The cerebral white matter is significantly affected by aging (Cees De Groot et al., 2000; de Leeuw et al., 2001). Previous work suggests that, in comparison with superficial gray matter, subcortical white matter has greater tissue loss due to aging and is more susceptible to hypoperfusion (Gunning-Dixon et al., 2009; Hase et al., 2019; Li et al., 2020). Indeed, white matter lesions might impair cognitive function more than gray matter lesions (Reber et al., 2021), underscoring the importance of understanding the biological mechanisms of aging-related white matter degeneration for targeted interventions.

Cerebral small vessel disease (CSVD) refers to a range of pathological processes affecting small arterioles, capillaries, and venules supplying the white matter and deep structures of the brain. CSVD is a common cause of stroke and an important contributor to age-related cognitive decline and dementia (Pantoni, 2010; Smith and Markus, 2020). Most CSVD-related strokes affect subcortical white and deep gray matter. In addition, there is increased awareness of the role of CSVD in accelerating the pathogenesis of Alzheimer’s disease (AD), with some studies suggesting the possibility that white matter changes are the starting point of AD (Defrancesco et al., 2014; Esiri et al., 1999; Radanovic et al., 2013; Snowdon et al., 1997). Despite this growing awareness, our mechanistic understanding of aging-related changes in microcirculation as a function of depth in cortex and underlying white matter is incomplete.

Aerobic exercise is a promising strategy to improve neurocognitive function in aging and reduce the risk of age-related neurological disorders (Barnes et al., 2003; Yaffe et al., 2001). Most studies have thus far focused on exercise-responsive molecules that could lead to improvement of neural physiology and, thereby, cognitive performance (De Miguel et al., 2021; Islam et al., 2021; Valenzuela et al., 2020; Wang and Holsinger, 2018). Yet, how exercise may exert beneficial effects on vascular contributions to brain aging remain to be fully understood. In particular, it is unclear how exercise normalizes cerebral microcirculation, and whether there are differential effect across brain regions, including the gray and white matter.

In this study, we compared young (3–6 months old) versus old (19–21 months old) mice to assess the effects of normal aging, and then asked whether 5 months of voluntary aerobic exercise can alter or rescue brain microcirculation in old 20-month-old mice. Cerebral microvascular perfusion and oxygenation in the cortex and subcortical white matter were quantified with two-photon microscopy (2PM) and optical coherence tomography (OCT) in awake mice.

Our results showed age-related declines in capillary red-blood-cell (RBC) flux and capillary oxygen partial pressure (pO₂) in the deep cortical layers and subcortical white matter, while voluntary exercise improved these measures, including the cerebral blood flow (CBF) in cortical ascending venules. Interestingly, the regions that experienced the highest decline were also the ones that benefited the most from the exercise. These microcirculatory effects were accompanied by an improvement in cognitive function. Our results may provide insights into how sedentary aging and aerobic exercise affect cerebral microvascular physiology and particularly emphasize the physiologic importance of effects in the deep cortex and subcortical white matter.

In this study, we observed depth-dependent decreases in cerebral microvascular perfusion and oxygenation in aged sedentary mice. The decrease was mitigated by 5 months of exercise in a depth-dependent manner. The key findings include (1) age-associated reduction in capillary RBC flux in the white matter that was moderated by exercise; (2) a decrease in the mean capillary pO₂ in cortical layer IV with aging and the overall improvement in capillary pO₂ with exercise, with a particularly pronounced pO₂ increase in layer IV; (3) an increase in cortical microvascular density with exercise; and (4) improvement of short-term memory function with exercise.

