One of the major concern of the public health system is represented by the growing number of people suffering of sarcopenia, a disease characterized by a progressive loss of skeletal muscle force, quality and mass during aging which results in increased debility and death. Despite several studies carried out on the various aspects of this disease, no cure has been established, so far. In our previous work, we showed that GDF5 overexpression prevents age-related muscle wasting, however, a deeper report on mechanisms and consequences of GDF5 implement on aged muscle was missing. We now present an extensive characterization of the physiological and molecular effects of GDF5 in muscle during aging and show its “rejuvenating signature”. Based on this proof of concept, we defined a cutting-edge therapeutic approach describing how the recombinant GDF5 treatment is able to fight the age-related skeletal muscle wasting in mice and represents a strong curative potential on humans.