Transcriptome analysis of age-, gender- and diet-associated changes in murine thymus - PubMed (original) (raw)
Comparative Study
doi: 10.1016/j.cellimm.2007.03.008. Epub 2007 May 17.
Ashani T Weeraratna, William W Wood 3rd, Diane Teichberg, Dorothy Bertak, Arnell Carter, Suresh Poosala, Jeffrey Firman, Kevin G Becker, Alan B Zonderman, Dan L Longo, Dennis D Taub
Affiliations
- PMID: 17499630
- PMCID: PMC2271048
- DOI: 10.1016/j.cellimm.2007.03.008
Comparative Study
Transcriptome analysis of age-, gender- and diet-associated changes in murine thymus
Ana Lustig et al. Cell Immunol. 2007 Jan.
Abstract
The loss of thymic function with age may be due to diminished numbers of T-cell progenitors and the loss of critical mediators within the thymic microenvironment. To assess the molecular changes associated with this loss, we examined transcriptomes of progressively aging mouse thymi, of different sexes and on caloric-restricted (CR) vs. ad libitum (AL) diets. Genes involved in various biological and molecular processes including transcriptional regulators, stress response, inflammation and immune function significantly changed during thymic aging. These differences depended on variables such as sex and diet. Interestingly, many changes associated with thymic aging are either muted or almost completely reversed in mice on caloric-restricted diets. These studies provide valuable insight into the molecular mechanisms associated with thymic aging and emphasize the need to account for biological variables such as sex and diet when elucidating the genomic correlates that influence the molecular pathways responsible for thymic involution.
Figures
Fig. 1
Gene expression profiles of genes which change with age. (a) This profile was created using the Ingenuity program for the genes that exhibited the greatest degree of change when comparing the oldest thymic group to the youngest. The brighter the red, the higher the expression level above the mean for all genes, and the brighter the green the lower the expression level. Expression levels are statistically significant in the 24-month age group. The other age groups are included to exhibit expression trends and may or may not be statistically significant. (b) Comparison of the total numbers of genes affected at each age group.
Fig. 2
Confirmation of age-associated changes in gene expression data in thymic tissue. (a) Side-by side comparison of the array results for the genes for the heavy chains, IgM and IgG and the results when comparing young and old thymocyte and thymus samples using real-time PCR. (b) Age-associated differences in immunoglobulin protein expression are evident when comparing protein lysates derived from the total thymocytes of young (1 month) and old (24 months) mice.
Fig. 3
Expression profile of genes exhibiting the greatest differences when comparing the oldest CR mice to the oldest AL mice. (a) This profile was created using the Ingenuity program for the genes that exhibited the greatest degree of change when comparing the oldest (24 months) CR group to the oldest AL group. The brighter the red, the higher the expression level above the mean for all genes, and the brighter the green the lower the expression level. Expression levels are statistically significant at the 24-month age group. The other age groups are included to exhibit expression trends and may or may not be statistically significant. (b) Comparison of the total numbers of genes affected at each age group.
Fig. 4
Relative percentages of genes that changed with age and were affected by CR in each of the top categories of gene type (a) and gene function (b). In each graph, the percentage of age and CR-affected genes are shown together for a direct comparison.
Fig. 5
Expression profiles of genes that demonstrate expression differences with gender. (a) This profile was created using the Ingenuity program for the genes that exhibited the greatest degree of change when comparing the oldest female ad libitum group to the oldest male ad libitum group. The brighter the red, the higher the expression level above the means for all genes, and the brighter the green the lower the expression level. Expression levels are statistically significant for the 24-month age group. The other age groups are included to display expression trends and may or may not be statistically significant. (b) Comparison of the total numbers of genes affected in each gender in the context of age.
Fig. 6
Western analysis of protein lysates from young and old thymocytes using antibody to eIF4G. In 24-month-old mice, levels of eIF4G protein are significantly decreased as compared to young mice.
Fig. 7
Possible pathways for cellular senescence (a) and CR rescue (b) involving the glucocorticoid receptor, androstane receptor and heat-shock proteins. These pathways were designed by the Ingenuity program by compiling published associations between genes in the lists whose expression levels changed with age and were then reversed by a CR diet. (c) Western blot analysis of protein lysates derived from thymocytes of C57BL/6 mice of designated ages confirm that GR is changed in aging thymocytes. (d,e) Whole thymus was also analyzed for GR expression by immunohistochemistry. Sections were stained with a nuclear DAPI stain (blue) and a mouse anti-GR following a standard protocol for DAB staining of paraffin sections. The images (100× magnification) clearly show the GR staining in the young thymus is much darker than that in the old thymus in both the cortex (d) and medulla (e). Data are representative of three experiments, each with one sample from each age.
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