Fight Aging!

In recent years researchers have investigated changes in alternative splicing in the context of aging and age-related disease. It is thought to be important in cellular senescence, for example, but that is just one line item in the bigger picture. A given gene can code for multiple different proteins, and alternative splicing is the name given to the processes by which those different proteins are produced. A gene contains discrete DNA sequences called exons and introns, the former passed into the protein production process, and the latter removed during RNA splicing. The canonical protein produced from this genetic blueprint contains all of the exons, joined in sequence, but alternative splicing may drop exons, resulting in a different protein.

The balance between the proteins produced from a given gene tends to shift with age. This might be a harmful downstream consequence of underlying molecular damage, or an evolved reaction to attempt to compensate for that damage in some way. All too little mapping of these age-related changes in alternative splicing has been carried out, but we might regard it as yet another form of gene expression regulation, akin to epigenetic changes that alter the pace of production of proteins.

Intron retention is another possible form of alternative splicing. Instead of an intron being removed, it is included in the process of producing a protein. This also results in a different protein with different characteristics. In today's open access paper, researchers look specifically at intron retention in flies, mice, and humans, finding that rates of this phenomenon correlate with age and neurodegenerative disease. The water is muddied somewhat by the point that this alternative splicing does take place to some degree in young individuals, as a normal part of the operation of cellular metabolism. Nonetheless, it seems likely that someone might produce an intron retention clock analogous to the epigenetic clocks presently demonstrated to measure age quite well.

Alternative splicing is a regulatory mechanism that generates multiple mRNA transcripts from a single gene. While this process is essential for many biological processes such as neurogenesis, alteration in the splicing patterns is also prevalent during aging and may contribute to many age-onset diseases like Alzheimer's disease (AD). Intron retention (IR) occurs when a specific intron remains unspliced in the mature polyadenylated mRNA. As an IR may trigger nonsense-mediated decay (NMD) of mRNA or introduce mutation in the translated protein, it has been widely considered as an aberrant splicing event that is associated with various diseases.

For instance, dysregulated IR is one of the drivers of transcriptome diversity in cancer and can lead to inactivation of different tumor-suppressor genes. IR in endoglin and EAAT2 gene also leads to cellular senescence and amyotrophic lateral sclerosis, respectively. Interestingly, dietary restriction in worms could reduce aberrant IR caused by defective splicing during aging, suggesting that IR at specific genes can be used as disease biomarkers or targets for therapeutic intervention. Accumulated evidence indicated that IR may also play an important regulatory role during normal development, including translational inhibition in response to hypoxic stress, regulation of mRNA expression patterns during hematopoiesis and neurogenesis. Therefore, defining age-associated changes to IR may allow a far better understanding into how IR may regulate the transition from healthy to the pathological state during aging.

To this end, we analyzed the in-house RNA-sequencing data of aging male Drosophila heads and observed a global increase in the level of IR as the animals aged. Interestingly, IR affects functionally distinct groups of genes at different stages of an adult lifespan. Consistent with the role of chromatin structure in regulating RNA splicing, we found that nucleosome positioning within a subset of introns in young flies correlated with their differential retention in older animals. Further analyses of transcriptome from mouse and human brain tissues suggest that the global increase in IR during aging may be evolutionarily conserved. The differentially retained introns identified from different species share several similar characteristics, including shorter length when compared to spliced introns and not susceptible to NMD.

Notably, several differential IR genes identified from aging Drosophila and human brain tissues are linked to AD-related pathways, postulating that the pattern of IR may undergo further changes during AD progression. To test this possibility, we analyzed AD datasets from the cerebellum and frontal cortex, and observed a global increase in the level of IR in AD brain tissues when compared to the control samples. These differentially retained introns have a shorter length and higher GC content compared to the spliced introns. Differential IR genes are enriched for functions associated with RNA processing and protein homeostasis, with more than a hundred of them having an altered level of protein expression in AD frontal cortex. Taken together, our results suggest that a global increase in IR may be a transcriptional signature of aging that is conserved across species and differential IR at specific genes may contribute to the etiology of late-onset sporadic AD.

Link: https://doi.org/10.1111/acel.12928