CellAge – Synthetic biology meets senolytics
By Steve Hill and Elena Milova
CellAge, together with a leading synthetic biology partner, Synpromics, are poised to develop a technology allowing for the identification and removal of harmful senescent cells. Senescent cells accumulate with age until they reach pathological levels and contribute to age-related diseases and chronic inflammation by secreting harmful signals that also poison neighboring cells.
CellAge founder Mantas Matjusaitis (BSc Biomedical Science and PhD student in the field of synthetic biology in the University of Edinburgh) had been following the field of senescent cell removal (senolytics) for some time and saw it had therapeutic potential for treating age-related diseases. Mantas has been involved in the SENS Education programme, resulting in a publication. He met a likeminded person who was working on technology that allowed accurate precision targeting cells using synthetic promoters. They discussed the idea of merging the two approaches together and soon realized there was huge potential here and shortly after, at the end of 2015, CellAge was formed.
We took the opportunity to catch up with Mantas to ask him about aging research and the CellAge project and his hopes and plans for the future.
Can you please tell us why do you think that aging is a bad thing?
I believe that there is a lot of unnecessary suffering, both mental and physical, in old age. This comes from particular diseases, like cancer, atherosclerosis, cataracts etc., but also from the general loss of health and fitness with time. This prevents many people from enjoying their later years to the fullest. We are working hard and want to see a future, where after working most of your life, you can spend your retirement doing the sports and hobbies you enjoy, travelling freely, being independent, seeing your grandkids grow up, and really, doing anything that you want. This is the future we believe is possible and this is a future we want to help build.
In the 2013 paper Hallmarks of aging the authors identified nine categories of aging “damage” and of course SENS identifies seven damage categories which overlap with this and are essentially the same. What would you say are the top three damages we need to address first?
I believe the three areas that we should address first are the following: better ways to deal with cancerous cells, replenishing tissues with healthy (stem) cells and removing senescent cells. The main reason why I think these areas are the most potent is because the therapies and tools to address them are very close to being clinically approved (or are already approved in some cases) and they would have a significant effect not only on increasing general healthspan, but also treating some diseases which are not related to ageing per se.
Firstly cancer is something that many research groups are focusing on and it gets a lot of money, so we have to hope that the therapies will get better over time.
The second area will be dealt with (at least initially) by the rise of cell-based therapies. Multiple clinical trials are underway and some cell-based therapies are already been offered. I believe that very soon, the repertoire of healthy cells that we can transplant into the patients will increase exponentially and that will no doubt help increase healthspan and lifespan.
The last area that I think is key to address as early as possible is senescent cells removal and the reasoning is simple. These cells contribute to general tissue quality decline and tumorigenesis. Which means that unless you remove senescent cells periodically, you will have more incidences of cancer to deal with and healthy cells that you transplant into the body will be sabotaged. So in the end, we have to solve all these problems together to really see the benefits that we want to see. It will take time, but we are getting there.
Please tell us more about senolytics and your project. What are senescent cells and why are they a problem?
Senescent cells are cells in your body which have stopped replicating either due to damage or due to replicative exhaustion. These cells have some important positive short term effects such as helping to prevent some cells from becoming cancerous and helping with wound healing. However, in the long term they start to accumulate and then damage the surrounding tissues and cells. The idea is to periodically (every couple months or years for example) remove these cells from your body to prevent these long term negative effects but maintain positive short term effects. This has been shown to increase mice healthspan (the length of time spent free of serious illness) and lifespan. CellAge is one of the groups who are trying to translate this research into medicine.
The body does not have a problem with them when you are young so why do they become a problem when you age?
It’s about a couple of things really. Firstly, these cells take time to cause a negative effect. Their effect is rather chronic causing damage over time to the surrounding cells and so diseases start to manifest with age. Secondly, and more importantly, the amounts of these cells increase with age, and that strengthens their effect. Early in life, we do not have too many of these cells because they are efficiently removed by the immune system. However, as we age, more senescent cells appear (due to exhaustion and cellular stress) and less are removed (due to the aging immune system). As a result, these cells contribute to many age-related diseases. So in short, the answer is because it takes time for them (i) to build up, (ii) have a negative effect and (iii) because their removal becomes impaired.
