Abstract Body (Do not enter title and authors here): Animals during hibernation suffer no ischemic consequences from their very much decrease heart/respiration rates, otherwise incompatible with life, but humans lost the ability to hibernate (presumably when their ancestors gained independence from the weather) and are highly vulnerable to ischemia. In a snail hibernation model, we isolated a brain metabolite only present in the plasma and brain of hibernating snails, and we characterized it with HPLC/MS. We found it is an activator of PHLPP1, a critical phosphatase in the conserved AMPK/mTOR signaling networks implicated in hibernation and fuel sensing (O₂, glucose, amino acids). We synthesized it chemically and named it Snail Neurometabolite Activator of PHLPP1 (SNAP). We hypothesized that SNAP may induce
hibernation in snails as well as mouse cells and organs that normally do not exhibit hibernation.
We utilized in vivo, in vitro and ex vivo models, using Alberta snails, mouse-derived fibroblasts and ischemia and reperfusion (IR) injury model with Langendorff-perfused mouse hearts, to assess the effects of SNAP on snail hibernation, as well as the fuel deprivation-induced stress resistance in mouse-derived cells and hearts.
SNAP injections in snails induced reversible hibernation indistinguishable from physiologic.
SNAP specifically dephosphorylates the PHLPP1 targets p-S6K and p-AKT (downstream of mTOR and AMPK respectively) in fibroblasts cultured in hypoxic and low-glucose conditions for 3 days, significantly suppressed O₂ consumption, apoptosis, and cell-cycle progression, but enhanced autophagy formation. Upon discontinuation of SNAP and return to normal culture conditions, the SNAP-treated cells had preserved metabolism and re-entered the cell cycle at much higher rates compared to the vehicle, suggesting protection from ischemia and reperfusion (IR) injury and entrance in a reversible hibernation-like state. Furthermore, SNAP conferred cardioprotective effects during IR injury by preserving LV pressure, max and min dp/dt and re-entering normal function much earlier at reperfusion compared to the vehicle.
SNAP offers protection from IR injury, inducing a hibernation-like state in mice cells and hearts, with wide implications for heart attack/stroke, preservation of donated organs for transplantation or even ultra-long space travel.