A large body of evidence report about the positive effects of physical activity in some pathophysiological conditions associated with age. Physical exercise alone or in combination with other medical therapies, unquestionably, causes reduction of symptoms in chronic non-transmissible diseases often leading to significant amelioration or complete healing. The molecular basis of this exciting therapeutic outcome, however, remain obscure. Epigenetics, exploring at the interface between the environment and the remodelling of chromatin structure, promises to shed light on this intriguing matter possibly contributing to the identification of novel therapeutic targets. In this review, we shall focalize on the role of class III histone deacetylases (HDACs), sirtuins (Sirts), which altered function has been frequently associated to the pathogenesis of aging-associated diseases including cancer, cardiovascular, muscular, neurodegenerative, bones and respiratory diseases, often with a controversial role. Numerous studies, in fact, demonstrate that Sirt-dependent pathways are activated upon physical and cognitive exercises linking the modulation of mitochondrial function, DNA structure and gene expression to designed medical therapies eventually leading to tangible beneficial outcomes. However, in similar conditions, other studies assign to sirtuins a negative pathophysiological role. Nevertheless, to study sirtuins in chronic diseases might lead to improve life quality in the elderly.