Activation of the immune response is a key feature of aging in mice

Abstract

The process of aging is complex involving numerous factors centered on transcriptional changes with advanced age. This study was aimed at elucidating mechanisms involved in mouse aging by conducting both gene expression and biochemical analyses on isolated mouse brain, heart and kidney. The gene expression analysis was not aimed at solely highlighting age-related transcriptional changes but also revealing regulated biological processes, cellular compartments, signaling and metabolic pathways. We have uncovered a conserved increase in the expression of genes mediating immune responses in all the tissues analyzed. In addition, elevated levels of lipid hydroperoxides (LPO)—an indicator of increased levels of radical oxygen species, implicate an oxidative stress-mediated activity of NF-kB signaling. In summary, these results suggest that transcriptional changes are most probably the downstream effect of environmental and endogenous factors constantly affecting the organism during its lifetime. In addition, we propose LPO as a potential biomarker of aging.

Fig. 1

Results of the global expression data analysis. The figure shows a the sample clustering and b the corresponding correlation coefficients (R ²) derived from whole genome gene expression analyses for young and aged mouse whole brain, heart and kidney. Correlation coefficients are colored as follows: red = 0.90–1.00, orange = 0.80–0.90, white = 0.70–0.80 and gray <0.70. c Confirmation of microarray-derived data for relevant genes by Real-Time PCR. d Western blot analysis of complement component C3 on homogenates derived from brain, heart and kidney tissues (y: young; a: aged). In all three tissues we see an increased protein expression in the aged tissue compared to the respective young control. GAPDH was used as loading control (color figure in online)

Fig. 2

STRING analysis of the overlapping age-regulated target genes. The overlapping target genes from Table 2 were analyzed together with NF-kB (Rela) to show possible interactions. The figure shows that NF-kB is potentially connected to some of our conserved age-regulated target genes (e.g. Ii, Lyz, Ctss). The use of more interaction partners in the analysis also connects several other genes to the network (e.g. the complement components and the Fc-receptors; data not shown)

Fig. 3

Lipid hydroperoxide (LPO) concentrations (μM) in extracts of young and aged mouse tissues. The figure shows that LPO could be detected in the aged brain, heart and kidney, but not in the corresponding young tissues. This result suggests a higher degree of oxidative stress in aged mice independent of the tissue. The concentrations of LPO were measured by the use of a standard curve method

Fig. 4

ROS-mediated activation of innate immunity. The figure presents a model of ROS-mediated activation of innate immunity via the NF-kB signaling pathway. As the activation of innate immunity was shown by transcriptional analysis and the increase of oxidative stress by the measurement of LPO, the involvement of NF-kB is hypothetical and based on literature (Schreck et al. ; Gosselin and Abbadie ; Salminen et al. 2008)