Sedentary aging is associated with a longitudinal decline
in cerebral blood ﬂow (CBF)1,2 and cerebrovascular reac-
tivity to carbon dioxide (CVRCO2),2 impairments that increase
the risk of cognitive decline, dementia,3 and stroke4 in either
healthy or diseased populations. Given that curative treat-
ments are currently unavailable, major efforts have focused on
prevention including modiﬁable risk factors such as physical
In support, emerging evidence suggests that regular aerobic
exercise and the corresponding improvements in cardiorespi-
ratory ﬁtness conﬁrmed by an elevation in maximal oxygen
O2MAX) can increase CBF across the human adult
lifespan.1 From a clinical perspective, moderate to high lev-
els of cardiorespiratory ﬁtness are associated with a markedly
lower risk of stroke mortality5 and improved cognition,6 fur-
ther conﬁrming the neuroprotective beneﬁts of physical activ-
ity though the underlying mechanisms remain unknown.
However, to what extent lifelong physical activity impacts
CVRCO2 remains to be established despite short-term improve-
ments that have been observed after 3 to 6 months of exercise
training in healthy adults7 and stroke survivors.8 To address this
and extend earlier work,1 we compared both CBF and CVRCO2
across the extremes of aging and physical activity in a select
sample of healthy males to conﬁrm whether these hemody-
namic indices are indeed positively associated with
Materials and Methods
After ethical approval and written informed consent, we recruited
both young (aged ≤30 years) and old (≥60 years) males who accord-
ing to self-report lifetime physical activity levels9 were either trained
(≥150 minutes of moderate to vigorous intensity recreational aero-
bic activity/week sustained during the adult lifespan consistent with
Background and Purpose—Age-related impairments in cerebral blood ﬂow and cerebrovascular reactivity to carbon dioxide
(CVRCO2) are established risk factors for stroke that respond favorably to aerobic training. The present study examined to
what extent cerebral hemodynamics are improved when training is sustained throughout the adult lifespan.
Methods—Eighty-one healthy males were prospectively assigned to 1 of 4 groups based on their age (young, ≤30 years
versus old, ≥60 years) and lifetime physical activity levels (trained, ≥150 minutes recreational aerobic activity/week versus
sedentary, no activity). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound), mean arterial
pressure (MAP, ﬁnger photoplethysmography), and end-tidal partial pressure of carbon dioxide (PETCO2, capnography) were
recorded during normocapnia and 3 mins of iso-oxic hypercapnea (5% CO2). Cerebrovascular resistance/conductance
indices (CVRi/CVCi) were calculated as MAP/MCAv and MCAv/MAP, respectively, and CVRCO2 as the percentage
increase in MCAv from baseline per millimeter of mercury (mm Hg) increase in PETCO2. Maximal oxygen consumption
O2MAX, online respiratory gas analysis) was determined during cycling ergometry.
Results—By design, older participants were active for longer (49±5 versus 6±4 years, P<0.05). Physical activity attenuated
the age-related declines in
O2MAX, MCAv, CVCi, and CVRCO2 and increase in CVRi (P<0.05 versus sedentary). Linear
relationships were observed between
O2MAX and both MCAv and CVRCO2 (r=0.58–0.77, P<0.05).
Conclusions—These ﬁndings highlight the importance of maintaining aerobic ﬁtness throughout the lifespan given its
capacity to improve cerebral hemodynamics in later-life. (Stroke. 2013;44:3235-3238.)
Key Words: aerobic exercise ◼ aging ◼ cerebrovascular circulation ◼ perfusion ◼ stroke
Elevated Aerobic Fitness Sustained Throughout
the Adult Lifespan Is Associated With Improved
Damian M. Bailey, PhD, FPVRI, FRSC, FACSM*; Christopher J. Marley, MPhil*;
Julien V. Brugniaux, PhD; Danielle Hodson, MPhil; Karl J. New, PhD; Shigehiko Ogoh, PhD;
Philip N. Ainslie, PhD*
Received June 21, 2013; accepted July 15, 2013.
From the Neurovascular Research Laboratory, University of South Wales, UK (D.M.B., C.J.M., J.V.B., D.H., K.J.N.); the Department of Biomedical
Engineering, Toyo University, Kawagoe-Shi, Saitama, Japan (S.O.); and the School of Health and Exercise Sciences, University of British Columbia
Okanagan, Kelowna, Canada (P.N.A.).
*Dr Bailey, C.J. Marley, and Dr Ainslie contributed equally.
Correspondence to Damian M. Bailey, PhD, FPVRI, FRSC, FACSM, Neurovascular Research Laboratory, University of South Wales, UK CF37 4AT.
