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Grna-61-11-06 1166.1170

Journal of Gerontology: MEDICAL SCIENCES Copyright 2006 by The Gerontological Society of America 2006, Vol. 61A, No. 11, 1166–1170 Exercise: An Active Route to Healthy Aging Aerobic Exercise Training Increases Brain Volume in Aging Humans Stanley J. Colcombe,1 Kirk I. Erickson,1 Paige E. Scalf,1 Jenny S. Kim,1 Ruchika Prakash,1 Edward McAuley,2 Steriani Elavsky,2 David X. Marquez,2 Liang Hu,2 and Arthur F. Kramer1 1Beckman Institute & Department of Psychology and 2Department of Kinesiology, University of Illinois, Urbana.
Background. The present study examined whether aerobic fitness training of older humans can increase brain volume in regions associated with age-related decline in both brain structure and cognition.
Methods. Fifty-nine healthy but sedentary community-dwelling volunteers, aged 60–79 years, participated in the 6- month randomized clinical trial. Half of the older adults served in the aerobic training group, the other half of the olderadults participated in the toning and stretching control group. Twenty young adults served as controls for the magneticresonance imaging (MRI), and did not participate in the exercise intervention. High spatial resolution estimates of grayand white matter volume, derived from 3D spoiled gradient recalled acquisition MRI images, were collected before andafter the 6-month fitness intervention. Estimates of maximal oxygen uptake (VO2) were also obtained.
Results. Significant increases in brain volume, in both gray and white matter regions, were found as a function of fitness training for the older adults who participated in the aerobic fitness training but not for the older adults whoparticipated in the stretching and toning (nonaerobic) control group. As predicted, no significant changes in either gray orwhite matter volume were detected for our younger participants.
Conclusions. These results suggest that cardiovascular fitness is associated with the sparing of brain tissue in aging humans. Furthermore, these results suggest a strong biological basis for the role of aerobic fitness in maintaining andenhancing central nervous system health and cognitive functioning in older adults.
BEGINNING in the third decade of life the human brain among others (12). The end result of these structural shows structural decline, which is disproportionately changes is a better interconnected brain that is more plastic large in the frontal, parietal, and temporal lobes of the brain and adaptive to change (8,13). Given that cardiovascular (1). This decline is contemporaneously associated with exercise has similar effects on human cognitive function that deterioration in a broad array of cognitive processes (2).
might be predicted from the structural changes in nonhuman Given the projected increase in the number of adults sur- animals, it seems likely that similar structural changes viving to advanced age, and the staggering costs of caring would be engendered in human brain tissue following for older individuals who suffer from neurological decline, chronic exercise, but research examining the impact of identifying mechanisms to offset or reverse these declines exercise on brain structure has overwhelmingly relied upon has become increasingly important.
nonhuman animals, due to the highly invasive methods Cardiovascular exercise has been associated with im- typically required to assess changes in brain structure.
proved cognitive functioning in aging humans (3,4). These With the advent of noninvasive in vivo brain imaging effects have been shown to be the greatest in higher order technologies such as structural and functional magnetic cognitive processes, such as working memory, switching resonance imaging (MRI), it is possible to address questions between tasks, and inhibiting irrelevant information, all of about changes in the underlying brain structure of humans.
which are thought to be subserved, in part, by the frontal In one such study (14), we found that older adults with a lobes of the brain (3). However, very little is known about lifelong history of cardiovascular exercise had better pre- the structural brain changes, if any, which underlie these served brains than did age-matched sedentary counterparts.
benefits in humans. Previous research with nonhuman Interestingly, the structural preservation was greatest in the animals has shown that chronic aerobic exercise can lead frontal and parietal regions of the brain, which are thought to the growth of new capillaries in the brain (5,6), increase to subserve aspects of higher order cognition, such as working the length and number of the dendritic interconnections memory, task switching, and the inhibition of irrelevant between neurons (7), and even increase cell production in information. However, owing to the cross-sectional nature the hippocampus (8). These effects likely result from of that study, it is conceivable that a number of factors increases in growth factors such as brain-derived neuro- influence both brain volume and aerobic fitness. It is even trophic factor (7,9) and insulin-like growth factor (10,11), possible that the relationship is reversed. That is, those older FITNESS AND BRAIN HEALTH Table 1. Demographic Information on Aerobic Exercising and participate in either an aerobic exercise program or a non- Nonaerobic Exercising Control Older Adults aerobic stretching and toning exercise program.
