In the process of producing proteins from genetic blueprints, the first step is transcription, the generation of RNA molecules, generally called transcripts. In today's open access paper, researchers present data to support an interesting observation: that age-related changes in the abundance of specific RNA transcripts correlate with transcript length. They offer some suggestions as to mechanisms that might contribute to this effect, such as stochastic DNA damage or dysregulated RNA splicing. RNA splicing is the part of transcription in which RNA to match specific intron and exon sections of a gene are joined together to form the transcript. In recent years researchers have noted that dysfunction arises in the splicing process with age, and that this might cause further downstream issues.
Finding a way to link stochastic DNA damage to the common manifestations of aging has been a challenge. In and of itself, near all stochastic DNA damage doesn't do much obvious harm to any given cell: most of the altered genes are not used in that cell, and, with the exception of the risk of cancer, most of the mutational alterations to DNA are not that important. Further, this sort of damage is completely different in every cell it happens in. So how does it give rise the fairly uniform set of changes noted in aging? Possibilities include (a) somatic mosaicism, in which only the few problematic changes occurring in stem cells matter, as they spread throughout tissues, and (b) the recently discovered way in which double strand break repair might cause epigenetic alterations characteristic of aging, by exhausting resources needed for the correct maintenance of chromatin.
In the context of today's data, it is interesting to consider ways in which stochastic DNA damage might cause uniform disarray in RNA splicing. This might perhaps occur through a similar mechanism to the above mentioned double strand break repair mechanism, some form of resulting alteration in epigenetic patterns as a response to damage that leads to changed expression of critical splicing factors, for example.
Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan.
Perhaps the most pressing question relates to the origin of the length-associated transcriptome imbalance during aging. Our findings about the genes with the shortest and longest transcripts enriching for genes with different roles toward longevity could be viewed as support for longevity-related roles of genes driving the evolution of their transcript length. However, this explanation would presently only appear to account for a fraction of the genes that show a transcript length-associated change during aging.
Turning to earlier literature, a length-associated transcriptome imbalance does not appear specific to aging itself. Moreover, there seem to be multiple potential molecular origins for a length-associated transcriptome imbalance. Most prominent among the specific molecular mechanisms, DNA damage has been explicitly demonstrated to yield a length-associated transcriptome imbalance with a relative fold decrease of the longest transcripts in a progeroid model of aging. Heat shock, which challenges proteostasis, a hallmark of aging, leads to a length-associated transcriptome imbalance by causing premature transcriptional termination through cryptic intronic polyadenylation. Similarly, loss of splicing factor proline/glutamine (Sfpq), encoded by the gene that displays the strongest differential splicing during human aging, has been shown to yield a length-associated transcriptome imbalance by interfering with transcriptional elongation of long genes. Methyl CpG binding protein 2 (MeCP2) opposes a length-associated transcriptome imbalance by dysregulating transcriptional initiation according to the length of the gene body. Further, patients with Alzheimer's disease show a length-associated transcriptome imbalance whose onset has been suspected to stem from somatic mutations that affected transcript stability.
Jointly, these observations invite the unsupported hypotheses that during aging there may not be a single origin for the length-associated transcriptome imbalance and that the length-associated transcriptome imbalance in aging instead represents an intermediate step through which multiple environmental and internal conditions simultaneously affect multiple downstream outputs. The length-associated transcriptome imbalance thus may offer itself as an explanation for the recent observation of inter-tissue convergence of gene expression during aging. Further arguing in favor of an integrative role of the length-associated transcriptome imbalance, we find evidence that several distinct antiaging interventions counter the length-associated transcriptome imbalance against long transcripts despite these different antiaging interventions partially affecting different aspects of cellular and organismal physiology.