Higher cardiorespiratory fitness (CRF) and physical activity (PA) in old age are associated with greater brain structural and functional integrity, and higher cognitive functioning. However, it is not known how different aspects of lifestyle such as sedentariness, light PA (LI-PA), or moderate-to-vigorous physical activity (MV-PA) relate to neural activity in aging. In addition, it is not known whether the effects of PA on brain function differ or overlap with those of CRF. Here, we objectively measured CRF as oxygen consumption during a maximal exercise test and measured PA with an accelerometer worn for 7 days in 100 healthy but low active older adults (aged 60–80 years). We modeled the relationships between CRF, PA, and brain functional integrity using multivariate partial least squares analysis. As an index of functional brain integrity we used spontaneous moment-to-moment variability in the blood oxygenation level-dependent signal (SD BOLD ), known to be associated with better cognitive functioning in aging. We found that older adults who engaged more in LI-PA and MV-PA had greater SD BOLD in brain regions that play a role in integrating segregated functional domains in the brain and benefit from greater CRF or PA, such as precuneus, hippocampus, medial and lateral prefrontal, and temporal cortices. Our results suggest that engaging in higher intensity PA may have protective effects on neural processing in aging. Finally, we demonstrated that older adults with greater overall WM microstructure were those showing more LI-PA and MV-PA and greater SD BOLD . We conclude that SD BOLD is a promising correlate of functional brain health in aging. Future analyses will evaluate whether SD BOLD is modifiable with interventions aimed to increase PA and CRF in older adults.

Funding: This work was supported by the National Institute on Aging (NIA) grant (R37-AG025667) and a grant from Abbott Nutrition through the Center of Nutrition, Learning and Memory at the University of Illinois. A.Z.B was supported by the “Changing Viewpoints” grant from the Robert Bosch Foundation ( http://www.bosch-stiftung.de/content/language2/html/39607.asp ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction

Higher cardiorespiratory fitness (CRF) and physical activity (PA) in old age is associated with greater brain structural and functional integrity, and higher cognitive functioning [1–3]. In this study we extend our understanding of the different and overlapping roles of CRF and PA in brain resting state function in healthy but low-active older adults.

There are three main challenges in understanding how physical health and lifestyle PA relate to brain function in older adults. First, it is not known how non-exercise lifestyle activities, such sedentariness (prolonged and uninterrupted periods of sitting, such as watching TV) or light PA (LI-PA; housework, gardening, relaxed walking) relate to brain function, although they account for the majority of daily waking time. This is because lower intensity PA, in contrast to exercise-related moderate-to-vigorous PA (MV-PA, e.g. jogging, walking stairs, biking), is not well captured by self-reports [4]. This is important, as sedentariness and MV-PA are associated with different physiological mechanisms and may differentially affect brain health. For example, general sedentariness may negate or weaken the benefits of sporadic MV-PA: it is possible to be an “active couch potato” who has normal CRF due to bouts of exercise, but is not immune to glucose and fat metabolism risk caused by prolonged sitting [5–7]. Second, it is not known how the effects of CRF and PA differ or overlap with respect to brain function. CRF, measured as maximal oxygen consumption during maximal physical effort, is a sum of various factors, such as pulmonary diffusion capacity, cardiac output, erythrocyte levels, muscle capillary density and respiration rate [8–10], many of which are genetically determined, at least in part [11]. Therefore, although CRF and PA tend to be related, they may not be equivalent in their relationships to brain health. Indeed, our recent work indicates that PA is more predictive of white matter (WM) microstructure than CRF, and different levels of PA intensity relate to different aspects of WM health. Specifically, less time spent sitting was related to microstructure of WM near the hippocampus, more LI-PA was related to temporal lobe microstructure, while older adults spending more time in MV-PA had lower volume of WM lesions [12]. Still, these objective measures of time spent in different intensities of PA have not yet been related to functional brain health in aging. To address these two challenges, we objectively measured PA with an accelerometer, which was worn for 7 consecutive days during all waking hours, in addition to CRF.

The third challenge is measuring brain function and the interpretation of the fitness- and PA-brain function relationships. For example, depending on brain region and task, greater CRF is associated with either increased or decreased change in blood oxygenation level dependent (BOLD) signal, a proxy for neural activity [13–15]. As a result, it is unclear whether high or low amplitudes of BOLD signal reflect optimal functional brain health, and how this association varies regionally throughout the brain. Similarly, a moderate intensity walking intervention was related to increased functional connectivity within the default mode network [16], while the association between CRF and functional connectivity in middle-aged adults was both positive and negative, depending on whether local or long-distance connections were considered [17]. To overcome the challenges in interpretation of conventional positive/negative task-related changes in BOLD signal or different scales of functional synchrony between distinct brain regions, here we employed a more general measure of neural function: moment-to-moment variability in the BOLD signal during spontaneous brain activity.

Moment-to-moment variability in the BOLD signal (SD BOLD ) is known to reflect the dynamic range of neural processing, such as the modulation of functional networks and is suggested to be a promising tool in mapping neural correlates of cognitive abilities in aging [18,19]. Specifically, lower SD BOLD in certain brain regions is associated with older age, slower, and less consistent performance on a perceptual matching task [20], as well as lower performance on memory and reasoning tasks [21]. These findings suggest there is some optimal range of SD BOLD that may be decreasing with age in certain brain regions, and that older adults differ in their deviation below this optimum, which is associated with individual differences in cognitive performance.

In this study, we sought to determine how the level of physical fitness (measured as CRF) and PA (measured via accelerometer) are related to functional brain health measured as SD BOLD . To this end, we collected resting functional magnetic resonance BOLD data from 100 healthy older participants (60–80 years). We modeled the relations between whole-brain voxel-wise SD BOLD , CRF, and PA (mean daily sedentary time, time spent in LI-PA, and MV-PA) within a multivariate partial least squares framework [22]. Given that: 1) advancing age is associated with decreasing SD BOLD; and 2) greater CRF, PA, and lower sedentariness are associated with better cognitive and brain health outcomes in older adults, we predicted that greater SD BOLD in certain regions would reflect greater brain health and therefore positively correlate with CRF and PA, and negatively with sedentariness. Although the relevance of SD BOLD in the brain for physical fitness is not yet known, we hypothesized that some of the regions where conventional measures of structural and functional brain integrity have been previously associated with greater CRF (e.g. hippocampus, temporal lobe, core regions of the default mode network (precuneus and medial prefrontal cortex), fronto-parietal regions of the central executive network, anterior cingulate, insula, and thalamus) would show this CRF/PA—SD BOLD relationship [13–16,23–25].

In sum, we have shown previously that more active and less sedentary older people have greater WM microstructural integrity and lower volume of WM lesions [12], that WM microstructure is positively related to behaviorally relevant SD BOLD [21], and that overall WM microstructure provides a scaffold for neural processing in the grey matter (GM) [26]. Therefore, we tested the hypothesis that WM microstructural integrity should be positively associated with CRF/PA-related SD BOLD . To this end, we used diffusion tensor imaging (DTI) to infer about WM microstructure by quantifying the magnitude and directionality of diffusion of water within a tissue. We used fractional anisotropy (FA) averaged over all major WM tracts as a summary measure of fiber density, coherence, and myelination degree [27–29].