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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.
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472 Review TRENDS in Neurosciences Vol.30 No.9
... Individuals that exercised regularly for 28 days exhibited reduced plasma homocysteine levels and increased endothelial progenitor cells in peripheral blood, factors that protect against vascular damage and cognitive impairment (Choi, Moon et al. 2014). Exercise-induced structural and functional changes have been well documented in various brain regions but have been best studied in the hippocampus (Cotman, Berchtold et al. 2007). ...
... Healthy microglia survey the brain environment and phagocytize Aß; prolonged activation of microglia leads to neuroinflammation resulting in Aß accumulation and continued recruitment of additional microglia and peripheral immune cells leading to cytotoxicity (Kloske and Wilcock 2020). Cotman et al provides evidence that exercise modulates inflammation based interferences in growth factor signaling thereby reducing inflammation (Cotman, Berchtold et al. 2007). ...
... An emerging fundamental concept is that brain health and cognitive function are modulated by the interplay of various central and peripheral factors (Cotman, Berchtold et al. 2007). As indicated here prior, brain function is compromised by the presence of peripheral risk factors, a group of disorders generalized and conceptualized as "metabolic syndrome" (Yaffe 2007). ...
Alzheimer’s disease (AD) is a neurodegenerative disorder with insidious onset and slow progression. AD research has traditionally been based on neuronal and glial dysfunction due to hallmark beta-amyloid and tau pathologies. Although literature supports an association between AD and cardiovascular disease and/or cardiovascular risk factors, vascular dysfunction as an etiology of AD has been overlooked. Cardiovascular risk factors have been associated with both cardiovascular and cerebrovascular disease in midlife individuals, an age at which modifiable risk factor management may be the most beneficial. Up to half of AD cases worldwide and in the USA are attributable to modifiable risk factors. Until recently, despite years of research, treatments for AD have been purely symptomatic. Given the absence of disease-modifying treatments, as well as evidence supporting AD pathological changes occur decades prior to clinical onset of symptoms, non-pharmacological intervention approaches, such as exercise, have the potential improve or mitigate AD pathology and symptoms. One proposed mechanism of exercise benefits is the reduction of peripheral vascular risk factors. This risk factor reduction is due to exercise induced increases in circulating growth factors that either directly or indirectly mediate neurogenesis and angiogenesis and reduce systemic inflammation. Health care providers often fail to diagnose AD in early stages therefore current and future AD researcher should be based on the 2018 NIA-AA Research Framework, a diagnostic framework in which AD onset can be detected based on biological changes in the brain and body prior to clinical onset of symptoms. This framework is based on widely used and validated biomarkers. Although highly accurate and reliably predictive, the current AD biomarkers are invasive, expensive, and not practical for early detection and/or longitudinal assessment. Disease altered protein expression in the peripheral blood can be measured via a simple venipuncture; identifying blood-based biomarkers of cognitive decline and determining whether they can be modified by exercise could provide mechanistic insight into a potential AD intervention. This study provides a unique opportunity to determine whether exercise can modify blood based general health markers and peripheral growth factor concentrations in midlife humanized, APOE4 mice and midlife community participants. Animal studies allowed us the ability to produce equal numbers of APOE genotypes compared to that of community participants where the limitations of human studies prevented matched sample sizes however overall, using serum collected from each group and high throughput analytic assays, we see published growth factor increases and similar mouse to human trends with regards general health markers and growth factor increases as a result of exercise.
... Over a dozen influential reviews (Cotman et al., 2007;Hillman et al., 2008;Hötting & Röder 2013;Voss et al., 2013;Prakash et al., 2015;Basso & Suzuki 2017;Alkadhi 2018;Stimpson et al., 2018;Vecchio et al., 2018;Voss et al., 2019;Stillman et al., 2020;Valenzuela et al., 2020;Walsh et al., 2020;Bliss et al., 2021;Hashimoto et al., 2021;Townsend et al., 2021;Arida & Teixeira-Machado 2022;Sujkowski et al., 2022) and several popular books (Ratey 2008;Chen 2017a,b) have been published to illustrate the neurobiological mechanisms of the cognitive benefits of physical activity. To our knowledge, however, none of them have linked the neurobiological mechanisms to normal exercise physiology to help the readers gain a more advanced, comprehensive understanding of the phenomenon. ...
... The growth factor cascade has been the most well-studied mechanism that mediates the physical activity benefits on brain plasticity (Cotman et al., 2007;Hötting & Röder 2013;Voss et al., 2013;Stimpson et al., 2018). Physical activity increases the release of growth factors including BDNF, IGF-1, and VEGF in the peripherals into the blood, which can then pass the brain-blood barrier (BBB) and enter the brain (Poduslo & Curran 1996;Pan et al., 1998). ...
