Review

Exercise and the brain: something to

chew on
Henriette van Praag
Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging,
National Institutes of Health, Baltimore, MD 21224, USA

Evidence is accumulating that exercise has profound Similar to exercise, nutrition affects brain function.
benefits for brain function. Physical activity improves Consumption of food high in saturated fats and cholesterol
learning and memory in humans and animals. Moreover, increases the risk of cognitive decline, whereas dietary
an active lifestyle might prevent or delay loss of cogni- restriction benefits learning and protects the brain from
tive function with aging or neurodegenerative disease. oxidative stress [10]. There is also increasing evidence that
Recent research indicates that the effects of exercise on dietary supplements enhance learning and memory. Of
the brain can be enhanced by concurrent consumption of interest are the omega fatty acids, certain spices, teas
natural products such as omega fatty acids or plant and fruits [11]. Interestingly, these supplements enhance
polyphenols. The potential synergy between diet and the benefits of exercise for brain function [11–13]. Possible
exercise could involve common cellular pathways common mechanisms of action for exercise and diet on
important for neurogenesis, cell survival, synaptic cognition are discussed.
plasticity and vascular function. Optimal maintenance
of brain health might depend on exercise and intake of
Exercise and cognition
natural products.
Young and aged humans
Introduction Few studies pertaining to exercise and cognition have been
‘To get back my youth I would do anything in the world, carried out in children and young adults [6]. However, a
except take exercise, get up early, or be respectable’ (Oscar positive correlation between physical activity and learning
Wilde, The Picture of Dorian Gray, 1891). and intelligence scores was reported in a meta-analysis of
Unfortunately for those of us who subscribe to this school-age children [14]. In addition, in college students
outlook, physical activity is the most effective way to reaction time [15] and vocabulary learning were faster
maintain a healthy body and mind. This might seem immediately after intense running [16]. Similar results
obvious; however, the evidence that exercise is beneficial were obtained in young adults after 12 weeks of aerobic
for general health (i.e. prevention of hypertension, heart training (average age 33) [17]. This research indicates that,
disease, type II diabetes, osteoporosis and depression) rather than observing a ceiling effect of exercise in young
began to be taken seriously in western society only towards people, being active makes a functional difference. In
the end of the previous century. Indeed, in 1975 it was addition, aerobic exercise in childhood might increase
observed that ‘physical fitness and physical education have the resilience of the brain later in life, resulting in a so-
no respected place in the American public health move- called cognitive reserve. Indeed, a positive correlation
ment. Their practitioners have been labeled by at least one between physical activity at ages 15–25 and information
elder statesman of public health as ‘‘the big-muscle boys’’, processing speed in older men (62–85) was reported [18].
and this contemptuous attitude has persisted to this day’ In aging humans the cortex and hippocampus atrophy
[1]. However, a decade later, in view of the increasing [19] and memory function declines [20]. These deleterious
evidence for the health benefits of exercise ‘the Public consequences of aging might be attenuated by exercise [6].
Health Service specified ‘‘Physical Fitness and Exercise’’ Physically fit aged individuals, identified by self-report of
as 1 of the 15 areas of greatest importance for improving activity level, performed better on measures such as
the health of the public’ [2]. reasoning, working memory, vocabulary and reaction time
Study after study has now shown that the risk of con- than their sedentary counterparts [21]. In intervention
tracting cardiovascular, metabolic and metastatic diseases studies healthy sedentary adults between the ages of 60
is mitigated by exercise and a diet containing fruits and and 85 years participate in an exercise regime several
vegetables [3,4]. However, it is not as well appreciated that times per week over the course of several months to several
exercise and a healthy diet also provide substantial years. Cognition and fitness is assessed before and after
benefits for brain function. Physical activity improves the intervention. Although studies vary in duration, inten-
cognition and might delay age-related memory decline sity and type of exercise, overall physical activity improves
[5,6]. In addition, exercise protects against brain damage cognitive function [6,22]. This positive outcome is reflected
caused by stroke [7], promotes recovery after injury [8] and in neurophysiological measures such as electroencephalo-
is an antidepressant [9]. gram, event related potential (ERP) and functional mag-
netic resonance imaging (MRI) studies [6]. For example,
Corresponding author: van Praag, H. (vanpraagh@mail.nih.gov) ERP latency is decreased and amplitude is increased in
0166-2236/$ – see front matter . Published by Elsevier Ltd. doi:10.1016/j.tins.2008.12.007 Available online 6 April 2009 283
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aerobically fit individuals indicating improved neuronal running wheel for one month improved their acquisition
conduction and cortical activation [23]. Moreover, MRI and retention of the water maze task [37]. Furthermore,
studies showed that prefrontal and temporal gray matter treadmill training (15 min per day for 7 weeks) improved
volume was increased in active elderly subjects as com- learning in the Morris water maze in aged rats [38].
