Biotech Startup SENISCA Develops a RNA Splicing Approach to the Treatment of Aging

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.

SENISCA seeks funding for senescence reversal

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."

SENISCA

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.

Comments

The "Saturating Removal Model" (https://www.nature.com/articles/s41467-019-13192-4) suggests that it is the linear increase in rate of senescent cell production with age that is the underlying problem, and that declining removal efficiency with age results mainly from that (from the growing population of senescent cells), not from aging per se (i.e., without increased production rate, one might never see a reduced removal rate). Thus it may very will turn out that slowing/reversing senescent cell production (vs. removal) is the more effective path in the long run.

Posted by: dtkamp at August 5th, 2020 7:50 PM

Hi dtkamp! Just a 2 cents. That's a good study (thanks for the link)/observation.

I would say this is Really great, I was not aware that splicing factor creation restoration would have such dramatic impact; I had guessed it was part of the epigenome/transcription/splicing at large whole ecosystem; but alone itself would not revert whole thing. It is clear that 'preventing' senescent cell formation, in the first place/altogether, is better than removing them after (letting them) appearing; which that would cause damage by SASP for however long the stayed before removed.

It's spectacular effect this splicing reversal, it reverses DNA damage, reverses senescent cell markers (p21, p16, p53, TNF-a, caspase...), reduces the production of senescent cells and rejuvenates the cell/organ..it is nearly akin to Yamanaka epireprogramming....

In the study, they show that splicign factors recreation in old cells brings them back to young cells (nearly), not just reduce senescent cells numbers - Reverse Senescent State/Replicative Senescence of the cell itself...they go back into division/reenter cell cycling...!....so that the cell is pretty much just like how it was 'when young/in low passages/double populations cell cycles rounds'. And this is Very important, the telomeres are increased anew, they said the telomeres are roughly 1.3-2.5 times taller after splicing reinstauration...that is a True Rejuvenation of the old cell - back to young state/signature.

They detected that LAMP/HSPs/autophagy (lysosomal chaperones) are back in function...they are crucial for function and long-lived animals all have chaperones that 'fold' proteins correctly (restore unfolded, oxidized or aggregated essential proteins) and ahve function lysosome-junk docking for autophagosome destruction.

What worries me more is they did small molecule approach to find elements that could naturally restore splicing function in old age....but they used senolytics..like resveratrol..they resveralogs...which I mean is great...we know that resveratrol/trans-resveratrol and other SIR/senolytics like quercetin really do reduce senescent; and here they say/show that resveratrol (found in red wine's red grapes) is capable of restoring splicing function/factors creation in old cells; so it is true rejuvenation that resveratrol/resveralogs do....for example, it was shown that red wine makes a long lifespan (by resveratrol content in it)...same thing with japanese knot weed; Very rich in resveratrol...this herb..or other knotweeds...does this make you live to 122 like Jeanne Calment - she drank porto red wine..daily...but Other people did the same...took resveratrol daily and did not reach her age. Another example, is the japanese quail bird..was fed japanese knotweed its whole lief..it live much longer...normally it lived like a year or so..but fed whole life with knotweed it could live nearly 2-5 times longer.....my take is taht a human on resveratrol/splicing mimetics...would get about 1.5-2x times lifespan extension - to the maximum of 122; no more. So a 60 years old person dieing young at 60...could boost to 90..maybe 100-110..perhaps 120..due to resveratrol activating the splicing factors recreation.`

The researches need to boost the effect of this splicing reversal; so that it ends drastically stronger than resveraterol...because red wine/red grapes/resveratrol..will not make you live much above 122 like her (tops 130 or so)...nearly 100% sure...people have been consuming red wine since the antiquity...and they never lived longer than her record of 122. 99% of the supercentenarians claiming 130-140...150..160..are bogus/been debunked solidly....right now that 122 is the record/'guiness' book record of max specie human aging. 99% of humans who reach 120...do not even reach 121; that's to tell you; 120 is like the big hard limit but she pushed it 2 more and nobody did in entire history (or well let's say from all teh litterature that was recorded by 'extreme longevity' in people of the ancient past).

I so so hope that this does end up an underwhelming avenue...it does rejuvenate truly...but it seems the effect is still not that Huge...they saw 1.5-2x telomere lengthening that is Huge...but does it stick like that for your whole ilfe.....I don't think so that's the problem...we found out that telomere length is important of course..but what's more important is the rate of loss of it. It doesn't matter if taller telomers - but you lose them 3times faster...I am guessing the telomere rate must have slown down; and this lengthening is What cause the longevity of the cell now (it can resume cell cycling despite being old cell that falters on dividing/cyling..that is Clearly due to telomere lenghtening). I mean we have been consuming resveratrol...in the food we eat..it sure helped but to say we will be 120 becayse of this is Very optimistic, too much so. People ahve been taking resveratrol 'indirectly' in their food since who knows when and many did not reach that venerable age of 100-120...Despite taking it at the same time. I took resveratrol to reverse my atherosclerosis..let'S just say it worked a bit...not much than that. It did rejuvenate my skin/made me look yougner..but my disease continued its course. Itself it did not stop it despite me taking daily red wine. But I'll get back on it for sure (expensive resvertrol supplement...buy red wine/red grapes instead but...all this adds up to 'Supplement cost tally' per month..need cash/not free).

I am cautiously optimistic that this is incredible and it just needs be honed better and we at least know we can reverse splicing loss with resveratrol/fruit supplement..that'S good...but need more than that; we want to Stop splicing loss with age and make sure teloemres too stop shortening....that Will be truest rejuvenation ever and will make Much longer lifespan possible; I wuold wager we will beat 122 then; as long as we start earliest (but this study is very recomforting for old people - you can reverse the clock/aging - despite being old). It's one more therapy to our arsenal (which all of this will be costly$$/the big problem).

Just a 2 cents.

Posted by: CANanonymity at August 5th, 2020 9:40 PM

PS: ''I so so hope that this does *not* end up an underwhelming avenue'' (typo).

Posted by: CANanonymity at August 5th, 2020 10:01 PM

Hi CANanon. wrt centenarians, I'm skeptical about making too much of them since most of them reached that age by dumb luck (i.e., they just missed getting hit by that bus, just missed that last mutation to give them breast cancer, etc.) Plus, nearly all centenarians look like centenarians, being quite frail and vulnerable (google some pics, including Okinawans). Hopefully we are beginning now to dream bigger (such as a 100 year old with health and appearance of a 50 year old) now that the more important levers of aging are beginning to be revealed.

Posted by: dtkamp at August 6th, 2020 8:22 AM

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