007)

ns/15–19 m/AD WR/3 w Exercise improved spatial memory in the radial-arm water maze andincreased the levels of neuroprotective markers in the hippocampus ofTg2576 mice

Parachikova et al.(2008)

ns/24 m/AD TM/12 w/12 m/m60 min

Exercise improved spatial learning and reduced neuronal cell death inthe hippocampus of aged transgenic Tg-NSE/PS2m mice

Um et al. (2011)

ns/22 m/AD WR/4 w Exercise reduced age-related synaptic abnormalities in peripheralneuromuscular synapses, but had no effect on motor neuron number

Valdez et al. (2010)

M/2.5 m/HD WR/10 w Exercise accelerated disease onset and increased motor impairmentsand striatal volume reduction. In addition, hippocampal neurogenesis,dentate gyrus volume, spatial learning and lifespan were not enhancedby exercise

Potter et al. (2010)

M/2 m/A� plaque; AD WR/3 w Exercise reduced stereotypes, but had no effects on neuropathologicalparameters, did not improve cognition, and positively correlated withplaque burden

Richter et al. (2008)

M/1 m/HD WR/4 w Exercise delayed onset of a motor co-ordination deficit and rear-pawclasping, and did not ameliorate brain atrophy and protein aggregates

van Dellen et al. (2008)

F/2.5–13.5 m/AD WR/44 w Exercised did not improve spatial learning or hippocampalneurogensis, but downregulated hippocampal and cortical growthfactors

Wolf et al. (2006)

A lzheimt eters

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bbreviations: F: females; M: males; B: females and males; H: healthy mice; AD: Areadmill; WR: wheel running; EE: environmental enrichment; V: vitamin; m/m: m

t al., 2007; Molteni et al., 2002; Tong et al., 2001). When the effectf wheel running on BDNF expression was compared in rodents ofifferent ages, BDNF protein levels increased after 1 week of exer-ise in young (2 months), middle-aged (15 months) and old (24onths) animals but only young animals maintained a significant

ncrease in this factor above basal levels after 4 weeks of expo-ure (Adlard et al., 2005). A recent study analyzed the expressionf 24,000 hippocampal genes in mice exposed for a 16 months toither a sedentary lifestyle or physical activity (running wheels)Stranahan et al., 2010). After a learning period on the water maze,


ice with an active lifestyle showed increased activation of hip-ocampal genes related to neuroplasticity, mitochondrial function,ell excitability, insulin signaling and MAP kinase and Wnt path-ays. Moreover, the expression of genes associated with oxidative

er Disease; min: minutes; h: hours; d: days; w: weeks; m: months; y: years; TM:/minutes; MWM: morris water maze; HD: Huntington’s disease; ns: not specified.

stress and lipid metabolism decreased. These results indicate thatexercise-induced cognitive improvement may be related to geneexpression changes in response to learning.

Differences in gene responses to exercise training in young andold rats have been detected not only in the hippocampus but also inother brain areas such as noradrenergic and dopaminergic nuclei,the substantia nigra, locus coeruleus and the ventral tegmentalarea (Tümer et al., 2001; Murray et al., 2010). Although transcrip-tional responsiveness seems to vary throughout life, many braingenes still seem to be modulated by exercise in aged animals. The


transcriptional effect of exercise has also been analyzed in ani-mal models for neurodegenerative diseases. Inflammatory markersseem to correlate with cognitive impairment in mild-to-moderateAD patients, and their expression patterns were studied in the hip-

dx.doi.org/10.1016/j.arr.2011.05.002

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ocampus of sedentary and exercised AD mouse model (Tg2576)nd age-matched healthy control mice (Parachikova et al., 2008). In5–19-month-old healthy mice, 3 weeks of voluntary wheel run-ing increased chemokines and their receptors, but no differences

n cognitive function were detected between sedentary and exer-ised animals in these conditions. In contrast, in aged Tg2576 miceith symptoms of AD, voluntary exercise improved spatial learn-

ng and increased mRNA levels for 5 chemokines including CXCL1nd CXCL12, which are involved in neuroprotection from A� in theippocampus and in neuron–glia/neuron–neuron communication,espectively.