pared with sedentary controls [24]. Similar results were obtained in studies using transgenic
Objective measurements of aerobic fitness and exercise mouse models for AD. Specifically, long-term exercise
intensity, such as VO2 max, would optimize research started 5 months before disease onset improved water-
validity. In a recent intervention study in subjects with maze learning. In addition, running reduced the load of
mild cognitive impairment all participants wore a ped- b-amyloid plaques in both hippocampus and cortex [39].
ometer during the 6 month study and recorded the number Moreover, short-term running (3 weeks), initiated after
of steps per day [25]. Independent measures of activity are disease onset [40], improved both working and reference
particularly important given the extrinsic and intrinsic memory in aged AD mutant mice. Thus, exercise is
sources of variance within the human population. Indeed, beneficial for cognition in normal rodents and in transgenic
with the advent of the identification of Alzheimer’s Disease mouse models of dementia, even if started late in life or
(AD)-related genes, research has begun to focus on specific after the onset of disease symptoms.
population groups. For example, Apoliprotein (ApoE)-e4
allele carriers are considered to be at increased risk for AD Diet and cognition
[26]. In recent years the benefits of exercise in ApoE-e4- In recent years there is increasing evidence that changes in
positive subjects have been analyzed. Epidemiological stu- diet can benefit cognition. The most rigorous alterations
dies showed that this particular subpopulation could are intermittent fasting and caloric restriction. Research in
benefit relatively more from maintaining an active lifestyle animals has shown these regimens enhance learning, neu-
than non-carriers [27]. In older ApoE-e4-positive women rogenesis and neurotrophin levels. In humans limited
aerobic fitness was positively correlated with better per- calorie intake correlates with a reduced risk for AD [10].
formance on auditory, visual and spatial learning tasks However, dietary restriction regimens are difficult to main-
[28]. In another study a positive correlation between exer- tain. In fact, the search for caloric restriction mimetics is a
cise, temporal cortex activation during a learning task and focus of intense research [41]. A variety of dietary supple-
cognition was reported that was stronger in carriers than ments have been reported to be beneficial for learning in
non-carriers of this gene [29]. However, in a 6 month animals and humans. Positive effects on brain function
intervention study there was an attenuated effect of exer- have been reported for fish oil, teas, fruits, folate, spices
cise in ApoE-e4 carriers that showed symptoms of memory and vitamins [11]. Particularly interesting are plant-
decline [25]. Further studies are needed to determine derived products such as grapes, blueberries, strawberries,
whether early intervention with an active lifestyle (com- tea and cocoa, which benefit memory in rodents [42].