Full-text available
Physical activity is one of the modifiable factors of cognitive decline and dementia with the strongest evidence. Although many influential reviews have illustrated the neurobiological mechanisms of the cognitive benefits of physical activity, none of them have linked the neurobiological mechanisms to normal exercise physiology to help the readers gain a more advanced, comprehensive understanding of the phenomenon. In this review, we address this issue and provide a synthesis of the literature by focusing on five most studied neurobiological mechanisms. We show that the body's adaptations to enhance exercise performance also benefit the brain and contribute to improved cognition. Specifically, these adaptations include, 1), the release of growth factors that are essential for the development and growth of neurons and for neurogenesis and angiogenesis, 2), the production of lactate that provides energy to the brain and is involved in the synthesis of glutamate and the maintenance of long-term potentiation, 3), the release of anti-inflammatory cytokines that reduce neuroinflammation, 4), the increase in mitochondrial biogenesis and antioxidant enzyme activity that reduce oxidative stress, and 5), the release of neurotransmitters such as dopamine and 5-HT that regulate neurogenesis and modulate cognition. We also discussed several issues relevant for prescribing physical activity, including what intensity and mode of physical activity brings the most cognitive benefits, based on their influence on the above five neurobiological mechanisms. We hope this review helps readers gain a general understanding of the state-of-the-art knowledge on the neurobiological mechanisms of the cognitive benefits of physical activity and guide them in designing new studies to further advance the field.
... A recent review has summarized the multiple pathways mediated by inflammatory cytokines that might modulate cognition, synaptic plasticity and neurogenesis (Bourgognon and Cavanagh, 2020). Of interest, Bourgognon and Cavanagh (2020) reported that a chronic neuroinflammatory state may impair synaptic plasticity, synaptogenesis and neurogenesis by the disturbing effect of proinflammatory cytokines on neurotrophic growth factor signaling ( Fig. 1) (Cotman et al., 2007;Bourgognon and Cavanagh, 2020). Interestingly, Bourgognon and Cavanagh (2020) describe that the effect is dependent of the intensity and duration of the inflammatory activity. ...
... Our systematic review included some preliminary evidence that also in people with SCI, neurotrophic factors are induced by acute or chronic exercise interventions (Rojas Vega et al., 2008;Zeller et al., 2015;Han et al., 2016;Leech and Hornby, 2017;Goldhardt et al., 2019;Nishimura et al., 2022). In addition, exercise induced several pathways that modulate inflammation, as reviewed by others (Cotman et al., 2007). The most extensively studied pro-inflammatory marker is IL-6, which is released from muscle tissue during exercise (Pedersen, 2019). ...
Full-text available
VINTS, W.A.J, O. Levin, N. Masiulis, J. Verbunt, C.C.M. van Laake. Myokines may target accelerated cognitive aging in people with spinal cord injury: a systematic and topical review. NEUROSCI BIOBEHAV REV X(X) XXX-XXX, 2022. - Persons with spinal cord injury (SCI) can suffer accelerated cognitive aging, even when correcting for mood and concomitant traumatic brain injury. Studies in healthy older adults have shown that myokines (i.e. factors released from muscle tissue during exercise) may improve brain health and cognitive function. Myokines may target chronic neuroinflammation, which is considered part of the mechanism of cognitive decline both in healthy older adults and SCI. An empty systematic review, registered in PROSPERO (CRD42022335873), was conducted as proof of the lack of current research on this topic in people with SCI. Pubmed, Embase, Cochrane and Web of Science were searched, resulting in 387 articles. None were considered eligible for full text screening. Hence, the effect of myokines on cognitive function following SCI warrants further investigation. An in-depth narrative review on the mechanism of SCI-related cognitive aging and the myokine-cognition link was added to substantiate our hypothetical framework. Readers are fully updated on the potential role of exercise as a treatment strategy against cognitive aging in persons with SCI.
... During mature neurogenesis, growth factors influence the proliferation, differentiation and survival of newly formed cells. The effects of growth factors are complementary, but the outcome of exercise on learning is mainly regulated by IGF-1 and BDNF, while exercise-dependent stimulation of angiogenesis and neurogenesis appears to be regulated by IGF-1 and VEGF [44]. Particularly interesting are the results of the latest studies which shown that positive effect of physical activity on the central nervous system may arise from the influence on secretion of glycosylphosphatidylinositol -specific phospholipase D (Gpld-1) released from the liver under the influence of physical exercise. ...