Participant characteristics are documented in Table 1. The Measured Variable only significant difference between the aerobic and non- aerobic training group participants was in the maximal oxy- t(58) ¼ 2.05, p , .025 2) change measure (i.e., the cardiovascular improvement from pre- to post-training). The Institutional Review Board at the University of Illinois approved this research. Written informed consent was obtained from all Notes: All values except the change in VO2 outcome represent participant Exercise Intervention Protocols characteristics at the onset of study participation.
The aerobic exercise intervention was designed to HRT includes participant's self-report of either opposed or unopposed improve cardiorespiratory fitness with an exercise intensity estrogen therapy, and participants included in the hypertensive category were prescription derived from peak heart rate (HR) responses to those who were diagnosed as hypertensive prior to their participation in thestudy.
baseline graded exercise testing. Intensity levels began at Standard errors are in parentheses.
40%–50% HR reserve increasing (15) to 60%–70% HR MMSE ¼ Mini-Mental State Examination score; NS ¼ not significant; reserve over the course of the trial. Intensity levels and HRT ¼ hormone replacement therapy.
exertion were recorded in daily exercise logs and monitoredby trained exercise leaders. Participants in the older adults who have relatively well preserved brains may be nonaerobic exercise control group followed the same differentially able to maintain participation in a physically activity schedule and format as the aerobic exercise group active lifestyle, through better preserved cognitive abilities did, but engaged in a program of whole-body stretching and or some other set of genetic or environmental variables that toning designed for individuals 60 years old or older. As the affect both somatic and brain health.
individual's level of flexibility increased, stretches with To address this issue, we randomly assigned 59 older increasing levels of difficulty were incorporated into the adults to participate in either a cardiovascular exercise group program. Participants in both the aerobic and control or a nonaerobic exercise control group for a 6-month period.
exercise groups attended three 1-hour exercise training We scanned these participants in a high-resolution structural sessions per week for the 6-month period of the inter- MRI protocol immediately before and after participation vention. Compliance in the exercise sessions was excellent, in the exercise program. We then compared changes in exceeding 85% for all participants. Each group participated regional brain volume from preintervention to postinterven- in their sessions at separate geographical locations around tion for aerobic exercisers and nonaerobic exercise control campus to reduce the probability of any crossover effects participants using an optimized voxel-based morphometric occurring between the groups.
technique which can assess tissue volume in a point-by-point fashion throughout the brain (see Methods). We Assessment of Cardiorespiratory Fitness additionally analyzed high-resolution brain scans of 20 Participants completed a graded exercise test on a motor- younger adults; these scans were collected at the same driven treadmill. Peak oxygen uptake (VO2peak) was mea- intervals as those from the older adults. The younger adults sured from expired air samples taken at 30-second intervals did not participate in an exercise intervention, and served until the highest VO2peak was attained at the point of voli- largely as methodological controls as we did not expect to tional exhaustion. The aerobic fitness training group showed see any appreciable change in the volume of younger adult a significant 16.1% in increase in VO2peak, whereas the older brains within the 6-month time frame of the study.
control participants showed a nonsignificant 5.3% change inVO2peak across the 6-month intervention.
Imaging Protocols and Analyses We acquired a high-resolution T1 weighted structural image for each participant, 1 week prior to the intervention Fifty-nine older (60–79 years) and 20 younger (18–30 and within 1 week after cessation of the exercise program.
years) right-handed, neurologically intact adults took part in Twenty-two of the older adults and eight of the younger the 6-month study. All participants were screened for adults were scanned in a 1.5 Tesla GE Signa MRI scanner neurological defect (e.g., possible dementia, self-report of (1 3 1 3 1.3 mm; Niskayuna, NY) at both times 1 and 2 and neurological disease such as multiple sclerosis, brain tumor, the remaining older and younger adults were scanned in a and Parkinson's disease) and appropriateness for testing in 3 Tesla Siemens Allegra MRI scanner (1 3 1 3 1.3 mm; an MRI environment (e.g., no metallic implants that could Malvern, PA) at both times 1 and 2. None of the results interfere with testing, no claustrophobia). Older adults were reported in this study were significantly impacted by the additionally required to obtain physician approval for scanner type used to acquire the MRI images.
participation in an exercise program before beginning any Our voxel-based morphometry analyses largely followed phase of the study. Older participants were randomly as- those methods described elsewhere (16), with the exception signed by the project coordinator during recruitment to that we adapted our protocol to include a highly optimized

Figure 1. Regions showing a significant increase in volume for older adults who participated in an aerobic fitness training program, compared to nonaerobic (stretching and toning) control older adults. A and B, Neurologically oriented axial slices through the brain, at þ2 and þ34 mm, respectively, in stereotaxic space. C,Sagittal slice 2 mm to the right of the midline of the brain. Blue regions: Gray matter volume was increased for aerobic exercisers, relative to nonaerobic controls.
