In recent years, increasing attention has been given to RNA splicing as a mechanism of interest in aging. RNA splicing is the process of combining intron and exon regions derived from a gene's DNA sequence into the final RNA sequence transcribed from that gene. Introns are usually dropped, exons are usually included, but this process of combination allows multiple proteins to be derived from one gene.
Characteristic changes in splicing take place with age, such as alterations in the proportions of different proteins produced from the same gene via different combinations of introns and exons. The regulation of splicing becomes more ragged in general, such as by allowing introns into RNA sequences when they should be excluded, and this is thought to contribute to metabolic disarray, cellular senescence, and other manifestations of aging. As for many of the mechanisms implicated in aging, there is as yet no robust placement of splicing changes in a chain of cause and consequence. It is unclear as to why exactly splicing runs awry, or the degree to which it contributes to specific higher level manifestations of aging.
The fastest way to achieve this understanding is most likely to selectively suppress splicing changes and see what happens as a result. This strategy has the added bonus of offering a chance at a treatment of aging if successful. Suppression of age-related changes in splicing is the intent of the founders of SENISCA, one of many biotech startup companies recently founded to swell the ranks of the growing longevity industry. They have found that forcing a reversal of some splicing changes can reverse cellular senescence, a normally irreversible cell state, and thus stop the senescent cells that accumulate with age from producing inflammatory secretions that cause great harm to old tissues. There is some debate over whether this is a good idea, versus forcing the destruction of these cells via senolytic treatments, as senescent cells are likely damaged in ways that might increase cancer risk if left alive and actively non-senescent. But again, the studies will be carried out and we'll see what results.
Deep in the labs at the University of Exeter's College of Medicine and Health (CMH), a new company is emerging. Co-founded by Professor Lorna Harries, SENISCA is developing "senotherapeutic interventions" that reverse cellular senescence. Through modulation of RNA splicing, the company has developed a way to effectively turn back the aging clock in old cells and is working on developing new treatments for the diseases and aesthetic aspects of aging.
"I'm an academic, but my ambition also has always been that anything that we discover that shows clinical potential is pursued and followed through to the clinic. Having shown that splicing regulation declines during aging, the million dollar question for me then was - what happens if you turn it back on?" This question led Harries to the study, which showed that cells could not only be brought out of senescence but that, by doing so, the cells were also rejuvenated.
"When we did that, we were utterly, utterly amazed. While there had been research that showed aging could be reversed in animal models by removing senescent cells, this was different. So we're not removing senescent cells, we are rejuvenating them. The cells regain pretty much all of the features of young cells. They're still old cells, but they're not senescent, so they're not throwing out inflammatory proteins, which is what's doing the damage to our bodies. We learned that yes, you can target those pathways and you can reverse senescence. The molecules were used to do that were already in the clinic as anti-cancer agents, so we knew they were safe and specific, so that proved that we'd found the right pathway."
Our founders have discovered that levels of splicing factors change during ageing, compromising our ability to carry out this 'fine tuning' of gene expression. This is a fundamental reason why cells become senescent. Compromised molecular resilience is a major cause of the ill health and frailty that accompanies ageing. We have demonstrated that restoration of splicing factor levels to those seen in younger cells is able to effectively turn back the ageing clock in old cells, bringing about reversal of senescence.
At SENISCA, we are taking a two-faceted approach for modulation of splicing factor levels. Firstly, we are identifying small molecules capable of restoring splicing factor levels. Secondly, we are targeting the genes that control splicing factor levels directly. Both approaches will reset splicing factor levels and reverse senescence. We anticipate that understanding the molecular basis of rejuvenation will highlight new treatments for the diseases and aesthetic aspects of ageing. More importantly, it is likely that preventative approaches based on rejuvenation will be developed reducing both disease incidence and severity.