The metabolome as a biomarker of mortality risk in the common marmoset

Abstract

Recently, the common marmoset has been proposed as a non-human primate model of aging. Their short lifespan coupled with pathologies that are similar to humans make them an ideal model to understand the genetic, metabolic, and environmental factors that influence aging and longevity. However, many of the underlying physiological changes that occur with age in the marmoset are unknown. Here, we attempt to determine if individual metabolites are predictive of future death and to recapitulate past metabolomic results after a change in environment (move across the country) was imposed on a colony of marmosets. We first determined that low levels of tryptophan metabolism metabolites were associated with risk of death in a two-year follow-up in the animals, suggesting these metabolites may be used as future biomarkers of mortality. We also discovered that betaine metabolism and methionine metabolism are associated with aging regardless of environment for the animals, or of metabolomic assay technique. These two metabolic pathways are therefore of particular interest to examine as future targets for health and lifespan extending interventions. Many of the pathways associated with age in our first study of marmoset metabolomics were not found to have significant age effects in our second study, suggesting more work is needed to understand the reproducibility of large scale metabolomic studies in mammalian models. Overall, we were able to show that while several metabolomics markers show promise in understanding health and lifespan relationships with aging, it is possible that choice of technique for assay and reproducibility in these types of studies are still issues that need to be examined further.Authorship JMH, DELP, and DPJ designed the experiment. CR and ST were in charge of marmoset husbandry and sample collection. VT and DPJ completed the metabolomic analyses. JMH analyzed the data, made the figures, and wrote the first draft of the manuscript.

Comparative Metabolomic Study of Drosophila Species with Different Lifespans

“…The design of the comparative study was based on the difference in lifespans across the Drosophila species and, from the literature, the existence of age-associated metabolic alterations [ 10 , 19 , 20 , 21 , 22 ]. At first, the Drosophila species were grouped into three cohorts according to their life expectancy (long-lived, medium-lived, and short-lived species).…”

“…Due to the dramatic lifespan fluctuation across the species, individuals of different species with similar chronological ages are at various stages of life. In addition, the metabolomic composition of model organisms changes significantly throughout life [ 19 , 20 , 21 , 22 ]. In this case, the hallmarks of aging may be expected to have detectable effects on the metabolome that can prevent a correct selection of relevant metabolites.…”

Tryptophan metabolism is differently regulated between large and small dogs

“…This pattern supports recent research suggesting that tryptophan metabolism may be an integral part of aging and longevity. High tryptophan (van der Goot and Nollen 2013) and low kynurenine (Sutphin et al 2017) have been shown to promote longevity in worms, and low tryptophan levels were associated with increased risk of mortality in marmosets (Hoffman et al 2018b).…”

“…Over the past decade however, attention has focused more on the details of metabolic regulation which has emerged as a major contributor to the aging phenotype. Metabolomic studies have been increasingly used in both model (e.g., Fuchs et al 2010;Hoffman et al 2014;Houtkooper et al 2011) and non-model (Ball et al 2018;Hoffman et al 2018b;Hoffman et al 2016;Lewis et al 2018;Viltard et al 2019) organisms, leading to the discovery of common conserved pathways associated with aging and longevity. Also, diet as shown by dietary restriction, the most robust method to increase lifespan and health in model organisms, has been found to profoundly modify metabolic regulation (Matyi et al 2018).…”

“…One method to identify molecular networks underlying complex physiological processes is metabolomics, the analysis of thousands of individual metabolites in an organism to understand how changes in metabolism are associated with specific phenotypes of interest. Metabolomics has been used extensively in model organisms to understand aging and longevity (e.g., Fuchs et al 2010;Hoffman et al 2014;Houtkooper et al 2011), as well as non-human primates (Hoffman et al 2018b;Hoffman et al 2016) and humans (Darst et al 2019;Menni et al 2013). Previous research has suggested that individual dog breeds show different metabolomic profiles (Lloyd et al 2016;Nicholatos et al 2019;Viant et al 2007) and that metabolomic profiles change in response to diet and obesity (Forster et al 2018;Soder et al 2017), as well as with specific diseases (e.g., Gookin et al 2018;Hasegawa et al 2014;Minamoto et al 2015).…”