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Exercise Builds Brain Health: Key Roles of Growth Factor Cascades and Inflammation


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Human and other animal studies demonstrate that exercise targets many aspects of brain function and has broad effects on overall brain health. The benefits of exercise have been best defined for learning and memory, protection from neurodegeneration and alleviation of depression, particularly in elderly populations. Exercise increases synaptic plasticity by directly affecting synaptic structure and potentiating synaptic strength, and by strengthening the underlying systems that support plasticity including neurogenesis, metabolism and vascular function. Such exercise-induced structural and functional change has been documented in various brain regions but has been best-studied in the hippocampus - the focus of this review. A key mechanism mediating these broad benefits of exercise on the brain is induction of central and peripheral growth factors and growth factor cascades, which instruct downstream structural and functional change. In addition, exercise reduces peripheral risk factors such as diabetes, hypertension and cardiovascular disease, which converge to cause brain dysfunction and neurodegeneration. A common mechanism underlying the central and peripheral effects of exercise might be related to inflammation, which can impair growth factor signaling both systemically and in the brain. Thus, through regulation of growth factors and reduction of peripheral and central risk factors, exercise ensures successful brain function.
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Exercise builds brain health: key roles
of growth factor cascades and
Carl W. Cotman, Nicole C. Berchtold and Lori-Ann Christie
University of California, Irvine Institute for Brain Aging and Dementia, 1113 Gillespie Building, Irvine, CA 92617-4540, USA
Human and other animal studies demonstrate that
exercise targets many aspects of brain function and has
broad effects on overall brain health. The benefits of
exercise have beenbest defined for learning and memory,
protection from neurodegeneration and alleviation of
depression, particularly in elderly populations. Exercise
increases synaptic plasticity by directly affecting synaptic
structure and potentiating synaptic strength, and by
strengthening the underlying systems that support
plasticity including neurogenesis, metabolism and vas-
cular function. Such exercise-induced structural and func-
tional change has been documented in various brain
regions but has been best-studied in the hippocampus
– the focus of this review. A key mechanism mediating
these broad benefits of exercise on the brain is induction
of central and peripheral growth factors and growth
factor cascades, which instruct downstream structural
and functional change. In addition, exercise reduces per-
ipheral risk factors such as diabetes, hypertension and
cardiovascular disease, which converge to cause brain
dysfunction and neurodegeneration. A common mechan-
ism underlying the central and peripheral effects of exer-
cise might be related to inflammation, which can impair
growth factor signaling both systemically and in the
brain. Thus, through regulation of growth factors and
reduction of peripheral and central risk factors, exercise
ensures successful brain function.
Much evidence is converging on the concept that lifestyle
factors such as exercise can improve learning and memory,
delay age-related cognitive decline, reduce risk of neuro-
degeneration, and play a part in alleviating depression. As
we delineate in the first part of this review, the evidence
that exercise can affect these endpoints has become better
established in the past few years, and provides a founda-
tion for elucidating more precisely the mechanisms
through which exercise modulates brain function. In the
subsequent two sections, by focusing primarily on the
hippocampus, we discuss how exercise can affect brain
structure, from increased neurogenesis and angiogenesis
to greater dendritic complexity, and we define the under-
lying mechanisms. It is increasingly clear that a central
mechanism is exercise-dependent peripheral and central
regulation of growth factors, which operate in unique
cascades to orchestrate structural and functional change.
In turn, mechanisms that interfere with growth factor
signaling – specifically inflammation – are modulated by
exercise in the periphery and in the central nervous system
(CNS), as outlined in the last section. We propose that
reduction of inflammation by exercise is a common means
by which exercise reduces peripheral risk factors for cog-
nitive decline and neurodegeneration. We conclude with a
brief analysis of future directions and approaches to opti-
mize the impact of exercise on brain function.
Various functional modalities are improved by
Exercise enhances learning and plasticity
In humans, robust effects of exercise have been most clearly
demonstrated in aging populations, where sustained exer-
cise participation enhances learning and memory, improves
executive function, counteracts age-related and disease-
related mental decline, and protects against age-related
atrophy in brain areas crucial for higher cognitive processes
[1–3]. Interestingly, a dose–response relationship between
exercise duration/intensity and health-related quality of life
has been reported, whereby the best outcomes are associ-
ated with moderate exercise [4]. Consistent with research in
humans, rodent studies demonstrate that exercise can facili-
tate both acquisition and retention in young and aged
animals in various hippocampus-dependent tasks including
the Morris water maze [5,6], the radial arm maze [7], passive
avoidance [8] and object recognition [9]. Not all studies,
however, have consistently demonstrated improvements
in both acquisitionand retention: some have shown benefits
in acquisition or retention only. This variability is probably
related to differences in the exercise protocol (voluntary
versus forced), in combination with the intensity (in forced
exercise models) and duration of exercise exposure. Alth-
ough both forced exercise and voluntary exercise benefit
acquisition and/or learning, voluntary exercise seems to
produce benefits more reliably, especially after shorter
exercise duration. In addition, although some studies show
improvements after 1 week of exercise [6,10], most benefits
have been associated with longer-term exercise (3–12
weeks) [5,7–9].
Along with improved behavioral performance, exercise
facilitates synaptic plasticity in the hippocampus, a key
structure for spatial learning. Facilitated plasticity is most
Review TRENDS in Neurosciences Vol.30 No.9
Corresponding author: Cotman, C.W. (
Available online 31 August 2007. 0166-2236/$ see front matter . Published by Elsevier Ltd. doi:10.1016/j.tins.2007.06.011
evident in the dentate gyrus (DG), where exercise
enhances both short-term potentiation and long-term
potentiation (LTP) [11] – synaptic analogs of learning.
In particular, exercise enhances potentiation in response
to theta [11] and high-frequency [9,12] stimulation, and
reduces the threshold of theta stimulation required for
LTP induction in the perforant path [11]. Exercise-facili-
tated LTP in the DG is paralleled by altered cytoarchitec-
ture in the DG, including increases in dendritic length,
dendritic complexity, spine density and neural progenitor
proliferation [13]. Interestingly, no potentiation in res-
ponse to high-frequency stimulation has been reported
in the CA1 after exercise [12]; however, exercise effects
in the CA1 have been studied less extensively than those in
the DG. In parallel with the effects of exercise on hippo-
campal cytoarchitecture and electrophysiological proper-
ties, exercise increases the levels of synaptic proteins
(synapsin and synaptophysin [14]), glutamate receptors
(NR2b and GluR5 [11]) and the availability of several
classes of growth factor including brain-derived neuro-
trophic factor (BDNF) [15] and insulin-like growth fac-
tor-1 (IGF-1) [16], which can enhance plasticity. The
potential central role of growth factors in exercise-depend-
ent benefits in brain maintenance, health and function is
explored in more detail below.
Although strong evidence supports the idea that
exercise can facilitate learning in humans and other
animals, there is a gap in our knowledge regarding the
types of learning that are improved with exercise. For
example, human studies on exercise-dependent effects
on cognition have focused on frontal-brain-dependent
tasks (executive function), whereas animal studies have
assessed effects primarily on hippocampus-dependent
learning and plasticity. A key area of future research will
be to refine animal studies investigating the cognitive
effects of exercise to increase their relevance and translat-
ability to humans.
Exercise is neuroprotective
In addition to benefitting learning and memory, extensive
research demonstrates that exercise has neuroprotective
effects. These effects have been best defined with respect to
reducing brain injury, and to delaying onset of and decline
in several neurodegenerative diseases. For example,
engaging individuals affected by stroke in post-stroke thera-
peutic exercise programs accelerates functional rehabilita-
tion (reviewed in Ref. [17]). Clinical trials assessing the
efficacy of post-stroke exercise typically combine cardiovas-
cular training (treadmill or exercise bike) with weight train-
ing or targeted movement therapy, and the improvements
are probably due to the combination of interventions.
Animal models of ischemia (middle cerebral artery occlu-
sions) suggest, however, that cardiovascular training thera-
pies alone can reduce stroke damage and improve recovery.
Notably, reduced infarct volume and improved function
have been observed when animals engage in either forced
[18] or voluntary [19] running, and both pre-stroke [18] and
post-stroke [19] exercise shows efficacy. An essential future
goal will be to define the type, timing and intensity of
exercise interventions to determine how exercise will aid
in post-stroke rehabilitation.
