The Dog Aging Project has in recent years enrolled thousands of companion animals into multiple cohorts and studies, including a study of the effects of rapamyin as a treatment to slow aging in dogs. Much of the value of the Dog Aging Project taken as a whole lies in the generation of a large database of omics data that can then be mined for insights into aging in this species, some fraction of which will be applicable more generally to aging in other mammals – such as our own species.
In today’s open access paper, researchers present their findings from an analysis of metabolomic data derived from the Dog Aging Project’s smaller Precision Cohort, 784 dogs for whom more extensive biological data was gathered. Aging modifies circulating levels of a sizable fraction of the 133 metabolites measured in blood plasma from this cohort, which could be used as the basis for an aging clock, or inspected more closely for single measures that serve as biomarkers of aging.
The data points to increased levels of various acetylated amino acids as biomarkers of aging, the acetylated forms of phenylalanine, tryptophan, alanine, and glutamine that are produced when acetylated proteins are broken down. Changes in levels of these modified amino acids correlate with declining kidney function. It will be interesting to see whether human data exhibits a similar pattern; there is a fair amount of literature on the connection between protein acetylation and aging, similarly for protein acetylation and cellular senescence, and for other related topics.
Our understanding of aging has grown through the study of systems biology, including single-cell analysis, proteomics, and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) aims to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs.
Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP, 784 animals. By incorporating extensive metadata and whole genome sequencing, we overcome the limitations inherent in breed-based estimates of genetic effects, and probe the physiological basis of the age-related metabolome. We identified effects of age on approximately 36% of the 133 measured metabolites. We also discovered a novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which are generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. The only known source of free ptmAAs is the breakdown of protein, and we found additional evidence for protein catabolism within the metabolome. We found that clinical measures of kidney function at least partially mediate the age associations of the ptmAAs. These results suggest that ptmAAs accumulate with age among dogs and may serve as a biomarker of aging physiology.
This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.