bined with certain dietary supplements) might be particu- The importance of natural plant products for cognition
larly beneficial for this at-risk population. has been underestimated, in part because the active ingre-
dient(s) in the plant extracts remained unknown, limiting
Young and aged rodents data interpretation. In the majority of studies the com-
In recent years many exercise and cognition studies have pounds under investigation are a mixture of ingredients in
been carried out in adult rodents. This research strongly which the most potent factor is likely to be diluted. Indeed,
supports the benefit of exercise for brain function and has animal studies were often performed in aged rodents or
provided insight into the underlying cellular mechanisms. transgenic mouse models for neurodegenerative disease
Both voluntary and forced exercise paradigms enhanced [43] because compounds had minimal effects in normal
spatial memory in Morris water maze, Y-maze, T-maze and young subjects [44]. However, it seems that plant poly-
radial arm maze tests [30]. Running also improved per- phenols, which are the principal sources of flavanols, a
formance in hippocampus-dependent tasks that require subclass of phytochemicals known as flavonoids, might
limited movement, such as contextual fear conditioning, mediate the observed cognitive effects [42]. In cell culture,
passive avoidance learning and novel object recognition flavanols have neuroprotective, antioxidant and antiapop-
[31,32]. Moreover, non-hippocampal dependent, anxiety- totic properties [45]. In vivo, individual flavanols can
related behavior, such as performance in the elevated plus enhance synaptic plasticity and learning [12,46]. The fla-
maze [33], benefits from voluntary and forced exercise. vanol ()epicatechin is of particular interest because this
Interestingly, it remains to be determined whether volun- compound crosses the blood–brain barrier after ingestion
tary and forced exercise is equivalent. Differences have in food or drink [12,42]. Consumption of this flavanol
been reported in the extent of behavioral and cellular improved retention of spatial memory in the water maze,
effects even when activity parameters in both paradigms whereas the approved AD drug memantine did not [12].
are closely matched [34]. Interestingly, ()epicatechin was especially effective in
Similar to elderly humans, the ability to learn new tasks enhancing memory function and synaptic plasticity when
decreases with age in rodents. On the cellular level, the combined with voluntary exercise [12]. Similar results
number of synaptic contacts, synaptic strength and were reported for the combination of fish oil and wheel
plasticity are reduced in the hippocampus [35] and cortex running in rats. Omega-3 fatty acid consumption boosted
[36]. Recent research has shown that physical activity the effect of exercise on spatial learning, synaptic plasticity
benefits spatial memory in aging rodents, even upon la- and hippocampal brain-derived neurotrophic factor
te-life onset. Housing aged C57Bl/6 male mice with a (BDNF) protein levels [13]. This research indicates that

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effects of dietary supplementation and physical activity on Several studies have addressed the issue of whether
brain function are synergistic. dietary changes can enhance neurogenesis. Caloric restric-
tion increases the production of new neurons [57]. Dietary
Mechanisms that mediate the effects of exercise and folic acid deficiency decreases dentate gyrus cell prolifer-
nutrition on the brain ation [58]. Interestingly, systemic injection of the phyto-
Research pertaining to mechanisms underlying the effects chemical curcumin enhances the new hippocampal cell
of exercise on brain function has focused on changes in survival by 15% [59]. Other plant extracts, such as gin-
neurotransmitters, neurotrophins and vasculature [5]. seng and the flavonoid containing gingko biloba might also
Specific to the hippocampus, a brain area important for improve neurogenesis [60–62]. It remains unclear which
learning and memory, is the robust increase in new component(s) of these natural products affects neurogen-
neurons with exercise [30]. The beneficial effects of run- esis. For example, the individual flavanol ()epicatechin
ning on cognition could be mediated, at least in part, by had no effect on new cell survival in the dentate gyrus [12].
enhanced hippocampal neurogenesis [30,47]. Elucidation Overall, neurogenic effects of dietary supplements are
of effects of nutrition on the brain, by contrast, has con- modest in comparison with exercise.
