Companion dogs: sentinels for multimorbidity of human neurocognitive-sensory aging and susceptibility to Alzheimer’s disease and related dementias

与年龄相关的认知和感觉器官损伤的共同发生加剧了对老年人健康，生活方式和生活质量的负面影响。这些与年龄相关的多发病包括阿尔茨海默病和阿尔茨海默病相关痴呆（AD/ADRD），以及感觉减退，如视力、听力和嗅觉（嗅觉）丧失。我们假设这些多发病共享共同的神经毒物的危险因素，在家庭环境中存在。随着近年来在家中度过的时间的增加，人类暴露于家庭环境中的神经毒物正在发生变化。然而，这些变化对神经认知-感觉衰老和AD/ADRD风险的影响尚不清楚，需要几十年才能在人类中了解。我们建议研究宠物（伴侣）狗作为一个有效的哨兵模型，对人类健康的影响，家庭环境源性神经毒物。宠物狗是很有前途的哨兵，因为它们与人类共享室内和室外的家庭环境，在家中暴露于类似的有毒物质，但具有较短的毒性作用发作潜伏期。狗的寿命明显短于人类，但两个物种都经历了类似的神经认知-感觉衰老的多病性。因此，对狗的流行病学研究可以帮助我们快速了解危险因素暴露变化对人类健康的影响。我们将确定共享的人/狗神经毒物暴露和狗的神经认知感觉结果相关的一组常见的神经毒物在家庭环境中发现，有毒重金属砷，镉，铬，汞和铅。这些金属在神经组织中积累，具有明确的神经毒性作用，但其对年龄相关的神经功能衰退的影响尚不清楚。在目标1中，我们将建立共同的风险多发病的神经认知感觉老化的同居人类和狗。我们将确定与狗的衰老相关的认知和感觉功能下降，并将狗的下降轨迹与同居的人类下降联系起来。在目标2中，我们将通过比较饮用水和房屋灰尘中重金属的浓度与狗和人的血液中重金属的浓度来验证伴侣狗作为人类和环境重金属暴露的哨兵。在目标3中，我们将确定高重金属负荷对狗神经认知-感觉衰老多发病以及血液代谢的影响。这项工作的结果将建立伴侣狗作为人类年龄相关的神经认知感觉下降和AD/ADRD风险的相关，方便的替代模型，并确认人类和狗共享家庭环境重金属风险因素，增加代谢功能障碍和神经认知感觉下降的风险。未来的研究可以利用这种哨兵狗模型来测试有前途的治疗方法，然后再翻译给人类。这项工作与多个NIH研究所的使命相关，因为它包括衰老、认知衰退、感觉衰退和神经认知-感觉衰老的毒性风险因素以及相关动物模型中加速时间轴的AD/ADRD风险等重要主题。

The co-occurrence of age-related cognitive and sensory organ impairments exacerbates negative effects on the health, lifestyle, and quality of life of older adults. These age-related multimorbidities include Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD), in addition to sensory declines such as loss of vision, hearing, and olfaction (sense of smell). We hypothesize that these multimorbidities share common neurotoxicant risk factors that are present in the home environment. With the recent increase in time spent at home, the human exposure to home environment neurotoxicants is changing. However, the effects of these changes on the risk of developing neurocognitive-sensory aging and AD/ADRD are unknown and will take many decades to understand in humans. We propose to study pet (companion) dogs as an efficient sentinel model for the human health impacts of home environment-derived neurotoxicants. Pet dogs are promising sentinels as they share the human indoor and outdoor home environment, share similar exposure to toxicants in the home, yet have shorter latency of onset of toxic effects. Dog lifespan is significantly shorter than humans, yet both species experience similar multimorbidities of neurocognitive-sensory aging. Therefore, epidemiologic studies in dogs could help us quickly understand the human health implications of changes in risk factor exposure. We will determine shared human/dog neurotoxicant exposure and dog neurocognitive-sensory outcomes related to a common group of neurotoxicants found in the home environment, the toxic heavy metals As, Cd, Cr, Hg and Pb. These metals accumulate in neurologic tissues and have well-defined neurotoxic effects, but their effect on age-related neurologic decline is unclear. In Aim 1 we will establish shared risk of multimorbidity of neurocognitive-sensory aging in cohabiting humans and dogs. We will determine the cognitive and sensory function declines associated with aging in dogs and relate the trajectory of dog declines to cohabiting human declines. In Aim 2 we will validate companion dogs as sentinels for human and environmental heavy metal exposure by comparing drinking water and house dust concentrations of heavy metals with dog and human blood concentrations of heavy metals. In Aim 3 we will determine the impact of high heavy metal burden on dog neurocognitive-sensory aging multimorbidities, and on metabolism in the blood. The outcomes of this work will establish the companion dog as a relevant, expedient surrogate model of human age-related neurocognitive-sensory decline and AD/ADRD risk and confirm that humans and dogs share home environment heavy metal risk factors that increase the risk of metabolic dysfunction and neurocognitive-sensory decline in aging. Future studies could utilize this sentinel dog model to test promising therapeutics prior to translation to humans. This work is relevant to the mission of multiple NIH institutes as it encompasses the important topics of aging, cognitive decline, sensory decline, and toxicant risk factors for neurocognitive-sensory aging and AD/ADRD risk in a relevant animal model with an accelerated timeline.