Fig. 6

The schematic mechanism of action of AICAR and NAM. a AMP binds to the gamma subunit of AMPK, allosterically increases the exposure of T172 to the activating upstream kinases like LKB1 and CaMKK-beta, and hinders the access of upstream phosphatases like PP2A to this residue. b AMPK may undergo a series of phosphorylations by inhibitory upstream kinases like GSK3, AKT, and ERK; GSK3 phosphorylates the ST loop of the alpha subunit and primes the subsequent phosphorylations for others. Later on, the alpha subunit changes its conformation, and the T172 gets exposed to the inhibitory phosphatases. c Acting like AMP, AICAR increases T172 phosphorylation of the alpha subunit by facilitating the phosphorylation and hindering the dephosphorylation. Following that, AMPK activates autophagy in general. Additionally, AMPK increases the biogenesis of new mitochondria and the degradation of dysfunctional and damaged ones. Moreover, NAM increases SIRT1 activity. In turn, SIRT1 increases the LKB1 activity and indirectly increases the AMPK activity. Furthermore, it increases the functionality of mitochondria and decreases ROS production by damaged mitochondria. These sequence of events prevents the MSCs to age and to show senescence-associated changes like dysfunctional autophagosome accumulation, and enlarged and flattened morphology