Guebel Daniel V, Torres Néstor V
Biotechnology Counselling ServicesBuenos Aires, Argentina; Systems Biology and Mathematical Modelling Group, Departamento de Bioquímica, Microbiología, Biología Celular y Genética, Facultad de Ciencias, Universidad de La LagunaSan Cristóbal de La Laguna, España.
Systems Biology and Mathematical Modelling Group, Departamento de Bioquímica, Microbiología, Biología Celular y Genética, Facultad de Ciencias, Universidad de La Laguna San Cristóbal de La Laguna, España.
Front Aging Neurosci. 2016 Oct 5;8:229. doi: 10.3389/fnagi.2016.00229. eCollection 2016.
In the brain of elderly-healthy individuals, the effects of sexual dimorphism and those due to normal aging appear overlapped. Discrimination of these two dimensions would powerfully contribute to a better understanding of the etiology of some neurodegenerative diseases, such as "sporadic" Alzheimer. Following a system biology approach, top-down and bottom-up strategies were combined. First, public transcriptome data corresponding to the transition from adulthood to the aging stage in normal, human hippocampus were analyzed through an optimized microarray post-processing (Q-GDEMAR method) together with a proper experimental design (full factorial analysis). Second, the identified genes were placed in context by building compatible networks. The subsequent ontology analyses carried out on these networks clarify the main functionalities involved. Noticeably we could identify large sets of genes according to three groups: those that exclusively depend on the sex, those that exclusively depend on the age, and those that depend on the particular combinations of sex and age (interaction). The genes identified were validated against three independent sources (a proteomic study of aging, a senescence database, and a mitochondrial genetic database). We arrived to several new inferences about the biological functions compromised during aging in two ways: by taking into account the sex-independent effects of aging, and considering the interaction between age and sex where pertinent. In particular, we discuss the impact of our findings on the functions of mitochondria, autophagy, mitophagia, and microRNAs. The evidence obtained herein supports the occurrence of significant neurobiological differences in the hippocampus, not only between adult and elderly individuals, but between old-healthy women and old-healthy men. Hence, to obtain realistic results in further analysis of the transition from the normal aging to incipient Alzheimer, the features derived from the sexual dimorphism in hippocampus should be explicitly considered.
在健康老年人的大脑中，性二态性的影响与正常衰老的影响似乎相互重叠。区分这两个维度将有力地有助于更好地理解某些神经退行性疾病的病因，如“散发性”阿尔茨海默病。遵循系统生物学方法，将自上而下和自下而上的策略相结合。首先，通过优化的微阵列后处理（Q-GDEMAR方法）以及适当的实验设计（全因子分析），分析了对应于正常人类海马从成年到衰老阶段转变的公共转录组数据。其次，通过构建兼容网络将鉴定出的基因置于相应背景中。随后对这些网络进行的本体分析阐明了所涉及的主要功能。值得注意的是，我们可以根据三组来识别大量基因：那些仅取决于性别的基因、那些仅取决于年龄的基因以及那些取决于性别和年龄的特定组合（相互作用）的基因。针对三个独立来源（衰老的蛋白质组学研究、衰老数据库和线粒体遗传数据库）对鉴定出的基因进行了验证。我们通过两种方式得出了关于衰老过程中受损生物学功能的几个新推论：考虑衰老的性别独立效应，以及在相关情况下考虑年龄和性别的相互作用。特别是，我们讨论了我们的发现对线粒体、自噬、线粒体自噬和微小RNA功能的影响。本文获得的证据支持海马体中存在显著的神经生物学差异，不仅在成年人和老年人之间，而且在健康老年女性和健康老年男性之间。因此，为了在从正常衰老到早期阿尔茨海默病转变的进一步分析中获得实际结果，应明确考虑海马体中性二态性衍生的特征。
