There is increasing evidence that an active lifestyle benefits both body and brain. However, not everyone may be able to exercise due to disease, injury or aging-related frailty. Identification of cellular targets activated by physical activity may lead to the development of new compounds that can, to some extent, mimic systemic and central effects of exercise. This review will focus on factors relevant to energy metabolism in muscle, such as the 5’ adenosine monophosphate-activated protein kinase (AMPK) - sirtuin (SIRT1) - Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1 α ) pathway, and the molecules affecting it. In particular, putative exercise-mimetics such as AICAR, metformin, and GW501516 will be discussed. Moreover, plant-derived polyphenols such as resveratrol and (-)epicatechin, with exercise-like effects on the body and brain will be evaluated.