Transcriptional Signatures of Aging

Abstract

Genome-wide studies of aging have identified subsets of genes that show age-related changes in expression. Although the types of genes that are age regulated vary among different tissues and organisms, some patterns emerge from these large data sets. First, aging is associated with a broad induction of stress response pathways, although the specific genes and pathways involved differ depending on cell type and species. In contrast, a wide variety of functional classes of genes are downregulated with age, often including tissue-specific genes. Although the upregulation of age-regulated genes is likely to be governed by stress-responsive transcription factors, questions remain as to why particular genes are susceptible to age-related transcriptional decline. Here, we discuss recent findings showing that splicing is misregulated with age. While defects in splicing could lead to changes in protein isoform levels, they could also impact gene expression through nonsense-mediated decay of intron-retained transcripts. The discovery that splicing is misregulated with age suggests that other aspects of gene expression, such as transcription elongation, termination, and polyadenylation, must also be considered as potential mechanisms for age-related changes in transcript levels. Moreover, the considerable variation between genome-wide aging expression studies indicates that there is a critical need to analyze the transcriptional signatures of aging in single-cell types rather than whole tissues. Since age-associated decreases in gene expression could contribute to a progressive decline in cellular function, understanding the mechanisms that determine the aging transcriptome provides a potential target to extend healthy cellular lifespan.

Keywords: aging; splicing; transcription.

Figure 1

Co-transcriptional RNA processing could be misregulated with age. Processes that have been shown to be up or downregulated with age are indicated by the red and blue arrows respectively. Processes that could be misregulated with age, but have not yet been examined in sufficient detail are indicated by grey question marks. CTD, carboxy-terminal domain of RNA polymerase II, PIC, pre-initiation complex; CTD; RNA pol II, RNA polymerase II.

Figure 2

An overview of age-associated transcriptome changes. Only 2 – 3 % of the whole genome (upper panel) shows age-associated changes in transcript levels. These changes between young and old cells are depicted in the two lower panels. Transcripts are shown with exons depicted as boxes, and introns and untranslated regions as lines. Transcripts that increase or decrease with age are shown in red and blue respectively, versus unchanged transcripts in black. Potential splice variants are shown in purple that include intron retention (third transcript from top) and exon skipping (bottom right).