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重疾病包括阿尔茨海默病和阿尔茨海默病相关的痴呆症（AD/ADRD），以及视觉、听力和嗅觉（嗅觉）丧失等感官衰退。我们假设这些多重疾病共享存在于家庭环境中的共同神经毒性危险因素。随着近年来在家时间的增加，人类暴露于家庭环境中的神经毒物正在发生变化。然而，这些变化对发生神经认知-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）狗作为家庭环境源性神经毒物对人类健康影响的有效哨兵模型。宠物狗是很有希望的哨兵，因为它们共享人类的室内和室外家庭环境，在家中同样暴露于有毒物质，但毒性作用的发作潜伏期较短。狗的寿命比人类短得多，但这两个物种都经历了类似的神经认知-感觉衰老的多重疾病。因此，对狗的流行病学研究可以帮助我们快速了解风险因素暴露变化对人类健康的影响。我们将确定人类/狗共同的神经毒物暴露和狗的神经认知-感觉结果与家庭环境中发现的一组常见神经毒物，有毒重金属As， Cd, Cr， Hg和Pb有关。这些金属在神经组织中积累并具有明确的神经毒性作用，但它们对与年龄相关的神经功能衰退的影响尚不清楚。在Aim 1中，我们将在同居的人类和狗中建立神经认知-感觉衰老多病的共同风险。我们将确定狗的认知和感觉功能衰退与衰老有关，并将狗的衰退轨迹与同居人类的衰退联系起来。在目标2中，我们将通过比较饮用水和室内灰尘中的重金属浓度与狗和人类血液中的重金属浓度，来验证伴侣犬作为人类和环境重金属暴露的哨兵的作用。在Aim 3中，我们将确定高重金属负荷对狗神经认知-感觉衰老多种疾病以及血液代谢的影响。本研究的结果将建立伴侣犬作为人类年龄相关神经认知-感觉衰退和AD/ADRD风险的相关、便捷的替代模型，并证实人类和狗共享家庭环境重金属危险因素，这些危险因素会增加衰老过程中代谢功能障碍和神经认知-感觉衰退的风险。未来的研究可以利用这种哨兵犬模型来测试有前途的治疗方法，然后再应用于人类。这项工作与多个NIH研究所的使命相关，因为它包含了衰老，认知能力下降，感觉能力下降以及神经认知-感觉衰老和AD/ADRD风险的毒性风险因素等重要主题，并在相关动物模型中加速了时间。

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.