In humans, a limited number of microarray studies haveescribed mitochondrial and metabolic improvements in skeletaluscle in response to exercise in aged subjects, although there

s some controversy regarding the exercise-induced plasticity inuscle and mitochondrial function in older subjects (reviewed by

jubicic et al., 2010). Healthy elderly humans when compared withoung adults presented mitochondrial impairment and muscleeakness, both of which were significantly reversed at the phe-otypic and transcriptome level following 6 months of resistancexercise training (Melov et al., 2007). Power training exercise for 12onths during the early stages of the postmenopause also induced

ranscriptional modulation of gene clusters in human skeletaluscle related to mitochondrial function, energy metabolism and

ontraction responses. These changes partially overlap with thosectivated by hormone replacement therapy, suggesting that theyay help reduce the risk for aging-related muscle weakness

Pöllänen et al., 2010).

. Epigenetics and exercise

As described above, an increasing number of studies suggest thathysical activity has positive physiological and cognitive effectsediated by changes in transcriptional profiles. However, theolecular mechanisms responsible are unknown. In this context,

ecent studies have examined the epigenetic impact of exercise.lthough the experimental data that link physical exercise and epi-enetics are still limited, they open new avenues that could helpesign innovative medical and lifestyle interventions. For example,

t has been shown in rodents that an environmental enrichmenthat includes voluntary exercise increases synaptic integrity andeuroplasticity in the brain, while improving memory, learningnd stress response. Such effects have been correlated to epigenetichanges in the hippocampus and cerebral cortex that start within

h and persist for at least 2 weeks (Fischer et al., 2007). Althoughhese effects cannot be directly attributed to exercise becausehe enriched environment also includes visual, somatosensorialnd social stimulation, this study clearly indicates that a lifestylentervention can improve cognitive functions through epigenetic

echanisms. Recent findings from Reul’s group have revealedhat regular physical exercise induces epigenetic modifications athe dentate gyrus which may regulate gene expression responsesnvolved in neuroplastic and cognitive responses to stressful eventsCollins et al., 2009). They found lower levels of anxiety in exer-ised versus sedentary rats when exposed to a novel environment.fter 30 min of exposure, exercised rats just lie and sleep whereasedentary controls showed continuous exploratory behavior con-istent with an anxious and vigilant state. In a forced swim,edentary and exercised rats showed indistinguishable behavior,uch as struggling and swimming, but in the forced swim re-test,xercised rats displayed significantly more immobility behavior,


hich seems to be an adaptive response to increase survival. Theseehavioral responses to exercise were found to correlate withhanges in the levels of histone H3 acetylation at lysine 14 andhosphorylation at Ser 10, as well as changes in c-fos induction


which are involved in the immobility response (Chandramohanet al., 2008). Intriguingly, exercise may also exert intergenera-tional epigenetic effects, as suggested by a study showing thatpups from exercised young pregnant rats had higher hippocam-pal BDNF gene expression at birth, which decreased at postnataldays 28 and 40. Offspring from exercised mothers showed animprovement in spatial learning compared to age-matched controlrats (Parnpiansil et al., 2003). The concept of an exercise-inducedtrait-transmission to subsequent generations deserves furtherexamination.

In humans, McGee et al. (2009) examined the effect of exer-cise in global histone modifications in skeletal muscle. They foundthat during exercise histone deacetylases HDAC4 and 5, which ingeneral function as transcriptional repressors, were exported fromthe nucleus. Interestingly, class IIa HDAC nuclear export is inducedby a phosphorylation mechanism dependent on AMP-activatedprotein kinase (AMPK) and the calcium–calmodulin-dependentprotein kinase II (CaMKII), both of which were found to be acti-vated by exercise. Recently, the effect of high-intensity walking for6 months (3.9 ± 1.2 days/week; 52.2 ± 18.5 min/day) was studiedin an elderly group (n = 230) and compared with young sedentarycontrols (n = 34) and older sedentary controls (n = 153) (Nakajimaet al., 2010). Methylation of the pro-inflammatory ASC gene, whichis responsible for IL-1� and IL-18 secretion, decreased significantlywith age, indicating an age-dependent increase in ASC expression.Notably, the ASC methylation levels were higher in the older exer-cise group than in the older controls. Neither exercise nor ageaffected the methylation of the cancer-related protein P15. There-fore, chronic moderate exercise appears to buffer the age-relatedincrease in pro-inflammatory cytokines through epigenetic regu-lation of ASC expression. MicroRNAs (miRNAs) represent anothermechanism of epigenetic regulation through attenuation or silenc-ing of protein translation. A study in healthy men (19–30 years old),who performed ten 2-min bouts of cycle ergometer exercise sep-arated by 1-min rest, revealed that exercise significantly alteredthe expression of 38 miRNAs in neutrophils (Radom-Aizik et al.,2010).

