Lorna Harries is a Professor of Molecular Genetics at the University of Exeter Medical School. She is also the CSO and R&D lead at SENISCA Ltd. Like many other companies, and as evidenced by the name, SENISCA targets senescent cells, albeit using an unusual mRNA-based approach. After Lorna gave a fascinating talk at our Ending Age-Related Diseases 2021 conference announcing a new hallmark of aging, we knew we had to share some more of her scientific wisdom with you.
In your talk at EARD-2021, dysregulated RNA processing was presented as a new hallmark of aging. Could you explain the rationale behind that?
Some of the criteria for a hallmark are that it happens in normal aging, that it happens in multiple species, and that its modification yields attenuation of aging phenotypes.
We have shown that dysregulation of mRNA processing demonstrably happens in normal aging – the genes that regulate these processes are amongst the most dysregulated during age in multiple populations. We also have evidence that splicing factors are dysregulated in conditions of premature aging.
We have also shown they are predictively linked with multiple aging phenotypes. Moreover, we have shown this also in multiple species – splicing factor expression is linked with median strain lifespan in mice and with response to dietary restriction.
Finally, we have shown that restoration of splicing factor expression results in reversal of multiple aspects of cellular senescence. To my mind, taken together, this evidence suggests it’s reasonable to classify dysregulated mRNA processing as a hallmark.
That talk was focused on how dysregulated RNA processing affects cellular senescence, which itself is a hallmark of aging. Is RNA processing linked to any other hallmarks?
There are interconnections between all the hallmarks. We have evidence that disrupted mRNA processing is also linked with mitochondrial dysfunction, but we haven’t yet explored this exhaustively. Since mRNA processing affects 98% of all genes, I would be very surprised if it did not affect most, if not all, of the hallmarks, as it will affect most of the genes involved in these processes.
I understand that what you and your company SENISCA are working on is not exactly senolytics, since you seek to control or reverse senescence rather than to clear out senescent cells. Could you tell us more about your approach?
Ours is the senostatic approach. Yes, this means that we are aiming not to remove senescent cells but rather to stop their pathogenic features. There are some tissues that are cell-poor, so removal of cells may pose downstream issues. There is also an open question about the long-term consequences of just removing the senescent cells – the endogenous stressors are still there as a provocation for senescence in remaining cells. mRNA processing is a pivotal part of molecular stress response. By restoring the ability of the cells to respond to their internal and external environment, we should not just address the problem of the existing senescent cells but also remove some of those endogenous stresses and hopefully slow the rate of accumulation of new senescent cells.
Some people express concern about putting senescent (hence, potentially damaged) cells back to work. How are you addressing this issue?
This is a logical and important question. We have the ability to uncouple reversal of senescence from resumption of cell cycle, so we will be able to attenuate phenotype without inducing renewed proliferation. So, our approach is to remove some of the more deleterious aspects of senescence, i.e. SASP [Senescence-Associated Secretory Phenotype], rather than restore cells’ ability to divide.
It’s important to remember that all the cells in an older person are potentially damaged, though, senescent or otherwise, and no one is suggesting removing all of them. It’s interesting to note that the small molecules that we initially used to explore the potential of this have all been linked with lower cancer risk in animal models, and some of them are actually in the clinic as anti-cancer drugs.
How does your pipeline currently look?
We have two main strands. One is a computational chemistry approach to identify compounds with the same characteristics as those we know work, for use in the aesthetic aging sector. This is well underway.
The other, for medical indications, is using an oligonucleotide modality to address the ‘master control genes’ of splicing factor regulation, in particular the interaction between these regulators and their regulated genes, so we can target very specifically. There are some real advantages to oligonucleotides: they can be used in tiny doses and delivered to specific tissues or even cell types very specifically, and when used locally, as we will be using them, they have very little systemic distribution, so off-target effects are minimal. The chemistries, kinetics and toxicity profiles are also very well understood compared with a new small molecule. We have a number of existing validated targets, and we are currently optimizing the chemistries of our novel oligonucleotides to maximize effects, but once we are happy with them, we will be moving through the well-established steps to IND submission.
Cellular senescence is still not a particularly well-defined phenomenon. Do we have enough knowledge for your and other companies to base their work on?
It’s true that senotherapeutics are in their infancy and we still have loads to learn. In our case, we are restoring normal physiological processes in the cell; senescence reversal is almost a consequence of this rather than an explicit aim. We’re just making the cells do what younger cells do naturally.
Senescent cells are sometimes useful, and there are lots of subtypes. Because what we seek to do is to restore the normal homeostatic regulatory processes of the cell, we think that our approaches should specifically target the deleterious aspects of senescence rather than senescence per se.
We have enough knowledge to start to build on this in our case. Things may be different for more ‘artificial’ situations where cells are treated with things that they don’t usually encounter, but if scientists don’t explore this, there will never be progress. One could say the same for many drugs – we often don’t have complete knowledge of all their potential models of action.
