J Appl Physiol 111: 1505–1513, 2011.

First published April 28, 2011; doi:10.1152/japplphysiol.00210.2011. Review

HIGHLIGHTED TOPIC Physiology and Pathophysiology of Physical Inactivity

Exercise, brain, and cognition across the life span

Michelle W. Voss,1,2 Lindsay S. Nagamatsu,3,4,5,6 Teresa Liu-Ambrose,3,4,5 and Arthur F. Kramer1,2
1
The Beckman Institute and Department of Psychology, University of Illinois at Urbana-Champaign, Urbana; 2Department
of Psychology, University of Illinois at Urbana-Champaign, Champaign, Illinois; 3The Brain Research Centre and the
4
Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia; 5The Centre for Hip Health
and Mobility, Vancouver Coastal Health Research Institute, Vancouver, British Columbia; and 6Department of Psychology,
University of British Columbia, Vancouver, British Columbia, Canada
Submitted 16 February 2011; accepted in final form 25 April 2011

Voss MW, Nagamatsu LS, Liu-Ambrose T, Kramer AF. Exercise, brain, and
cognition across the life span. J Appl Physiol 111: 1505–1513, 2011. First
published April 28, 2011; doi:10.1152/japplphysiol.00210.2011.—This is a brief
review of current evidence for the relationships between physical activity and
exercise and the brain and cognition throughout the life span in non-pathological
populations. We focus on the effects of both aerobic and resistance training and
provide a brief overview of potential neurobiological mechanisms derived from
non-human animal models. Whereas research has focused primarily on the benefits
of aerobic exercise in youth and young adult populations, there is growing evidence
that both aerobic and resistance training are important for maintaining cognitive
and brain health in old age. Finally, in these contexts, we point out gaps in the
literature and future directions that will help advance the field of exercise neuro-
science, including more studies that explicitly examine the effect of exercise type
and intensity on cognition, the brain, and clinically significant outcomes. There is
also a need for human neuroimaging studies to adopt a more unified multi-modal
framework and for greater interaction between human and animal models of
exercise effects on brain and cognition across the life span.
physical activity; aerobic training; strength training; brain function; brain structure;
mental health

IT IS INCREASINGLY PREVALENT in the print media, television, and
the internet to be bombarded with advertisements for products
and programs to enhance mental and physical health in a
relatively painless fashion through miracle elixirs, computer-
based training or gaming programs, or brief exercise programs.
Although there is little convincing scientific evidence for many
such claims (46), there have been some promising develop-
ments in the scientific literature with regard to physical activity
and exercise effects on cognitive and brain health. In fact, a
number of our forefathers appear to have anticipated some of
the potential benefits of an active lifestyle. For example,
Thomas Jefferson argued, “a strong body makes the mind
strong.” Hugh Blair, a Scottish Theologian from the 18th
century suggested that, “Exercise is the chief source of im-
provement in our faculties.” One of the first noted scientist/
physicians, Hippocrates, opinioned, “If we could give every
individual the right amount of nourishment and exercise, we
would have found the safest way to health.”
Address for reprint requests and other correspondence: A. F. Kramer,
Beckman Institute for Advanced Science and Technology, Dept. of Psychol-
ogy, Univ. of Illinois at Urbana-Champaign, 405 N. Mathews Ave, Urbana, IL
61801 (e-mail: akramer@cyrus.psych.illinois.edu).
http://www.jap.org 8750-7587/11 Copyright © 2011 the American Physiological Society
Indeed, there is an increasing amount of research, much of it
epidemiological, that argues for numerous long-term health
benefits of regular physical activity and exercise. For example,
studies have reported an inverse relationship between physical
activity and the risk of type II diabetes (58), cardiovascular-
related disease and death (89), osteoporosis (52), colon and
breast cancer (62), and mental disorders (29). Despite this
increasing wealth of knowledge concerning the relationship
between physical activity and health we have become an
increasingly sedentary society. For example, it has been esti-
mated that less than 50% of children (6 –11 yr) and only 8% of
adolescents (12–19 yr) are active the recommended 60 min
most days of the week, whereas only less than 5% of adults
(20 –59 yr) and elderly (60⫹ yr) are active the recommended
30 min a day for this age group (99). Furthermore, it has been
suggested that our current sedentary nature represents a mal-
adaptation of our evolutionary history in which high levels of
physical activity were required for survival (6).