8. Exercise and telomeres

Mammalian telomere length regulation is increasingly associ-ated with particular states of heterochromatic structure. Whenchromatin compaction in telomeres is altered, there is a lossof telomere length control and conversely, telomere shorteninggives rise to chromatin compaction at telomeric and subtelomericrepeats, activating alternative mechanisms for telomere mainte-nance. Moreover, it has recently been described that telomeres aretranscribed to express UUAGGG-repeat containing TelRNAs/TERRA,non-coding RNAs that may regulate telomere length and chro-matin states (Schoeftner and Blasco, 2010). Therefore, there is alevel of chromatin regulation that defines the epigenetic status oftelomeres and although the mechanisms are still unknown, any fac-tor with the capacity to modulate mammalian telomere dynamicsmight be acting through epigenetic chromatin remodeling.

In this context, recent studies have analyzed the impact of phys-ical exercise on telomere length and telomerase activity. Mice on a3-week or 6-month voluntary running program exhibited upregu-lated telomerase activity in cardiac cells, circulating mononuclearcells and thoracic aorta compared with sedentary controls (Werneret al., 2008, 2009). Mice with schizophrenia-like behavior, due tomaternal challenge with a viral-like infection during pregnancy,


showed decreased telomerase activity in neural precursor cellsfrom birth to adulthood. After 10 days of voluntary wheel runningat postnatal day 50, mouse telomerase activity in neural precursorcells recovered control levels (Wolf et al., 2011).

dx.doi.org/10.1016/j.arr.2011.05.002

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Fig. 2. Putative association between Sirt1 activity and exercise. Parallelism withcaloric restriction and resveratrol. In mammals, Sirt1 locates in the cell nucleus,where it regulates tumor suppressor p53, as well as NF-�B and other transcriptionfactors via its deacetylase activity. Downstream sirtuin 1 substrates, such as p53,PPAR� coactivator-� (PGC-1�), FoxO or NF-�B, exert key metabolic and survivalfunctions in most cellular contexts and tissues. Caloric restriction (CR) and resvera-trol intake have been proposed as interventions that may promote successful brainaging through a protective mechanism activated by Sirt1. Although still poorly doc-



In humans, exercise also seems to induce telomerase activity.eukocytes isolated from young and middle-aged endurance ath-etes showed increased telomerase activity, telomere-stabilizingrotein expression, cell-cycle inhibitor downregulation and lowerelomere erosion compared with untrained individuals (Wernert al., 2009). Moderate but not low or high exercise energy expen-iture in adults from 50 to 70 years of age seems to provide arotective effect on telomere length in peripheral blood mononu-lear cells (Ludlow et al., 2008). Although shortened telomeres wereetected in skeletal muscle of athletes suffering from exercise-ssociated fatigue (Collins et al., 2003), healthy individuals with

history of strength training did not show abnormal shortening ofelomeres in muscle biopsies (Kadi et al., 2008).

. Sirtuins: an exercise target?

Sirtuins are a highly conserved family of proteins with a pos-ible key role in cell survival (Pallas et al., 2008). They were firstound in yeast (Sir2), although currently seven human homologuesf Sir2 have been described (Sirt1 to Sirt7), three of which (Sirt1,irt6 and Sirt7) are nuclear proteins. Sirtuin-dependent deacetylasend ADP-ribosylase activities have been described and a putativeole for sirtuins as metabolic or oxidative sensors that respond tohe cellular environment has been proposed (Frye, 1999). In yeast,ir2 maintains gene silencing by removing H4K16 acetylation.ir2 expression decreases with age and thus H4K16 acetylationncreases in subtelomeric regions (Dang et al., 2009). In mammals,irt1 locates in the nucleus, where it regulates tumor suppres-or p53, as well as NF-�B and other transcription factors via itseacetylase activity (Michishita et al., 2005). Sirt2 is a cytoplas-ic protein that colocalizes with microtubules and deacetylates

ubulin. Sirt2 expression increases during mitosis, which suggestshat it is involved in cell-cycle functions. On the other hand, Sirt3

odulates mitochondrial activity through the reduction of reactivexygen species production. Sirt4 and Sirt5 are also located in theitochondrion, which is highly sensitive to aging and metabolic

rocesses. Sirt6 and Sirt7 are associated with heterochromaticegions and the nucleolus, where Sir2 is known to act in yeast. Inummary, sirtuins participate in numerous cellular functions thatnclude cell survival, cell-cycle regulation and life span extensionDenu, 2003; Guarente and Kenyon, 2000).

