Fight Aging!

A gene sequence consists of a mix of shorter sequences, only some of which are used to manufacture the protein encoded in that gene. Exon sequences are included and intron sequences are excluded. Nothing is ever quite that simple, of course, but changes in which exons and introns end up in a protein enable multiple proteins to be produced from a single gene sequence. Sometimes this is an accident, as some genes are prone to accidental production of truncated or extended proteins that are toxic. Sometimes this is an evolutionary reuse in which a gene produces several different vital proteins with quite different functions.

The process by which a gene sequence is interpreted to manufacture messenger RNA (mRNA) molecules for a given protein (some or all exons, none of the introns) is called RNA splicing. Alternative splicing is what happens when the dominant protein is not produced, but rather some other protein is made instead. Splicing is a complex and highly regulating process, and like all such processes in the cell, it runs awry with age. Changes in the gene expression of splicing factors and other forms of change and damage in the cell can alter the distribution of different mRNAs produced from a given gene, or lead to a greater production of malformed, toxic proteins.

As for all of the changes taking place in the machinery of gene expression, we might well ask where alternative splicing fits into the complex web of interacting causes and consequences of degenerative aging. Are these changes closer to being a root cause of aging, with many harmful downstream effects resulting from disruption of RNA splicing? Or are these changes far downstream, with little further damage and dysfunction resulting from dysregulated RNA splicing? There is a sea of data, but it remains hard to argue for a given position without acknowledging the surplus of evidence that supports all of the other positions. For what it is worth, methods of slowing aging tend to correlate with lesser disruption of RNA splicing. The most interesting research here is by groups like SENISCA that are attempting to restore youthful organization of RNA splicing, and have achieved some success on this front. It remains to be seen as to how this will turn out, given that it remains a comparatively new area of research and development.

Age-Related Alternative Splicing: Driver or Passenger in the Aging Process?

A wide range of changes in cellular mechanisms involving both transcriptional and post-transcriptional regulation have been linked to normal aging. While age-related variations in the cellular environment lead to eventual molecular changes, it is also possible that the molecular changes accelerate aging and age-related disorders (ranging from hypertension to cardiovascular disease, cancer, and neurodegeneration). Furthermore, different tissues and organs may experience different age-related alterations in transcriptional and post-transcriptional regulation. In higher eukaryotic genomes, alternative splicing (AS) of both protein and non-coding genes not only profoundly contributes to increasing the functional diversity and complexity of the whole transcriptome, but it also seems to be a master regulator of cellular and individual aging.

Although the majority of variations in alternative splicing events occur during development, it is estimated that approximately 30% of all alternative splicing alterations occur during aging. As rodents and humans consistently exhibit age- and tissue-related variations in the expression of genes involved in splicing, age-related changes in splicing may be caused by the age-related decline in splicing factor expression. On the other hand, the main categories of genes with age-related altered splicing include those encoding genes with neuronal-specific activities such as synaptic transmission in the human brain, as well as those implicated in collagen production and post-translational modification in the human Achilles tendon. These observations suggest that age-dependent splicing changes are more likely to occur in at least some of the same categories of tissue-specific genes that show transcriptional decline with aging.

Aging-dependent splicing alterations can explain why some genes show a tissue-specific decrease in expression. Splicing errors during pre-mRNA processing can result in the incorrect usage of alternative splice sites, leading to intron retention in the mature mRNA transcript rather than proper exon joining. Intron retention introduces premature termination codons that target the aberrant transcripts for degradation through nonsense-mediated decay (NMD). This differs from frameshift mutations caused by small insertions or deletions during splicing, which can also introduce premature stop codons but do not always trigger transcript degradation by NMD, and may allow some protein production from the altered transcripts.

The interplay between splicing and aging has major implications for aging biology, though differentiating correlation and causation remains challenging. Declaring a splicing factor or event as a driver requires comprehensive evaluation of the associated molecular and physiological changes. A greater understanding of how RNA splicing machinery and downstream targets are impacted by aging is essential to conclusively establish the role of splicing in driving aging, representing a promising area with key implications for understanding aging, developing novel therapeutic options, and ultimately leading to an increase in the healthy human lifespan.