RNA splicing is the assembly of exons (and discarding of introns) to form a protein. Many genes contain the instructions for multiple proteins, and which protein is produced is governed by the operation of the splicing machinery. That operation is known to change with age, but the question remains open as to just how important RNA splicing is to age-related degeneration. Researchers here use a novel approach to identify genes with age-related alterations in expression that are similar in all tissues, and find that the results are biased towards RNA splicing machinery. The interesting part of the paper is the speculation in the discussion section regarding the reasons why alterations in RNA splicing activities could be important in aging, suggesting a connection to DNA damage. This line of thinking is particularly interesting given recent evidence for repeated activation of DNA repair processes to trigger the epigenetic changes characteristic of aging. Looking at DNA damage, epigenetic change, and altered alternative splicing may be three viewpoints into the same process of aging centered on the structure and function of nuclear DNA and its surrounding machineries of gene expression.
Although transcriptomic changes are known to occur with age, the extent to which these are conserved across tissues is unclear. Previous studies have identified little conservation in age-modulated genes in different tissues. Here, we sought to identify common transcriptional changes with age in humans (aged 20 to 70) across tissues using differential network analysis, assuming that differential expression analysis alone cannot detect all changes in the transcriptional landscape that occur in tissues with age. Our results demonstrate that differential connectivity analysis reveals significant transcriptional alterations that are not detected by differential expression analysis. Combining the two analyses, we identified gene sets modulated by age across all tissues that are highly enriched in terms related to "RNA splicing" and "RNA processing".
Alternative splicing is a fundamental process in eukaryotes that allows the same gene to encode multiple different transcripts, with approximately 95% of multi-exon genes producing transcripts that undergo alternative splicing. Therefore, it is intuitive that alterations in the splicing machinery would have systemic effects on the biological network. Indeed, aging appears to be accompanied by a high incidence of aberrant splicing and intron retentions. Changes in alternative splicing are also observed in several age-related diseases. Modulation of specific splicing factors has been shown to increase lifespan in model organisms, and splicing appears to be modulated in model organisms during dietary restriction and mTOR inhibition, two known lifespan-promoting interventions.
Determining the cause of this increased incidence of aberrant splicing is currently impossible. One hint is the presence of genes associated with DNA repair and DNA damage response. The idea that DNA alterations cause aging is one of the most classic theories of aging, and DNA damage is a hallmark of aging. It is possible, therefore, that damage to DNA is leading to aberrant splicing. Indeed, there seems to be a connection between RNA splicing and DNA damage response, even at the transcriptional level.
From the results described here, it is reasonable to imagine a scenario in which the age-associated increase in aberrant mRNAs, proteins, and eventually organelles, which were negatively affected by malfunctioning proteins, may impose significantly on catabolic processes such as RNA catabolism, protein catabolism, and autophagy. Lifespan extension by mTOR inhibition may thus be working by inducing the clearance of these defective components. Since these clearance mechanisms seem upregulated with age, mTOR inhibition is enhancing a naturally occurring attempt at adaptation by the cells.
Link: https://doi.org/10.18632/aging.206347
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