Abstract
Among several animal groups (eutherian mammals, birds, reptiles), lifespan positively correlates with body mass over several orders of magnitude. Contradicting this pattern are domesticated dogs, with small dog breeds exhibiting significantly longer lifespans than large dog breeds. The underlying mechanisms of differing aging rates across body masses are unclear, but it is generally agreed that metabolism is a significant regulator of the aging process. Herein, we performed a targeted metabolomics analysis on primary fibroblasts isolated from small and large breed young and old dogs. Regardless of size, older dogs exhibited lower glutathione and ATP, consistent with a role for oxidative stress and bioenergetic decline in aging. Furthermore, several size-specific metabolic patterns were observed with aging, including the following: (i) An apparent defect in the lower half of glycolysis in large old dogs at the level of pyruvate kinase. (ii) Increased glutamine anaplerosis into the TCA cycle in large old dogs. (iii) A potential defect in coenzyme A biosynthesis in large old dogs. (iv) Low nucleotide levels in small young dogs that corrected with age. (v) An age-dependent increase in carnitine in small dogs that was absent in large dogs. Overall, these data support the hypothesis that alterations in metabolism may underlie the different lifespans of small vs. large breed dogs, and further work in this area may afford potential therapeutic strategies to improve the lifespan of large dogs.
Highlights
Domestic dogs are the most morphologically and physiologically diverse mammal species known [1], and the underlying consequences of this diversity span all levels of organization
Creatine increases were linked to muscle wasting with increased age [7] and lactate concentration in urine increased in older dogs [7], demonstrating a shift into a glycolytic phenotype similar to our studies using primary fibroblast cells [3]
Prior work has demonstrated that primary fibroblast cells isolated from dogs retain whole-animal, breed-specific metabolic qualities [3, 12]
Summary
Domestic dogs are the most morphologically and physiologically diverse mammal species known [1], and the underlying consequences of this diversity span all levels of organization. Small breed dogs live significantly longer than large breed dogs [2], and at the cell level, this whole-animal trait is accompanied by increased cellular aerobic metabolism and mitochondrial proton leak as dogs of each size age, with increases in glycolytic rate in large breed dogs across their life span [3]. The plasma metabolome associated with aging showed changes in amino acids and a decline in lipid metabolism with increasing age, while in urine, several Krebs’ cycle metabolites decreased with age [4]. Metabolomics analysis has mainly been at the level of urine and plasma, and includes a life-long project on Labrador retrievers stratified as control animals vs those calorically restricted (CR) for life. The only association to weight in metabolomics in the domestic dog has been a negative correlation with tryptophan metabolism [6]
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