Aerobic exercise reverses aging-induced depth-dependent decline in cerebral microcirculation
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eLife assessment
This important study shows that exercise improves cerebrovascular function during aging using convincing methods, the authors show that aerobic exercise reverses aging-induced deficits in microvascular perfusion and oxygenation and potentially improves short-term memory. This work will be of broad interest to researchers and clinicians studying vascular function, age-related cognitive decline, and the effects of aerobic exercise on reversing age-related dysfunction.
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Abstract
Aging is a major risk factor for cognitive impairment. Aerobic exercise benefits brain function and may promote cognitive health in older adults. However, underlying biological mechanisms across cerebral gray and white matter are poorly understood. Selective vulnerability of the white matter to small vessel disease and a link between white matter health and cognitive function suggests a potential role for responses in deep cerebral microcirculation. Here, we tested whether aerobic exercise modulates cerebral microcirculatory changes induced by aging. To this end, we carried out a comprehensive quantitative examination of changes in cerebral microvascular physiology in cortical gray and subcortical white matter in mice (3–6 vs. 19–21 months old), and asked whether and how exercise may rescue age-induced deficits. In the sedentary group, aging caused a more severe decline in cerebral microvascular perfusion and oxygenation in deep (infragranular) cortical layers and subcortical white matter compared with superficial (supragranular) cortical layers. Five months of voluntary aerobic exercise partly renormalized microvascular perfusion and oxygenation in aged mice in a depth-dependent manner, and brought these spatial distributions closer to those of young adult sedentary mice. These microcirculatory effects were accompanied by an improvement in cognitive function. Our work demonstrates the selective vulnerability of the deep cortex and subcortical white matter to aging-induced decline in microcirculation, as well as the responsiveness of these regions to aerobic exercise.
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eLife assessment
This important study shows that exercise improves cerebrovascular function during aging using convincing methods, the authors show that aerobic exercise reverses aging-induced deficits in microvascular perfusion and oxygenation and potentially improves short-term memory. This work will be of broad interest to researchers and clinicians studying vascular function, age-related cognitive decline, and the effects of aerobic exercise on reversing age-related dysfunction.
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Reviewer #1 (Public Review):
The authors have investigated the effect of aerobic exercise on the decline in cerebral blood flow and cognitive function in old mice. Using appropriately two-photon microscopy and optical coherence tomography they found that aerobic exercise restored capillary blood flow and oxygenation in the white matter more than in the grey matter in old female mice. Interestingly, this aerobic exercise also ameliorated cognitive performance in these mice. The data obtained strongly supports the hypothesis and supports the conclusion of the study. Nevertheless, it would be important to compare the effects of aerobic exercise in old mice to its effects in young animals. It will be also interesting to know if the protective effect of exercise is similar in male mice.
This work brings new insights into the comprehension of …
Reviewer #1 (Public Review):
The authors have investigated the effect of aerobic exercise on the decline in cerebral blood flow and cognitive function in old mice. Using appropriately two-photon microscopy and optical coherence tomography they found that aerobic exercise restored capillary blood flow and oxygenation in the white matter more than in the grey matter in old female mice. Interestingly, this aerobic exercise also ameliorated cognitive performance in these mice. The data obtained strongly supports the hypothesis and supports the conclusion of the study. Nevertheless, it would be important to compare the effects of aerobic exercise in old mice to its effects in young animals. It will be also interesting to know if the protective effect of exercise is similar in male mice.
This work brings new insights into the comprehension of the age-associated changes in cerebral microcirculation and in the protective effects of aerobic exercise.
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Reviewer #2 (Public Review):
While aging is known to cause cerebral blood flow deficits, some studies suggested that exercise could reverse - at least partially - these deficits. In this study, the authors used technically-challenging techniques and approaches to test the hypothesis that 5 months of voluntary exercise reverses impairments in cerebrovascular function and cognition. Overall, I find the evidence for a favorable impact of exercise on microvascular perfusion and oxygenation convincing. The impact of exercise was most evident in the white matter and deep cortical tissues, which I believe to be a major finding of the study. The methods are very well-detailed and easy to follow. It is not clear, however, why the authors chose to study only one sex (female mice). This is an important consideration given that age-dependent …
Reviewer #2 (Public Review):
While aging is known to cause cerebral blood flow deficits, some studies suggested that exercise could reverse - at least partially - these deficits. In this study, the authors used technically-challenging techniques and approaches to test the hypothesis that 5 months of voluntary exercise reverses impairments in cerebrovascular function and cognition. Overall, I find the evidence for a favorable impact of exercise on microvascular perfusion and oxygenation convincing. The impact of exercise was most evident in the white matter and deep cortical tissues, which I believe to be a major finding of the study. The methods are very well-detailed and easy to follow. It is not clear, however, why the authors chose to study only one sex (female mice). This is an important consideration given that age-dependent hormonal changes could play a role in the findings. There are a few instances where it is unclear whether the number of vessels or animals were used for statistical analyses. It'd be very useful for the reader to understand why whisker stimulation led to a reduction in detected light intensity that reflects hyperemia as previously published by the authors (Sencan et al., 2022 JCBFM).
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Reviewer #3 (Public Review):
The manuscript by Shin et al, "Aerobic exercise reverses aging-induced depth-dependent decline in cerebral microcirculation", addresses fundamental questions on the mechanism by which aerobic exercise can reverse several age-related dysfunctions in the cerebral vasculature. This work is solid as they use a wide range of complementary in vivo imaging modalities including two-photon fluorescent imaging, optical coherence tomography, and measurements of PO2 as well as behavioral tests. The experiments specifically examined region-specific differences in the young and aged vasculature and the response to aerobic exercise in superficial cortical areas and importantly in deeper white matter areas. This is a solid contribution because it provides additional understanding of age-related changes in the white matter …
Reviewer #3 (Public Review):
The manuscript by Shin et al, "Aerobic exercise reverses aging-induced depth-dependent decline in cerebral microcirculation", addresses fundamental questions on the mechanism by which aerobic exercise can reverse several age-related dysfunctions in the cerebral vasculature. This work is solid as they use a wide range of complementary in vivo imaging modalities including two-photon fluorescent imaging, optical coherence tomography, and measurements of PO2 as well as behavioral tests. The experiments specifically examined region-specific differences in the young and aged vasculature and the response to aerobic exercise in superficial cortical areas and importantly in deeper white matter areas. This is a solid contribution because it provides additional understanding of age-related changes in the white matter microcirculation, a brain region where our understanding is incomplete. This work effectively sets the stage to further examine aging-related white matter degeneration, how aerobic exercise ameliorates the vascular decline in aging, and will potentially lead to novel interventions targeting the white matter.
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