FOXO genes are a fairly new target in longevity research. Could you tell us a bit more about this “family of foxes”, as you call them in your talk?
FOXO genes are a fundamental part of cellular stress response. They regulate genes involved in many important processes within the cell, from immunity to cell division. As such, they are not unexpectedly tightly associated with longevity.
Genes in this family were amongst the first to be associated with lifespan effects in invertebrate model systems, and genetic variation in the FOXO3 gene has been associated with extreme longevity in multiple human populations. Some of this effect may be due to the fact that the variants in question affect the portfolio of FOXO3 isoforms produced, with truncated forms lacking in functionality.
Peptides targeted to FOXO4 are already being evaluated as potential therapeutics, and, of course, FOXO1 itself is one of the genes we have found to have a role in age-related dysregulation of splicing factors. Because FOXO proteins have so many roles in the cell, however (they can be activators or inhibitors depending on context), the challenge is to dissect the specific action you want to target – in our case, splicing regulation. This is where going for downstream targets, or interaction between target and regulator, is useful.
Various expressions of FOXO genes are associated with increased longevity. How strong is the connection? Do you think that by manipulating genes in vivo, we could achieve a considerable extension in lifespan and/or healthspan?
These are some of the most important genes in determination of lifespan and healthspan. Because they have so many roles, care is needed in targeting them. So, I prefer to target downstream effectors, where you can achieve much more precise specificity. I do think that by these means, we will be able to make an impact on healthspan. As far as lifespan is concerned, we already know that manipulation of FOXO orthologs extends lifespan in invertebrates – they were actually amongst the first lifespan genes ever discovered. Whether this holds true in more complicated species remains to be determined. At the current time, healthspan extension is our focus.
Circular RNAs are regulators of gene expression that we’ve only recently learned about. What do we know already, and how could this discovery impact the longevity field?
We know hardly anything about circRNAs! They are actually another type of splicing event. Normally, exons are joined 5′ to 3′, but in the case of circRNAs, you see the 3′ end of one exon coming round and being joined upstream of the 5′ exon, forming a circle. We know that they are regulated independently of their linear counterparts – they sometimes don’t track the linear expression patterns of these – but we don’t yet know exactly what signals cause them to be up- or downregulated. We know that there are some that come from very important lifespan and healthspan genes, like FOXO3, and also that like miRNAs, they can be secreted in extracellular vesicles and travel round the body, but we don’t yet fully understand how they work.
It’s known that their abundance generally increases with age (as they are so stable compared to other RNAs), particularly in the brain, and we have shown that there are many more circRNAs in the peripheral blood of older people than in younger people. We’ve also shown that some of these are associated with lifespan and with downstream aging outcomes and that some show altered expression in senescent cells of different cell types. Our knowledge of these RNA species is in its infancy, however, but my hunch is that they represent another layer of transcriptomic regulation that may turn out to be just as important, if not more so, than other non-coding RNA species like miRNAs.
For me, such major discoveries are both encouraging and frustrating, because they show how little we know and how long the road ahead is. What about you: does this make you feel optimistic or pessimistic?
It actually makes me very hopeful. Discoveries and innovations are happening all the time. These new discoveries are a source of future therapeutic approaches. At the moment, we’re trying to do a jigsaw with only half of the picture to refer to, so the more of that picture we can build, the more possibilities there will be. It’s also not completely necessary to do the whole picture – sometimes there is enough completed to be able to see what’s shown!
Please offer us your general thoughts on the state of affairs in the longevity field. What are the current problems and opportunities? Where could a new breakthrough or breakthroughs come from?
I actual think we have reason for a lot of optimism here. We’re beginning to understand some of the really fundamental processes and how we might manipulate them for new drugs. It’s a time of immense possibility. There are caveats, obviously: we need better biomarkers, better ways of assessing our outcomes, and more public understanding that the passage of time is inevitable, but some of the worst aspects of aging may not be.
In terms of what I am most excited about, I think the whole senotherapeutics field is incredibly exciting. There is still lots to uncover, and we haven’t got the whole story yet; of course, it needs more finesse, but the data coming out on this approach is incredibly promising. I also think that targeting various aspects of cellular aging may be a fruitful strategy. There are some very nice data coming out on epigenetic reprogramming and on attenuating mitochondrial dysfunction. Some of these potential approaches may be stand-alone, but there‘s also the possibility of using them in combination to target multiple aspects of cell aging simultaneously.
And, of course, there will be future breakthroughs where we least anticipate them! Some of the most exciting breakthroughs come completely out of left field. Our finding that dysregulated splicing might be a useful senotherapeutic target was definitely one of these! We weren’t looking for this when we found it! I think we’re poised at the threshold of a whole new way of holistically treating age-related diseases, and I’m excited to be part of it.