In the present brief review we focus on the relationship
between physical activity and cognitive and brain health. We
briefly review molecular and cellular exercise-related changes
in our discussion of the animal literature. However, the major-
ity of our review will focus on aerobic and strength training
effects on human cognition and brain health across the life span
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1506 EXERCISE EFFECTS ON BRAIN AND COGNITION
in healthy populations. Finally, we conclude with prescriptions
for additional research on this important topic.
EFFECTS OF AEROBIC TRAINING ON BRAIN STRUCTURE,
BRAIN FUNCTION, AND COGNITION
As we progress from elementary to high school, our brains
rapidly develop structural and functional circuitry that support
higher-level cognitive abilities, such as our ability to regulate
and inhibit behavior, multi-task, and resist distraction (13).
Consequently, behaviors that affect brain function play a vital
role in facilitating optimal cognitive development during child-
hood. Physical activity is no exception. Research indicates that
childhood physical inactivity, and subsequently reduced aero-
bic fitness, is associated with poorer academic achievement
(15, 19) and lower performance on standard neuropsycholog-
ical tests (9, 90). The majority of scientific literature supports
a general benefit of aerobic fitness on childhood cognitive
performance. For example, a meta-analysis that aggregated
results across 44 studies found an overall effect size of 0.32 for
the association between childhood physical activity and fitness
and cognition, with significant effects across a range of abili-
ties, such as perceptual skills (0.49), creativity and concentra-
tion (0.40), academic readiness (0.39) and achievement (0.30),
IQ (0.34), and math (0.20) and verbal (0.17) tests (90).
Still some studies have shown selective benefits of exercise
on childhood cognition (for review, see Ref. 97). For example,
one study increased task difficulty and thus pushed the limits of
prefrontal function beyond what other studies have done (77).
This is consistent with a training study that found 3 mo of
aerobic exercise training improved prefrontally mediated ex-
ecutive function abilities in 7- to 11-year-old overweight chil-
dren (27). Other studies demonstrating a selective association
have shown, in agreement with a large animal literature, that
aerobic fitness is preferentially associated with a type of
memory supported by the hippocampus, relational memory,
rather than item memory (17, 18). Unlike item memory,
relational memory requires forming associations, such as re-
membering not only the face of a person you met last week, but
also remembering his name, what you talked about, and where
you met him. Finally, overall there is stronger support for
aerobic fitness benefits on accuracy rather than speed of pro-
cessing (9, 17, 18, 47, 77), which is consistent with the idea
that accuracy may be a better measure of cognitive develop-
ment than speed (26). Yet the majority of literature on physical
activity, aerobic fitness, and childhood cognition is cross-
sectional in nature, therefore more training studies with tem-
porally extended follow-up testing are needed for stronger
support of these summarized findings.
Nevertheless, neuroimaging research provides additional ev-
idence for both general and selective effects of exercise on
childhood cognition. Functional brain imaging studies using
event-related potentials (ERPs) have shown that more aerobi-
cally fit children have larger P300s during information pro-
cessing (47, 48, 77), an ERP component whose amplitude is
associated with our ability to effectively focus attention and
that is thought to emerge, in part, from the temporoparietal
cortex (76). ERP brain recordings also indicate that aerobically
fit children better regulate and monitor their mistakes, or
processing errors, abilities made possible by the anterior cin-
gulate and prefrontal cortices (47, 77). For example, Hillman
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and colleagues (47) found that higher-fit children who outper-
formed lower-fit children on the Eriksen flanker task (a test of
conflict resolution) showed a smaller error-related negativity
(ERN) on error trials, an ERP component thought to index
conflict monitoring and error evaluation; higher-fit children
also showed a larger positivity error (Pe) component, thought
to index awareness of one’s mistakes. Overall, higher-fit chil-
dren were more accurate in trials following errors of commis-
sion, while showing a smaller ERN and larger Pe, suggesting
higher-fit children’s brains monitor conflict more efficiently
(see also 77). Neuroanatomically, childhood aerobic fitness is
associated with more brain volume in structures important for
demanding information processing and relational memory,
such as the dorsal striatum (16) and the hippocampus (17),
respectively.
In sum, cross-sectional and longitudinal training studies
support a positive association between aerobic fitness and
enhanced performance in both the classroom and laboratory
(for reviews, see Refs. 90, 97). Furthermore, neuroimaging
evidence supports a beneficial association between childhood
aerobic fitness and improved brain function and structure.