In addition to the benefits of exercise in stroke,
retrospective and cross-sectional studies suggest that
participation in physical activity delays onset of and
reduces risk for Alzheimer disease (AD), Huntington’s
disease and Parkinson’s disease, and can even slow func-
tional decline after neurodegeneration has begun [2–4,20].
Intervention studies demonstrate that individuals with
AD who exercise show improved function on the daily
living scale, slowed rate of decline in cognitive tests,
improved physical function and decreased depressive
symptoms, as compared with non-exercisers who show
continued decline [21,22]. Recent evidence suggests that
exercise might have the most cognitive benefits in individ-
uals with the ApoE4 genotype (a risk factor for AD) [23],
although this area remains controversial [20]. Similar to
studies on AD, clinical intervention studies in individuals
with Parkinson’s disease demonstrate that aerobic train-
ing improves movement initiation and aerobic capacity
[24], and improves activities of daily living [25]. In parallel
with clinical studies, exercise has been shown to improve
function in several animal models of neurodegenerative
diseases by, for example, delaying symptom onset and
slowing cognitive decline in mice transgenic for Hunting-
ton’s disease [26], and improving spatial learning and
memory in transgenic mouse models of AD [27].
Mechanisms underlying the benefits of exercise in
neurodegeneration are in the early stages of investigation
in animal models such as transgenic mouse models of AD. In
these models, exercise reduces the load of amyloid-b(Ab)
plaques in the hippocampus and cortex, possibly by regulat-
ing processing of the amyloid precursor protein and/or
increasing degradation and clearance of Ab[27,28].Impor-
tantly, exercising animals show improved hippocampus-
dependent learning [27], indicating that the benefits of
exercise are functionally significant in this neurodegenera-
tive condition.
Exercise is therapeutic and protective in depression
Emerging evidence suggests that exercise has therapeutic
and preventative effects on depression. The prevention and
treatment of depression are important areas to define:
depression is linked to cognitive decline [29] and is con-
sidered to cause a worldwide health burden greater than
that of ischemic heart disease, cerebrovascular disease or
tuberculosis [30]. Therapeutic effects of exercise on depres-
sion have been most clearly established in human studies.
Randomized and crossover clinical trials demonstrate the
efficacy of aerobic or resistance training exercise (2–4
months) as a treatment for depression in both young
[31] and older [32,33] individuals. The benefits are similar
to those achieved with anti-depressants [32]. They are also
dose dependent: greater improvements are seen with
higher levels of exercise [33].
Furthermore, therapeutic effects of exercise on
depressive symptoms have been demonstrated in con-
ditions of neurodegeneration in humans. Specifically, in
a randomized clinical trial, 3 months of exercise interven-
tion improved depressive symptoms in individuals with
AD, whereas non-exercising subjects showed worsening of
depressive symptoms [21]. In addition to a therapeutic
effect, evidence from human studies shows that exercise
Review TRENDS in Neurosciences Vol.30 No.9 465
can provide some protection from the development of
depression [34], although further studies are needed to
resolve inconsistent findings. A protective effect of sus-
tained exercise (>2 weeks) has been clearly demonstrated
in animal models of depression, including stress-induced
learned helplessness [35,36]. In addition, a therapeutic
effect of exercise on exiting depression has been recently
established in an animal model [37]; this therapeutic effect
parallels that observed in human studies.
Although exercise seems to have both preventative and
therapeutic effects on the course of depression, the under-
lying mechanisms are poorly understood. Protective effects
of exercise from stress have focused on the hippocampus,
where exercise-induced neurogenesis [38] and growth fac-
tor expression [39] have been proposed as potential
mediators, although not without controversy [40]. Other
proposed mechanisms include exercise-driven changes in
the hypothalamic–pituitary–adrenal axis that regulates
the stress response [31], and altered activity of dorsal
raphe serotonin neurons implicated in mediating learned
helplessness behaviors [36]. It is important to note that
the translatability of animal studies is dependent on the
animal model of depression and how well it parallels
the human condition – an area that remains under active
Mechanisms of exercise effects on brain health
In parallel with its benefits in learning and depression,
exercise modulates a range of supporting systems for brain
maintenance and plasticity including neurogenesis,
enhanced CNS metabolism and angiogenesis. Neurogen-
esis and other exercise-induced alterations in neuronal
circuitry and function must be met by an adequate nutrient
and energy supply, which in turn is supported by changes
in metabolic function and blood flow.
Enhanced hippocampal neurogenesis is one of the
most reproducible effects of exercise in the rodent brain
[12,16,41], and might be a key mechanism mediating
exercise-related improvements in learning and memory
and resistance to depression (although the role of neuro-
genesis in these functions is controversial at present). In
both young and old animals, exercise stimulates prolifer-
ation of the neural progenitor population, increases
the number of new neurons, and promotes survival of
these new cells [12,16,41]. These new neurons become
functionally integrated into the hippocampal architec-
ture [42], but they are unique from mature granule cells
in that they have a lower threshold of excitability [43].
This feature makes these new neurons well suited to
mediate exercise-stimulated enhanced plasticity, such
as facilitated perforant-path LTP [11].Hippocampal
neurogenesis has been linked to learning and memory
[44,45] and might be related to the therapeutic effects
of antidepressants ([46];butseeRef.[40])–twofunc-
tional endpoints that are improved by exercise. The
functional consequences of hippocampal neurogenesis
remain under intense debate, and it will be important
to determine whether the enhancement of hippocampal
neurogenesis with exercise contributes to facilitated
plasticity, improved learning and memory, or protection
from stress.
To support exercise-induced changes in brain function
such as enhanced plasticity, neurogenesis and resilience to
insult, the brain must meet increased nutrient and energy
needs. Such demands are met with higher expression of
enzymes involved in glucose use and metabolism in the
hippocampus [47,48] and in other brain regions. In
addition, exercise leads to widespread growth of blood
vessels in the hippocampus [5], cortex [49] and cerebellum
[50]; these blood vessels provide increased nutrient and
energy supply. Indeed, a recent in vivo imaging study in
humans (ages 21–45) has shown that 12 weeks of cardio-
vascular training increases blood flow in the DG, and this
increase is correlated with improved rate of learning in a
hippocampus-dependent task [51]. In turn, these changes
ensure that the enhanced brain function stimulated by
exercise can be supported and maintained. In addition,
exercise-induced increases in microglia and astrocytes
[52], observed in several brain regions, also might help
to maintain enhanced brain health and function with
exercise. The significance of changes in glia and astrocytes
in response to exercise has not been defined and merits
further study.
Growth factors are central to the benefits of exercise
for the brain
Exercise modulates both plasticity and various supporting
systems that participate in maintaining brain function and
health. To understand how exercise achieves these effects,
the regulatory mechanisms underlying these changes need
to be defined. At first glance, it would seem unlikely that
common mechanisms could mediate the varied effects of
exercise on learning, depression, neurogenesis, angiogen-
esis and overall brain health. An emerging overarching
concept, however, is that exercise increases brain avail-
ability of several classes of growth factors that modulate
nearly all of the functional endpoints enhanced by exercise.
At present, BDNF, IGF-1 and vascular endothelial-
derived growth factor (VEGF) are the principal growth
factors known to mediate the effects of exercise on the
brain. These growth factors work in concert to produce
complementary functional effects, modulating both over-
lapping and unique aspects of exercise-related benefits in
brain plasticity, function and health. Effects of exercise on
learning and depression are predominantly regulated by
IGF-1 and BDNF, whereas exercise-dependent stimu-
lation of angiogenesis and hippocampal neurogenesis
seems to be regulated by IGF-1 and VEGF (Figure 1).
Role of growth factors in exercise-induced benefits in
learning and plasticity
Abundant evidence from animal and human research
supports the idea that BDNF is essential for hippocampal
function, synaptic plasticity, learning, and modulation of
depression [53]. In animal studies, exercise increases
BDNF in several brain regions, and the most robust and
enduring response occurs in the hippocampus [54]. After
several days of exercise, BDNF gene and protein pro-
duction by neurons is increased in all hippocampal sub-
fields, and remains higher for weeks with sustained
exercise [15]. Regulation of hippocampal BDNF by exercise
is mediated by neurotransmitter systems (reviewed in Refs
466 Review TRENDS in Neurosciences Vol.30 No.9
[54,55]), by neuroendocrine systems [54], and by IGF-1
[56]. Like BDNF, IGF-1 gene expression is increased in
hippocampal neurons in response to exercise, occurring
several days after exercise onset [56]. In addition, periph-
eral circulating levels of IGF-1 are rapidly increased in
response to exercise (within 1 h) [57], and the peripheral
increase in IGF-1 seems to be essential for exercise-
induced neurogenesis [16] and improved memory [56].
