The Physiological Conundrum That is the Domestic Dog.

Across Mammalia, body size and lifespan are positively correlated. However, in domestic dogs, the opposite is true: small dogs have longer lives compared with large dogs. Here, I present literature-based data on life-history traits that may affect dog lifespan, including adaptations at the whole-organism, and organ-level. Then, I compare those same traits to wild canids. Because oxidative stress is a byproduct of aerobic metabolism, I also present data on oxidative stress in dogs that suggests that small breed dogs accumulate significantly more circulating lipid peroxidation damage compared with large breed dogs, in opposition to lifespan predictions. Further, wild canids have increased antioxidant concentrations compared with domestic dogs, which may aid in explaining why wild canids have longer lifespans than similar-sized domestic dogs. At the cellular level, I describe mechanisms that differ across size classes of dogs, including increases in aerobic metabolism with age, and increases in glycolytic metabolic rates in large breed dogs across their lifespan. To address potential interventions to extend lifespan in domestic dogs, I describe experimental alterations to cellular architecture to test the "membrane pacemaker" hypotheses of metabolism and aging. This hypothesis suggests that increased lipid unsaturation and polyunsaturated fatty acids in cell membranes can increase cellular metabolic rates and oxidative damage, leading to potential decreased longevity. I also discuss cellular metabolic changes of primary fibroblast cells isolated from domestic dogs as they are treated with commercially available drugs that are linked to lifespan and health span expansion.