A gene coding for a protein consists of multiple exon and intron sequences of DNA. During gene expression, the full DNA sequence of exons and introns is first transcribed into a RNA sequence, the primary transcript. That primary transcript undergoes a series of alterations that include RNA splicing. This splicing process removes the introns and stitches together the remaining exons to form a messenger RNA molecule. That messenger RNA is then used as a template by a ribosome manufacture many copies of the protein that it encodes.
Interestingly, many genes can undergo alternative splicing to produce several different messenger RNAs and proteins. A specific intron is not always excluded, a specific exon is not always retained. In some cases this is normal and expected, in other cases it has the look of an error that produces toxic proteins. The landscape of alternative splicing across all of the proteins encoded in the genome shifts with age, altering the balance of proteins produced via gene expression. Some research groups consider this to be a component of degenerative aging and a potential target for therapies to slow aging.
Species life span and the aging of individuals are related but may be driven by distinct mechanisms. Learning more about the determinants of species life span may or may not yield insights that are relevant to making individuals of any given species life longer. Differences in the regulation of alternative splicing may be important in determining species life span, but the research community is still at the early stages of gathering data to shed more light on this question. Today's open access paper is an example of this sort of exploration.
The Implications of Alternative Splicing Regulation for Maximum Lifespan
Alternative splicing (AS) is a post-transcriptional or co-transcriptional regulatory mechanism by which a single gene generates multiple distinct mature transcript isoforms, leading to protein diversity in higher eukaryotes. Up to 95% of multi-exon human genes undergo AS, often exhibiting tissue- or cell-type dependent regulation and dynamically controlled in distinct cellular processes. The association between AS and the intertwined realms of aging and longevity remains unclear. Age-associated splicing changes have been reported in different experimental systems, albeit in a piecemeal fashion, and alterations in certain splicing factor expressions in the spleen have been linked to differences in lifespan. These initial findings hint that splicing regulation might impact lifespan, but a comprehensive comparative analysis of maximum lifespan (MLS) as a species trait across species with widely varying maximum lifespans has not yet been conducted.
In this study, we systematically investigated MLS-associated AS events across multiple mammalian species spanning a broad range of maximum lifespans to uncover potential links between splicing and lifespan regulation. Our results suggest alternative splicing as an important factor correlated with both the evolved differences in mammalian lifespan and the human aging, and show potential molecular mechanisms (e.g., RNA processing, neural regulation, intrinsically disordered proteins, RNA-binding protein regulators) underlying these effects. Remarkably, nearly half of the highly conserved alternative splicing events show a significant association with maximum lifespan in at least one tissue. While many of these splicing associations are consistent across different tissues, the effects in the brain stand out as particularly distinct. Although the precise functions of many of these brain-specific events are unclear, previous studies have suggested a critical role for AS in regulating neuronal longevity and animal survival.
These findings suggest alternative splicing as a distinct, transcription-independent axis of lifespan regulation, offering new insights into the molecular basis of longevity.
View the full article at FightAging
