Figure 4.

The overlapping actions of metformin and rapamycin. Rapamycin acts by directly inhibiting mTOR and therefore translation regulation, which has a major influence of highly regulated processes such as mitochondrial biogenesis and autophagy. Metformin acts indirectly on the mTOR pathway through inhibition of complex I and activation of AMPK signaling. Metformin also reduces reactive oxygen species (ROS) via inhibitory action on complex I and NAD(P)H oxidase having an overall effect as a redox regulator. Downstream of metformin action, low level ROS can indirectly trigger signals for mitochondrial biogenesis and turnover of organelles and proteins via autophagy. Vice versa, maintenance of healthy mitochondrial networks involving autophagy and mitochondrial biogenesis further reduces build-up of damaging levels of ROS.