Effects of metformin, rapamycin, and resveratrol on cellular metabolism of canine primary fibroblast cells isolated from large and small breeds as they age.

Small breed dogs have longer lifespans than their large breed counterparts. Previous work demonstrated that primary fibroblast cells isolated from large breed young and old dogs have a persistent glycolytic metabolic profile compared with cells from small breed dogs. Here, we cultured primary fibroblast cells from small and large, young and old dogs and treated these cells with three commercially available drugs that show lifespan and health span benefits, and have been shown to reduce glycolytic rates: rapamycin (rapa), resveratrol (res) and metformin (met). We then measured aerobic and anaerobic cellular respiration in these cells. We found that rapa and res increased rates of non-glycolytic acidification in small and large breed puppies and basal oxygen consumption rates (OCR) in small and large breed puppies. Rapa increased proton leak and non-mitochondrial respiration in small and large breed puppies. Maximal respiration was significantly altered with rapa treatment but in opposing ways: large breed puppies showed a significant increase in maximal respiration when treated with rapa, and small old dogs demonstrated a significant decrease in maximal respiration when treated with rapa. In opposition to rapa treatments, met significantly decreased basal OCR levels in cells from small and large breed puppies. Our data suggest that rapa treatments may be metabolically beneficial to dogs when started early in life and more beneficial in larger breeds.