Both BDNF signaling and IGF-1 signaling are crucial
mechanisms underlying improved learning in response to
exercise, as has been established by using blocking anti-
bodies in combination with exercise. BDNF signaling can
be blocked with antibodies to TrkB (anti-TrkB), the re-
ceptor for BDNF. Intra-hippocampal injection of anti-TrkB
attenuates the beneficial effects of exercise on hippo-
campus-dependent learning, specifically blocking improve-
ments in both the acquisition and the retention of a spatial
learning task [6,14]. In addition, anti-TrkB attenuates the
exercise-dependent induction of synaptic proteins (e.g.
synaptophysin and synapsin) in the hippocampus [6,14].
These results demonstrate that BDNF signaling must be
active for the effects of exercise on hippocampal plasticity
to manifest.
In parallel, function-blocking antibodies to IGF-1
(anti-IGF-1) also demonstrate that IGF-1 signaling has
an essential role in exercise effects on hippocampus-depend-
ent learning and plasticity. Intra-hippocampal injection of
anti-IGF-1 prevents enhancement of spatial recall, but
not acquisition [56]. In addition, anti-IGF-1 attenuates
exercise-dependent induction of synapsin I and blocks
exercise-induced activation of the calmodulin kinase II
and mitogen-activated protein kinase II (MAPKII) path-
ways [56] – effects that seem to be mediated by IGF-1-
dependent regulation of BDNF signaling [56].Thislast
study could not differentiate whether the effects were due
to a block of peripherally derived or centrally produced IGF-
1, and IGF-1 from both sources potentially could be involved.
Much evidence indicates that there are points of
convergence between IGF-1 and BDNF signaling. First,
IGF-1 increases BDNF signaling in response to exercise.
Blocking IGF-1 signaling in vivo prevents the induction of
hippocampal BDNF in response to exercise and, in paral-
lel, attenuates the exercise-dependent induction of synap-
tic proteins (e.g. synapsin I) downstream from TrkB
signaling [56]. Second, IGF-1 increases neuronal levels
of TrkB in hippocampal cultures, thereby increasing
BDNF signaling [58] – an effect that might also occur in
vivo. Third, BDNF, but not IGF-1, modulates the exercise-
dependent enhancement of synaptic plasticity mechan-
isms that are thought to underlie learning and memory.
For example, BDNF, similar to exercise, facilitates LTP
(reviewed in Ref. [59]) and activates MAPK [60] – a signal
transduction pathway that is important for LTP. By con-
trast, a direct role for IGF-1 in LTP has not been shown,
and IGF-1 is only a weak activator of the MAPK pathway in
comparison to BDNF [60]. These results suggest that IGF-
1 and BDNF work in concert, and that there is a conver-
gence on BDNF signaling as a final common downstream
mechanism mediating exercise effects on hippocampal
plasticity and learning.
Figure 1. Exercise regulates learning, neurogenesis and angiogenesis through growth factor cascades. Insulin growth factor-1 (IGF-1), brain-derived neurotrophic factor
(BDNF) and vascular endothelial growth factor (VEGF) derived from central and peripheral sources act in concert to modulate exercise-dependent effects on the brain.
(a) Exercise enhances learning by induction of BDNF and IGF-1. Neurotransmitters, including NMDA receptors and the noradrenergic (NE) system [54,55], peripheral IGF-1
and possibly centrally derived IGF-1, mediate the induction of hippocampal BDNF with exercise. In turn, BDNF signaling is likely to be a hub for effects of exercise on
learning, including acquisition, retention and LTP. (b) Exercise stimulates neurogenesis in the hippocampus through the interactive effects of IGF-1 with VEGF. Peripheral
IGF-1 and VEGF cross the blood–brain barrier (BBB) and drive enhanced proliferation and survival. (c) Exercise stimulates angiogenesis through the effects of IGF-1 and
VEGF on endothelial cell proliferation and vessel growth. Peripheral sources of the growth factors (and possibly also central sources) mediate the effects. The role of BDNF
in exercise-mediated neurogenesis and angiogenesis has not been directly tested.
Review TRENDS in Neurosciences Vol.30 No.9 467
Role of growth factors in exercise-induced benefits in
The hippocampus is one brain region implicated in the
pathophysiology of depression, and exercise-dependent
induction of BDNF in the hippocampus might be a mech-
anism contributing to the protective and therapeutic effect
of exercise on this disorder. This idea is based on the
observation that hippocampal infusion of BDNF or over-
expression of TrkB receptors produces antidepressant-like
effects in preclinical models of behavioral despair [61,62],
whereas mice lacking BDNF show impaired antidepress-
ant responses [63]. Furthermore, human genetic studies
demonstrate that impaired BDNF availability is associ-
ated with susceptibility to depression and other mood
disorders [64]. Lastly, evidence indicates that BDNF-
mediated TrkB signaling is both sufficient and necessary
for antidepressant-like effects in rodents [65]. These data
suggest that exercise-dependent induction of hippocampal
BDNF might contribute to protective or therapeutic effects
of exercise on depression. In addition, exercise and phar-
maceutical antidepressants seem to act synergistically to
upregulate BDNF in the hippocampus, suggesting that
there is a convergent mechanism between these thera-
peutic interventions [66].
Similar to BDNF, antidepressant effects have been
reported for IGF-1: ventricular IGF-1 injection produces
antidepressant-like (anxiolytic-like) effects that endure for
a week or more [67]. Although the evidence for IGF-1 is not
as compelling as that for BDNF, increases in both of these
growth factors in the CNS might contribute to anxiolytic or
anti-depressant benefits of exercise. The mechanism by
which growth factors might have antidepressant effects is
largely unknown. It has been recently proposed, however,
that neurotrophic factors themselves do not control mood,
but rather they facilitate the activity-dependent modu-
lation of networks that are required to induce antidepress-
ant effects [39]. If BDNF signaling does play a central part
in exercise-induced benefits in depression, it will be
important to determine whether exercise interacts with
BDNF polymorphisms, particularly the valine–methionine
polymorphism that causes impaired BDNF transport and
release [68].
Role of growth factors in exercise effects on
neurogenesis and angiogenesis
Whereas IGF-1 and BDNF mediate behavioral
improvements with exercise, the interactive effects of
IGF-1 with VEGF seem to orchestrate exercise-induced
neurogenesis and angiogenesis. Both IGF-1 and VEGF are
increased in the periphery by exercise and cross the blood–
brain barrier to enter the brain [16,41,69]. Peripheral
sources of IGF-1 and VEGF mediate stimulation of neu-
rogenesis and angiogenesis with exercise, as has been
demonstrated by using blocking antibodies. For example,
blocking either IGF-1 [16] or VEGF [41] signaling (by
blocking peripheral growth factor entry to the brain) pre-
vents exercise-induced proliferation of neural precursors in
the hippocampus, and blocking IGF-1 partially blocks the
survival-promoting effect of exercise on newly generated
neural precursors [16] (the effects of anti-VEGF on survival
have not been assessed).
In addition to a role in neurogenesis, peripheral IGF-1 is
necessary for exercise-induced vessel remodeling in the
brain [69], an effect that might be mediated in part by
induction of VEGF. Exercise-induced angiogenesis is associ-
ated with an increase in brain VEGF mRNA and protein
[49]; this increase has potent mitotic activity specific to
vascular endothelial cells, affecting proliferation, survival,
adhesion, migration and capillary tube formation [70].A
role for BDNF in exercise-dependent neurogenesis or angio-
genesis has not been directly tested. We can predict, how-
ever, that induction of BDNF participates in increasing
proliferation and survival of new neurons because BDNF
regulates baseline neurogenesis in vivo [71].
Downstream regulation of signal transduction, gene
transcription and protein expression
Although it is clear that growth factors and growth factor
signaling cascades are central regulatory mechanisms
underlying the effects of exercise in the CNS, there is less
information on the mechanisms by which these growth
factors and other effectors regulate the structural, meta-
bolic and functional endpoints.