We first assessed the spatial distribution of capillary RBC flux across the cortical and subcortical regions and how it responds to aging and exercise. In aged sedentary mice, the capillary RBC flux in the subcortical white matter tended to be lower than that in the gray matter (Figure 1a). Young sedentary mice showed the opposite trend, consistent with our previous finding in anesthetized young adult mice (3–5 months old) showing a higher capillary RBC flux in the subcortical white matter compared to the gray matter (Li et al., 2020). Importantly, we observed a large discrepancy in the capillary RBC flux between young and aged sedentary mice in the white matter with preserved capillary RBC flux in the superficial gray matter. Cerebral white matter is known to be more susceptible to hypoperfusion compared to the gray matter, potentially because it is located further downstream with respect to the arterial blood supply (Gunning-Dixon et al., 2009; Markus et al., 2000). White matter vulnerability to ischemic injury increases with age (Baltan et al., 2008), and white matter lesions and lacunar infarcts are common in elderly people with CSVD and hypertension (Breteler et al., 1994; van Swieten et al., 1991). The vulnerability of white matter to such pathological conditions could be related to our observation of a severe decrease in blood flow in the white matter during normal aging.

Five months of exercise restored the spatial distribution trend of capillary RBC flux close to its distribution in the young sedentary mice (Figure 1a). Exercise was associated with a decreased CV of the capillary RBC flux in subcortical white matter, suggesting more homogeneous microvascular blood flow in that region that could potentially facilitate improved oxygen delivery to tissue. Increased capillary perfusion in the white matter was accompanied by increased blood flow in ascending venules, as measured by Doppler OCT (Figure 1d, e). In contrast to smaller ascending venules having their branches being distributed mostly over the upper cortical layers, large venules likely extend further to subcortical white matter where the increased capillary perfusion was observed (Duvernoy et al., 1981; Kirst et al., 2020; Xiong et al., 2017). Venules smaller than 20 μm in diameter were excluded from analysis as the small venules tend to have slower flow and may have smaller absolute changes in the blood flow compared to larger venules with higher flow and thus the flow change may not be easily distinguishable due to the relatively low precision of the speed measurement based on Doppler OCT (±0.7 mm/s, see Spectral-domain OCT for more details) (Fan et al., 2020; Santisakultarm et al., 2012). The increased venous flow in the aged exercise group could be associated with an increased arterial flow, possibly affected by exercise-induced changes in heart strength, brain blood flow regulation, and vascular anatomy. However, flow measurement in arterioles could not be performed with our OCT setup because the flow in many diving arterioles exceeded the maximum measurable limit of the flow measurement by Doppler OCT.

Previous studies in mice reported conflicting results regarding the effects of exercise on cortical microcirculation (Dorr et al., 2017; Falkenhain et al., 2020; Lu et al., 2020). However, these observations have been limited to the blood flow in gray matter, which was shown in this study to be less responsive to exercise than that in deeper brain regions. Human MRI data acquired after short-term (1 week) exercise showed that exercise induced a selective increase in hippocampal CBF with no or negligible changes in the gray matter CBF (Steventon et al., 2021). Our findings suggest that cerebral subcortical microcirculation is more responsive to both age-related and exercise-induced changes than cortical microcirculation.

The change in cortical microvascular oxygenation was also depth dependent. In aged sedentary mice, the mean capillary pO₂ increased from layer I to II/III and reached a plateau in layer II/III (Figure 2a, b). A different trend was observed in young sedentary mice, which showed a gradual increase in the mean capillary pO₂ from layer I to IV (Li et al., 2019). In contrast to aged sedentary controls, mice from the aged exercise group showed a similar trend to young sedentary mice, with a pronounced increase in the mean capillary pO₂ in layer IV among all assessed cortical layers. In the mouse somatosensory cortex, layer IV exhibits the highest neuronal and capillary densities and the strongest staining for the cytochrome c oxidase, potentially implying the highest oxidative demand during activation and/or at rest throughout all cortical layers (Blinder et al., 2013; Lefort et al., 2009). In an immunohistochemical study performed using an anti-Glut-1 antibody, high plaque load and decreased blood vessel density were observed, particularly in layer IV of the somatosensory cortex in aged, 18-month-old transgenic AD mice, while younger AD mice did not demonstrate any difference compared to the wild-type mice (Kuznetsova and Schliebs, 2013). The decrease in capillary mean pO₂ in layer IV in aged sedentary mice could be associated with the larger mismatch in the oxygen delivery and consumption compared with the more superficial cortical layers. However, due to technical limitations, we did not assess the microvascular oxygenation in the deeper cortical layers and subcortical white matter. Because RBC flux exhibits the largest discrepancy between sedentary aged and young mice in the subcortical white matter, it is possible that intravascular pO₂ also exhibits the largest discrepancy in this brain region.

