Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafè M
Department of Experimental Pathology, University of Bologna, Italy.
Exp Gerontol. 1999 Dec;34(8):911-21. doi: 10.1016/s0531-5565(99)00068-6.
Under an evolutionary perspective, antigens can be considered nothing else than chronic stressors that constituted the major selective pressure for immune system emergence and evolution. In this review, recent data are discussed under the hypothesis that human immunosenescence is the consequence of the continuous attrition caused by chronic antigenic overload/stress. The advantage of this theoretical approach is that a unifying hypothesis is proposed, which tries to fill in the current gap between the conceptualizations concerning the mechanisms which counteract aging and favor longevity in invertebrates and vertebrates. The hypothesis is that the immune system is, at a higher level of biological organization and complexity, the counterpart of the anti-stress response network identified in invertebrates as the major determinant of survival. We argue that some of the most important characteristics of immunosenescence, i.e. the accumulation and the clonal expansion of memory and effector T cells, the reduction/exhaustion of naive T cells, and the shrinkage of T cell repertoire, are compatible with this assumption. Thus, immunosenescence can be envisaged as a global reduction of the "immunological space." Concomitantly, immunosenescence results in the progressive generation of cellular mosaicism which is the consequence of the heterogeneous replicative histories and telomere shortening of T and B cell subsets, as well as hemopoietic stem cells. Most of the parameters affected by immunosenescence appear to be under genetic control, and future research on biomarkers should address this point. On the whole, immunosenescence can be taken as a proof that the beneficial effects of the immune system, devoted to the neutralization of dangerous/harmful agents early in life and in adulthood, turn to be detrimental late in life, in a period largely not foreseen by evolution. This perspective fits with basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy.
从进化的角度来看，抗原可被视为慢性应激源，它们构成了免疫系统出现和进化的主要选择压力。在本综述中，我们将基于人类免疫衰老乃慢性抗原过载/应激所致持续损耗的结果这一假设，来讨论近期的数据。这种理论方法的优势在于提出了一个统一的假设，试图填补当前在关于无脊椎动物和脊椎动物中对抗衰老及促进长寿机制的概念化之间的空白。该假设认为，在更高层次的生物组织和复杂性水平上，免疫系统相当于在无脊椎动物中被确定为生存主要决定因素的抗应激反应网络。我们认为，免疫衰老的一些最重要特征，即记忆和效应T细胞的积累与克隆扩增、初始T细胞的减少/耗竭以及T细胞库的缩小，与这一假设相符。因此，免疫衰老可被设想为“免疫空间”的整体缩小。与此同时，免疫衰老导致细胞镶嵌性的逐渐产生，这是T和B细胞亚群以及造血干细胞不同复制历史和端粒缩短的结果。大多数受免疫衰老影响的参数似乎受基因控制，未来关于生物标志物的研究应关注这一点。总体而言，免疫衰老可以证明，免疫系统在生命早期和成年期致力于中和危险/有害因子的有益作用，在生命后期却变得有害，而这一时期在很大程度上是进化未预见到的。这一观点符合衰老进化理论的基本假设，如拮抗多效性。