Following the rapid cognitive development in childhood,
young adulthood (i.e., 18 –35 yr) is characterized by relative
stability and peak cognitive performance. This may be one
reason that comparatively fewer studies examine cognitive
enhancements associated with physical activity and aerobic
fitness training during this part of the life span. This may also
be the reason that studies have generally found mixed support
for the association between aerobic fitness and cognition in
young adulthood (1, 85, 88). Yet several neuroimaging studies
have shown evidence for increased efficiency of brain function
without differences in behavioral performance (51, 95, 96). For
example, similar to the findings of Hillman and colleagues (47)
with children, one study showed that higher-fit young adults
also had smaller ERNs coupled with larger Pe amplitude,
specific to trials with errors of commission (95). Despite these
neuroelectric differences, there were no differences in behav-
ioral performance between lower- and higher-fit adults. Studies
like these suggest that aerobic fitness effects on behavior may
only emerge in this high-functioning group when the task is
extremely difficult or that young adults have a greater range of
compensatory strategies compared with children and older
adults to achieve enhanced performance. There are very few
training studies with young adults; however, some studies do
support the effectiveness of aerobic training for improving
cognition at this age (74, 92), particularly for those with a
genetic predisposition for impaired cognition due to lower
dopamine levels in the brain (93). Thus overall, whereas
cross-sectional behavioral results are mixed with young adults,
neuroimaging and training results seem to support a positive
association between greater aerobic fitness and brain function.
Future research that examines the effect of task difficulty, uses
more diverse imaging techniques, and examines the long-term
effects of aerobic fitness during adulthood will help clarify
many unanswered questions for this age group.
Older adulthood mirrors childhood in some interesting ways,
when brain structure and function again enter a period of high
interindividual variability and lifestyle factors, such as physical
activity, increasingly impact mental health. Although epidemi-
ological and prospective studies largely support the role of
physical activity and aerobic fitness in healthy cognitive (80,
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109) and brain (83) aging and preventing the onset of all types
of dementia (60, 64), it is less clear from training studies
whether increased aerobic fitness per se is the key ingredient
for improved brain and cognition from behavior changes as-
sociated with this lifestyle factor (22, 35). Much evidence,
however, does support the notion that aerobic exercise benefits
cognitive performance (22, 32, 57), brain function (10, 23,
108), and brain structure (21, 68) in elderly adults.
Specifically, aerobic training in late life preferentially ben-
efits executive functions, including brain processes such as
multi-tasking, planning, and inhibition, all largely supported by
the prefrontal cortex (22, 23, 57). Several fMRI studies have
examined the effects of aerobic training on brain function.
Colcombe and colleagues (23) examined the effects of a 6-mo,
three times weekly aerobic training program for sedentary
adults on task-related brain activation during the Eriksen
flanker task. Aerobically trained older adults had greater in-
creases in brain activity in the frontal and parietal cortices from
pre- to postintervention, brain areas involved in processes
important for task performance, such as conflict resolution and
selective attention. Aerobically trained adults also had greater
reduction in anterior cingulate cortex activation, a brain area
involved in conflict and error monitoring. This pattern of
activation changes suggests that aerobic training led to in-
creased efficiency of conflict and error monitoring and en-
hanced regulatory response from the prefrontal cortex follow-
ing signals of conflict from the anterior cingulate (8). In line
with this theoretical account, functional improvements were
coupled with improvement in conflict regulation performance.
This study demonstrated that participating in an aerobic train-
ing program improves the aging brain’s ability to effectively
engage task-relevant resources, particularly under cognitively
challenging conditions. Thus aerobic training had a selective
rather than general effect on task-related brain function.
Another way to assess brain function is to examine not how
much the brain activates under controlled cognitive conditions,
but rather how different areas of the brain communicate under
little to no cognitive demand. The benefit of the latter is an
absence of group differences in behavioral performance or
strategy that could potentially confound differences in task-
related brain activation. Voss and colleagues (108) examined
changes in functional communication, or connectivity, in sed-
entary older adults following a 1-yr, three times weekly aerobic
training program. The study examined whether aerobic training
would enhance communication in the Default Network (a
network whose dysfunction is proposed to be a biomarker for
normal cognitive decline and Alzheimer’s Disease), as well as
brain networks involved in higher-level executive functions,
spatial attention, motor control, and audition. Of all the net-
works examined, the Default Network was the primary brain
network showing enhanced connectivity following aerobic
training, in addition to increased connectivity between the left
and right prefrontal cortices in an Executive Control network.