It is known that exercise controls signal transduction
pathways and gene expression, which then effect down-
stream change. For example, exercise can activate the
MAPK and phosphatidylinositol 3-kinase (PI3K) pathways
in neurons [56]; these pathways can augment LTP and
production of additional growth factors. In addition, exer-
cise regulates activity of transcription factors such as
CREB [72], which is crucial for learning and memory.
Furthermore, proteomic and microarray analyses have
shown that many classes of proteins, in addition to growth
factors, are regulated by exercise [47,48], including those
involved in metabolism, inflammation and synaptic
plasticity. Lastly, as described above, exercise – through
gene and protein expression – controls proliferation of
various types of cell in the CNS, including neural progeni-
tors, glia and epithelial cells.
Growth factors orchestrate most, if not all, of the brain
responses to exercise through either direct or indirect
effects. As the field evolves, these and other downstream
effects will be further defined as probable mechanisms that
mediate the neuroprotective, structural, metabolic and
functional changes elicited by exercise.
Systemic mechanisms: exercise reduces peripheral
risk factors
An emerging fundamental concept is that brain health and
cognitive function are modulated by the interplay of var-
ious central and peripheral factors. Specifically, brain
function is compromised by the presence of peripheral risk
factors for cognitive decline, including hypertension,
hyperglycemia, insulin insensitivity and dyslipidemia –
a cluster of features that have been conceptualized as
the ‘metabolic syndrome’ [73]. Of the various aspects of
the metabolic syndrome, the most crucial for cognitive
function are hypertension and glucose intolerance [73].
A common feature of many of these conditions is systemic
inflammation, which contributes to most if not all of the
conditions of the metabolic syndrome. Furthermore,
systemic inflammation exacerbates CNS inflammation
468 Review TRENDS in Neurosciences Vol.30 No.9
[74] and correlates with cognitive decline [75,76].
Remarkably, exercise reduces all of these peripheral risk
factors, improving cardiovascular health, lipid–cholesterol
balance, energy metabolism, glucose use, insulin sensi-
tivity and inflammation [77,78]. Exercise is thus uniquely
positioned to improve brain health and function by redu-
cing the peripheral (indirect) risk factors for cognitive
decline and, in parallel, by directly enhancing brain health
and cognitive function.
The central and peripheral effects of exercise that
improve brain health and cognitive function might be
mediated through common mechanisms that converge on
modulating growth factor signaling. Specifically, exercise
can improve growth factor signaling by directly increasing
growth factor levels (see above) and by reducing pro-
inflammatory conditions, which impair growth factor sig-
naling. The effects on peripheral and central IGF-1 sig-
naling are one example. The presence of pro-inflammatory
cytokines impairs insulin–IGF-1 signal transduction and
is a mechanism of insulin resistance [79,80]. Peripheral
IGF-1 is essential in glucose metabolism, tissue mainten-
ance [57] and cerebrovascular function [81], and a low level
of IGF-1 places individuals at risk for cognitive impairment
[82]. Exercise increases peripheral IGF-1, leading to
improved insulin sensitivity [83], restored insulin–IGF-1
signaling [84] and improved brain health and cognitive
function [85]. Furthermore, pro-inflammatory cytokines
impair IGF-1 signal transduction in neurons [86,87]. Exer-
cise might counteract the negative effects of this inflam-
mation by acting to restore IGF-1 signaling, because it
reduces circulating pro-inflammatory cytokines [88].In
addition to effects on IGF-1 signal transduction, reduction
of inflammation by exercise could also improve BDNF
signaling in the brain. Inflammation and pro-inflamma-
tory cytokines impair BDNF signaling in neurons, leading
to a condition referred to as ‘neurotrophin resistance’,
which is conceptually similar to insulin resistance [87].
Recent data indicate that exercise improves the overall
immune condition of the brain, for example, by reducing
brain IL-1b(a pro-inflammatory cytokine) in a mouse
model of AD [89], and by reducing brain inflammation in
response to stroke [90] or peripheral infection [91].In
addition, exercise could attenuate levels of pro-inflamma-
tory cytokine in the brain of individuals with AD by redu-
cing the load of Ab, which itself has pro-inflammatory
effects [92]. Thus, the reduction of peripheral and central
inflammation by exercise can serve as a common mechan-
ism to reduce the risk for both diabetes and cognitive
Conclusion and future directions
Human and animal studies indicate that exercise targets
many aspects of brain function and has broad effects on
overall brain health, resilience, learning and memory, and
depression, particularly in elderly populations. Exercise
sets into motion an interactive cascade of growth factor
signaling that has the net effect of stimulating plasticity,
enhancing cognitive function, attenuating the mechanisms
driving depression, stimulating neurogenesis and improv-
ing cerebrovascular perfusion. IGF-1 signaling converges
on BDNF signaling, which might be a hub for effects of
exercise on learning and depression. In addition to central
mechanisms, exercise reduces several peripheral risk fac-
tors for cognitive decline. A common mechanism between
many of these peripheral risk factors is inflammation,
which interferes with growth factor signaling in the per-
iphery and in the brain. Exercise might improve growth
factor signaling by both reducing pro-inflammatory con-
ditions and directly increasing growth factor levels. A
unifying concept is that exercise mobilizes growth factor
Figure 2. Exercise induces growth factor cascades, a central mechanism mediating exercise-dependent benefits in cognition, synaptic plasticity, neurogenesis and vascular
function. In addition, exercise reduces peripheral risk factors for cognitive decline such as hypertension and insulin resistance, components of the metabolic syndrome that
converge to increase the risk for brain dysfunction and neurodegeneration. Inflammation, which can impair growth factor signaling, exacerbate the metabolic syndrome
and accelerate cognitive decline, is reduced by exercise. Overall, exercise induces growth factor cascades and reduces peripheral risk factors for cognitive decline, all of
which converge to improve brain health and function, and to delay the onset of and slow the decline in neurodegenerative diseases including Alzheimer disease (AD) and
Parkinson’s disease (PD).
Review TRENDS in Neurosciences Vol.30 No.9 469
cascades – both peripherally and centrally – that
act synergistically and drive exercise-mediated brain
responses (Figure 2).
Although much progress has been made in animal
studies, there is a need for rigorous clinical intervention
trials on exercise that are guided by this knowledge from
animal models. We can identify three areas where
additional research is needed to facilitate translation to
clinical trials. First, findings from animal behavioral stu-
dies must be translated to humans and, conversely, animal
studies must be refined to increase their relevance to
humans. Second, the extent, frequency and types of exer-
cise that result in functional benefits must be defined.
Third, we need to identify and to target mechanisms by
which exercise might act synergistically with key pharma-
ceuticals to augment improvements observed with either
exercise or medication alone. Overall, exercise increases
brain health – just as it improves body health – and thus
represents an exciting lifestyle intervention technique to
improve brain plasticity, function and resistance to neu-
rodegenerative diseases.
Support provided in part by grant NIA AG00538 and a donation from
Rich Muth.
1 Colcombe, S. and Kramer, A.F. (2003) Fitness effects on the cognitive
function of older adults: a meta-analytic study. Psychol. Sci. 14, 125–
2 Weuve, J. et al. (2004) Physical activity, including walking, and
cognitive function in older women. J. Am. Med. Assoc. 292, 1454–
3 Heyn, P. et al. (2004) The effects of exercise training on elderly persons
with cognitive impairment and dementia: a meta-analysis. Arch. Phys.
Med. Rehabil. 85, 1694–1704
4 Larson, E.B. et al. (2006) Exercise is associated with reduced risk for
incident dementia among persons 65 years of age and older. Ann.
Intern. Med. 144, 73–81
5 van Praag, H. et al. (2005) Exercise enhances learning and
hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685
6 Vaynman, S. et al. (2004) Hippocampal BDNF mediates the efficacy of
exercise on synaptic plasticity and cognition. Eur. J. Neurosci. 20,
7 Schweitzer, N.B. et al. (2006) Exercise-induced changes in cardiac gene
expression and its relation to spatial maze performance. Neurochem.
Int. 48, 9–16
8 Radak, Z. et al. (2006) The effects of training and detraining on
memory, neurotrophins and oxidative stress markers in rat brain.
