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Transcriptional and signaling analysis as a means of investigating the complexity of aging processes in human and mouse.


Brink,  Thore
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Brink, T. (2009). Transcriptional and signaling analysis as a means of investigating the complexity of aging processes in human and mouse. PhD Thesis, Freie Universität Berlin, Berlin.

There has been a dramatic increase in the life expectancy of men and women in the last century. Along with the increased life span the incidence of age-related diseases such as Alzheimer’s disease has also increased. This increase has led to an elevated interest to understand and investigate the mechanisms that underlie age-related diseases. Consequently, there is an increased awareness of the necessity to understand the mechanisms of aging to better cope with age-related diseases. However, the process of aging is complex and many different mechanisms are involved, including transcriptional regulation occurring with advanced age. Studies investigating age-related transcriptional changes mainly revealed that the magnitude of these changes is small and that it is difficult to find conserved regulated age-related genes between diverse species and tissues using microarray analysis. This study was aimed at elucidating mechanisms involved in human skin and general mouse aging as well as potentially conserved mechanisms involved in mammalian aging by conducting microarray analyses using RNA derived from male and female human skin biopsies and mouse brain, heart and kidney tissues and using the same array platform and standardized parameters. The data analysis was not solely based on highlighting age-related genes but also biological processes, cellular compartments and pathways. The influence of age-dependent hormonal decline on gene expression has also been tested on a different microarray platform using two different human skin cell types – sebocytes and fibroblasts. These experiments revealed that human skin aging is accompanied by a reduction in skin collagen structure. Furthermore, the potential involvement of WNT signaling in human skin aging was observed for the first time. The analysis of hormone-treated skin cells revealed significant differences between cell types and underscores the potential that age-related transcriptional changes are cell-type specific. The studies on mouse aging identified a conserved increase of immune responses on the transcriptional level. In addition, elevated levels of radical oxygen species (ROS) suggest the oxidative stress-mediated activity of NF-kB signaling. Comparisons of the human and mouse results confirm the conserved involvement of immune responses and of metabolism-related processes including for instance glutathione metabolism a regulator of endogenous ROS levels in mammalian aging. In summary, the results suggest that transcriptional changes are most probably the downstream effect of environmental and endogenous factors constantly affecting the organism during age. In addition, the finding that similar processes are age-regulated including different genes in varying tissues such as immune and metabolism-related genes, suggests that aging is not dependent on single genes but rather on a network of genes. However, it remains unclear, which mechanisms are responsible for the induction of mammalian aging.