The present study was designed to determine whether cognition, neurogenesis, and angiogenesis in aged mice could be increased by exercise. We found that both learning and hippocampal neurogenesis were enhanced in aged running mice. There was no detectable decline in blood vessel surface area or perimeter in the aged groups. These parameters were only increased in the young runners. Interestingly, although the aged mice only started running at 19 months of age, the average running distance did not differ significantly from that of 3-month-old runners. However, our equipment could not measure whether the old mice ran more slowly or spent more time in the wheel than the young mice.
Exercise enhanced acquisition of the hidden platform task in the water maze in old mice compared with age-matched sedentary controls. This finding is consistent with research by some investigators who found that passive-avoidance learning is improved in physically active aged mice (Samorajski et al., 1985
). However, others have reported that there was no effect of exercise on spatial learning in aged rats (Barnes et al., 1991
). In the latter study, forced treadmill training was used rather than voluntary wheel running. In addition, mice were tested on the circular platform maze instead of the more physically demanding water maze (Barnes et al., 1991
). However, enhanced fitness in runners is probably not the main reason for improved learning. Performance on the probe trial, which is more indicative of recall ability than fitness of the subject, was better in both young and old runners than in sedentary controls. It should be noted, however, that the aged mice had been sedentary until they were 19 months of age. It is possible that earlier onset of running would have maintained cognitive function to an even greater extent.
Previous studies have suggested that cognitive decline in aging may be attributable to decreased dentate gyrus neurogenesis (Kempermann et al., 1998
; Drapeau et al., 2003
; Merrill et al., 2003
; Bizon et al., 2004
). Several researchers have shown that cell genesis can be restored in the aged brain. Administration of insulin-derived growth factor-1 (IGF-1) (Lichtenwalner et al., 2001
) and epidermal and fibroblast growth factor (Jin et al., 2003
), reduction of corticosterone levels by adrenalectomy (Cameron and McKay, 1999
), and environmental enrichment (Kempermann et al., 1998
) increase new cell numbers in aged animals. However, learning was only tested and found to be improved in the enrichment studies (Kempermann et al., 1998
). Exercise in young and aged animals enhances cell proliferation (van Praag et al., 1999a
; Kim et al., 2004
). In aged runners, cell survival returned to the level of young controls. However, the functional contribution may depend on the percentage of cells that become neurons.
Consistent with previous work, we found that relatively more cells became neurons in runners compared with age-matched controls (van Praag et al., 1999a
). The greatest percentage of new neurons was found in the young runners (~81.3%). In addition, although the total number of BrdU+
cells was similar in young controls and aged runners, there was more neurogenesis in young sedentary mice (49.9%) than in active aged mice (25.6%). Interestingly, the probe trial indicated that old runners may learn better than young controls. Thus, there appears to be no simple relationship between the number of new neurons and learning. For example, changes in the physiological properties of new cells may occur with exercise. Furthermore, other factors associated with running, such as increased neurotrophin and neurotransmitter levels, may contribute to improved learning (Cotman and Berchtold, 2002
), although it is not known whether these changes occur in aged runners. The percentage of cells that become neurons in aged sedentary mice (9.5%) was consistent with previous work (Kempermann et al., 1998
; Heine et al., 2004
), although some researchers report up to 50% BrdU/NeuN cells in aged animals (Drapeau et al., 2003
; Bizon et al., 2004
). The increase in neurogenesis observed with exercise is comparable with enrichment data in aged mice (Kempermann et al., 1998
). Neither exercise nor enrichment affected the percentage of cells that became glia in either age group.
To investigate how the aged hippocampal environment influences new neurons, mice were injected with a retrovirus selective for dividing cells (van Praag et al., 2002
). Four weeks after injection, dendritic length, dendritic branching, and spine density of the new cells in the aged brain were similar to those in the young brain, suggesting that the function of the new cells in the aged brain was intact. However, more detailed physiological studies and a time course of the further development of these cells are needed to draw a more definite conclusion. Full maturation of new neurons takes several more weeks (van Praag et al., 2002
) and may be delayed in the aged brain (Rao et al., 2005
). In addition, new cells in the old brain may lose functional synapses much faster than in the young brain as a result of diminished trophic support (Sonntag et al., 1997
). Furthermore, because of the limitations of the retroviral labeling technique, spine number was compared only between young and aged runners and was found not to differ between the groups. We do not know whether spine quantity increases as a function of running in aged animals. In young mice, however, spine density does not differ between controls and runners (C. Zhao, E. M. Teng, R. G. Summers, and F. H. Gage, personal communication).
In the present study, we found no decline in dentate gyrus blood vessel size or number with aging. Exercise did enhance the perimeter and surface area of blood vessels in young but not in aged mice. The findings for the young mice are consistent with other studies. For example, activity matched to a motor skill-learning task enhanced capillary density in the cerebellum (Black et al., 1990
). More recently, voluntary wheel running has been found to increase angiogenesis in the motor cortex, cerebellum, and hippocampus (Swain et al., 2003
; Lopez-Lopez et al., 2004
). The lack of vascular plasticity with exercise in the older animals may be a result of reduced IGF-1 (Sonntag et al., 1997
) and vascular endothelial growth factor levels (Shetty et al., 2005
). In addition, decreased mitochondria content in capillary endothelial cells has been reported previously (Burns et al., 1981
). However, lack of exercise-induced angiogenesis is not a rate-limiting factor for neurogenesis, given the significant increase in new neurons in aged runners.
In summary, exercise restores spatial learning and neurogenesis in aged mice. Interestingly, the properties of new neurons do not appear to change with aging, suggesting that the local hippocampal environment of the aged dentate gyrus can sustain neurogenesis.