centrated on the antioxidant and neuroprotective aspects
of various dietary supplements. More recent work, how- Synaptic plasticity
ever, indicates that diet might exert direct effects on The structural changes associated with exercise are
neuronal signaling [42]. The effects of diet and exercise reflected in improvements in synaptic plasticity in rodents
could be additive and/or synergistic through activation of that run. Long-term potentiation (LTP) was enhanced in
common intracellular pathways (Figure 1). hippocampal tissue slices in the dentate gyrus of running
versus sedentary mice [63] and in vivo in rats that had been
Neurogenesis housed with a running wheel [64] or given forced treadmill
The adult mammalian brain produces new neurons in the exercise [32]. This change in synaptic plasticity seems to be
olfactory bulb and dentate gyrus of the hippocampus specific for the dentate gyrus, indicating that neurogenesis
throughout life. Many extrinsic and intrinsic (epi)genetic might be important [30]. Indeed, although the new cells are
factors can regulate the production of new neurons [48]. a small percentage of the granule cell layer, individual new
Increasing evidence indicates that this process has a role in neurons have a transient increase in LTP amplitude and a
learning and memory. Ablation of the new cells results decreased induction threshold [65,66]. A proposed mech-
in spatial memory deficits [49]. In addition, using markers anism is increased expression of N-methyl-D-aspartic acid
for immediate early gene expression it has been shown (NMDA) NR2B receptors in new neurons [66]. Thus, an
that the new cells are preferentially activated during exercise-induced 3–4-fold increase in highly plastic cells in
learning tasks [50]. Furthermore, an increase in neurogen- the dentate gyrus might explain, in part, the profound
esis is associated with improved cognition. The strongest effect of physical activity on memory function.
neurogenic stimulus is exercise. Wheel running in rodents Effects of dietary changes on synaptic plasticity have
results in a 3–4-fold or even greater increase in the also been investigated. Caloric restriction does not seem to
production and survival of new neurons in the dentate change basal levels of LTP but does protect against aging-
gyrus of the hippocampus [30]. The onset of the effect of [67] and injury-related [68] decline in synaptic plasticity.
running on cell genesis is rapid. Cell genesis peaks at three In addition, several dietary supplements have been shown
days. After 32 days of running the pro-proliferative effect to influence LTP, albeit all under conditions of aging, drug
has returned to baseline. Interestingly, the number of treatment or injury. The flavanol gingko biloba enhanced
immature neurons continues to increase at this time-point synaptic plasticity in aged rats [69]. Ginseng reversed a
[51]. reduction in LTP associated with chronic morphine treat-
The robust effect of exercise on neurogenesis is main- ment [70]. In addition, the green tea polyphenol ()-epi-
tained throughout life in rodents. In mice that exercised gallocatechin-3-gallate facilitated LTP in a mouse model
continuously from young to middle age, the normal age- for Down’s syndrome [71]. The aforementioned studies all
related decline in cell genesis was significantly less than in include mixtures of polyphenols, leaving the active ingre-
their sedentary counterparts [51]. Moreover, in mice that dient unknown. The only study in which a single plant
started wheel running in middle age [52] or old age [37], product induced LTP, the hippocampal tissue slices were
new neuron number was elevated. Furthermore, recent pre-exposed to a weak tetanic stimulation [46]. Thus, the
studies showed that physical activity can reverse preg- dietary effects on synaptic plasticity are modest. These
nancy- [53] and radiation-treatment-related [54] decline in mild beneficial effects could be additive or synergistic with
hippocampal neurogenesis. It should be noted however, those of exercise.
that in certain transgenic mouse models for neurological
disease the beneficial effect of physical activity on neuro- Spine density
genesis is equivocal [30]. Transgenic mice that express The positive effects of physical activity extend to fine cell
human presenilin-1 variants linked to early-onset familial morphology. In particular, exercise affects the properties of
AD [55] and a mouse model for Huntington’s disease [56] do dendritic spines, which are actin-rich protusions on the
not show exercise induced neurogenesis. Therefore, the dendrites that contain excitatory synapses. Changes in
neurogenic and cognitive effects of physical activity should spine size and quantity are associated with LTP induction
be evaluated carefully across the spectrum of neurological and are considered to support changes in synaptic
diseases. strength. In a recent study it was shown that running

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Figure 1. Diet and exercise enhance synaptic plasticity and learning. (a) Exercise and probably diet enhance neurotransmitter and trophic factor levels. These factors
directly enhance the function of mature neurons and stimulate the production of new neurons in the hippocampus. (b) Nutrition and exercise affect neuronal signaling
pathways important for synaptic plasticity and cognitive function. BDNF and glutamate act at receptors that regulate calcium/calmodulin-dependent protein kinase II
(CaMKII) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) systems. Flavanols might activate similar signaling pathways, raising the
possibility that natural compounds have a selective neuronal receptor (? indicates a hypothetical receptor). BDNF also influences the phosphatidylinositol 3-kinase (PI3K)/
Akt and the FOXO subfamily of forkhead transcription factors, elevating expression of genes important for learning and memory. Running mouse image photo courtesy of
Marc Lieberman.