Thus aerobic fitness training benefits not only task-related
magnitude of brain activation, but also the resting coherence of
brain networks important for cognition and neurological dis-
ease status.
In addition to functional brain changes, studies also support
significant changes in regional brain volume following aerobic
training. Following a 6-mo, three times weekly aerobic pro-
gram, Colcombe and colleagues (21) found gray matter in-
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1507
creases in the lateral prefrontal anterior cingulate and lateral
temporal cortices and increased anterior white matter volume.
Furthermore, another study found that a 1-yr, three times
weekly aerobic training program increased volume of the
anterior hippocampus, which houses the dentate gyrus subre-
gion linked to neurogenesis in animal studies (38, 74, 103);
whereas there were no volumetric benefits for the posterior
hippocampus, thalamus, or caudate nucleus (33). Also consis-
tent with the animal literature, increased anterior hippocampus
volume was associated with increased peripheral brain-derived
neurotrophic factor (BDNF) for only the aerobic group. The
significance of BDNF will be discussed in more depth below.
Finally, while this study found memory improvements for the
aerobic and nonaerobic control group, increased anterior hip-
pocampal volume was associated with improved memory for
only the aerobic group, trends not shown in the caudate or
thalamus. However, change in BDNF was not associated with
changes in memory. Thus one caveat of most human studies is
the inability to unequivocally determine the nature of the
cellular and molecular changes that underlie the observed
changes in brain volume and cognitive function. Although one
study indicated that cerebral blood volume, potentially an in
vivo marker of neurogenesis, is at least one factor that may be
involved with increased hippocampal volume and correspond-
ing increases in learning performance (74). Nevertheless, these
studies provide continuing support that beginning an aerobic
exercise program in late life can still translate into meaningful
benefits for the brain and cognition.
EFFECTS OF RESISTANCE/STRENGTH TRAINING ON BRAIN
STRUCTURE, BRAIN FUNCTION, AND COGNITION
Although resistance training has a broad range of systemic
benefits (7, 61), very few studies to date have specifically
focused on the role of resistance training in promoting cogni-
tive health across the life span. To our knowledge, no studies
have specifically assessed the effect of resistance training on
cognitive and brain function in children. A lack of such studies
may be partly due to the common misperception that resistance
training is unsafe for children. Likewise, there is a general void
in the literature regarding the role of chronic resistance training
in promoting cognitive and brain function in young adults.
For older adults, evidence regarding whether resistance
training has cognitive benefit has been equivocal. However, we
note that the trials with negative results were limited by small
sample sizes (i.e., 13–23 participants per experimental group)
or short intervention periods (i.e., 8 –16 wk) (32, 55, 75, 100).
For example, Tsutsumi and colleagues (100) demonstrated no
cognitive benefit of resistance training in their 12-wk random-
ized controlled trial that compared the effect of high-intensity/
low-volume resistance training and low-intensity/high-volume
resistance training with no exercise controls on cognitive
function in 42 community-dwelling older adults (i.e., 14 par-
ticipants per group). Recently, Kimura and colleagues (55) also
demonstrated no effect of resistance training on the executive
process of task switching despite including 119 participants in
their 12-wk training study. In addition to sufficient duration of
resistance training, the intensity or load of training appears to
be a key requirement to produce cognitive benefits. For exam-
ple, Lachman and colleagues (59) conducted a 6-mo random-
ized controlled trial of home-based resistance training among
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1508 EXERCISE EFFECTS ON BRAIN AND COGNITION
210 sedentary community-dwelling older adults and found no
significant between-group differences in memory. The home-
based resistance training program was a 35-min videotaped
program of 10 exercises using elastic bands. Participants were
instructed to use bands of greater resistance when they could
complete greater than 10 repetitions of an exercise without
significant fatigue. This is a lower intensity protocol compared
with three recent randomized controlled trials with positive
findings that used loading protocols ranging from 50 to 80% of
a single-repetition maximum lift (i.e., 1 RM) (14). It is impor-
tant to highlight that while there were no significant between-
group differences in cognitive performance, Lachman and
colleagues (59) found that the change in resistance used by
those in the intervention group was positively associated with
change in memory performance, after controlling for baseline
age, education, sex, and disability level. Hence, the investiga-
tors suggested that resistance training can benefit memory
among older adults, especially when using higher resistance
levels.
