Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD⁺ levels are reduced in multiple tissues and organs, including the brain. We found that NAD⁺ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase (Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase (Cask) as a potential downstream effector in response to age-associated NAD⁺ reduction in the hippocampus. Cask expression is responsive to NAD⁺ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD⁺ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD⁺ availability through supplementation of NAD⁺ intermediates, such as NMN.

认知功能障碍是全球人口老龄化中最令人关注的结果之一。但是，在衰老过程中削弱认知功能的机制仍然难以捉摸。已经确定NAD ⁺水平在包括脑在内的多个组织和器官中降低。我们发现NAD ⁺在衰老过程中，海马的水平下降，尽管我们观察到老年小鼠对空间学习/记忆能力的与年龄相关的影响最小，但我们发现它们在情境恐惧条件试验中对厌恶刺激产生了认知超敏反应。这种认知超敏性似乎与衰老过程中情绪（恐惧/焦虑）和感觉处理（休克敏感性）的改变有关，而不是反映出真正的调理/保持作用。补充烟酰胺单核苷酸（NMN）改善了超敏反应的感觉处理方面，并可能改善了其他相关行为。烟酰胺磷酸核糖基转移酶的特异性敲除（Nampt）在CA1区（而不是在齿状回）中，概括了这种在老年小鼠中观察到的认知超敏反应。我们确定钙/钙调蛋白依赖性丝氨酸蛋白激酶（Cask）作为响应年龄相关的NAD ⁺海马减少的潜在潜在效应子。木桶表达对NAD ⁺变化有响应，并且在衰老过程中海马中也降低。短期补充NMN可以增强老年小鼠海马中Cask的表达。其启动子活性以Sirt1依赖性方式调节。总而言之，NAD ⁺CA1区域的减少会导致与年龄相关的认知功能障碍的发展，可以通过补充NAD ⁺中间体（例如NMN）来增强NAD ^+的可用性来预防或治疗其中的某些方面。