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DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging, but their underlying principles appear to be evolutionarily conserved, as they have now been successfully developed for many mammalian species. Here, we describe reliable and highly accurate epigenetic clocks shown to apply to 93 domestic dog breeds. The methylation profiles were generated using the mammalian methylation array, which utilizes DNA sequences that are conserved across all mammalian species. Canine epigenetic clocks were constructed to estimate age and also average time to death. We also present two highly accurate human–dog dual species epigenetic clocks (R = 0.97), which may facilitate the ready translation from canine to human use (or vice versa) of antiaging treatments being developed for longevity and preventive medicine. Finally, epigenome-wide association studies here reveal individual methylation sites that may underlie the inverse relationship between breed weight and lifespan. Overall, we describe robust biomarkers to measure aging and, potentially, health status in canines.

Modern dogs are distinguished among domesticated species by the vast breadth of phenotypic variation produced by strong and consistent human-driven selective pressure. The resulting breeds reflect the development of closed populations with well-defined physical and behavioral attributes. The sport-hunting dog group has long been employed in assistance to hunters, reflecting strong behavioral pressures to locate and pursue quarry over great distances and variable terrain. Comparison of whole-genome sequence data between sport-hunting and terrier breeds, groups at the ends of a continuum in both form and function, reveals that genes underlying cardiovascular, muscular, and neuronal functions are under strong selection in sport-hunting breeds, including ADRB1 , TRPM3 , RYR3 , UTRN , ASIC3 , and ROBO1 We also identified an allele of TRPM3 that was significantly associated with increased racing speed in Whippets, accounting for 11.6% of the total variance in racing performance. Finally, we observed a significant association of ROBO1 with breed-specific accomplishments in competitive obstacle course events. These results provide strong evidence that sport-hunting breeds have been adapted to their occupations by improved endurance, cardiac function, blood flow, and cognitive performance, demonstrating how strong behavioral selection alters physiology to create breeds with distinct capabilities., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)