Randomized controlled trials of resistance training that are 6
mo or greater in duration and delivered high-loading protocols
collectively provide emerging evidence that resistance training
has cognitive benefits. Cassilhas and colleagues (14) demon-
strated that 6 mo of either three times weekly moderate or
high-intensity resistance training improved memory perfor-
mance and verbal concept formation among 62 community-
dwelling senior men ages 65 to 75 yr. Moderate intensity was
defined as 50% of 1 RM and high intensity was defined as 80%
of 1 RM. Using a protocol similar to Cassilhas (14), recent
work by Busse and colleagues (11) suggests that resistance
training may also be beneficial for sedentary older adults at
greater risk for Alzheimer’s disease—those with objective mild
memory impairment.
The work of Cassilhas and colleagues (14) also provides
valuable insight into the possible mechanisms underlying the
benefit of resistance training on cognitive performance. They
found serum insulin-like growth factor-1 (IGF-1) levels were
higher in the resistance training groups than in the control
group. IGF-1 promotes neuronal growth, survival, and differ-
entiation and improves cognitive performance (24), which will
be discussed further below. In older adults, resistance training
also reduces serum homocysteine (107). Increased homocys-
teine levels are associated with impaired cognitive perfor-
mance (84), Alzheimer’s Disease (87), and cerebral white
matter lesions (106), although the cognitive relevance of re-
ductions in homocysteine in longitudinal study remain unclear
(e.g., 3).
Finally, Liu-Ambrose and colleagues (65) demonstrated that
12 mo of either once weekly or twice weekly progressive
resistance training improved selective attention and conflict
resolution performance among 155 community-dwelling se-
nior women aged 65 to 75 yr. Enhanced selective attention and
conflict resolution was also associated with increased gait
speed. Clinically, improved gait speed predicts a substantial
reduction in both morbidity (82) and mortality (31, 45). These
results illustrate the clinical significance of cognitive gains
induced by resistance training. Davis and colleagues (28) also
provided novel evidence that cognitive benefits associated with
resistance training are sustained for 1 yr after the intervention
has ended.
J Appl Physiol • VOL
Thus, while there is less literature across the life span on the
effects of resistance training on brain and cognition, compared
with aerobic training, preliminary evidence highlights its im-
portance for future study.
POTENTIAL MECHANISMS FROM ANIMAL MODELS
Animal models of exercise effects on brain physiology and
structure have indicated several key pathways through which
aerobic and resistance training may enhance brain function.
These pathways include improvement in both the structural
integrity of the brain (i.e., growth of new neurons and blood
vessels) and increased production of neurochemicals that pro-
mote growth, differentiation, survival, and repair of brain cells.
In addition, animal models have begun to shed light on how
aging interacts with these molecular and cellular models of
exercise effects on brain and cognition.
Many studies now suggest that aerobic training results in
neurogenesis, or the generation of new neurons, in the hip-
pocampus (102, 103), which has been subsequently linked to
improved hippocampal function (25, 74). To our knowledge
hippocampal neurogenesis has not been studied in animal
models in the context of other forms of exercise programs (e.g.,
aerobic vs. exercise analogous to resistance training in ro-
dents), therefore future research is needed to understand the
specificity of neurogenesis following different forms of exer-
cise. Furthermore, although the rate of hippocampal neurogen-
esis declines with normal aging, animal studies generally
support some protection from such decline with aerobic exer-
cise training (54, 104). Age does appear to attenuate the effect
of aerobic exercise on neurogenesis compared with young
adult animals and for 15- and 19-mo-old animals, respectively
(54, 104). One study showed no training-induced neurogenesis
in old (22 mo) animals despite some improvement on a spatial
pattern separation task and positive evidence for young animals
(25). Other studies have also found that neurogenesis is not
necessary for improved performance (e.g., 53) or that neuro-
genesis is associated with improvement in some tasks (e.g.,
spatial memory) and not others (e.g., motor performance,
conditioning) (20). Therefore, while hippocampal neurogen-
esis is a highly replicable effect following aerobic exercise,
there are still some questions about how it supports behavioral
improvements following aerobic exercise compared with other
exercise-related factors.
