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

项目摘要 年龄是人类许多疾病的单一最大风险因素，包括大多数主要死亡原因。 在实验室环境中对短寿命模式生物的研究揭示了保守的分子 与衰老相关的通路。然而，我们不知道这些发现在多大程度上解释了 在自然人口中观察到的老龄化速度有相当大的差异，包括人类。大规模的人类 研究可以教给我们很多关于衰老决定因素的知识，但这些研究费用高昂，可能需要数十年的时间。我们 需要一个翻译相关的模型来帮助我们理解遗传和环境因素 塑造自然界的衰老，这可以揭示这些关系背后的机制，那就是 适用于测试我们可能考虑在人类群体中使用的干预措施。为了解决这一未得到满足的需求，我们 创建了狗老化项目，这是一项对伴侣犬健康衰老的长期纵向研究 家族性狼疮。这只狗是一个理想的模型。它们不仅在大小、形状和行为上有巨大的差异，而且 在预期寿命和与年龄相关的疾病风险方面也是如此。狗和我们一样分担着我们的疾病负担 拥有先进的医疗保健系统来诊断、治疗和预防疾病。鉴于他们的 相对较短的寿命，我们可以从狗身上学到人类需要几十年才能学到的东西。狗狗老龄化项目 开始于2018年，创建了一个高度协作的团队，拥有构建这款游戏所需的广泛经验- 改变学习。我们的团队已经建立了一个强大的基础设施来招募数千名参与其中的狗主人 对，并收集业主报告的调查数据、公开可用的环境数据和用于 全基因组测序、临床化学和经济学测量。到目前为止，我们已经招募了超过44,000名学生 狗进入这项长期的研究，远远超过了我们最初的目标。犬只老化项目数据和生物制品 不仅被狗老化项目的研究人员研究，而且还被感兴趣的人访问 团队外的研究人员，履行狗老化项目作为开放科学资源的承诺。 狗狗老龄化项目在实现U19的总体目标方面取得了很好的进展，这些目标是1)到 通过虚弱、多发病和炎症的新指标定义狗的衰老；2)解释狗的衰老 通过发现影响衰老的遗传和环境因素，以及通过识别中间 分子特征-代谢组、微生物组和表观基因组-通过这些特征这种影响展开；以及3) 干预衰老，在首个双盲、安慰剂对照的兽医临床试验中，评估了 有希望的药物，雷帕霉素，对伴侣犬的寿命和健康寿命。我们取得了很好的进展 由五个核心和四个项目以确保整个狗的方式协作成为可能 老龄化工程远远大于各部分之和。宠物狗老龄化项目将对 老年科学和兽医科学，并将吸引公众的支持，使整个领域 福利。

Project Summary Age is the single greatest risk factor for many diseases in humans, including most major causes of mortality. Studies in short-lived model organisms in the laboratory environment have revealed conserved molecular pathways associated with aging. However, we do not know to what extent these discoveries explain the considerable variation in rates of aging observed in natural populations, including humans. Large-scale human studies can teach us a great deal about determinants of aging, but they are costly and can take decades. We need a translationally relevant model that can help us understand the genetic and environmental factors that shape aging in the natural world, that can reveal the mechanisms underlying these relationships, and that is suitable for testing interventions that we might consider in human populations. To address this unmet need, we created the Dog Aging Project, a long-term longitudinal study of healthy aging in the companion dog, Canis lupus familiaris. The dog is an ideal model. They vary tremendously not only in size, shape, and behavior, but also in life expectancy and age-related risk of disease. Dogs share our disease burden as well as our environment, and have a sophisticated health care system to diagnose, treat and prevent diseases. Given their relatively short lifespan, we can learn from dogs what would take decades in humans. The Dog Aging Project began in 2018, creating a highly collaborative team with the breadth of experience needed to build this game- changing study. Our team has built a powerful infrastructure to recruit thousands of participating dog-owner pairs, and to collect owner-reported survey data, publicly available environmental data, and biospecimens for whole genome sequencing, clinical chemistry, and -omic measures. To date, we have enrolled over 44,000 dogs into this long-term study, far surpassing our original goal. Dog Aging Project data and biospecimens are not only being studied by researchers on the Dog Aging Project, but are also being accessed by interested researchers outside of the team, fulfilling the promise of the Dog Aging Project as an Open Science resource. The Dog Aging Project has made excellent progress towards the overarching goals of this U19, which are 1) to define aging in dogs through novel indices of frailty, multimorbidity 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. Our excellent progress has been made possible by the five Cores and four Projects that collaborate in a way that ensures the whole of the Dog Aging Project is far greater than the sum of its parts. The Dog Aging Project will have a major impact on geroscience and veterinary science, and will engage the support of the general public such that the entire field benefits.