Age-related Gene Expression Signatures (AGES) in rats demonstrate early, late, and linear transcriptional changes from multiple tissues

Abstract

In order to understand changes in gene expression that occur as a result of age, which might create a permissive or causal environment for age-related diseases, we produced a multitimepoint Age-related Gene Expression Signature (AGES) from liver, kidney, skeletal muscle and hippocampus of rats, comparing 6, 9, 12, 18, 21, 24 and 27-month old animals. We focused on genes that changed in one direction throughout the lifespan of the animal, either early in life (early logistic changes); at mid-age (mid-logistic); late in life (late-logistic); or linearly, throughout the lifespan. The pathways perturbed as a result of chronological age demonstrate organ-specific and more global effects of aging, and point to mechanisms that might be counterregulated pharmacologically in order to treat age-associated diseases. A small number of genes were regulated by aging in the same manner in every tissue, suggesting they may be more universal markers of aging. 4 changes with age throughout the animal's lifespan (at 6, 12, 15, 18, 21, 24 and 27 months) in liver, gastrocnemius muscle, kidney and hippocampus. Rats were chosen because we had previously shown that rats are an excellent model for sarcopenia -the age-related loss of skeletal muscle (Ibebunjo et al., 2013). Here we are applying that experience to other tissues to develop a full multi-tissue aging signature. We discovered genes that change in common in every tissue; genes which are regulated in early-logistic, mid-logistic, late-logistic and linear fashion in particular tissues, and pathways that are regulated in multiple tissues, giving some indication of common mechanisms of aging. It is our hope that this dataset will serve as a valuable resource for further molecular insights into mechanisms of aging. RESULTS Transcriptional profiling of liver, gastrocnemius muscle, kidney, and hippocampus throughout the rat lifespanWe sought to establish both tissue-specific and more global aging gene signatures, which could serve as a basis for understanding the overall aging process. We were interested in genes that changed in a particular direction (either consistently up-regulated or consistently downregulated) throughout the lifespan of the animal. Sprague-Dawley (SD) rats live approximately 2.5 -3 years under laboratory conditions (Sengupta, 2013). The mortality rate of these rat cohorts at 21 months is ~22%, at 24 months is ~30% and at 27 months ~50% (Shavlakadze et al., 2018). In order to identify genes whose expression pattern is influenced by age, we performed gene expression profiling by RNAseq of liver, gastrocnemius muscle, kidney and hippocampus from male SD rats aged 6, 9, 12, 18, 21, 24 and 27 months. The gene expression data are available at the NIH Sequence Read Archive under the BioProject accession number 5 PRJNA516151, and Supplementary table 1A-D contains the Log2 fold change and respective p values (raw and adjusted for the false discovery rate, FDR) for all genes in searchable excel format. Genomic data are visually presented as Volcano plots in Supplement...

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