For example, another consistent effect in animal models is
exercise-induced increases in angiogenesis, or the growth of
new blood vessels (25, 74, 104), which has in turn been linked
to improved learning and memory (53, 74). Like neurogenesis,
no studies to our knowledge have examined the specificity of
angiogenesis following different types of exercise. Unlike
neurogenesis, aerobic training produces angiogenesis outside
of just the hippocampus, including areas directly activated by
locomotion such as the cerebellum (4, 50) and primary motor
cortex (56, 94). Furthermore, at least two studies have shown
aerobic training-related increases in hippocampal angiogenesis
in young but not aged mice (22 and 19 mo, respectively) (25,
104). Similar to effects described above, the study by Creer and
colleages (25) showed that despite no significant hippocampal
angiogenesis (or neurogenesis), aerobically trained old rodents
still showed moderate improvements in performance. Thus
while angiogenesis is consistently found in response to aerobic
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EXERCISE EFFECTS ON BRAIN AND COGNITION
exercise in young animals, the role of training-induced angio-
genesis in cognitive improvements across the life span is also
a topic in need of future study.
Animal models have also indicated several candidates for
circulating neurochemicals that may mediate effects of exer-
cise on brain health. Two that have received the most empirical
support include BDNF and IGF-1. BDNF is endogenously
produced throughout the brain, with particularly high concen-
trations in the hippocampus (71), and in animals is known to
increase in the brain during single acute bouts (79) and fol-
lowing chronic aerobic exercise training (72, 73). While BDNF
is also produced in the periphery, some studies have suggested
that peripheral BDNF in humans at rest and during an acute
bout of aerobic exercise is predominantly brain-derived (esti-
mated from arterial-to-venous difference of radial artery and
the internal jugular vein), although it may dip during recovery
(79). Also, at least one training study from the same group has
shown that 3 mo of aerobic training increases human resting
peripheral brain-derived BDNF but did not affect peripheral
estimates of brain-derived BDNF during aerobic exercise (86).
Another study showed that peripheral BDNF in blood serum
was selectively increased following 30 min of high intensity
(⬃85% of heart rate max) compared with lower intensity
(⬃70% of heart rate max) aerobic exercise (39). Finally, it is
interesting to note that there is evidence that resting peripheral
serum BDNF is selectively upregulated in humans following
chronic aerobic (111) but not resistance training (63). Overall,
these studies suggest that BDNF release in the human cortex
and hippocampus during exercise and at rest can be estimated
in the periphery from blood plasma or serum and demonstrate
that examining the effects of acute bouts of exercise on the
brain may help build links to animal models and (although it is
unknown whether the mechanisms are the same) may inform
how the brain adapts to cumulative changes in different types
of exercise behavior. A noted limitation of these studies,
however, is small sample sizes of young adults; thus, it will be
important for these results to be replicated with larger samples
of a broader age range.
Understanding how exercise affects BDNF production is
important because BDNF is considered a critical factor in
exercise-induced benefits on learning and memory. For exam-
ple, Farmer and colleagues (38) demonstrated that BDNF is
associated with aerobic exercise-induced increases in long-
term potentiation (LTP), which facilitates synaptic plasticity
and is considered a cellular model of learning and memory.
Furthermore, blocking BDNF receptors during exercise abol-
ishes downstream effects on metabolic factors (43) and cogni-
tive performance (43, 44, 105). Although there is overwhelm-
ing evidence in support of BDNF as an important factor in
exercise-induced improvement in brain and cognition, more
research is needed that investigates how age interacts with
these results. For example, Garza and colleagues (41) showed
that aged rodents (22 mo) had increased hippocampal BDNF
mRNA following short (i.e., 2 days) and chronic (i.e., 20 days)
bouts of running; however, there were substantial differences
in the regional pattern of sensitivity for exercise-induced in-
creases in BDNF, which the authors suggested may reflect
age-related shifts in hippocampal physiology that in turn im-
pact how exercise affects hippocampal structure and function
in old age. Another study found that chronic aerobic exercise
was not associated with increases in hippocampal BDNF pro-
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1509
tein for aged rodents (24 mo), despite positive results for young
rodents (2).
