A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus

Abstract

Primates tend to be long-lived for their size with humans being the longest lived of all primates. There are compelling reasons to understand the underlying age-related processes that shape human lifespan. But the very fact of our long lifespan that makes it so compelling, also makes it especially difficult to study. Thus, in studies of aging, researchers have turned to non-human primate models, including chimpanzees, baboons, and rhesus macaques. More recently, the common marmoset, Callithrix jacchus, has been recognized as a particularly valuable model in studies of aging, given its small size, ease of housing in captivity, and relatively short lifespan. However, little is known about the physiological changes that occur as marmosets age. To begin to fill in this gap, we utilized high sensitivity metabolomics to define the longitudinal biochemical changes associated with age in the common marmoset. We measured 2104 metabolites from blood plasma at three separate time points over a 17-month period, and we completed both a cross-sectional and longitudinal analysis of the metabolome. We discovered hundreds of metabolites associated with age and body weight in both male and female animals. Our longitudinal analysis identified age-associated metabolic pathways that were not found in our cross-sectional analysis. Pathways enriched for age-associated metabolites included tryptophan, nucleotide, and xenobiotic metabolism, suggesting these biochemical pathways might play an important role in the basic mechanisms of aging in primates. Moreover, we found that many metabolic pathways associated with age were sex specific. Our work illustrates the power of longitudinal approaches, even in a short time frame, to discover novel biochemical changes that occur with age.

Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans

“…Investigations into the metabolism-aging interplay focusing on changes at the level of the metabolome have been increasingly reported in a variety of model organisms (Hoffman et al, 2016; Laye et al, 2015; Lewis et al, 2018; Ma et al., 2015; Pontoizeau et al, 2014). Studies have also been conducted in humans, including one report linking several lipid species to human longevity (Gonzalez-Covarrubias et al, 2013) and another noting associations among citric acid cycle intermediates and bile acids on the lifespan in humans (Cheng et al, 2015).…”

“…Studies have also been conducted in humans, including one report linking several lipid species to human longevity (Gonzalez-Covarrubias et al, 2013) and another noting associations among citric acid cycle intermediates and bile acids on the lifespan in humans (Cheng et al, 2015). However, arriving at consensus changes that define the aging metabolome has proven somewhat elusive, given the inherent complexity of the metabolome, as well as other variables across studies (De Guzman et al, 2013; Hoffman et al, 2016; Kim et al, 2014; Ma et al., 2015). Furthermore, to what extent changes to the aging metabolome are amenable to interventions such as DR, and more important, the human relevance of these observations, is not well understood.…”

“…The metabolomic profile of aging has also been assessed in a number of other species, including Drosophila melanogaster (Hoffman et al, 2014), naked mole rat (Mitchell et al, 2007), marmoset (Hoffman et al, 2016), and humans (Cheng et al, 2015). Tissue-specific metabolomic signatures were reported to correlate with body mass and lifespan across a diverse number of species, and some tissue metabolites were found that discriminated long-lived rodents from controls (Ma et al, 2015).…”

Proteomics and metabolomics in ageing research: from biomarkers to systems biology

“…For example, age-related changes in protein concentrations are seen in mosquitoes [84], honeybees [85], sea urchins [86], and macaque hearts [87], and age-related longitudinal changes in metabolites have been measured in the common marmoset [88]. In addition, metabolite concentrations are correlated with longevity across 26 mammalian species [89], leading to new insights into how metabolite concentrations change across species with highly variable lifespans.…”

“…Work in Drosophila found significant down-regulation of fatty acid and sugar metabolism with age [69], and a study of metabolite pathway enrichment in dietary restricted flies showed a global decline in amino acid metabolism in response to dietary restriction [35]. Metabolomic profiles in aged mouse brains show significant changes in amino acid and nucleotide metabolism [82], and nucleotide metabolism is significantly altered with age longitudinally in the common marmoset [88]. In addition, energy metabolism and amino acid metabolism are significantly altered in Alzheimer’s patients compared with cognitively normal individuals [94].…”