OVERALL – THE DOG AGING PROJECT: GENETIC AND ENVIRONMENTAL DETERMINANTS OF HEALTHY AGING IN COMPANION DOGS ABSTRACT Age is the single greatest risk factor for nearly every major cause of mortality in developed nations. Studies in relatively short-lived model organisms show that a diverse array of genetic and environmental factors influence aging through evolutionarily conserved pathways. However, we are still far from understanding the extent to which these factors explain age-related variation in natural populations, and whether interventions that affect aging in the lab can do so in a real-world setting. Large-scale studies in people can reveal some of the genetic and environmental factors that are associated with especially long-lived individuals, but tell us relatively little about the mechanisms that allowed those individuals to age well. To bridge the gap from lab animals to humans, geroscientists need a model in which they can determine: a) how genes and environment shape an individual's aging trajectory; and b) not only when an individual dies, but also why it dies. Ideally, it would be a model whose environmental variation is similar to that found in human populations, and a model that is suitable for testing the sorts of interventions that one might consider in humans. These challenges are extremely well met by the companion dog, Canis lupus familiaris. Dogs vary tremendously, not only in size, shape, and behavior, but also in how long they live and their causes of death. Dogs share our environment, our disease burden and attendant risk factor of age, and they have a sophisticated health care system. This U19 brings together a tremendously talented and collaborative team to create the Dog Aging Project, a nationwide, long- term longitudinal study of aging in 10,000 companion dogs. The overarching goals of this U19 are 1) to define aging in dogs through novel indices of frailty, comorbidity and inflammaging; 2) to explain aging in dogs by discovering the genetic and environmental factors that influence aging, and by identifying intermediate molecular traits – metabolome, microbiome, and epigenome – through which this influence unfolds; and 3) to intervene in aging, in the first double-blind, placebo-controlled clinical trial to assess the effects of a promising drug, rapamycin, on lifespan and healthspan in companion dogs. These aims will be accomplished through a set of four highly interactive Projects supported by four Cores, whose synergistic efforts create a whole that is truly greater than the sum of its very strong parts. A sustainable biobank will store tissue samples from participating dogs, enabling continued discovery even after the original cohort has died. These stored samples, along with the data generated by this U19, will be made public as an Open Science resource, facilitating long- term research by scientists worldwide. A greater mechanistic understanding of how genotype and environment interact to modulate aging in dogs...