A known neurotrophic factor important for both aerobic and
resistance training is IGF-1. IGF-1 is produced both in the
central nervous system and in the periphery in response to
aerobic (12, 30, 98) and resistance (14) exercise. Furthermore,
studies have shown that blocking entry of peripheral IGF-1 into
the brain during aerobic training also blocks exercise-induced
hippocampal neurogenesis (98), angiogenesis (66), and exer-
cise-facilitated brain injury recovery (12). Studies have also
supported a dependence between IGF-1 and exercise-induced
increases in BDNF (12, 30). For example, one study demon-
strated that blocking IGF-1 receptors in the hippocampus
during exercise abolished exercise effects on increased hip-
pocampal BDNF mRNA and protein expression, and similar
effects were found for hippocampal levels of markers of
synaptic plasticity that are presumed to be end-products of
BDNF action (exercise-induced increases in synapsin I, p-
CAMKII, p-MAPKII) (30). In turn, researchers that have
found attenuated exercise-related enhancement of BDNF in
aged rodents have speculated that this may be partly due to the
reduction in IGF-1 associated with aging (2, 67).
Thus animal models have shown that BDNF and IGF-1 play
important roles in mediating the effects of exercise on brain
health and performance. Other neurotrophic factors and neu-
ropeptides shown to change with exercise behavior include
nerve growth factor (70), fibroblast growth factor type 2 (42),
vascular endothelial growth factor (36), and VGF growth
factor (49) and galanin (101). Furthermore, aerobic exercise
also enhances several neurotransmitter systems in the brain,
including increasing circulating dopamine (78), serotonin (5),
and acetylcholine (40). Relatively less research has been done
on the mechanisms by which exercise affects production of
these neurochemicals with links to cognition and learning and
memory. Therefore, the extent to which these neurochemicals
also contribute to benefits of exercise across the life span
deserves future study.
In summary, animal models have revealed much about the
potential neurobiological mechanisms of exercise effects on
brain and cognition across the life span. Aerobic exercise has
a concentrated benefit on the hippocampus, increasing the
growth of new neurons and new blood vessels, and increasing
synaptic plasticity, which helps facilitate the integration of
hippocampal neurons into existing brain networks. Several
important neurotrophins are integral to the effects of exercise
on brain and cognition. While aerobic exercise seems to
selectively upregulate central BDNF, both aerobic and resis-
tance exercise upregulate central and peripheral IGF-1. Both
are key players in exercise-induced increases in learning and
memory, and IGF-1 may be particularly important in mediating
the effects of BDNF and promoting exercise-induced neuro-
genesis and angiogenesis. However, it should be noted that
animal models often use cognitive measures of learning and
memory that rarely conceptually overlap with the cognitive
paradigms used in human research. Thus the extent to which
the reviewed potential mechanisms account for benefits of
exercise on executive function in humans is a topic that
deserves future consideration. In addition, future research is
needed to clarify the role of these molecular and cellular
pathways in models of aging and exercise. Research has
generally supported the idea that aerobic exercise attenuates
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1510 EXERCISE EFFECTS ON BRAIN AND COGNITION
age-related declines in neurogenesis and learning and memory,
but it is still unclear how much overlap there is between the
exercise model for young and aged animals.
CONCLUDING COMMENTS, UNRESOLVED ISSUES,
AND FUTURE DIRECTIONS
The reviewed literature provides an overview of the effects
of exercise on brain and cognition throughout the life span.
Whereas research has focused primarily on the benefits of
aerobic exercise in youth and young adult populations, there is
growing evidence that both aerobic and resistance training are
important for maintaining cognitive and brain health in old age.
Our review also points out gaps in the literature and important
future directions for the field.
Clearly there is a need for more research that investigates the
effect of exercise type on the brain and cognition, and in turn,
clinically significant outcomes such as quality of life, memory
complaints, mobility, falls risk, and mortality. While standard
neuropsychological tests and brain imaging data provide valu-
able data for characterizing the specific brain systems affected
by exercise behavior, the translation of these results into
clinically relevant outcomes is also important for building a
more interactive relationship between basic research findings
and clinical practice. Also important for translating research
into practice will be a greater understanding of how individual
differences mediate or moderate the effects of different exer-
cise types on brain and cognition. For instance, it is possible
that aerobic training will be more effective for some individ-
uals whereas resistance training would benefit others more, and
their combination may be best for yet another group. Some
factors important to examine may include (but not be limited
to) genetics, personality, and personal health history or disease
status. Greater understanding of the role of these factors in the
effects of exercise training on brain and cognitive health may
also help clarify the relative importance of aerobic fitness gains
compared with engaging in physical activity without focus on
fitness gains per se. These issues have important practical
significance for affecting public health recommendations for
physical activity behavior to improve brain and cognition.
