Jovanović Ivan, Ugrenović Slađana, Ljubomirović Miljana, Vasović Ljiljana, Cukuranović Rade, Stefanović Vladisav
University of Niš, Medical Faculty, Department of Anatomy, Dr Zoran Djindjić 81 Blvd., 18000 Niš, Serbia.
University of Niš, Medical Faculty, Department of Anatomy, Dr Zoran Djindjić 81 Blvd., 18000 Niš, Serbia.
Med Hypotheses. 2014 Oct;83(4):501-5. doi: 10.1016/j.mehy.2014.08.018. Epub 2014 Aug 23.
Some evidence has suggested that, with age, the hypothalamic-pituitary-adrenal (HPA) axis becomes less resilient, leading to higher glucocorticoids nocturnal levels and a flattening of the circadian profiles. Such age-related changes in the activity of the HPA axis has overexposed the brain and peripheral organs to the effects of the glucocorticoids, increasing the morbidity and mortality rates of the elderly. Debate among scientists regarding the contributions of HPA axis age-related changes of impaired feedback regulation vs. direct overactivation persists. Supporters of impaired feedback regulation assumed that this effect might be the consequence of the hippocampal age-related neuronal loss and the reduction of the number of mineralocorticoid and glucocorticoid receptors. On the other hand, healthy elderly individuals are characterized by an increase of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, and the development of a chronic low-grade inflammatory state, known as inflammaging. Cytokines central to inflammaging send signals to the brain, activate HPA axis, and, by increased cortisol secretion, down-regulate inflammaging in a process known as anti-inflammaging. Even as these cytokines act at the level of the hypothalamic paraventricular nucleus, they are hampered by the intact blood-brain barrier. Further, the corticotropes in the anterior pituitary do not express cytokine receptors, and the density of folliculo-stellate cells generally increases with age. Therefore, we assumed that folliculo-stellate cells were the target structures through which the elevated levels of cytokines, as a part of the inflammaging phenomenon, would cause the overactivation of the HPA axis in healthy elderly individuals. Folliculo-stellate cells are non-endocrine cells that were originally considered to act as supporting cells for the endocrine cells. Despite the fact that FS cells do not produce any of the established hormones of the anterior pituitary, they secrete paracrine agents that act locally to modulate pituitary responses to hypothalamic and peripheral signals. There is evidence of cytokines characteristically involved in inflammaging. For example, IL-1 and TNF-α are thought to stimulate folliculo-stellate cells to release various paracrine agents, including IL-6, IL-11, leukemia inhibitory factor, and macrophage migration inhibitory factor. Through different mechanisms, these agents induce ACTH release by corticotropes. Therefore, it can be concluded that folliculo-stellate cells may act as potent mediators of the age-related HPA axis hyperactivity induced by cytokines characteristic of the inflammaging phenomenon in healthy elderly individuals.
一些证据表明，随着年龄增长，下丘脑-垂体-肾上腺（HPA）轴的弹性会降低，导致夜间糖皮质激素水平升高以及昼夜节律曲线变平。HPA轴活性的这种与年龄相关的变化使大脑和外周器官过度暴露于糖皮质激素的影响之下，增加了老年人的发病率和死亡率。科学家们对于HPA轴与年龄相关变化中反馈调节受损与直接过度激活的作用仍存在争议。反馈调节受损的支持者认为，这种效应可能是海马体与年龄相关的神经元丢失以及盐皮质激素和糖皮质激素受体数量减少的结果。另一方面，健康的老年人具有促炎细胞因子增加的特征，包括白细胞介素-1（IL-1）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α），并会发展出一种慢性低度炎症状态，即炎症衰老。炎症衰老的关键细胞因子会向大脑发送信号，激活HPA轴，并通过增加皮质醇分泌，在一个被称为抗炎症衰老的过程中下调炎症衰老。即使这些细胞因子作用于下丘脑室旁核水平，它们也会受到完整血脑屏障的阻碍。此外，垂体前叶的促肾上腺皮质激素细胞不表达细胞因子受体，而滤泡星状细胞的密度通常会随着年龄增长而增加。因此，我们推测滤泡星状细胞是细胞因子水平升高的靶结构，作为炎症衰老现象的一部分，细胞因子水平升高会导致健康老年人的HPA轴过度激活。滤泡星状细胞是非内分泌细胞，最初被认为是内分泌细胞的支持细胞。尽管滤泡星状细胞不产生垂体前叶的任何一种既定激素，但它们会分泌旁分泌因子，这些因子在局部起作用，调节垂体对下丘脑和外周信号的反应。有证据表明细胞因子与炎症衰老有特征性关联。例如，IL-1和TNF-α被认为会刺激滤泡星状细胞释放各种旁分泌因子，包括IL-6、IL-11、白血病抑制因子和巨噬细胞迁移抑制因子。通过不同机制，这些因子会诱导促肾上腺皮质激素细胞释放促肾上腺皮质激素（ACTH）。因此，可以得出结论，滤泡星状细胞可能是炎症衰老现象中细胞因子诱导的与年龄相关的HPA轴功能亢进的有效介质，这种现象存在于健康老年人中。
