Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G
Department of Experimental Pathology, University of Bologna, Italy.
Ann N Y Acad Sci. 2000 Jun;908:244-54. doi: 10.1111/j.1749-6632.2000.tb06651.x.
In this paper we extend the "network theory of aging," and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as "inflamm-aging," is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
在本文中，我们扩展了“衰老网络理论”，并认为应对各种应激源的能力全面下降以及促炎状态随之逐渐增加是衰老过程的主要特征。我们将这种现象称为“炎症衰老”，它是由持续的抗原负荷和应激引发的。基于进化研究，我们还认为免疫反应和应激反应是等效的，抗原只不过是特定类型的应激源。我们还提议让巨噬细胞回归其应有的位置，使其不仅成为炎症反应和免疫的核心参与者，也成为应激反应的核心参与者。达到促炎状态阈值（超过此阈值会引发疾病/残疾）的速率以及个体应对和适应应激源的能力被假定为具有遗传成分的复杂性状。最后，我们认为炎症刺激随时间的持续存在代表了有利于患年龄相关疾病/残疾易感性的生物学背景（首次打击）。对于具有炎症发病机制的明显器官特异性年龄相关疾病，如动脉粥样硬化、阿尔茨海默病、骨质疏松症和糖尿病，可能需要第二次打击（缺乏强大的基因变体和/或存在脆弱的基因变体）才会发病。按照这一观点，我们阐述并解释了健康百岁老人的几个悖论（炎症细胞因子、急性期蛋白和凝血因子血浆水平升高）。总之，根据衰老的拮抗多效性理论，在生命早期和成年期用于中和危险/有害因子的炎症的有益作用，在很大程度上是进化未预见到的生命后期却变得有害。
