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

狗衰老项目：伴侣犬健康衰老的遗传和环境决定因素

• 批准号: 10437998
• 负责人: Daniel Edward Promislow
• 金额: $ 61.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437998
• 关键词: Adult; Affect; Age; Age Factors; Aging; Ancillary Study; Animal Model; Animals; Attention; Behavior; Biological; Biological Models; Biology of Aging; Canis familiaris; Cause of Death; Cessation of life; Chronic; Clinical Trials; Collaborations; Companions; Complex; Controlled Environment; Data; Data Analyses; Data Science; Databases; Developed Countries; Development; Diagnosis; Diagnostic; Disease; Dose; Double-Blind Method; Drosophila genus; Economic Burden; Encapsulated; Enrollment; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; Evaluation; Exhibits; Experimental Models; Future; General Population; Genes; Genetic; Genetic study; Genome; Genomics; Genotype; Geroscience; Goals; Gray Wolf; Health; Healthcare Systems; Human; Inbreeding; Incidence; Individual; Inflammaging; Inflammation; Information Technology; Insurance; Internal Medicine; Intervention; Laboratory Animals; Longevity; Longitudinal Studies; Love; Medical; Medical Records; Methods; Modeling; Molecular; Molecular Analysis; Molecular Biology; Morbidity - disease rate; Mus; Nematoda; Outcome; Pathway interactions; Pharmaceutical Preparations; Placebos; Population; Privatization; Prognostic Marker; Prospective cohort; Quality of life; Quantitative Genetics; Randomized Controlled Trials; Research; Resources; Risk Factors; Rodent; Scientist; Shapes; Sirolimus; Sum; System; Systems Biology; Testing; Translations; Variant; Veterinarians; Work; Yeasts; age effect; age related; biodemography; burden of illness; cognitive function; cohort; comorbidity; data management; drug candidate; drug efficacy; epigenome; experience; frailty; healthspan; healthy aging; heart function; improved; indexing; metabolome; microbiome; middle age; mortality; multiple omics; novel; open data; placebo group; primary outcome; programs; recruit; secondary outcome; slow potential; social; statistics; tool; trait; treatment group

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.

总体而言——狗衰老项目：遗传和环境决定因素 伴侣犬的健康老龄化 抽象的 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。研究于 相对较短寿命的模式生物表明，多种遗传和环境因素会影响 通过进化上保守的途径衰老。然而，我们还远未了解其程度 这些因素解释了自然人群中与年龄相关的变化，以及干预措施是否会影响 实验室中的老化可以在现实世界中实现。对人类的大规模研究可以揭示一些遗传因素 以及与特别长寿的个体相关的环境因素，但告诉我们的信息相对较少 关于让它们能够很好地老化的机制。为了弥合实验室动物与人类之间的差距， 老年科学家需要一个模型来确定：a) 基因和环境如何塑造个体 老化轨迹； b) 不仅要了解一个人何时死亡，还要了解其死亡原因。理想情况下，它应该是一个模型 其环境变化与人类群体中发现的相似，并且模型适合 测试人们可能考虑对人类进行的各种干预措施。这些挑战都得到了很好的应对 由伴侣犬 Canis lupusamilis 提供。狗的差异很大，不仅在大小、形状和行为上， 还包括他们的寿命和死亡原因。狗与我们分享我们的环境、我们的疾病负担和 随之而来的危险因素是年龄，而且他们拥有完善的医疗保健系统。这个U19项目将创造 狗衰老项目，一项全国性的长期纵向研究，对 10,000 只伴侣犬进行衰老研究。这 该 U19 项目的总体目标是 1) 通过新的虚弱、合并症指标来定义狗的衰老 和发炎； 2）通过发现导致狗衰老的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—— 这种影响力通过它得以展现； 3）干预衰老，这是第一个双盲、安慰剂对照的研究 兽医临床试验，评估一种有前景的药物雷帕霉素对动物寿命和健康寿命的影响 伴侣犬。这些目标将通过一组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强大部分之和的整体。 狗老化项目还将创建一个资源和研究渠道，以促进有关狗老化的辅助研究 与人类健康相关的广泛研究。对基因型和基因型的机制有更深入的了解 环境相互作用调节狗的衰老将产生大量关于生物学的新假设 狗和人类的衰老。这项工作生成的数据作为开放科学项目公开， 将促进全世界科学家的长期研究。重要的是，考虑到人们爱他们的狗，这 U19 项目有潜力吸引公众对老年科学研究的支持， 整个领域受益于更多的关注和资源。因此，成功完成这些目标中的每一个 将改善狗和人类的生活质量。