Interventions during the Initiation Stage

What types of interventions could be implemented in the initiation stage of brain aging to promote successful aging? Clearly, the issue is to discover interventions that will in turn establish the validity of mechanistic predictions. One possibility is to regulate the expression of BDNF, a downstream product of the CREB signal transduction pathway. In general, behavioral modifications and exercise may have merit. Several years ago, we began to examine the possibility that simple behavioral interventions, such as voluntary running, could promote neuron function via increased expression of BDNF. The experimental design of these studies included providing rats with access to a running wheel and recording the distance traveled while allowing each animal to run voluntarily. Voluntary exercise increased BDNF mRNA in hippocampal areas after several hours (Oliff et al., 1998) or days (Neeper et al., 1995, 1996). Recently, we also have examined the possible involvement of CREB-mediated signal transduction and found that pCREB increased in response to the voluntary running paradigm during a period of seven days, while total levels of CREB were unchanged (Shen et al., in press). Recent data also suggest that exercise improves memory in aged humans (Binder et al., 1999; Grealy et al., 1999; Williams et al., 1997), but the cause of this improvement in cognition has not yet been determined. However, together these data suggest that exercise can be a driving force on plasticity mechanisms by enhancing the activation of factors that promote transcription of genes involved with neuron function and ultimate survival.

Other interventions may also increase the expression of BDNF and have functional consequences. Several studies have been examining this question; the work on environmental enrichment is particularly important (Kempermann et al., 1997, 1998). Three weeks of environmental enrichment significantly stimulated cell proliferation, BDNF expression and resistance to insults, and inhibited apoptotic cell death (Young et al., 1999). Proliferating cell nuclear antigen (PCNA) levels were increased and double-stranded DNA breaks (TUNEL) were decreased in the enrichment group relative to controls, suggesting that neurogenesis occurred in response to environmental enrichment. Furthermore, rats in the enriched environment were resistant to kainate-induced seizures, and neuron death in response to seizures was ameliorated (Young et al., 1999). Finally, the expression levels of BDNF were higher in the enrichment group relative to controls. Upstream of BDNF expression, the authors also showed that environmental enrichment increased the expression of CREB and pCREB, particularly in the proliferating zone of new neurons.

To summarize, many studies indicate that environmental enrichment and exercise, relatively modest interventions, can promote successful aging by modifying brain health at the single neuron level. Studies on behavioral



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