Neurochem. Int. 49, 387–392
9 O’Callaghan, R.M. et al. (2007) The effects of forced exercise on
hippocampal plasticity in the rat: a comparison of LTP, spatial- and
non-spatial learning. Behav. Brain Res. 176, 362–366
10 Vaynman, S. et al. (2007) The select action of hippocampal calcium
calmodulin protein kinase II in mediating exercise-enhanced cognitive
function. Neuroscience 144, 825–833
11 Farmer, J. et al. (2004) Effects of voluntary exercise on synaptic
plasticity and gene expression in the dentate gyrus of adult male
Sprague–Dawley rats in vivo.Neuroscience 124, 71–79
12 van Praag, H. et al. (1999) Running enhances neurogenesis, learning,
and long-term potentiation in mice. Proc. Natl. Acad. Sci. U. S. A. 96,
13 Eadie, B.D. et al. (2005) Voluntary exercise alters the cytoarchitecture
of the adult dentate gyrus by increasing cellular proliferation, dendritic
complexity, and spine density. J. Comp. Neurol. 486, 39–47
14 Vaynman, S.S. et al. (2006) Exercise differentially regulates
synaptic proteins associated to the function of BDNF. Brain Res.
1070, 124–130
15 Berchtold, N.C. et al. (2005) Exercise primes a molecular memory for
brain-derived neurotrophic factor protein induction in the rat
hippocampus. Neuroscience 133, 853–861
16 Trejo, J.L. et al. (2001) Circulating insulin-like growth factor I mediat es
exercise-induced increases in the number of new neurons in the adult
hippocampus. J. Neurosci. 21, 1628–1634
17 Rabadi, M.H. (2007) Randomized clinical stroke rehabilitation trials in
2005. Neurochem. Res. 32, 807–821
18 Ding, Y.H. et al. (2006) Exercise preconditioning reduces brain
damage and inhibits TNF-areceptor expression after hypoxia/
reoxygenation: an in vivo and in vitro study. Curr. Neurovasc. Res.
3, 263–271
19 Luo, C.X. et al. (2007) Voluntary exercise-induced neurogenesis in the
postischemic dentate gyrus is associated with spatial memory recovery
from stroke. J. Neurosci. Res. 85, 1637–1646
20 Podewils, L.J. et al. (2005) Physical activity, APOE genotype, and
dementia risk: findings from the Cardiovascular Health Cognition
Study. Am. J. Epidemiol. 161, 639–651
21 Teri, L. et al. (2003) Exercise plus behavioral management in patients
with Alzheimer disease: a randomized controlled trial. J. Am. Med.
Assoc. 290, 2015–2022
22 Stevens, J. and Killeen, M. (2006) A randomised controlled trial testing
the impact of exercise on cognitive symptoms and disability of residents
with dementia. Contemp. Nurse 21, 32–40
23 Rovio, S. et al. (2005) Leisure-time physical activity at midlife and
the risk of dementia and Alzheimer’s disease. Lancet Neurol. 4, 705–
24 Bergen, J.L. et al. (2002) Aerobic exercise intervention improves
aerobic capacity and movement initiation in Parkinson’s disease
patients. NeuroRehabilitation 17, 161–168
25 Crizzle, A.M. and Newhouse, I.J. (2006) Is physical exercise beneficial
for persons with Parkinson’s disease? Clin. J. Sport Med. 16, 422–425
26 Pang, T.Y. et al. (2006) Differential effects of voluntary physical
exercise on behavioral and brain-derived neurotrophic factor
expression deficits in Huntington’s disease transgenic mice.
Neuroscience 141, 569–584
27 Adlard, P.A. et al. (2005) Voluntary exercise decreases amyloid load
in a transgenic model of Alzheimer’s disease. J. Neurosci. 25, 4217–
28 Lazarov, O. et al. (2005) Environmental enrichment reduces Ablevels
and amyloid deposition in transgenic mice. Cell 120, 701–713
29 King, D.A. and Caine, E.D. (1996) Cognitive impairment in major
depression. In Neuropsychological Assessment of Neuropsychiatric
Disorders Vol. I. (Grant, I. and Adams, K.M.,eds), In pp. 200–217,
Oxford University Press
30 Murray, C.J. and Lopez, A.D. (1997) Global mortality, disability, and
the contribution of risk factors: Global Burden of Disease Study. Lancet
349, 1436–1442
31 Nabkasorn, C. et al. (2006) Effects of physical exercise on depression,
neuroendocrine stress hormones and physiological fitness in
adolescent females with depressive symptoms. Eur. J. Public Health
16, 179–184
32 Blumenthal, J.A. et al. (1999) Effects of exercise training on older
patients with major depression. Arch. Intern. Med. 159, 2349–2356
33 Singh, N.A. et al. (2005) A randomized controlled trial of high versus
low intensity weight training versus general practitioner care for
clinical depression in older adults. J. Gerontol. A Biol. Sci. Med. Sci.
60, 768–776
34 Strawbridge, W.J. et al. (2002) Physical activity reduces the risk of
subsequent depression for older adults. Am. J. Epidemiol. 156, 328–
35 Duman, R.S. (2005) Neurotrophic factors and regulation of mood: role
of exercise, diet and metabolism. Neurobiol. Aging 26 (Suppl. 1), 88–93
36 Greenwood, B.N. et al. (2003) Freewheel running prevents learned
helplessness/behavioral depression: role of dorsal raphe serotonergic
neurons. J. Neurosci. 23, 2889–2898
37 Greenwood, B.N. et al. Therapeutic effects of exercise: wheel running
reverses stress-induced interference with shuttle-box escape. Behav.
Neurosci. (in press)
38 Ernst, C. et al. (2006) Antidepressant effects of exercise: evidence for an
adult-neurogenesis hypothesis? J. Psychiatry Neurosci. 31, 84–92
39 Castren, E. et al. (2007) Role of neurotrophic factors in depression.
Curr. Opin. Pharmacol. 7, 18–21
470 Review TRENDS in Neurosciences Vol.30 No.9
40 Vollmayr, B. et al. Neurogenesis and depression: what animal models
tell us about the link. Eur. Arch. Psychiatry Clin. Neurosci. (in press)
41 Fabel, K. et al. (2003) VEGF is necessary for exercise-induced adult
hippocampal neurogenesis. Eur. J. Neurosci. 18, 2803–2812
42 van Praag, H. et al. (2002) Functional neurogenesis in the adult
hippocampus. Nature 415, 1030–1034
43 Schmidt-Hieber, C. et al. (2004) Enhanced synaptic plasticity in
newly generated granule cells of the adult hippocampus. Nature
429, 184–187
44 Leuner, B. et al. (2006) Is there a link between adult neurogenesis and
learning? Hippocampus 16, 216–224
45 Winocur, G. et al. (2006) Inhibition of neurogenesis interferes
with hippocampus-dependent memory function. Hippocampus 16,
46 Santarelli, L. et al. (2003) Requirement of hippocampal neurogenesis
for the behavioral effects of antidepressants. Science 301, 805–809
47 Ding, Q. et al. (2006) Exercise affects energy metabolism and neural
plasticity-related proteins in the hippocampus as revealed by
proteomic analysis. Eur. J. Neurosci. 24, 1265–1276
48 Tong, L. et al. (2001) Effects of exercise on gene-expression profile in the
rat hippocampus. Neurobiol. Dis. 8, 1046–1056
49 Ding, Y.H. et al. (2006) Cerebral angiogenesis and expression of
angiogenic factors in aging rats after exercise. Curr. Neurovasc. Res.
3, 15–23
50 Black, J.E. et al. (1990) Learning causes synaptogenesis, whereas
motor activity causes angiogenesis, in cerebellar cortex of adult rats.
Proc. Natl. Acad. Sci. U. S. A. 87, 5568–5572
51 Pereira, A.C. et al. (2007) An in vivo correlate of exercise-induced
neurogenesis in the adult dentate gyrus. Proc. Natl. Acad. Sci. U. S. A.
104, 5638–5643
52 Ehninger, D. and Kempermann, G. (2003) Regional effects of wheel
running and environmental enrichment on cell genesis and microglia
proliferation in the adult murine neocortex. Cereb. Cortex 13, 845–851
53 Kuipers, S.D. and Bramham, C.R. (2006) Brain-derived neurotrophic
factor mechanisms and function in adult synaptic plasticity: new
insights and implications for therapy. Curr. Opin. Drug Discov.
