Reversal of Glial and Neurovascular Markers of Unhealthy Brain Aging by Exercise in Middle-Aged Female Mice

Abstract

Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.

Age-related decrease in cerebrovascular-derived neuroprotective proteins: Effect of acetaminophen

“…In the current study, we show a significant decline in cerebrovascular-derived VEGF, PEDF and PACAP with age. These data are consistent with literature showing an age-related decrease in neuroprotective proteins such as VEGF, PEDF and PACAP in the CNS (Latimer et al, 2011; Van Kirk et al, 2011; Wu et al, 2006). …”

“…Neuronal viability and the ability of neurons to respond to injury and/or neuroprotective factors reflect complex, multifaceted processes in vivo . Although it is difficult to extrapolate data focused on specific proteins (such as VEGF, PEDF, PACAP) to overall neuronal function, the importance of neuroprotective proteins to brain health is supported by studies that show the beneficial effects of exercise on brain function are in part, attributable to increases in neuroprotective proteins, such as VEGF (Gomez-Pinilla et al, 2008; Latimer et al, 2011; Lau et al, 2011). Thus, the ability of acetaminophen to enhance vascular expression of neuroprotective proteins, as we document here, may hold promise for improving vascular and neuronal function in CNS.…”

Short-term environmental enrichment enhances synaptic plasticity in hippocampal slices from aged rats

“…A second factor known to be increased in the hippocampus by daily exercise (Latimer et al, 2011, Speisman et al, 2013) and decreased with age (Shetty et al, 2005) in rodents is vascular endothelial growth factor (Vegf). Thus, we compared Vegf immunoreactivity in the control and EE rats (Figure 5E).…”

“…We investigated molecular mediators suggested by previous work, such as BDNF (Young et al, 1999, Mora et al, 2007, Eckert and Abraham, 2013, Hu et al, 2013, Sale et al, 2014), phosphorylated CREB (Young et al, 1999, Hu et al, 2013), and Vegf (Latimer et al, 2011, Speisman et al, 2013). While BDNF was not clearly altered by EE, we detected an increase in CREB phosphorylation and Vegf expression.…”

Bridging animal and human models of exercise-induced brain plasticity

“…IGF-1 is also produced locally in the brain, probably by microglia, as has been shown in aged rodents [120]. In addition, 6 weeks of wheel running elevated VEGF protein levels in the cortex and hippocampus of middle-aged female mice [121]. …”