Pedersen W A, Wan R, Mattson M P
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Mech Ageing Dev. 2001 Jul 15;122(9):963-83. doi: 10.1016/s0047-6374(01)00250-0.
Throughout life organisms are challenged with various physiological and psychological stressors, and the ability to handle these stressors can have profound effects on the overall health of the organism. In mammals, the effects of stressors on the aging process and age-related diseases are complex, involving the nervous, endocrine and immune systems. Certain types of mild stress, such as caloric restriction, may extend lifespan and reduce the risk of diseases, whereas some types of psychosocial stress are clearly detrimental. We now have a basic understanding of the brain regions involved in stress responses, their neuroanatomical connections with neuroendocrine pathways, and the neuropeptides and hormones involved in controlling responses of different organ systems to stress. Not surprisingly, brain regions involved in learning and memory and emotion play prominent roles in stress responses, and monoaminergic and glutamatergic synapses play particularly important roles in transducing stressful sensory inputs into neuroendocrine responses. Among the neuropeptides involved in stress responses, corticotropin-releasing hormone appears to be a pivotal regulator of fear and anxiety responses. This neuropeptide is responsible for activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is critical for mobilizing energy reserves and immune responses, and improper regulation of the HPA axis mediates many of the adverse effects of chronic physical and psychosocial stress. In the brain, for instance, stress may contribute to disease processes by causing imbalances in cellular energy metabolism and ion homeostasis, and by inhibiting neuroprotective signaling pathways. There is considerable evidence that normal aging impacts upon neuroendocrine stress responses, and studies of the molecular and cellular mechanisms underlying the pathogenic actions of mutations that cause age-related neurological disorders, such as Alzheimer's disease, are revealing novel insight into the involvement of perturbed neuroendocrine stress responses in these disorders.
在整个生命过程中，生物体面临着各种生理和心理应激源，应对这些应激源的能力会对生物体的整体健康产生深远影响。在哺乳动物中，应激源对衰老过程和与年龄相关疾病的影响是复杂的，涉及神经、内分泌和免疫系统。某些类型的轻度应激，如热量限制，可能会延长寿命并降低患病风险，而某些类型的社会心理应激则明显有害。我们现在对参与应激反应的脑区、它们与神经内分泌途径的神经解剖学联系以及参与控制不同器官系统对应激反应的神经肽和激素有了基本的了解。不出所料，参与学习、记忆和情绪的脑区在应激反应中起重要作用，单胺能和谷氨酸能突触在将应激性感觉输入转化为神经内分泌反应中起特别重要的作用。在参与应激反应的神经肽中，促肾上腺皮质激素释放激素似乎是恐惧和焦虑反应的关键调节因子。这种神经肽负责激活下丘脑 - 垂体 - 肾上腺（HPA）轴，这对于调动能量储备和免疫反应至关重要，而HPA轴的调节不当介导了慢性身体和社会心理应激的许多不良影响。例如，在大脑中，应激可能通过导致细胞能量代谢和离子稳态失衡以及抑制神经保护信号通路而促成疾病过程。有大量证据表明正常衰老会影响神经内分泌应激反应，对导致与年龄相关神经疾病（如阿尔茨海默病）的突变致病作用的分子和细胞机制的研究正在揭示神经内分泌应激反应紊乱在这些疾病中的新见解。
