The Growth Differentiation Factor 11 (GDF11) has been controversially involved in the aging/rejuvenation process. To clarify whether GDF11 is differently expressed during aging, we have evaluated GDF11 levels in skeletal muscles and hippocampi of young and old mice, sedentary or subjected to a 12-weeks triweekly training protocol. The results of real-time PCR and Western blot analyses indicate that skeletal muscles of sedentary old mice express higher levels of GDF11 compared to young animals (p < 0.05). Conversely, in hippocampi no significant differences of GDF11 expression are detected. Analysis of long-term potentiation, a synaptic plasticity phenomenon, reveals that population spikes in response to a tetanic stimulus are significantly higher in sedentary young mice than in old animals (p < 0.01). Training induces a significant improvement of long-term potentiation in both young and old animals (p < 0.05), an increase (p < 0.05) of skeletal muscle GDF11 levels in young mice and a reduction of GDF11 expression in hippocampi of old mice (p < 0.05). Overall, data suggest that GDF11 can be considered an aging biomarker for skeletal muscles. Moreover, physical exercise has a positive impact on long-term potentiation in both young and old mice, while it has variable effects on GDF11 expression depending on age and on the tissue analyzed.