Devel. 9, 580–586
54 Cotman, C.W. and Berchtold, N.C. (2002) Exercise: a behavioral
intervention to enhance brain health and plasticity. Trends
Neurosci. 25, 295–301
55 Russo-Neustadt, A.A. and Chen, M.J. (2005) Brain-derived
neurotrophic factor and antidepressant activity. Curr. Pharm. Des.
11, 1495–1510
56 Ding, Q. et al. (2006) Insulin-like growth factor I interfaces with brain-
derived neurotrophic factor-mediated synaptic plasticity to modulate
aspects of exercise-induced cognitive function. Neuroscience 140, 823–
57 Schwarz, A.J. et al. (1996) Acute effect of brief low- and high-intensity
exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-
binding protein-3 and its proteolysis in young healthy men. J. Clin.
Endocrinol. Metab. 81, 3492–3497
58 McCusker, R.H. et al. (2006) Insulin-like growth factor-I enhances
the biological activity of brain-derived neurotrophic factor on
cerebrocortical neurons. J. Neuroimmunol. 179, 186–190
59 Soule, J. et al. (2006) Brain-derived neurotrophic factor and control of
synaptic consolidation in the adult brain. Biochem. Soc. Trans. 34, 600–
60 Zheng, W.H. and Quirion, R. (2004) Comparative signaling pathways of
insulin-like growth factor-1 and brain-derived neurotrophic factor in
hippocampal neurons and the role of the PI3 kinase pathway in cell
survival. J. Neurochem. 89, 844–852
61 Koponen, E. et al. (2005) Enhanced BDNF signaling is associated with
an antidepressant-like behavioral response and changes in brain
monoamines. Cell. Mol. Neurobiol. 25, 973–980
62 Shirayama, Y. et al. (2002) Brain-derived neurotrophic factor produces
antidepressant effects in behavioral models of depression. J. Neurosci.
22, 3251–3261
63 Monteggia, L.M. et al. (2004) Essential role of brain-derived
neurotrophic factor in adult hippocampal function. Proc. Natl. Acad.
Sci. U. S. A. 101, 10827–10832
64 Neves-Pereira, M. et al. (2002) The brain-derived neurotrophic factor
gene confers susceptibility to bipolar disorder: evidence from a family-
based association study. Am. J. Hum. Genet. 71, 651–655
65 Saarelainen, T. et al. (2003) Activation of the TrkB neurotrophin
receptor is induced by antidepressant drugs and is required for
antidepressant-induced behavioral effects. J. Neurosci. 23, 349–357
66 Russo-Neustadt, A. et al. (1999) Exercise, antidepressant medications,
and enhanced brain derived neurotrophic factor expression.
Neuropsychopharmacology 21, 679–682
67 Hoshaw, B.A. et al. (2005) Central administration of IGF-I and BDNF
leads to long-lasting antidepressant-like effects. Brain Res. 1037, 204–
68 Egan, M.F. et al. (2003) The BDNF val66met polymorphism affects
activity-dependent secretion of BDNF and human memory and
hippocampal function. Cell 112, 144–145
69 Lopez-Lopez, C. et al. (2004) Insulin-like growth factor I is required for
vessel remodeling in the adult brain. Proc. Natl. Acad. Sci. U. S. A. 101,
70 Ferrara, N. and Davis-Smyth, T. (1997) The biology of vascular
endothelial growth factor. Endocr. Rev. 18, 4–25
71 Lee, J. et al. (2002) Evidence that brain-derived neurotrophic factor is
required for basal neurogenesis and mediates, in part, the enhancement
of neurogenesis by dietary restriction in the hippocampus of adult mice.
J. Neurochem. 82, 1367–1375
72 Shen, H. et al. (2001) Physical activity elicits sustained activation of
the cyclic AMP response element-binding protein and mitogen-
activated protein kinase in the rat hippocampus. Neuroscience 107,
73 Yaffe, K. et al. (2007) Metabolic syndrome and cognitive decline in
elderly Latinos: findings from the Sacramento Area Latino Study of
Aging study. J. Am. Geriatr. Soc. 55, 758–762
74 Perry, V.H. (2004) The influence of systemic inflammation on
inflammation in the brain: implications for chronic neurodegenerative
disease. Brain Behav. Immun. 18, 407–413
75 Yaffe, K. et al. (2004) The metabolic syndrome, inflammation, and risk
of cognitive decline. J. Am. Med. Assoc. 292, 2237–2242
76 Dik, M.G. et al. Contribution of metabolic syndrome components to
cognition in older persons. Diabetes Care DOI:10.2337/dc06-1190
77 Pedersen, B.K. (2006) The anti-inflammatory effect of exercise: its role
in diabetes and cardiovascular disease control. Essays Biochem. 42,
78 Carroll, S. and Dudfield, M. (2004) What is the relationship between
exercise and metabolic abnormalities? A review of the metabolic
syndrome. Sports Med. 34, 371–418
79 Strle, K. et al. (2004) Proinflammatory cytokine impairment of insulin-
like growth factor I-induced protein synthesis in skeletal muscle
myoblasts requires ceramide. Endocrinology 145, 4592–4602
80 Broussard, S.R. et al. (2003) Cytokine-hormone interactions: tumor
necrosis factor aimpairs biologic activity and downstream activation
signals of the insulin-like growth factor I receptor in myoblasts.
Endocrinology 144, 2988–2996
81 Sonntag, W.E. et al. (2000) The effects of growth hormone and IGF-
1 deficiency on cerebrovascular and brain ageing. J. Anat. 197, 575–
82 Landi, F. et al. (2007) Free insulin-like growth factor-I and cognitive
function in older persons living in community. Growth Horm. IGF Res.
17, 58–66
83 Gill, J.M. (2007) Physical activity, cardiorespiratory fitness and insulin
resistance: a short update. Curr. Opin. Lipidol. 18, 47–52
84 Chibalin, A.V. et al. (2000) Exercise-induced changes in expression and
activity of proteins involved in insulin signal transduction in skeletal
muscle: differential effects on insulin-receptor substrates 1 and 2. Proc.
Natl. Acad. Sci. U. S. A. 97, 38–43
85 Carro, E. et al. (2001) Circulating insulin-like growth factor I mediates
the protective effects of physical exercise against brain insults of
different etiology and anatomy. J. Neurosci. 21, 5678–5684
86 Venters, H.D. et al. (2001) Tumor necrosis factor-aand insulin-like
growth factor-I in the brain: is the whole greater than the sum of its
parts? J. Neuroimmunol. 119, 151–165
87 Tong, L. et al. Interleukin-1bimpairs brain derived neurotrophic
factor-induced signal transduction. Neurobiol. Aging (in press)
88 Petersen, A.M. and Pedersen, B.K. (2005) The anti-inflammatory effe ct
of exercise. J. Appl. Physiol. 98, 1154–1162
89 Nichol, K.E. et al. (2006) Exercise alters the immune profile in
aged Tg2576 (APP) toward an adaptive response coincident with
Review TRENDS in Neurosciences Vol.30 No.9 471
improved cognitive performance. In Society for Neuroscience
90 Ding, Y.H. et al. (2005) Exercise preconditioning ameliorates
inflammatory injury in ischemic rats during reperfusion. Acta
Neuropathol. (Berl.) 109, 237–246
91 Nickerson, M. et al. (2005) Physical activity alters the brain Hsp72 and
IL-1bresponses to peripheral E. coli challenge. Am. J. Physiol. Regul.
Integr. Comp. Physiol. 289, R1665–R1674
92 Weisman, D. et al. (2006) Interleukins, inflammation, and mechanisms
of Alzheimer’s disease. Vitam. Horm. 74, 505–530
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472 Review TRENDS in Neurosciences Vol.30 No.9
... Physical activity increases the availability of different classes of growth factors that stimulate hippocampal neurogenesis (21), neuronal plasticity (22), and the reduction of symptoms of depression (23). Several studies show, especially in the early stages of the disease, that stimulation and participation in various types of activities help to counterbalance the cognitive changes related to the pathology, thanks to cognitive plasticity (24,25). ...
... Several studies show, especially in the early stages of the disease, that stimulation and participation in various types of activities help to counterbalance the cognitive changes related to the pathology, thanks to cognitive plasticity (24,25). Although in a recent review it emerged that the results of studies on the subject are inconsistent and of poor quality (26), other studies suggest that physical activity is able not only to delay the onset and reduce the risk of Alzheimer's disease but also to slow the functional decline after the onset of neurodegeneration (23,27). ...