enhanced spine density in the dentate gyrus, area CA1 and expression of genes associated with neurite extension and
entorhinal cortex layer III [72], extending previous work synaptic plasticity was enhanced [12].
[73]. Physical activity also accelerates the maturation of
dendritic spines in newborn neurons [74]. Angiogenesis and vascular growth factors
The effects of plant products on neuronal morphology Exercise influences brain vasculature. In particular,
have mainly been studied in culture, in which research physical activity increases the proliferation of brain endo-
showed that plant polyphenols enhance neurite outgrowth thelial cells and angiogenesis throughout the brain [5]. The
[45]. Interestingly, in vivo the effect of dietary supplement- growth factors insulin-like growth factor (IGF) and vascu-
ation with the flavanols on neuronal morphology was very lar endothelial growth factor (VEGF) have an important
effective combined with running. Using DiI labeling it was role in the angiogenic and neurogenic effects of exercise on
shown that spine density was significantly increased in the brain. Running enhances hippocampal IGF gene
hippocampal granule cells. Upon microarray analysis of expression [75] and increases serum levels of both IGF
hippocampal tissue of mice that consumed this compound, [75] and VEGF [76]. These factors also play an important

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part in hippocampal neurogenesis. Hippocampal gene systems in the brain. Initial research into the central
transfer of VEGF [77] and peripheral infusion of IGF-1 effects of exercise indicated that the ‘joggers high’ resulted
enhanced neurogenesis [78]. Blockade of peripheral VEGF from enhanced opioid function [86]. More recently, exercise
and IGF-1 inhibited the increase in neurogenesis observed has been found to upregulate genes related to synaptic
with running [76,79]. plasticity. In particular, the glutamatergic system is
Although vasculature and neurogenesis are closely enhanced [87]. Running increased both NR2A and NR2B
associated [80], it is unclear whether cell genesis requires subtypes of the NMDA receptor in the hippocampus
angiogenesis. Using MRI imaging in mice and humans a [64,87]. In addition, in mice lacking the NMDA receptor
correlation between exercise, dentate gyrus blood flow and e1 subunit (NR2A) the increase in neurogenesis and BDNF
neurogenesis was reported. It was suggested that changes protein levels did not change with exercise [88]. Interest-
in brain blood flow might be an indirect measure for ingly, the predominant effect of physical activity seems to
neurogenesis in humans [17]. However, the MRI findings be on NMDA-receptor-mediated glutamatergic trans-
were not accompanied by histological evidence for running- mission. It remains to be determined whether more subtle
induced changes in vasculature in mice [17]. In contrast to changes such as enhanced recruitment of AMPA receptors
the MRI study, in aged mice voluntary exercise did not affect to the synapse occur with exercise.
angiogenesis but did enhance neurogenesis [37]. Moreover, Physical activity also activates the monoamine system
in young mice limited running robustly increased the sur- [89] and promotes recovery from depression [9]. Indeed, the
vival of newly generated cells with no change in angiogen- antidepressant effect of exercise in humans has been
esis [12]. These findings provide evidence for an uncoupling shown to be just as potent as that of serotonergic medi-
of neurogenesis and vascularization. cations [90]. Exercise increases tryptophan hydroxylase,
The effect of plant polyphenols on angiogenesis might be which is the rate-limiting enzyme of serotonin biosynthesis
superior to exercise [12]. Human research shows that in brainstem raphe neurons [89]. The dentate gyrus con-
flavanols improve cardiovascular function and lower blood tains 5-hydroxytryptamine 5-HT1A receptors and receives
pressure [81]. In addition, imaging studies in humans serotonergic input from the raphe nucleus. Similar to
drinking a flavanol-rich cocoa beverage showed enhanced exercise, serotonergic antidepressants such as fluoxetine
cortical blood flow [82]. In mice flavanols enhanced hippo- [91] can enhance cell genesis, whereas administration of
campal vascularization, especially in combination with the serotonin 5-HT1A receptor antagonists decreases cell
exercise [12]. It is of interest that both flavanols [83] proliferation in the dentate gyrus [92]. It has been
and exercise [84] increase endothelial nitric oxide syn- suggested that enhanced neurogenesis might be a common
thesis. Altogether, these findings indicate that a diet rich underlying treatment mechanism between exercise and
in plant products might stave off vascular dementia, antidepressants. However, it should be noted that exercise
especially when combined with exercise [85] (Figure 2). has acute and robust neurogenic effects, whereas fluoxe-
tine requires chronic administration and has variable
Neurotransmitters and growth factors effects on cell genesis [93–95].