Voluntary exercise significantly improved microvascular oxygenation compared to sedentary controls, particularly in layer IV. Similar to our finding of capillary RBC flux improvement due to exercise mostly in the white matter, exercise differentially affected cortical intravascular oxygenation, with the largest increase in the deeper layers and restored the spatial distribution trend of capillary pO₂ across cortical layers close to its distribution in the young sedentary mice. However, since the difference in both the Hct level and RBC line-density between the two groups was not significant (Figure 2c and Figure 1—figure supplement 3), factors other than increased Hct may be involved in the observed depth-dependent pO₂ increase in the gray matter. Interestingly, we found that the RBC line-density in both groups of aged mice was significantly higher in the subcortical white matter than in the gray matter. This was not observed in young adult mice (Li et al., 2020). However, this finding is consistent with previous simulation results that showed higher Hct levels in deep-reaching penetrating arterioles compared to arterioles whose branches connect to the capillary bed closer to the surface due to the plasma skimming effect (Gould et al., 2017).

Consistent with the small effect of exercise on cerebral microcirculation and oxygenation in superficial cortical areas, we observed no change in the relative peak amplitude or the latency of stimulus-induced hemodynamic response with exercise, assessed with OISI at 570 nm, which emphasizes the intrinsic signal originating from cerebral blood volume changes in the superficial cortical layers (Figure 3 and Figure 3—figure supplement 1; Malonek et al., 1997; Tian et al., 2011). Young sedentary mice (7 months old) showed a significantly larger relative response amplitude than aged mice, consistent with the reduced cerebrovascular reactivity with age in healthy adults and rodents (Bálint et al., 2019; Barnes, 2015; Cai et al., 2023; Jessen et al., 2017; Seker et al., 2021). The baseline CBF can have a strong effect on the magnitude of the hemodynamic response (Buxton et al., 2004; Corfield et al., 2001). While no statistically significant difference in the mean capillary RBC flux in the gray matter was found between the aged sedentary and aged exercise groups (Figure 1a), the aged exercise group had larger capillary density in the gray matter (Figure 4b), suggesting that cortical blood perfusion was possibly also higher in the aged exercise group. This was further supported by significantly higher blood flow in ascending venules in the same group (Figure 1d and e). Therefore, our data imply that with a similar level of the relative response amplitude between two groups, the aged exercise group potentially had a larger transient blood supply to the tissue during functional hyperemia.

Consistent with our findings, aging-associated decrease and exercise-induced increase in cerebral microvascular density have been observed across brain regions in both humans and rodents (Ding et al., 2006; Morland et al., 2017; Riddle et al., 2003). However, other studies showed no improvements in cerebral microvascular structure with regular exercise in the mouse sensorimotor cortex (Cudmore et al., 2017; Dorr et al., 2017; Falkenhain et al., 2020). Exercise can affect the brain through different mechanisms across different brain regions at various points in the lifespan (Stillman et al., 2020). Although it is unclear whether the difference in age or brain region (or both) contributed to the inconsistent results with some of the previous observations, we found significant morphological changes in the microvascular morphometric parameters due to chronic exercise in the somatosensory cortex of 20-month-old mice (Figure 4). Based on the observed changes in the microvascular RBC flux and pO₂, we anticipate that an even greater discrepancy in the capillary density between the two groups of mice may be observed in deeper cortical layers and subcortical white matter. It is compelling to hypothesize that higher microvascular density is one of the major contributors to the larger microvascular perfusion and oxygenation observed in mice from the aged exercise group. However, it is not clear whether the larger capillary density in the aged exercise group is mostly due to increased angiogenesis or decreased pruning of the capillaries in comparison with the aged sedentary group. In addition, if increased angiogenesis is present in the aged exercise group, it will be important to better understand the contribution of the new capillaries to oxygen delivery to tissue.

