The Dog Aging Project: Genetic and Environmental Determinants of Healthy Aging in Companion Dogs

整体-狗老化项目：遗传和环境的破坏者 伴侣犬的健康衰老 摘要 年龄是发达国家几乎所有主要死亡原因的最大风险因素。研究 相对短命的模式生物表明，一系列不同的遗传和环境因素的影响， 通过进化上保守的途径衰老。然而，我们还远远没有了解到 这些因素解释了自然人群中与年龄相关的变化，以及影响 实验室中的老化可以在现实世界中实现。对人的大规模研究可以揭示一些基因 以及与长寿个体相关的环境因素，但相对而言， 让它们能够健康衰老的机制。为了弥补实验动物与人类之间的差距， 老年科学家需要一个模型，在这个模型中他们可以确定：a）基因和环境如何塑造一个人的 老化轨迹;以及B）不仅是个体何时死亡，而且是为什么死亡。理想情况下，它应该是一个模型 其环境变化类似于在人类群体中发现的环境变化，以及适合于 在人类身上测试各种可能的干预措施。这些挑战都得到了很好的应对 被同伴狗家犬所杀狗的变化很大，不仅在大小，形状和行为， 还取决于他们的寿命和死因狗分享我们的环境，我们的疾病负担， 他们有一个复杂的医疗保健系统。这个U19项目将创建 狗老化项目，一项全国性的，长期的纵向研究老化的10,000伴侣狗。的 这个U19项目的首要目标是：1）通过新的脆弱指数、共病指数和年龄指数来定义犬的衰老。 和炎症; 2）通过发现遗传和环境因素来解释狗的衰老， 影响衰老，并通过鉴定中间分子特征-代谢组，微生物组和表观基因组- 通过这种影响的展开; 3）干预衰老，在第一个双盲，安慰剂对照 兽医临床试验，以评估一种有前途的药物，雷帕霉素，对寿命和健康的影响， 伴侣犬这些目标将通过一套四个高度互动的项目来实现。 由四个核心组成，它们的协同努力创造了一个真正大于其非常强大的部分之和的整体。 狗老化项目还将创建一个资源和研究管道，这将有助于辅助研究， 与人类健康相关的广泛研究。更深入地了解基因型和 环境相互作用来调节狗的衰老将产生许多关于生物学的新假设。 老化的迹象这项工作产生的数据，作为一个开放科学项目公开， 将促进全球科学家的长期研究。重要的是，考虑到人们喜欢他们的狗， U19项目有潜力吸引公众支持老年科学研究， 整个领域都受益于更多的关注和资源。因此，成功地完成每一个目标， 将改善狗和人类的生活质量。

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 them 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 Project will create the Dog Aging Project, a nationwide, long-term longitudinal study of aging in 10,000 companion dogs. The overarching goals of this U19 Project 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 veterinary 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. The Dog Aging Project will also create a resource and research pipeline that will facilitate ancillary studies on a wide range of studies of relevance to human health. A greater mechanistic understanding of how genotype and environment interact to modulate aging in dogs will generate a multitude of new hypotheses about the biology of aging in both dogs and humans. The data generated by this work, made public as an Open Science project, will facilitate long-term research by scientists worldwide. Importantly, given that people love their dogs, this U19 Project has the potential to engage the support of the general public for geroscience research, with the entire field benefiting from greater attention and resources. Thus, successful completion of each of these aims will improve the quality of life for dogs and for humans.