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

总体而言-狗的老龄化项目：遗传和环境决定因素 伴犬的健康衰老 摘要 在发达国家，年龄是几乎所有主要死亡原因的最大风险因素。研究项目： 寿命相对较短的模式生物表明，多种遗传和环境因素会影响 通过进化上保守的途径进行衰老。然而，我们仍然远未了解到什么程度 这些因素解释了自然人口中与年龄相关的变异，以及干预措施是否会影响 实验室中的衰老可以在真实世界中进行。在人体内进行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，但告诉我们的相对较少 关于让他们更好地衰老的机制。为了弥合实验室动物和人类之间的鸿沟， 老年学家需要一个他们可以确定的模型：a)基因和环境如何塑造一个人的 衰老轨迹；以及b)不仅是当一个人死亡时，而且还包括他为什么会死。理想情况下，它应该是一个模型 其环境变化类似于在人类种群中发现的变化，以及一个适合于 测试人们可能会考虑在人类身上进行的干预措施。这些挑战都得到了极好的应对 由同伴犬，家犬狼疮。狗的差异非常大，不仅在大小、形状和行为上， 还有它们的寿命和死亡原因。狗分享我们的环境，我们的疾病负担，以及 随之而来的危险因素是年龄，而且他们有完善的医疗保健系统。这个U19项目将创建 狗老化项目，一项全国性的、对10,000只伴犬进行的长期纵向老化研究。这个 该U19项目的首要目标是：1)通过新的虚弱、共病指标来定义狗的衰老 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，并通过识别中间分子特征-代谢组、微生物组和表观基因组- 这种影响通过它展开；以及3)干预衰老，在第一次双盲、安慰剂对照试验中 一项兽医临床试验，以评估一种有前途的药物雷帕霉素对中国人寿命和健康的影响 伴犬。这些目标将通过一套四个高度互动的项目来实现 四个核心，它们的协同努力创造了一个真正大于其非常强大部分的总和的整体。 犬类老化项目还将建立一个资源和研究渠道，以促进对 与人类健康相关的广泛研究。更深入地理解基因和基因如何 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说 狗和人都有衰老的迹象。这项工作产生的数据作为开放科学项目公之于众， 将促进世界各地科学家的长期研究。重要的是，考虑到人们喜欢他们的狗，这一点 U19项目有可能吸引公众对老年科学研究的支持， 整个领域都受益于更多的关注和资源。因此，这些目标中的每一个都能顺利完成 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.