Within the realm of brain imaging, when comparing the
effects of different exercise types, it will be important for
future research to incorporate more of a multi-modal frame-
work. Currently our knowledge of exercise effects in childhood
and young adulthood is based primarily from neuroelectric
methods, whereas training studies with older adults have used
primarily hemodynamic measures of brain function. Therefore,
it will be important for future research to incorporate multiple
methods of measuring brain function across the life span.
Along these lines, additional methods that will be important for
future research include measures of blood volume and blood
flow such as arterial spin labeling (ASL) and measures of white
matter microstructure, including diffusion tensor imaging
(DTI). For example, a recent study demonstrated the feasibility
of measuring resting and task-related cerebral blood flow with
ASL following an acute bout of exercise, which will be
important for studies examining effects of acute exercise on
fMRI activation (91). In addition, we know of only one study
(10) that has used ASL to examine effects of chronic exercise
exposure, which suggested increased hippocampal blood flow
following an aerobic exercise program. Given the increasing
J Appl Physiol • VOL 111 • NOVEMBER 2011 •
reports of effects of chronic exercise on fMRI activation, this
is an important gap to fill. Other cross-sectional research has
used DTI to show preliminary evidence for an association
between aerobic fitness and white matter integrity in the
uncinate fasciculus (connecting ventral frontal and temporal
lobes) and cingulum bundle (transversing the midline between
anterior and posterior areas) (68, 69). Finally, near-infrared
spectroscopy is another technology that could be applied dur-
ing exercise, making it another useful tool to compare effects
of acute and chronic exercise on brain and cognition (81, 110).
Overall, while these studies generally have relatively small
sample sizes and have examined targeted age groups, they
represent a starting point for future studies to expand on in both
sample size and diversity, and in longitudinal designs.
Finally, it will be important for future research to try to
integrate animal and human work. For example, more animal
studies that incorporate a life span perspective could help
characterize potential similarities and differences of neurobio-
logical mechanisms for exercise effects on brain and cognition
at different points in the developmental timeline. On the other
hand, it will be important for more human studies to incorpo-
rate measures of neurobiological markers such as peripheral
measures of BDNF and IGF-1 both during acute exercise and
following chronic exercise exposure. More work of this nature
will help build an understanding of how acute effects are
similar to or different from chronic benefits on brain and
cognition across the life span, ultimately furthering our under-
standing of the mechanisms for how different types of cumu-
lated exercise behaviors affect the brain and cognition. In this
spirit, future studies with humans may also gain valuable
insight from animal models about optimal methods for com-
bining interventions based on different exercise types and/or
exercise and cognitive training programs or diets. For example,
a study by Fabel and colleagues (37) supports the idea that the
functional significance of hippocampal neurogenesis resulting
from aerobic exercise is further promoted if followed by
environmental enrichment or cognitive training. This suggests
that while aerobic exercise would be a good starting point for
intervention programs, beneficial effects for brain and cogni-
tion may be further enhanced if followed by the addition of
other activity types, such as resistance training, cognitive
training, or some combination thereof.
Thus, while all exercise might not be painless or provide the
“easy fix” to enhance brain and cognition across the life span,
there is ample evidence to support it as one of the most
effective means available to improve mental and physical
health, without the side effects of many pharmacological treat-
ments. In this review we highlighted some of the best evidence
in support of exercise benefits for nonpathological populations,
but also pointed out important areas for future research to
advance the field. It is our hope that this will encourage greater
diversity of approaches and methodologies, applied to a larger
diversity of populations, in the field of exercise neuroscience.
Such advancements promise to improve translation of positive
findings in the research laboratory to improved quality of life
from childhood to late life.
GRANTS
Preparation for this manuscript was supported by funding from the National
Institute on Aging at the National Institutes of Health (Grant Numbers
05-R370-AG025667, RO1-AG25032) for private investigator A. Kramer. T.
www.jap.org

EXERCISE EFFECTS ON BRAIN AND COGNITION
Liu-Ambrose is a Canadian Institute Health Research New Investigator, and
Michael Smith is a Foundation for Health Research Scholar.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
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