Tryptophan metabolism is differently regulated between large and small dogs

Abstract

Companion dogs have recently been promoted as an animal model for the study of aging due to their similar disease profile to humans, the sophistication of health assessment and disease diagnosis, and the shared environments with their owners. In addition, dogs show an interesting life history trait pattern where smaller individuals are up to twofold longer lived than their larger counterparts. While some of the mechanisms underlying this size and longevity trade-off are strongly suspected (i.e., growth hormone/IGF-I), there are likely a number of undiscovered mechanisms as well. Accordingly, we have completed a large-scale global metabolomic profiling of dogs encompassing a range of sizes and ages from three cities across the USA. We found a surprisingly strong location signal in the metabolome, stronger in fact than any signal related to age, breed, or sex. However, after controlling for the effects of location, tryptophan metabolism emerged as significantly associated with weight of the dogs, with small dogs having significantly higher levels of tryptophan pathway metabolites. Overall, our results point toward novel, testable hypotheses about the underlying physiological mechanisms that influence size and longevity in the companion dog and suggest that dogs may be useful in sorting out the complexities of the tryptophan metabolic network.

Metabolomics of aging in primary fibroblasts from small and large breed dogs

“…Data from the current study supports that increases in glycolysis are associated with glucose oxidation rather than lactate production (since lactate did not change). Using a metabolomics approach, others have found a negative correlation between glycolysis and age in whole-blood samples from dogs (Hoffman et al, 2020)…”

“…The metabolome is defined as the collection of metabolites in a cell or organism (Mishur and Rea 2012). To better understand the complexity of changes during aging, a metabolome-wide approach can be applied to pinpoint key metabolic steps that may determine lifespan in dogs (Soltow et al, 2010; Tombline et al, 2019; Hoffman et al, 2020). In rats, 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 (Mishur & Rea 2012).…”

“…Urine seems to more consistently give predictive measures of age, whereas serum analysis yields different metabolites (Richards et al, 2013). Thus far, the only association to weight in metabolomics in the domestic dog has been a negative correlation with tryptophan metabolism (Hoffman et al, 2020).…”

Physiological regulation of bone length and skeletal proportion in mammals

“…Recent studies have used companion dogs as animal models for the study of ageing as their disease profile is similar to that of humans (Hoffman et al., 2020). Dogs have a unique life history pattern that allows them to provide important information regarding body size and longevity.…”

“…The weights of dogs were used as an approximation of longevity as a 50‐fold variation in body mass is negatively associated with a two‐fold range in lifespan (Fleming et al., 2011; O'Neill et al., 2013). A particular study conducted a large‐scale global metabolomic profiling of dogs over a range of sizes and ages (Hoffman et al., 2020) and found that tryptophan was strongly associate with dog weight and that smaller dogs had significantly higher levels of tryptophan pathway metabolites, supporting that tryptophan metabolism may play an essential role in influencing ageing and longevity. Given that tryptophan metabolism is strongly implicated in regulation of appetite and nutritional status (Le Floc'h et al., 2011), it could provide another potential mechanism contributing to the regulation of adult body sizes among different dog breeds.…”