Full-text available
Background and Study Aim. The results of many research indicate that systematic physical activity has also positive effect on functions of the central nervous system. For example, improvement of the cognitive functions level, such as memory and learning, under the influence of systematic physical training has been demonstrated. The positive effect of physical activity on the central nervous system is especially visible and widely described with regard to elderly people, who develop many adverse remodeling changes in the structure of the brain. However, particularly interesting are the studies which show that also among young people a positive effect of physical activity on cognitive processes is observed. Currently, several hypotheses are proposed, presenting potential mechanisms underlying the beneficial effects of physical activity on the central nervous system. The first hypothesis assumes the beneficial effect of physical activity on the expression of hippocampal genes related to synaptic plasticity. The second hypothesis assumes that physical effort per se is an inducer of the secretion of the growth factors (e.g., BDNF, IGF-1), which have a trophic effect on the nervous system. In addition, the results of the latest scientific studies indicate that the positive effect of physical activity on the central nervous system may be due to the action of phospholipase (Gpld-1), released to the bloodstream from the liver under the influence of physical exercise. This work indicates that due to the influence on cognitive functions, physical activity is absolutely essential to both elderly and young people population. Conclusions. It seems necessary to educate both young and elderly people that the proper level of physical activity is a key factor allowing to maintain both physical and mental health at an appropriate, desirable level.
... Studies have shown that exercise-induced neurotransmitter release and elevated neurotrophic factor activity contribute to neuroplasticity (87) and normal cortical activity (88). Glial cell-derived neurotrophic factor (GDNF), 5-HT, and vascular endothelial growth factor production are important not only for neurogenesis but also for neuronal maintenance and prevention of psychological disorders (89). These neurotrophic factors are induced by muscle contraction, causing changes that promote the formation of a more plastic and adaptive brain and enable the maintenance of the brain structure and function. ...
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Internet addiction (IA) has become an impulse control disorder included in the category of psychiatric disorders. The IA trend significantly increased after the outbreak of the new crown epidemic. IA damages some brain functions in humans. Emerging evidence suggests that exercise exerts beneficial effects on the brain function and cognitive level damaged by IA. This work reviews the neurobiological mechanisms of IA and describes the brain function impairment by IA from three systems: reward, execution, and decision-making. Furthermore, we sort out the research related to exercise intervention on IA and its effect on improving brain function. The internal and external factors that produce IA must be considered when summarizing movement interventions from a behavioral perspective. We can design exercise prescriptions based on exercise interests and achieve the goal of quitting IA. This work explores the possible mechanisms of exercise to improve IA through systematic analysis. Furthermore, this work provides research directions for the future targeted design of exercise prescriptions.
... The positive effects of physical activity/exercise on academic achievement (Alvarez-Bueno et al., 2017) have been speculated to stem from effects in cognitive functions, specifically attention/inhibition (Becker et al., 2014;Hillman et al., 2009). Physical exercise generates metabolic changes in the body that have been suggested to give rise to long-term modifications in the brain, both functionally and structurally (Cotman et al., 2007). ...
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Abstract Top-down attentional control seems to increase and suppress the activity of sensory cortices for relevant stimuli and to suppress activity for irrelevant ones. Higher physical activity (PA) and aerobic fitness (AF) levels have been associated with improved attention, but most studies have focused on unimodal tasks (e.g., visual stimuli only). The impact of higher PA or AF levels on the ability of developing brains to focus on certain stimuli while ignoring distractions remains unknown. The aim of this study was to examine the neural processes in visual and auditory sensory cortices during a cross-modal attention-allocation task using magnetoencephalography in 13-16-year-old adolescents (n = 51). During continuous and simultaneous visual (15 Hz) and auditory (40 Hz) noise-tagging stimulation, participants attended to either visual or auditory targets appearing on their left or right sides. High and low PA groups were formed based on seven-day accelerometer measurements, and high and low AF groups were determined based on the 20-m shuttle-run test. Steady-state (evoked) responses to the visual stimulus were observed in all the adolescents in the primary visual cortex, but some did not show responses in the primary auditory cortices to the auditory stimulus. The adolescents with auditory-tag-driven signals in the left temporal cortex were older than those who did not show responses. Visual cortices showed enhanced visual-tag-related activity with attention, but there was no cross-modal effect, perhaps due to the developmental effect observed in the temporal areas. The visual-tag-related responses in the occipital cortex were enhanced in the higher-PA group, irrespective of task demands. In summary, sensory cortices are unequally involved in cross-modal attention in the adolescent brain. This involvement seems to be enhanced by attention. Higher PA seems to be associated with a specific visual engagement benefit in the adolescent brain.
... First, four respondents belonged to Type 1: a powerful means of enhancing lesson concentration and academic performance. Cotman et al. [30] argued that exercise helps form neural networks that smoothly supply blood and nutrients to the brain and connect brain neurons. In particular, it can be explained that cognitive ability was improved by increasing the Brain Derived Neurological Factor (BDNF). ...