Caloric restriction (CR) and resveratrol intake are considereds interventions that may promote successful brain aging (Martint al., 2006; Barger et al., 2008). The proposed protective mech-nism elicited by CR and resveratrol is through their role asctivators of Sirt1. Downstream Sirt1 substrates, such as p53,PAR� coactivator-� (PGC-1�), FoxO or NF-�B (Fig. 2), exert keyetabolic and survival functions in most cellular contexts and

issues, where each one may promote a separate or converg-ng slow-down mechanism of the aging process (Nemoto et al.,005). Interestingly, synaptic plasticity and memory formation arenhanced by Sirt1 activation independently of its cell survival role,hrough an epigenetic regulatory mechanism involving the miRNA

iR-134 (Gao et al., 2010). These data are consistent with recentndings showing that mice lacking Sirt1 present impairments inynaptic plasticity, immediate memory, classical conditioning andpatial learning (Michán et al., 2010).

Indeed, some of the mechanisms triggered by CR and resvera-rol also seem to be modulated by physical exercise. The effect ofhysical exercise on Sirt1 expression and activity has started to be

nvestigated in the last few years. In aged rats, Sirt1 activity has been


eported to increase after a 6 weeks treadmill training program ineart and adipose tissue (Ferrara et al., 2008) and in skeletal mus-le (Koltai et al., 2010). In contrast, in rat cerebellum Sirt1 activityas decreased significantly with aging and it was not increased by

umented, similar mechanisms may be triggered by physical exercise, which has alsobeen shown to increase the expression of Sirt1 and modulate the activity of someof its substrates.

mild exercise training (Marton et al., 2010). In humans, three daysof cycling caused acute increases in mRNA of PGC-1� and Sirt-1(Dumke et al., 2009), high intensity interval training decreased Sirt1expresion but increased its activity in skeletal muscle (Gurd et al.,2010) and marathon running increased Sirt1 and other antiapop-totic gene expression in peripheral blood mononuclear cells (Marfeet al., 2010).

Interestingly, some downstream Sirt1 substrates are also sensi-tive to exercise training. The mRNA and protein levels of PGC-1�,which controls mitochondrial activity and is deacetylated and acti-vated by Sirt1, increase in response to exercise in both humansand animal models (Suwa et al., 2008; Baar et al., 2002; Teradaet al., 2002; Ikeda et al., 2006; Jeninga et al., 2010; Ruschke et al.,2010; Aoi et al., 2010; Safdar et al., 2011). Moreover, it has beenreported in human soleus skeletal muscle that a 45-min treadmillrun induces transcriptional metabolic responses which include anincrease in FoxO3A gene expression detected 24 h after the train-ing (Harber et al., 2009). While most of the effects of exercise onSirt1-dependent pathways have been described in peripheral tis-sues, these observations allow to hypothesize that some of thebeneficial neurophysiological effects of exercise could be mediatedby the modulation of Sirt1 activity, a topic that although currentlyspeculative, is undoubtedly worth exploring.

10. Conclusion: aging theories, epigenetics and exercise

Although laboratory models and studies in humans of acuteor chronic physical exercise are highly variable and differentresults have been reported depending on the particular experi-


mental conditions, there is abundant bibliography describing theneurophysiological aging-protective responses elicited by exercisetraining. Exercise seems to improve the function of most of themechanisms involved in aging. For example, improvement of the

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imbic-HPA axis response, increase in telomerase activity both ineripheral cells and in neuronal progenitor cells from hippocam-us, enhancement of antioxidant defense pathways in peripheralnd brain cells and induction of mitochondrial biogenesis. A limitedut fascinating field has begun to describe the epigenetic impact ofhysical exercise in peripheral tissues and in the brain. Unveilinghe exercise-responsive mechanisms of chromatin regulation andheir pathophysiological implications may lead to the developmentf new preventive and/or therapeutic interventions for age-relatedisorders, including neurodegenerative conditions such as AD.

cknowledgments

This study was has been supported by grant DPS2008-06998-02 (MP and RME) Spanish Ministry of Science and Innovation, andy grants PI080400 from the Fondo de Investigación Sanitaria andhe Instituto de Salud Carlos III (AC), BFU2009-09988/BMC (MP),AF-2009-13093 (MP) and SAF2010-15050 (PK) from the Spanishinistry of Science and Innovation (MICINN). We thank the Catalanovernment (Generalitat de Catalunya) for supporting the researchroups (2009/SGR00853) (AC). J.F.L. was supported by a predoctoralellowship from the Generalitat de Catalunya (FI-DGR 2011).

ppendix A. Supplementary data

Supplementary data associated with this article can be found, inhe online version, at doi:10.1016/j.arr.2011.05.002.

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