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.002589
3236 Stroke November 2013
current recommendations)10 or sedentary (no formal recreational ac-
tivity outside of everyday living). We speciﬁcally chose to exclude fe-
males given our inability to control for differences in estrogen levels
(during the menstrual cycle, menopause, and hormone replacement
therapy), which has been shown to cause intracranial vasodilatation
and increase CBF.11
All potential participants were subject to a detailed clinical examina-
tion that included a 12-lead ECG. They were included if they were
nonsmokers, nonobese (body mass index <30 kg/m2), and free of
any cardiovascular (eg, type 2 diabetes mellitus, coagulopathy, hy-
pertension), cerebrovascular (eg, stroke, transient ischemic attack,
migraine), or respiratory (eg, asthma, chronic obstructive pulmonary
disorder) diseases. Participants were also screened for any psychiat-
ric or neurological disorders, including dementia and depression and
were not prescribed any medications.
Eighty-one males were considered eligible for the study. They were
prospectively assigned to 1 of 4 groups based on their age and
physical activity levels and included the following: young sedentary
(n=19), young trained (n=20), old sedentary (n=19), and old trained
(n=23). Every attempt was made to match the trained groups for
(weekly) exercise duration, frequency, and intensity.
Cerebral Hemodynamics: CBF, MAP, and CVRCO2
The middle cerebral artery (MCA) was insonated using 2 MHz pulsed
transcranial Doppler ultrasound (Multi-Dop X4, DWL Elektroniche
Systeme GmbH, Sipplingen, Germany) and mean arterial pressure
(MAP) determined by ﬁnger photoplethysmography (Finometer
PRO, Finapres Medical Systems, Amsterdam, The Netherlands).
Data were sampled continuously at 1 kHz and stored for off-line
analysis. Cerebrovascular resistance and conductance indices (CVRi
and CVCi) were calculated as MAP/MCAv and MCAv/MAP respec-
tively. CVRCO2 was calculated as the percentage increase in MCAv
from baseline per mm Hg increase in PETCO2 determined by capnog-
raphy (ML 206, ADInstruments Ltd, Oxford, UK) in response to 3
minutes breathing 5% CO2 (balanced air).
Maximal oxygen consumption (
O2 MAX) was determined during an
incremental cycling test to volitional exhaustion. Expired gas frac-
tions were determined online (MedGraphics, Ultima Series) and
O2MAX conﬁrmed according to established criteria.2
After conﬁrmation of distribution normality using Shapiro–Wilk
W tests, between group differences were analyzed using a 2-way
(age, young versus old × status, sedentary versus trained) facto-
rial analysis of variance (ANOVA). After an interaction effect, dif-
ferences were located using a 1-way ANOVA and post hoc Tukey
tests. Relationships were determined using Pearson Product Moment
Correlations. Signiﬁcance was established at P<0.05 and data ex-
pressed as mean±SD.
By design, old participants were physically active for longer than
the young (49±5 versus 6±4 years, P<0.05). Aging was associ-
ated with a lower
O2MAX, MCAv, CVCi, and CVRCO2 and eleva-
tions in body mass index and CVRi, whereas MAP remained
unchanged (Table). Physical activity was associated with an
O2MAX and corresponding improvement in cere-
bral hemodynamics. Indeed, positive linear relationships were
O2MAX and both MCAv and CVRCO2 (pooled
sedentary and trained data sets) in both young and old partici-
pants (Figure, A–D). Furthermore, at an approximate average
MCAv of 50 cm/s and CVRCO2 of 2%/mm Hg, the difference
between trained and sedentary participants equated to ≈11- and
18-year reduction, respectively in the brain’s hemodynamic age.
In contrast, physical activity did not alter the age-related rate of
decline in MCAv (sedentary, –0.3 cm/s/year versus trained, –0.4
cm/s/year; P>0.05) or CVRCO2 (sedentary, –0.02%/mm Hg/year
versus trained, –0.02%/mm Hg/year; P>0.05).
The major ﬁnding of the present study is that elevated car-
diorespiratory ﬁtness was shown to attenuate the age-related
decline in cerebrovascular hemodynamics given its associa-
tion with improved cerebral perfusion and CO2 vasoreactiv-
ity. This highlights the neuroprotective beneﬁts of active
living given its capacity to improve cerebral hemodynamics
throughout the adult lifespan.
To our knowledge, this is the ﬁrst cross-sectional study to
assess the association between aerobic ﬁtness and both MCAv
and CVRCO2 across the extremes of healthy human aging. Our
ﬁndings conﬁrm the age-related decline in MCAv originally
documented by Ainslie et al1 and corresponding increase
incurred through regular exercise training. Indeed, when com-
paring the two extremes of chronological age, physical activity
was shown to reduce the brain’s hemodynamic age by more
than a decade, which is in agreement with previous estimates.1
Our study extends these original works by further document-
ing exercise-induced improvements in CVRCO2, which seemed
to be even more marked with physical activity conferring ≈18-
year reduction in the brain’s functional age. These ﬁndings are
in agreement with another transcranial Doppler–based study,2
though in conﬂict with recent MRI-based studies focused on
regional as opposed to global cerebral perfusion that have
used alternative hypercapneic challenges.12,13 Furthermore, the
consistent relationships observed between
O2MAX and both
MCAv and CVRCO2 conﬁrm that the beneﬁts of aerobic exer-
cise are not simply conﬁned to the cardiovascular circulation
but can equally extend to the cerebrovasculature. This was
clearly evident in later-life, indicating that the human brain
retains a life-long capacity for exercise adaptation further jus-
tifying exercise prescription in the elderly.
