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 will, first, present literature-based data on life-history traits that may affect dog lifespan, including adaptations at the whole-organism, and organ-level. At the cellular level, I will 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, a phenotype which could increase the likelihood of large breed dogs developing cancer. Because oxidative stress is a byproduct of aerobic metabolism, I will also present data on oxidative stress in dogs that point to the fact that small breeds of dogs accumulate significantly more lipid peroxidation damage (LPO) in their plasma compared with large breed dogs, in opposition to predicted lifespan predictions. And, that 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. To address potential interventions to extend lifespan in domestic dogs, I will describe experimental alterations to cellular architecture to test the “membrane pacemaker” hypotheses of metabolism and aging. This hypothesis suggests that increased lipid unsaturation and large amounts of polyunsaturated fatty acids (PUFAs) in cell membranes can increase cellular metabolic rates and oxidative damage, leading to potential decreased longevity. By decreasing total saturation of primary fibroblast cells from small and large breed dogs, we found that aerobic metabolism decreased compared with untreated cells, a trait associated with longer lifespans.