Hôpital Hôtel Dieu, Université Paris, France.
Biogerontology. 2010 Aug;11(4):387-99. doi: 10.1007/s10522-010-9262-y. Epub 2010 Feb 16.
Gerontological experimentation is and was always strongly influenced by "theories". The early decades of molecular genetics inspired deterministic thinking, based on the "Central Dogma" (DNA --> RNA --> Proteins). With the progress of detailed knowledge of gene-function a much more complicated picture emerged. Regulation of gene-expression turned out to be a highly complicated process. Experimental gerontology produced over the last decades several "paradigms" incompatible with simple genetic determinism. The increasing number of such detailed experimental "facts" revealed the importance of epigenetic factors and of posttranslational modifications in the age-dependent decline of physiological functions. We shall present in this review a short but critical analysis of genetic and epigenetic processes applied to the interpretation of the more and more precisely elucidated experimental paradigms of aging followed by some of the most relevant aging-mechanisms at the post-translational level, the posttranslational modifications of proteins such as the Maillard reaction, the proteolytic production of harmful peptides and the molecular mechanisms of the aging of elastin with the role of the age-dependent uncoupling of the elastin receptor, as well as the loss of several other receptors. We insist also on the well documented influence of posttranslational modifications on gene expression and on the role of non-coding RNA-s. Altogether, these data replace the previous simplistic concepts on gene action as related to aging by a much more complicated picture, where epigenetic and posttranslational processes together with environmentally influenced genetic pathways play key-roles in aging and strongly influence gene expression.
老年医学实验一直深受“理论”的影响。分子遗传学的早期几十年激发了基于“中心法则”（DNA→RNA→蛋白质）的决定论思维。随着对基因功能的详细知识的进步，出现了一幅更加复杂的图景。基因表达的调控原来是一个高度复杂的过程。在过去几十年中，实验老年医学产生了几个与简单遗传决定论不兼容的“范式”。越来越多的此类详细的实验“事实”揭示了表观遗传因素和翻译后修饰在生理功能随年龄下降中的重要性。我们将在这篇综述中对遗传和表观遗传过程进行简短但批判性的分析，应用于解释越来越精确阐明的衰老实验范式，然后介绍一些在翻译后水平上与衰老相关的最重要的机制，如蛋白质的翻译后修饰，如美拉德反应、有害肽的蛋白水解产生以及弹性蛋白的分子机制，以及弹性蛋白受体的年龄依赖性解耦联的作用，以及其他几个受体的丧失。我们还坚持认为，有充分文献记载的翻译后修饰对基因表达的影响以及非编码 RNA 的作用。总之，这些数据取代了以前关于与衰老相关的基因作用的简单概念，代之以一个更加复杂的图景，其中表观遗传和翻译后过程以及受环境影响的遗传途径在衰老中起着关键作用，并强烈影响基因表达。