Increased cerebral perfusion and oxygenation with exercise were accompanied by improved spatial short-term memory function, as evaluated by NORT (Figure 5a). The perirhinal cortex plays an important role in object recognition memory. It receives sensory inputs from its neighboring sensory cortices, such as the somatosensory cortex, where we found significant improvements in vascular function and structure due to exercise in aged mice (Antunes and Biala, 2012; Cohen and Stackman Jr., 2015). The NORT results depend on the exploration time in the test phase, which is related to the age-dependent decay of the novel object preference (Traschütz et al., 2018). Therefore, choosing an adequate time interval to calculate the DI is important to reliably detect novel object recognition, especially in aged mice. In our analysis, the DI score was calculated at four different time intervals: 1, 2, 3, and 5 min. The results showed an increased DI score in running mice compared to aged sedentary mice across all time intervals, which was also positively correlated with both the average and total running distance (Figure 5b). In contrast, we did not observe an increase in spontaneous alterations between the arms of the Y-maze (Figure 5c). Consistent with our findings, microcirculatory changes in the white matter have been associated with recognition memory function evaluated by NORT in rodents, while no associations were found with spatial memory function assessed with Y-maze test in the same studies (Blasi et al., 2014; Choi et al., 2015). However, we do not rule out the possibility that exercise may improve spatial memory function and suggest further investigation to evaluate different aspects of spatial memory function by applying other behavioral tests (e.g., Morris water maze test). As previously shown in several studies in mouse models of AD, each memory task depends on a variety of brain regions that can be differentially affected by exercise, which could also produce inconsistent results between different memory tasks (Kraeuter et al., 2019; Winters et al., 2004).

A recent study reported a positive correlation between the average daily running distance and cerebral tissue oxygenation in 6-month-old mice after three months of exercise (Lu et al., 2020). While mice in our aged exercise group had significantly higher white matter capillary RBC flux than aged sedentary mice, the mean capillary RBC flux in the white matter was negatively correlated with the average daily running distance (Figure 1—figure supplement 4). Although white matter capillary density was not assessed in this study, lower capillary RBC flux in the white matter could potentially be accompanied with higher capillary density. In this case, capillary RBC flux in the white matter can decrease but cerebral tissue oxygenation in this region can still increase in response to chronic exercise. This result also may be due to a non-proportional relationship between exercise and brain function, which could decrease after reaching the optimal intensity of exercise (Khakroo Abkenar et al., 2019). It is possible that 5 months of unrestricted exercise led some (or all) animals to over-exercise, which may adversely affect subcortical capillary blood flow and prevent achieving the maximum benefits of exercise on the microcirculation. Among different optical measurements performed in this study, only the capillary RBC flux in subcortical white matter tended to correlate with the running activity while no correlations were found between the parameters measured in cortical gray matter (e.g., venous flow, capillary pO₂, cortical hemodynamic response, and capillary density) and the average running distance. This could also be attributed to a higher responsiveness of subcortical white matter to exercise compared with the cortical gray matter. Correlations between the measured parameters and the total running distance were analyzed. Because of approximately the same number of days that all mice were running, total and average running distances share a common scaling factor (e.g., number of days) and show nearly identical correlations with all of the parameters measured (data not shown). The present study used female mice because the comparison with our previous studies in young adult female mice and prior data have shown that in comparison to male mice, female mice exhibit higher voluntary running activity that could potentially produce a greater effect on the brain (Jones et al., 1990; Konhilas et al., 2015; Rosenfeld, 2017). However, the effect may vary in male mice as the animal sex could differentially affect the age-related and exercise-induced changes in cerebral microcirculation due to sex-related hormonal differences (Bisset et al., 2022; McMullan et al., 2016). Although all the groups were subjected to the same housing conditions, isolated housing could be considered as a stressor that can influence the observed changes in the cerebral microcirculation and behavioral function. Aerobic exercise has been shown to enhance cell proliferation in the dentate gyrus regardless of housing condition in young and aged mice (Kannangara et al., 2011). Further investigation into the influence of environmental enrichment factors on the age-related and exercise-induced changes will help to identify the mechanisms that underlie these processes.

