Fig. 4: SIRT6 activates hepatic mitochondrial catabolic and anti-inflammatory pathways.

RNA-seq was carried out on the liver of 6 months old WT and SIRT6-tg mice from either sex. a Principal component analysis was performed on all expressed genes. Each data point represents an individual mouse. b Gene Set Enrichment Analysis showing the top pathways up- or down-regulated in SIRT6-tg mice, sorted by normalized enrichment scores (NES). FDR q-values are shown in orange. Pathways related to catabolism and to inflammation are presented in blue and red, respectively. c Four metabolic pathways up-regulated in livers from male SIRT6-tg mice. In the upper part, each vertical black bar represents a gene in the gene set and its corresponding location in the sorted gene list. In the lower part, corresponding heatmaps show the expression values of the top genes in each pathway, which contribute most to the NES. High expression is colored in red and low expression in blue. Bold text indicates genes validated by qPCR in (e). d Ingenuity upstream regulator analysis common to males and females, based on genes differentially expressed between WT and SIRT6-tg mice. p-values for PPARα are shown, calculated by Fisher’s exact test. e Real-time PCR validation of gene expression from the indicated pathways, and mtDNA content in the livers of young and old WT and SIRT6-tg males. Two-way ANOVA with Fisher’s LSD method, asterisks indicate values significantly different between WT and SIRT6-tg at the same age. n = 8 mice per group, except for old SIRT6 for Coq10a (n = 6) and G6pc (n = 7), and for young WT and young SIRT6 for mtDNA content (n = 6). Mice ages are 6 and 25 months. RQ, relative quantity. Bars represent mean ± SEM. Exact p-values are reported in the Source Data file. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.