The utilization of AMPK activators is another strategy with which to stimulate autophagy for therapeutic purposes. AMPK is an evolutionary conserved sensor for disturbances in cellular energy balance and a major inducer of autophagy [117,118]. We have recently reviewed the integrated signaling network through which AMPK regulates the aging process [119]. For instance, AMPK can activate autophagy by directly targeting ULK1 which triggers mitophagy [120]. Moreover, AMPK can inhibit the activity of the mTOR complex 1 (mTORC1), either phosphorylating the regulatory Raptor component or activating TSC2 which subsequently inhibit mTOR activity [118]. Interestingly, several studies have indicated that the responsiveness of AMPK signaling declines with aging [118] which could impair autophagic responses during aging. For instance, Reznick et al. [121] observed that physical exercise and AICAR, a chemical activator of AMPK, induced a robust increase in AMPKα2 activity in the skeletal muscles of young mice whereas in old rats no stimulation was apparent. In addition, Liu et al. [122] demonstrated in a mouse model that stroke induced a major activation of AMPK in young animals but no response occurred in