... /fneur. . physical activity (23,28). The WHO guidelines on reducing the risk of cognitive decline and dementia suggest that healthy elderly people perform at least 150 min of moderate-intensity aerobic physical activity per week (29). ...
Full-text available
Introduction Alzheimer's disease is a neurodegenerative syndrome characterized by cognitive deficits, loss of daily functions, and mental and behavioral disorders, which cause stress and negatively affect the quality of life. Studies in the field suggest that combining cognitive training with physical activity can reduce the risk of developing the disease and, once neurodegeneration has begun, it slows its progress. In particular, virtual reality and augmented reality administer cognitive stimulation while providing a link to autobiographical memory through reminiscence, enabling the improvement of the person's quality of life. The present protocol aims to evaluate the effectiveness of cognitive and physical treatments, integrated with the addition of virtual reality and reminiscence elements, using the Brainer software, in which people will find cognitive training, and the jDome ® BikeAround™ system, which will allow participants to pedal along a personalized path projected on a schematic, using an exercise bike connected to the system. Methods and analysis For this study, 78 patients with mild Alzheimer's dementia were recruited and divided into the Experimental Group (EG) and Control Group (CG). Sixteen treatment sessions of 60 min each were conducted for both groups (2 training sessions per week, for 8 weeks), including 1 patient at a time. The EG received cognitive treatment with Brainer and physical training with jDome, while the CG received cognitive treatment with Brainer and physical training with a classic bicycle. The evaluation mainly focused on the assessment of the person's cognitive status. Other analyses were conducted on the quality of life, mood, behavioral disorders, and physical function, which were considered secondary outcomes. Discussions The ultimate goal of the present study is to test the effectiveness of a treatment for people with mild Alzheimer's focused on the integration of cognitive training and aerobic physical activity, using an exercise bike, with the addition of virtual reality and reminiscence elements. Ethics and dissemination The study was approved by the Ethics Committee of the IRCCS INRCA. It was recorded in on 2 June 2022 with the number NCT05402423. The study findings will be used for publication in peer-reviewed scientific journals and presentations in scientific meetings.
... The exercise goal has many features that can modulate the brain function and have wide effects on total brain health [4]. The important mechanism mediating these benefits of exercise on the brain is influence of the growth factors and cascades of this factor, common mechanism subjacent the systemic effects of exercise that might be related to inflammation. ...
... This fact can impair growth factor signaling both systematically as in the brain. The exercise ensures both successful brain function as help in homeostasis maintenance [4]. ...
... Acute as well as chronic physical exercise may lead to an increase in the BDNF concentration 29,32 . These exercise-related increases may support a reduction in mood disorders and the protection and regeneration of various tissues, resulting in the facilitation of cognitive function 27,29,48 . It is worth adding that exercise-related upregulation of BDNF may help to compensate for age-dependent reductions in neurogenesis, synaptogenesis, synaptic plasticity, and learning and memory, leading to a more resilient brain in the context of age-related structural and functional changes 9,12,27,49 . ...
Full-text available
Programmed exercise interventions modulating both physical fitness and cognitive functions have become a promising tool to support healthy aging. The aim of this experiment was to determine the effect of a 12-week judo training (JEX) on cognitive processing and muscle function among the elderly. Forty participants were divided into two groups: the JEX group and the control group (CTL). Before and after 12-week of JEX, participants performed a battery of physiological and psychological tests. The peripheral level of brain-derived neurotrophic factor (BDNF) was analyzed. A 12-week JEX intervention led to improved Stroop performance reflected by a shortening of the response time related to Stroop “naming” interference. In addition, the peripheral concentration of BDNF was significantly increased following the JEX compared with the CTL group. In response to JEX, balance and lower limb strength significantly increased. The current results suggest that JEX could have beneficial effects on cognitive functions, denoted by elevated peripheral BDNF, as well as on balance and strength abilities. A combination of positive effects with respect to movement and cognition makes JEX an ideal preventive lifestyle modification for the aging population.
... It is likely that PA may influence neural systems (e.g., attention, learning and memory) [34]. It is also possible that moderate to vigorous PA may increase molecular mediators (e.g., brain-derived neurotrophic factor) and that PA may induce the development of the cellular environment and promote neurogenesis and improved vascular condition, thus improving cognition [32,35]. ...
Full-text available
The scientific literature shows a beneficial association between active methodologies and cognitive variables in university students. The purpose of this research was to determine the relationship between active methodologies in Physical Education and attention and concentration in a group of university students A total of forty-four undergraduate students from Pontifical University of Comillas of the Balearic Islands, Palma de Mallorca, Spain, participated in the present investigation (age: 20.48 ± 1.37 years; height: 170.77 ± 9.11 cm; weight: 68.84 ± 8.29 kg; body mass index: 23.51 ± 1.54). A D2 attention test was used to analyse their selective attention and concentration. Active methodologies were used to improve the students’ physical fitness, reflected in their VO2max, which was evaluated using an incremental cycloergometer test. A correlation analysis performed between the active methodologies used to improve physical fitness measures and the D2 test revealed a negative moderate correlation between HRmax and TR, TA and TR- (r = −0.30, p = 0.04; r = −0.38, p = 0.01; and r = −0.35, p = 0.02, respectively), and a positive moderate correlation between HRmax and C (r = −0.32, p = 0.03). Finally, a negative moderate correlation was found between VT and C (r = −0.48, p = 0.001). This correlation analysis was reinforced by the results of a regression analysis. In summary, the present research revealed that university students with better aerobic fitness, achieved through active methodologies and reflected in VT and higher HRmax, obtained better values in TA, TR and C. University students should be encouraged to engage in regular physical activity through active methodologies that tend to increase physical fitness.
... The integration of physical activity into teaching and learning attributes the increased effectiveness of learning partly to the increased number of memory channels (visual, kinesthetic and tactile) [4] and partly to the underlying neurophysiological principles, i.e., physical activity increases the growth of neurons and synapses [5][6][7]; assists the long-term memory [8,9]; increases integration of cognitive, motor, and sensory information between cerebral hemispheres [10]; increases oxygen flow due to increased heart rate [11]; and so on [2]. However, these facts do not focus on the psychophysiological responses of students during physical activity, so new learning models based on the latest neurological findings are still expected. ...
Full-text available
This study describes how wearable devices can be used in elementary schools to compare some aspects of different teaching approaches. Upper arm wearables were used as an objective tool to compare three approaches when teaching science: (i) classical frontal teaching, (ii) embodied (kinesthetic) teaching, and (iii) a distance teaching approach. Using the wearables, the approaches were compared in terms of their impact on students’ psychological arousal and perceived well-being. In addition, short-term and long-term knowledge gain and physiological synchronization between teacher and students during the lecture were assessed. A synchronization index was defined to estimate the degree of physiological synchronization. During distance teaching, by means of measurements with wearables, students were significantly less physically active and significantly less psychologically aroused. Embodied teaching allowed significantly higher physical activation than during the other two approaches. The synchronization index for all three teaching approaches was positive with the highest values for distance and frontal teaching. Moreover, knowledge gain immediately after the embodied lessons was higher than after frontal lessons. No significant differences in the long-term knowledge retention between the three different teaching methods were found. This pilot study proved that wearables are a useful tool in research in the field of education and have the potential to contribute to a deeper understanding of the mechanisms involved in learning, even in complex environments such as an elementary school classroom.
... On the other hand, there is an important bulk of knowledge showing a close relationship between physical activity and performance in several cognitive domains in the elderly [4,[37][38][39][40], or the risk of dementia [41]. Several mechanisms have been proposed to understand this beneficial effect of physical activity and/or exercise training, including a reduction in inflammation or the promotion of neurovascular integrity and brain plasticity through hormones and growth factors release [42][43][44]. ...
