Although alterations in the sympathetic nervous system (SNS) with age have been reported, and serious degenerative diseases of the autonomic nervous system such as multiple system atrophy are more likely to strike older people, connections between dysregulated adrenergic receptors and age-associated diseases and phenotypes have not been well studied. Two recent reports suggest that SNS may be more closely connected than previously appreciated. First, low nanomolar concentrations of Alzheimer's disease (AD)-associated Aβ42-amyloid oligomers alter signaling by SNS neurotransmitter norepinephrine (NE) to sufficiently activate kinase GSK3β to hyperphosphorylate tau, a key mediator of neurotoxicity in AD. Connecting beta-amyloid to tau in AD has been a key quest in understanding AD and developing therapeutics. The α2 adrenergic receptor inhibitory drug idazoxan reduces GSK3β activity and tau phosphorylation in AD mice with improved cognitive function, even in the presence of beta-amyloid deposits. In this study, SNS activation in the brain coupled with problematic Aβ42-amyloid oligomers result in serious consequences that can be ameliorated by reducing SNS signaling. A second example of the detrimental effects of increased SNS signaling is the premature graying of hair in response to stress. Secretion of NE resulting from stress causes differentiation of most hair pigment melanocyte stem cells (MeSCs) into melanocytes, rapidly depleting the hair follicle of pigment-producing cells as mature melanocytes undergo apoptosis and MeSCs are eventually eliminated. Blockade of NE SNS signaling preserves hair coloration in stressed animals. Increased SNS activation has serious apparently irreversible effects on homeostasis in both situations. Although neither report directly addresses aging, given that AD and the loss of hair pigmentation have strong age associations, it is of interest to better understand the role that SNS has in promoting age-associated phenotypes generally and determine if tuning the SNS through drug-mediated attenuation of SNS signaling may be of medical benefit.

中文翻译：

---

过于同情的危险：去甲肾上腺素在阿尔茨海默氏病和头发变白中。

尽管有随年龄改变交感神经系统（SNS）的报道，而严重的自主神经系统退行性疾病（如多系统萎缩）更可能打击老年人，但肾上腺素能受体失调与年龄相关的疾病和表型之间存在联系没有很好的研究。最近的两项报告表明，SNS的联系可能比以前更紧密。首先，低纳摩尔浓度的与阿尔茨海默氏病（AD）相关的Aβ42-淀粉样蛋白低聚物会改变SNS神经递质去甲肾上腺素（NE）的信号传导，从而充分激活激酶GSK3β从而使tau磷酸化，而tau是AD中神经毒性的关键介质。将β-淀粉样蛋白连接到AD中的tau是了解AD和开发治疗药物的关键任务。α2肾上腺素受体抑制剂伊达唑烷可降低认知功能改善的AD小鼠的GSK3β活性和tau磷酸化，即使存在β-淀粉样蛋白沉积物也是如此。在这项研究中，大脑中的SNS激活与有问题的Aβ42-淀粉样蛋白低聚物结合在一起会导致严重的后果，可以通过减少SNS信号传导来减轻这种后果。SNS信号增加的有害影响的第二个例子是响应压力而使头发过早变白。由压力导致的NE分泌会导致大多数头发色素黑素细胞干细胞（MeSC）分化为黑色素细胞，随着成熟的黑色素细胞发生凋亡而迅速耗尽色素生成细胞的毛囊，并最终消除MeSC。NE SNS信号传导的封锁可保护压力较大的动物的头发。在这两种情况下，增加的SNS激活对稳态均具有严重的不可逆作用。尽管两个报告都没有直接针对衰老，但鉴于AD和脱发现象与年龄之间存在很强的关联性，因此有兴趣更好地了解SNS在促进年龄相关表型方面的作用，并确定是否通过药物介导来调节SNS SNS信号传导的衰减可能具有医学益处。