The present ﬁndings need to be interpreted with a degree
of caution given some experimental limitations. A cross-
sectional design cannot establish causality and also relies on
self-report approaches when recalling lifelong participation
in physical activity.14 However, we sought to minimize this
potential confound through the combined use of a validated
physical activity questionnaire9 and direct measurement of
cardiorespiratory ﬁtness. Furthermore, we did not explore the
molecular mechanisms underlying enhanced neuroplasticity
such as exercise-induced increases in the vascular bioavail-
ability of nitric oxide, brain-derived neurotrophic factor, and
insulin-like growth factor.1,3,7 Likewise, it remains unclear
whether these hemodynamic adaptations would have trans-
lated into improved cognitive function and stroke risk in later-
life as previously suggested,3,5 which would have placed our
ﬁndings into clearer clinical context.
Bailey et al Active Living and Brain Health 3237
Rigorous inclusion criteria meant that we were only able to
recruit relatively small sample sizes into each group. However,
retrospective power analysis revealed that we were adequately
powered to detect main effects with values exceeding 0.90 for
all dependent variables examined. Furthermore, given that
our study was exclusively restricted to males, it would be of
future interest to determine whether physical activity has an
equivalent impact on females given the known sex differences
in baseline cerebral hemodynamics11 to make our ﬁndings
more applicable to the general population. Finally, we relied
on transcranial Doppler measurements of blood ﬂow veloc-
ity as an indirect surrogate of global CBF, a limitation that is
well established though MCAv is considered a reliable indica-
tor of cerebral perfusion both at rest and when assessing the
dynamic response to hypercapnia.15
In conclusion, the present ﬁndings highlight the importance
of being physically active and maintaining aerobic ﬁtness
throughout the lifespan given the improvements observed in
cerebrovascular hemodynamics. Larger-scale, longer-term,
mixed-sex, interventional studies are warranted to conﬁrm
Table. Participant Demographics
Age Young Old P Values
Activity Sedentary (n=19) Trained (n=20) Sedentary (n=19) Trained (n=23) Age Activity Interaction
Age, y 25±5 23±4 68±5 67±5 0.00* 0.19 0.76
BMI, kg·m-2 26.2±2.9 23.9±2.7 27.5±2.3 25.6±2.8 0.02* 0.00* 0.76
O2MAX, L·min-1 3.05±0.52 4.75±0.73* 1.77±0.25† 2.77±0.45*† 0.00* 0.00* 0.00*
•O2MAX, mL·kg-1·min-1 36±5 62±9* 24±4† 39±6*† 0.00* 0.00* 0.00*
MCAv, cm·s-1 52±11 64±13 37±8 46±11 0.00* 0.00* 0.44
MAP, mm Hg 89±11 85±6 89±7 88±7 0.42 0.16 0.51
CVRi, mm Hg·cm-1·s-1 1.77±0.43 1.38±0.33 2.45±0.46 2.02±0.56 0.00* 0.00* 0.86
CVCi (cm·s-1·mm Hg-1) 0.60±0.16 0.76±0.19 0.42±0.08 0.54±0.16 0.00* 0.00* 0.42
CVRCO2 (%·mm Hg-1) 2.10±0.73 3.78±0.84 1.45±0.74 2.88±1.03 0.00* 0.00* 0.51
BMI indicates body mass index; CVRi/CVCi/CVRCO2, cerebrovascular resistance/conductance indices/reactivity to carbon dioxide; MAP, mean arterial pressure; MCAv,
middle cerebral artery velocity; and V
•O2MAX, maximal oxygen uptake.
*/†Difference within/between age groups (P<0.05).
Figure. Relationships between cardiorespiratory ﬁtness and cerebrovascular hemodynamics in young (A and B) and old (C and D) adults
as a function of physical activity status. CVRCO2 indicates cerebrovascular reactivity to carbon dioxide; MCAv, middle cerebral artery
O2MAX indicates maximal oxygen uptake.
r = 0.58, P < 0.05
r = 0.67, P < 0.05
r = 0.59, P < 0.05
CVRCO2 (%.mmHg -1)
r = 0.77, P < 0.05
3238 Stroke November 2013
our ﬁndings and further explore the mechanistic bases under-
lying the neuroprotective beneﬁts of physical activity.
Sources of Funding
Funding was provided by the John Peter Rhys Williams Trust (to
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