Aging is characterized by cognitive decline affecting daily functioning. To manage this socio-economic challenge, several non-pharmacolog- ical methods such as physical, cognitive, and com- bined training are proposed. Although there is an important interest in this subject, the literature is still heterogeneous. The superiority of simultaneous train- ing compared to passive control and physical train- ing alone seems clear but very few studies compared simultaneous training to cognitive training alone. The aim of this pilot study was to investigate the effect of simultaneous exercise and cognitive training on several cognitive domains in healthy older adults, in comparison with either training alone. Thirty-five healthy older adults were randomized into one of three experimental groups: exercise training, cogni- tive training, and simultaneous exercise and cognitive training. The protocol involved two 30-min sessions per week for 24 weeks. Cognitive performance in several domains, pre-frontal cortex oxygenation, and baroreflex sensitivity were assessed before and after the intervention. All groups improved executive per- formance, including flexibility or working memory. We found a group by time interaction for inhibition cost (F(2,28) = 6.44; p < 0.01) and baroreflex sensitivity during controlled breathing (F(2,25)=4.22; p=0.01), the magnitude of improvement of each variable being associated (r=-0.39; p=0.03). We also found a decrease in left and right pre-frontal cortex oxygena- tion in all groups during the trail making test B. A simultaneous exercise and cognitive training are more efficient than either training alone to improve execu- tive function and baroreflex sensitivity. The results of this study may have important clinical repercussions by allowing to optimize the interventions designed to maintain the physical and cognitive health of older adults.
... According to a study, as compared to their wild-type littermates' hippocampi, Nrf2 deletion mice were more vulnerable to the inflammation caused by lipopolysaccharide (LPS), which was shown to increase microglial cells and the inflammatory markers iNOS, IL-6 and TNF-α [62]. The increase in peripheral IGF-1 that flows into the brain after exercise may also activate Nrf2 [63,64]. Rojo et al. recently demonstrated that Nrf2-deficient animals displayed increased astrogliosis and microgliosis [65]. ...
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Neuropathologies, such as neuroinflammaging, have arisen as a serious concern for preserving the quality of life due to the global increase in neurodegenerative illnesses. Nowadays, neuronutraceuticals have gained remarkable attention. It is necessary to investigate the bioavailability, off-target effects, and mechanism of action of neuronutraceuticals. To comprehend the comprehensive impact on brain health, well-designed randomized controlled trials testing combinations of neuronutraceuticals are also necessary. Although there is a translational gap between basic and clinical research, the present knowledge of the molecular perspectives of neuroinflammaging and neuronutraceuticals may be able to slow down brain aging and to enhance cognitive performance. The present review also highlights the key emergent issues, such as regulatory and scientific concerns of neuronutraceuticals, including bioavailability, formulation, blood–brain permeability, safety, and efficacy.
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Hydrogen sulfide (H 2 S) is one of the three known gas signal transducers, and since its potential physiological role was reported, the literature on H 2 S has been increasing. H 2 S is involved in processes such as vasodilation, neurotransmission, angiogenesis, inflammation, and the prevention of ischemia-reperfusion injury, and its mechanism remains to be further studied. At present, the role of post-translational processing of proteins has been considered as a possible mechanism for the involvement of H 2 S in a variety of physiological processes. Current studies have shown that H 2 S is involved in S-sulfhydration, phosphorylation, and S-nitrosylation of proteins, etc. This paper focuses on the effects of protein modification involving H 2 S on physiological and pathological processes, looking forward to providing guidance for subsequent research.
Purpose To compare the effects of yoga, aerobic exercise, and usual care on anxiety and depressive symptoms in non-treatment seeking adults with AUD. Method Parallel, three-group, open-label randomized (1:1:1) controlled trial with blinded follow-up assessment. Non-treatment seeking adults (aged 18–75 years) were recruited via advertisements in a free newspaper in Stockholm, Sweden. All participants had clinician-diagnosed AUD prior to randomization. This trial excluded those who were physically active, or for whom supervised physical activity was contraindicated. Participants were randomly assigned to 12-weeks of aerobic exercise, yoga, or usual care (telephone counselling). The secondary outcome of interest was the Hospital Anxiety and Depression Scale (HADS), assessed at baseline and 12-week follow-up. Primary analyses consisted of linear regression models and followed intention-to-treat (ITT) principals. Results In total, 140 participants (mean age 53.7 years, SD=11.8) were recruited. Follow-up was completed for 42/45 participants randomized to TAU, 42/49 to aerobic exercise and 43/46 to yoga. ITT analyses included 126 trial participants. There were statistically significant within-group improvements in total HADS in all three intervention groups. Effect sizes for usual care and aerobic exercise were small (Hedges’ g=0.48, 95% CI=0.16, 0.80 and g=0.41, 95% CI=0.09, 0.72, respectively), while yoga was associated with a large treatment effect (g=1.06, 95% CI=0.69, 1.43). There were significant between-group differences in these improvements favouring yoga (B=-2.15, 95% CI=-4.16, -0.15, p=.035) relative to usual care, but no significant differences between yoga and aerobic exercise. No injuries were reported. Conclusions Findings support the recommendation of yoga for non-treatment seeking adults with AUD.
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Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
Previous studies assessing protective effects of physical activity on depression have had conflicting results; one recent study argued that excluding disabled subjects attenuated any observed effects. The authors' objective was to compare the effects of higher levels of physical activity on prevalent and incident depression with and without exclusion of disabled subjects. Participants were 1,947 community-dwelling adults from the Alameda County Study aged 50-94 years at baseline in 1994 with 5 years of follow-up. Depression was measured using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Washington, DC: American Psychiatric Association, 1994). Physical activity was measured with an eight-point scale; odds ratios are based upon a one-point increase on the scale. Even with adjustments for age, sex, ethnicity, financial strain, chronic conditions, disability, body mass index, alcohol consumption, smoking, and social relations, greater physical activity was protective for both prevalent depression (adjusted odds ratio (OR) = 0.90, 95% confidence interval (Cl): 0.79, 1.01) and incident depression (adjusted OR = 0.83, 95% Cl: 0.73, 0.96) over 5 years. Exclusion of disabled subjects did not attenuate the incidence results (adjusted OR = 0.79, 95% Cl: 0.67, 0.92). Findings support the protective effects of physical activity on depression for older adults and argue against excluding disabled subjects from similar studies.
Research studies clearly indicate that age-related changes in cellular and tissue function are linked to decreases in the anabolic hormones, growth hormone and insulin-like growth factor (IGF)-1. Although there has been extensive research on the effects of these hormones on bone and muscle mass, their effect on cerebrovascular and brain ageing has received little attention. We have also observed that in response to moderate calorie restriction (a treatment that increases mean and maximal lifespan by 30–40%), age-related decreases in growth hormone secretion are ameliorated (despite a decline in plasma levels of IGF-1) suggesting that some of the effects of calorie restriction are mediated by modifying the regulation of the growth hormone/IGF-1 axis. Recently, we have observed that microvascular density on the surface of the brain decreases with age and that these vascular changes are ameliorated by moderate calorie restriction. Analysis of cerebral blood flow paralleled the changes in vasculature in both groups. Administration of growth hormone for 28 d was also found to increase microvascular density in aged animals and further analysis indicated that the cerebral vasculature is an important paracrine source of IGF-1 for the brain. In subsequent studies, administration of GHRH (to increase endogenous release of growth hormone) or direct administration of IGF-1 was shown to reverse the age-related decline in spatial working and reference memory. Similarly, antagonism of IGF-1 action in the brains of young animals impaired both learning and reference memory. Investigation of the mechanisms of action of IGF-1 suggested that this hormone regulates age-related alterations in NMDA receptor subtypes (e.g. NMDAR2A and R2B). The beneficial role of growth hormone and IGF-1 in ameliorating vascular and brain ageing are counterbalanced by their well-recognised roles in age-related pathogenesis. Although research in this area is still evolving, our results suggest that decreases in growth hormone and IGF-1 with age have both beneficial and deleterious effects. Furthermore, part of the actions of moderate calorie restriction on tissue function and lifespan may be mediated through alterations in the growth hormone/IGF-1 axis.
Cited By (since 1996): 24, Export Date: 23 March 2012, Source: Scopus, CODEN: GHIRF, doi: 10.1016/j.ghir.2006.11.001, PubMed ID: 17208483, Language of Original Document: English, Correspondence Address: Landi, F.; Department of Gerontology and Geriatrics, Catholic University of Sacred Heart, 00168 Roma, Italy; email:, Chemicals/CAS: growth hormone, 36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6; somatomedin C, 67763-96-6; IGFBP3 protein, human; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I, 67763-96-6, References: Fratiglioni, L., De Ronchi, D., Aguero-Torres, H., Worldwide prevalence and incidence of dementia (1999) Drug. Aging, 15, pp. 365-375;