Some recent research by Andrei Gudkov and his colleagues suggests that macrophages (cells that clear the body of junk) would be a good focus for senolytics. When they become senescent they stop working properly and actually contribute to inflammation and disease instead of clearing the body of waste such as senescent cells. What do you think about focusing on senescent macrophages with a senolytic therapy specifically?
Excellent question and thank you for giving me a chance to show why we believe in our technology so much. Only time and research will show if these senescent macrophages are the key cells that we should be focusing on. It might be the case, although I have my doubts, I think all the rest of the senescent cells play a critical role in lowering the regenerative capacity of tissues etc. At this point in time, there is not enough data to choose the target and ignore the rest. However, if it does turn out that only senescent macrophages need to be targeted this is where our technology has great potential.
If you used small molecules or generic promoters such as p16, it would be very hard (if not implausible) to only target senescent macrophages. If what you want to do is remove just these p16(Ink4a)/β-galpH6-positive macrophages you need more precise targeting and that is something our system could help develop. The synthetic promoters that we will create could target just senescent macrophages if need be and here is the reason why. The promoters that we will construct will be based on the input of cell types that we have, so if we use senescent fibroblasts, we will compile a sequence which only targets senescent fibroblasts. However, if we use senescent macrophages in our screen, the same is true. We find gene X is ON in senescent macrophages (e.g. F4/80) and use its promoter together with p16 promoter sequence to make a synthetic promoter which just target senescent macrophages. This is a very basic explanation of the technology, but it makes the point.
What is the main challenge/bottleneck for biotech startups in the field of aging research, how do you see it? What needs to be changed in order to bring new therapies to the market faster? Regulations, funding, public attitude, something else?
Firstly, biotech in the aging field have same challenges as any other biotech, which is high risk (and failure rate) at early stage, need for large capital to reach inflection points, long product development timeframes etc. However, in addition to these general sector bottlenecks, companies (and academic groups) focusing on ageing research have additional struggles. Firstly, its perception in the public that ageing is not amendable process. In the simplest form I can describe, ageing is a combination of accumulating damage which results in age-related diseases and we can improve or provide new pathways to help deal with this damage. I do not know if that would stop ageing, but it would definitely improve health in later years.
Secondly, this field is relatively new and so investors are still not fully aware of the possibilities and potential therapeutic interventions. This makes getting grants and funding very hard.
Lastly, regulatory agencies will have to adapt. Finding drugs which help delay or prevent age-related diseases (not cure them) will be hard to approve. These trials would take decades just to show that they can extend healthspan by preventing or delaying age-related diseases.
Imagine that you want to free society from Alzheimer’s. One type of drug could be to cure Alzheimer’s in people who already have it, and that is relatively a straightforward path in clinical trial (at least from a design point of view). Now imagine that you want to give a preventative therapy to people at the age of forty, so they never develop the disease in the first place. This trial would be much longer (and expensive) and harder to validate from an efficacy point of view as Phase II trial would need to be much larger in size. Also I think eradicating diseases, not curing them once they manifest, is what we should strive for as the ultimate goal.
Sometimes it is easier to attract helpers if you are a non-profit. Why did you decide to register as a commercial organization?
The only reason why we are registered as a commercial organization is that it would be extremely hard to fundraise when we reach preclinical and clinical trials if we are a non-profit. When you are talking about clinical trials, you are talking about very large amounts of money and most of the money comes from investors who are looking for a return of investment. If you cannot offer that to them, your therapy will never reach patients because quite simply investors will not invest money into it. I struggle to think of a single not-for-profit organization which has managed to bring a new drug all the way to the patients and even if there are a couple, such a path is significantly harder. Considering the hurdles we already have to jump over, we do not want to make the process even harder. The SENS Research Foundation are an example of this, they conduct or fund the initial high risk non-profitable research with community support but the resulting technology is developed by for-profit companies such as Oisin Biotechnology, Ichor Therapeutics and Unity Biotechnology for example.
Who will be the first person you are going to call to tell about the success of the project, apart from your team members and scientific advisers? Why this person?
It would have been my sister Zivile Matjusaityte who recently passed away. We had been researching and planning many of these things during our childhood. Then it was just a childish dream, now it is becoming a reality. She was a big supporter and really believed we can do this. Now I am doing this in her memory.
Thank you very much for these excellent detailed answers. We hope this dream will come true, and we wish you the best of luck with the ongoing crowdfunding campaign to finance the first stage of your research.