IP₃ Receptors, Mitochondria, and Ca²⁺ Signaling: Implications for Aging

Figure 4

A speculative antiaging strategy based on restoring IP₃R-mediated Ca²⁺ signaling and chemical induction of autophagy. Provided the concept that aging cells are characterized by suppressed IP₃ signaling or attenuated IP₃R, Ca²⁺-release activity is relevant in humans, and elevating IP₃ levels may compensate for the decline in the IP₃/IP₃R-signaling axis. This may contribute to a decline in the p66^Shc-mediated ROS production, an activation of sirtuin-dependent mitochondrial biogenesis, and the lowering of ROS production. The final step of this compensatory response consists in the autophagic removal of the damaged mitochondria. Hence, chemical induction of autophagy (e.g., by rapamycin or spermidine) is likely critical for successful and healthy aging in human beings. It is important to note that this concept is based on a recent report on C. elegans, in which ablations of inhibitors of EGF signaling enhance IP₃R signaling and promote healthy lifespan extension. Green arrows: stimulation; red lines: inhibition; black arrows: Ca²⁺ flux.