Yellow regions: White matter volume was increased for aerobic exercisers, relative to controls. (See also Table 2.) and robust longitudinal registration approach to perform the a set of unpaired t tests at each voxel. We initially subjected initial coregistration between participants' time 1 and time 2 the younger adult data to a simple t test against zero to images (17). The registration constrained spatial scaling by evaluate whether any changes occurred during the 6-month the skull to minimize any potential differences in scanner period for younger adults. These analyses yielded three geometry or misregistration due to soft-tissue changes.
statistical parametric maps for gray and white mater, which First, each participant's images were skull-stripped and described where (a) aerobic exercisers showed a greater segmented into 3D maps of gray matter, white matter, and increase in volume than stretching and toning controls, (b) cerebrospinal fluid, using a semi-automated algorithm that nonaerobic controls showed a greater increase in volume takes into account voxel intensity distributions as well as than aerobic exercisers, and (c) any change in volume, hidden Markov random fields to estimate tissue volume at positive or negative, was present in younger adults. We each voxel (18). Then, the 3D maps of gray and white performed a second set of analyses to examine whether the matters for each participant were registered to a common results of our initial analysis interacted with the two space (MNI) using a 12-parameter affine transformation.
different MRI scanners used in the study. In none of the These segmented images were then used as a priori regions presented in Figure 1 did the scanner used to collect templates for a second-level segmentation. In addition, the MRI data interact with the effects of interest. The a mean image was calculated from all participants, spatially resulting statistical parametric maps presented in Table 2 smoothed with a 12 mm full-width at half max kernel, and were statistically corrected for multiple comparisons at a subsequently used as a study-specific template. The use of p , .05 level for each cluster (19).
study-specific templates has been shown to reduce errorassociated with misregistration and, therefore, to provide a better estimate of brain volume differences between groups.
Descriptive information on the participants is presented The second-level analysis then consisted of a resegmentation in Table 1. Participant ages ranged from 60 to 79 years, with based on the a priori gray and white matter maps from stage a mean of 66.5 years. Overall, the sample was 55% female, 1 and a realignment to the study-specific template image.
and tended to be well educated, with an average 13.8 years These images provide a voxel-by-voxel estimation of the of education. The estimated VO volume of gray matter, white matter, and cerebrospinal fluid 2 scores ranged from 12.6 to contained within the particular voxel. These images werethen multiplied by the Jacobian determinant for each Table 2. Cluster Size, Peak Location, and Statistical Value for participant to preserve original volume and to control for Each of the Four Regions Where Aerobically Exercising differences in the extent of registration and possible Older Adults Showed a Significant Increase in Brain Volume interpolation error. Finally, the percent change in volume was computed at each voxel for each participant. All of these processes were conducted by an experimenter who was blind to the group assignment of each individual.
The maps representing the percent volume change in gray and white matter for each participant were then forwarded to Note: ACC/SMA ¼ anterior cingulate cortex, supplementary motor cortex; a group analysis, where we compared the changes in volume rIFG ¼ right inferior frontal gyrus; lSTL ¼ left superior temporal gyrus; AWM ¼ for aerobic exercising and nonaerobic control older adults in anterior white matter.
FITNESS AND BRAIN HEALTH 49.9. As shown in greater detail in Table 1, groups did not differ at program onset with respect to average VO2 score, In this study, we randomly assigned older adult partic- age, sex, years of education, hormone replacement therapy ipants to either an aerobic exercise group or a nonaerobic usage, hypertension, or Mini-Mental State Examination exercise control group for 6 months and then examined score. However, after the intervention the aerobically exer- whether participation in an aerobic exercise regimen would cising older adults showed a significant increase in VO2.
alter brain volume in an aged cohort. In short, we found that As predicted, no significant changes in either gray or participation in an aerobic exercise program increased white matter volume were detected for our younger par- volume in both gray and white matter primarily located in ticipants. However, when directly comparing the changes in prefrontal and temporal cortices—those same regions that are gray matter volume for older exercise and control par- often reported to show substantial age-related deterioration.