In the analysis of the capillary RBC flux and capillary pO₂, all capillaries identified within the field of view (FOV) were selected and used for analysis without considering their branching orders. In future studies, analysis based on different types of vessels classified by branching order could potentially provide additional insight into capillary blood flow and oxygenation, as we previously showed different characteristics of capillaries with low branching orders located close to precapillary arterioles compared with higher-order capillaries (Li et al., 2019).

In conclusion, leveraging our multimodal optical imaging tools, we quantified the changes in microvascular function, structure, and sensory-evoked functional hyperemia in response to aging and voluntary exercise in 20-month-old mice. Our results indicate that cerebral microcirculation and oxygenation in deeper cortical layers and subcortical white matter are more susceptible to age-related degeneration, but they are surprisingly more responsive to voluntary aerobic exercise, which induces significant improvements in capillary density, RBC flux, and intracapillary pO₂ . Improvements in cerebrovascular function and structure are accompanied by rescue of cognitive function. These findings may help us to better understand the patterns and consequences of age-related decline of microcirculation at different cortical depths and subcortical white matter, and how the neurologic effects of aging may be ameliorated by aerobic exercise.

Figure 3 - Source Data 1, Figure 3 - Source Data 2, Figure 3 - Source Data 3, Figure 4 - Source Data 1, Figure 4 - Source Data 2, Figure 4 - Source Data 3, Figure 5 - Source Data 1, Figure 6 - Source Data 1, and Figure 7 - Source Data 1 contain the numerical data used to generate the figures.

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Author details

1. Paul Shin

   Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   pshin2@mgh.harvard.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8301-1079

2. Qi Pian

   Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   Software, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. Hidehiro Ishikawa

   Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

4. Gen Hamanaka

   Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

5. Emiri T Mandeville

   Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

6. Shuzhen Guo

   Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

7. Buyin Fu

   Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

8. Mohammed Alfadhel

   1. Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
   2. Department of Bioengineering, Northeastern University, Boston, United States

   Contribution

   Software, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

9. Srinivasa Rao Allu

   1. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
   2. Department of Chemistry, University of Pennsylvania, Philadelphia, United States

   Contribution

   Resources, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

10. Ikbal Şencan-Eğilmez

    1. Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
    2. Biophotonics Research Center, Mallinckrodt Institute of Radiology, Department of Radiology, Washington University School of Medicine, St. Louis, United States

    Contribution

    Software, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-2903-041X

11. Baoqiang Li

    1. Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
    2. Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Contribution

    Software, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

12. Chongzhao Ran

    Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

    Contribution

    Resources, Supervision, Funding acquisition, Writing – review and editing

    Competing interests

    No competing interests declared

13. Sergei A Vinogradov

    1. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    2. Department of Chemistry, University of Pennsylvania, Philadelphia, United States

    Contribution

    Resources, Software, Supervision, Funding acquisition, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4649-5534

14. Cenk Ayata

    1. Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
    2. Stroke Service, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Writing – original draft, Writing – review and editing

    Competing interests

    No competing interests declared

15. Eng Lo

    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Writing – review and editing

    Competing interests

    No competing interests declared

16. Ken Arai

    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

    Contribution

    Conceptualization, Supervision, Funding acquisition, Investigation, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

17. Anna Devor

    1. Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
    2. Department of Biomedical Engineering, Boston University, Boston, United States

    Contribution

    Conceptualization, Resources, Software, Supervision, Funding acquisition, Methodology, Writing – original draft, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-5143-3960

18. Sava Sakadžić

    Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

    Contribution

    Conceptualization, Resources, Software, Supervision, Funding acquisition, Methodology, Writing – original draft, Project administration, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6318-1193

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