There is large a body of research showing that physical The effects of running on neurotrophin gene expression
activity can change the function of neurotransmitter and protein levels have also been investigated extensively

Figure 2. Exercise and diet have complementary and synergistic effects on brain function. The most profound effect of exercise is on hippocampal neurogenesis, whereas
the strongest influence of a flavanol-rich diet might be on vascularization of the brain. (A,B) Bromodeoxyuridine (BrdU) labeling of new cells in the dentate gyrus of the
hippocampus of C57Bl/6 mice. In comparison with sedentary controls (A), running wheel exercise (B) enhances the number of new cells. (C,D) Dendritic spines labeled with
DiI in mature hippocampal granule cells. Relative to controls (C), running and/or a flavanol-containing diet (D) increase neuronal spine density. (E,F) Tomato lectin staining
visualized hippocampal blood vessels; the granule cell layer of the dentate gyrus is outlined in white in the panels. A flavanol-rich diet enhanced dentate gyrus
vascularization, especially when combined with running (F), as compared with control mice (E). Abbreviations: CON, control group; EXP, experimental group. Panels A and
B were reproduced from Ref. [103]. Panels C, D, E and F: Copyright 2007 by the Society for Neuroscience.

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[5,96]. The neurotrophin BDNF is considered to be the influence on brain function is not well accepted. This is due,
most important factor upregulated by physical activity in part, to the large number of natural products that claim
because it has an important role in synaptic plasticity, cell benefits for cognition, the lack of identification of specific
genesis, growth and survival [5]. Interestingly, there is a active molecules and the limited number of intervention
positive interaction between BDNF expression and sero- studies in humans. Future studies could focus on identify-
tonin. Serotonin receptor activation enhanced BDNF ing the individual factor(s) in natural substances that are
expression in hippocampal cells [97], and BDNF treatment cognitive enhancers and select the most potent ones for
increased tryptophan hydroxylase expression in raphe further investigation. Of particular interest would be to
nucleus neurons [98]. With exercise, levels of BDNF mRNA investigate whether a selective receptor exists for such
in the hippocampus increased rapidly and remained elev- compounds. Finally, the common cellular mechanisms
ated for weeks. BDNF protein levels also increased with between diet and exercise remain to be defined. Even so,
running [5]. Selective knockout of the tyrosine receptor implementation can be immediate: ‘All is foreseen, but
kinase B (trkB) in hippocampal neural progenitor cells freedom of choice is granted’ (Rabbi Akiba, Perkei Avot,
prevented the exercise-induced increase in neurogenesis The Ethics of the Fathers, Chapter 3, Mishna 15).
[95]. Furthermore, intracerebral infusion of BDNF
increased cell genesis in the dentate gyrus [99], but not Acknowledgements
in the subventricular zone [100], consistent with data This review was supported by the Intramural Research Program of the
National Institutes of Health, National Institute on Aging
showing that the neurogenic effect of exercise is limited (www.nia.nih.gov). I thank Mark Mattson for comments on the
to the hippocampus [101]. manuscript, David J. Creer for editorial assistance and K.C. Alexander
The traditional view of natural products is that they are for figure preparation.
antioxidant and anti-inflammatory agents but do not
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