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The aim of this study is to explore the subjective perception types and characteristics of Korean middle school students regarding participation in the “0th period physical education class”, a class involving physical movement that takes place before the start of regular school classes in the morning. This goal was achieved by applying the Q methodology, which can categorize the subjective viewpoints of research participants. The selection of the final 25 Q-samples was done by composing the Q-population. Twenty middle school students were selected as the P-sample, and Q-sorting was performed on them. The PQ method program (version 2.35) was used to perform centroid factor analysis and varimax rotation. The study presented five types with a total variance of 87%. Types 1 to 5 (N = 4, 4, 4, 5, and 3) pertained to a potent means of enhancing lesson concentration and academic performance, efficient activities to improve physical ability and a healthy body image in adolescence, the motivating power behind a stable school life and sociability development, building an upright character and successful changes in daily life, and raising awareness of the importance of participating in sports and the importance of physical activity, with eigenvalues (EVs) of 3.89, 4.48, 3.96, 5.16, and 2.58, respectively, and explanatory variances of 0.10, 0.22, 0.13, 0.33, and 0.09, respectively. Moreover, consensus statements for each factor were demonstrated as being Q24 and Q25. The findings in this study supported the academic foundation for the official introduction and activation of “0th period physical education classes” in the Korean education community for the near future.
... Human and animal experimental studies suggest that the mechanisms underlying PA-induced improvements in cognitive function, including executive function, could be the upregulation of BDNF, IGF-1, and VEGF (Cotman et al., 2007;Soya et al., 2007), upregulation of neurogenesis (Inoue et al., 2015), increases in brain volume (Erickson et al., 2014) and functional connectivity (Voss et al., 2010), and increases in antiinflammatory effects (Di Benedetto et al., 2017). On the other hand, a previous study suggested that social participation (Kelly et al., 2017), mainly included in LPA, is associated with better executive function. ...
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Objective Previous studies have suggested a positive association between physical activity (PA) and executive function in older adults. However, they did not adequately consider the compositional nature of daily time use and accumulated PA patterns. Therefore, this study aimed to examine the association between intensity or accumulated PA patterns and executive functions (inhibitory control, working memory, and cognitive flexibility) in community-dwelling older adults, considering the interaction of daily time spent in PA, sedentary behavior (SB), and sleep. Method This cross-sectional study used baseline data from a randomized controlled trial on the effect of exercise on cognitive function conducted between 2021 and 2022. Data from 76 community-dwelling older adults were used in the analysis. The time spent in PA and SB was assessed using an accelerometer, and sleep duration was self-reported. The Stroop task (inhibitory control), N-back task (working memory), and task-switching task (cognitive flexibility) were conducted to evaluate the subcomponents of executive function. Considering various potential confounders, compositional multiple linear regression analysis and compositional isotemporal substitution were performed to examine the association of PA with executive function and to estimate predicted changes in executive function in response to the hypothetical time-reallocation of movement behaviors, respectively. Results A longer time spent in light-intensity PA (LPA), relative to remaining behaviors, was associated with better Stroop task performance. Moreover, this association was stronger in LPA lasting longer than 10 min than in sporadic LPA. Additionally, theoretical 30 min/day time reallocation from SB or sleep to LPA was associated with better Stroop task performance (corresponding to approximately a 5%−10% increase). On the other hand, no significant associations of time spent in moderate- to vigorous-intensity PA with any subcomponents of executive function were observed. Conclusion LPA was positively associated with inhibitory control, and this association was stronger in bouts of LPA than in sporadic LPA. Moreover, reducing the time spent in SB or sleep and increasing the time spent in LPA, especially long-bout LPA, could be important measures for managing inhibitory control in late life. Future large longitudinal and intervention studies are needed to confirm these associations and reveal the causality and underlying mechanisms.
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Adaptive neuroplasticity is a pivotal mechanism for healthy brain development and maintenance, as well as its restoration in disease- and age-associated decline. Management of mental disorders such as attention deficit hyperactivity disorder (ADHD) needs interventions stimulating adaptive neuroplasticity, beyond conventional psychopharmacological treatments. Physical exercises are proposed for the management of ADHD, and also depression and aging because of evoked brain neuroplasticity. Recent progress in understanding the mechanisms of muscle-brain cross-talk pinpoints the role of the myokine irisin in the mediation of pro-cognitive and antidepressant activity of physical exercises. In this review, we discuss how irisin, which is released in the periphery as well as derived from brain cells, may interact with the mechanisms of cellular autophagy to provide protein recycling and regulation of brain-derived neurotrophic factor (BDNF) signaling via glia-mediated control of BDNF maturation, and, therefore, support neuroplasticity. We propose that the neuroplasticity associated with physical exercises is mediated in part by irisin-triggered autophagy. Since the recent findings give objectives to consider autophagy-stimulating intervention as a prerequisite for successful therapy of psychiatric disorders, irisin appears as a prototypic molecule that can activate autophagy with therapeutic goals.
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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;