ticipants, we found that the previously sedentary aerobic The current findings are the first, to our knowledge, to exercising group showed a benefit in brain volume in several confirm benefits of exercise training on brain volume in aging regions after participation in an exercise training protocol.
humans. These findings both compliment and extend extant The blue regions in Figure 1 show areas of gray matter in human and nonhuman research on the benefits of exercise on which older adults who participated in the 6-month aerobic cognition and brain structure such as neuron proliferation and exercise program showed a significant increase in regional survival, growth of capillary beds, and increased dendritic brain volume, compared to older adult controls. As might be spines (5–13,25). These findings also highlight the potential expected from the human behavioral research on aerobic importance of aerobic exercise in not only staving off neural training effects on cognition (3,4), the largest changes in decline in aging humans, but also suggest promise as an volume were present in the frontal lobes of the brain, and effective mechanism to roll back some of the normal age- included regions of cortex that are implicated in a broad array related losses in brain structure (1,23).
of higher order attentional control and memory processes These results also directly bear on issues of public policy (20–22). The largest region subsumed portions of the dorsal and clinical recommendations in that they suggest a rather anterior cingulate cortex, supplementary motor area, and simple and inexpensive mechanism to ward off the effects of middle frontal gyrus bilaterally within the medial walls of the senescence on human brain tissue. Most importantly, the brain (ACC/SMA). The second region subsumed a moder- regions of cortex and white matter that show the greatest ately large portion of the dorsolateral region of the right sparing with aerobic fitness play central roles in successful inferior frontal gyrus, but also part of the posterior aspect of everyday functioning, and declines in these regions are the middle frontal gyrus (rIFG), and a third region included associated with a broad array of clinical syndromes. For the dorsal aspect of the left superior temporal lobe (lSTL).
example, the prefrontal cortex has been associated with The yellow region in Figure 1 shows the area in which critical cognitive processes ranging from inhibitory func- aerobically exercising participants showed a significant tioning (22) to measures of general intelligence (26). Losses increase in white matter volume after the 6-month in- in this area have been associated with devastating clinical tervention, compared to control participants. This region was syndromes such as schizophrenia. The temporal lobes are in the anterior white matter tracts (AWM), subtending associated with effective long-term memory function, and roughly the anterior third of the corpus callosum. Thesewhite matter tracts allow the left and right hemispheres of the losses in these areas of cortex have been associated with brain to communicate, and deterioration in these regions has Alzheimer's dementia in aging populations. Importantly, been implicated in age-related cognitive decline (23,24). See these are the same locations that we report brain volume Table 2 for peak locations, z scores, and cluster sizes.
increases with exercise.
Considering the detrimental impact of age-related brain These findings, as provocative as they are promising, volume loss on a broad spectrum of outcomes, it would be must be viewed with some caution. For example, the older interesting to investigate the potential for fitness to reduce adults in our sample were all very healthy and cognitively the risk of brain tissue loss during the intervention. To intact. It is not clear whether similar benefits will accrue in address this issue, we computed a binary outcome measure pathologically aging individuals. Furthermore, a detailed of volume change, in which volume loss was coded as neuropsychological battery was not collected on these a negative outcome. From this we computed, within each participants at each time point; therefore, we do not have cluster reported in Table 2, the relative reduction in risk for the data to assess how these volumetric changes relate to brain volume loss associated with participation in the changes in cognitive scores [but see Erickson and colleagues aerobic fitness training protocol. Older adults who partic- (27) for a cross-sectional examination of the relationship of ipated in the aerobic fitness training protocol showed fitness-related brain volume differences and cognition]. Our average reductions in risk, relative to participants in the relatively small sample size is also a limiting factor. Our stretching and toning control group, for brain volume loss of exclusionary criteria limit the interpretation of our results 42.1%, 33.7%, 27.2%, and 27.3%, in the anterior cingulate to a select group of individuals. Additionally, data from cortex (ACC/SMA), right superior temporal gyrus (rtSTG), nonhuman models suggest that the changes in brain volume right middle frontal gyrus (rtMFG), and anterior white seen in our study are likely due to changes in synaptic matter (AWM) clusters, respectively. We should note that interconnections, axonal integrity, and capillary bed growth, our sample is somewhat smaller than the recommended but very little is known about the relationship between the minimum for risk-reduction estimates, and as such, the risk voxel-based morphometry methodology used in this study, reduction estimates should be viewed with some caution.
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