I mentioned CellAge some weeks ago; a new entry to the collection of companies and research groups interested in developing the means to safely identify and remove senescent cells from old tissues. A few days later one of those companies, UNITY Biotechnology, announced a sizable $116 million venture round, which certainly put the field on the map for anyone who wasn't paying attention up until that point. In contrast, CellAge are taking a less commercial path for now, by raising funds from the broader community of supporters and intending to make some of the tools they create freely available to the field. Why are senescent cells important? Because they are a cause of aging, and removing them is a narrowly focused form of rejuvenation, shown to restore function and extend healthy life in animal studies. An increasing number of senescent cells linger in our bodies as we age, secreting signals that harm tissue structures, produce chronic inflammation, and alter the behavior of nearby cells for the worse. Senescent cells also participate more directly in some disease processes, such as the growth of fatty deposits, weakening and blocking blood vessels, that takes place in atherosclerosis. By the time that senescent cells come to make up 1% of the cell population in an organ, their presence causes noticeable dysfunction and contributes significantly to the progression of all of the common age-related diseases.
This coming Monday, the CellAge team will be hosting an /r/futurology AMA event - the post is up already if you want add your own questions for the scientists involved. Earlier this week, the CellAge principals launched a crowdfunding campaign with Lifespan.io: they are seeking $40,000 with stretch goals and rewards beyond that to get started on their vision for senescent cell therapies. If you've ever wanted the chance to have a DNA promoter sequence named after you ... well, here it is. This has certainly been a busy year for community fundraising in rejuvenation research: I imagine that things will heat up even more in the years ahead. The CellAge view of the field of senescent cell clearance is that the markers currently used to identify senescent cells are too crude and lacking in specificity. These researchers want to build the basis for the next generation of better senescent clearance therapies, those capable of identifying and removing far greater proportions of these unwanted cells. This is an admirable goal, given that those involved intend to make the initial results of their work freely available to to the research community. From my point of view, I'd say the current markers are absolutely good enough for a first pass, the production of a therapy that will produce significant benefits, and the results in mice and rats achieved over the past two years are an adequate demonstration on that front. I'm definitely in agreement that research and development doesn't stop at "good enough for a first pass," however. There should always be someone building the next and better generation of medicine around the time that the current generation is heading towards the clinic. So take a look at this fundraiser and see what you think; the technical details make for interesting reading.
Recently it has been demonstrated that senescent cells (cells which have ceased to replicate due to stress or replicative capacity exhaustion) are linked to many age-related diseases. Furthermore, removing senescent cells from mice has been recently shown to drastically increase mouse healthspan, the period of life free of serious diseases. 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. Our breakthrough technology will benefit both the scientific community and the general public.
In short, CellAge is going to develop synthetic promoters which are specific to senescent cells, as promoters that are currently being used to track senescent cells are simply not good enough to be used in therapies. The most prominently used p16 gene promoter has a number of limitations, for example. First, it is involved in cell cycle regulation, which poses a danger in targeting cells which are not diving but not senescent either, such as quiescent stem cells. Second, organism-wide administration of gene therapy might at present be too dangerous. This means senescent cells only in specific organs might need to be targeted and p16 promoter does not provide this level of specificity. Third, the p16 promoter is not active in all senescent cells. Thus, after therapies utilizing this promoter, a proportion of senescent cells would still remain. Moreover, the p16 promoter is relatively large (2.1kb), making it difficult to incorporate in present gene therapy vehicles. Lastly, to achieve the intended therapeutic effect the strength of p16 promoter to drive therapeutic effect might not be high enough.
CellAge will be constructing a synthetic promoter which has a potential to overcome all of the mentioned limitations. A number of gene therapy companies have successfully targeted other types of cells using this technology. With your help, we will be able to use same technology to develop tools and therapies for accurate senescent cell targeting. As our primary mission is to expand the interface between synthetic biology and aging research as well as drive translational research forward, we will offer our senescence reporter assay to academics for free. We predict that in the very near future this assay will be also used as a quality control step in the cell therapy manufacturing process to make cell therapies safer!
I recently had the chance to talk with the CellAge founder Mantas Matjusaitis about the initiative and his views of the broader field. After so many years of bootstrapping support for senescent cell research, it is definitely very welcome to see such an influx of interest in senescent cell therapies, and the arrival of many diverse approaches in this area of research and development.
How did you folk at CellAge meet? What made you decide that senescent cell clearance was the most needful accomplishment you could work on?
As many worthwhile efforts go, we didn't push CellAge into existence just because we wanted to start a company. I have been following ageing research for very long time and so I was aware what is happening in the field. At the same time, I emerged myself into synthetic biology where I am doing my PhD now. For a while, I have been exposed to these different fields and at some point things just connected. Recent publications on mouse models showed that there is a great promise in removing senescent cells and from my own end, some exciting technological opportunities presented themselves from the synthetic biology side. So CellAge is really a result of many coincidence that led to this project. After I discussed these ideas with more experienced people, some of whom are our advisors now, I came to realize that there is a real opportunity here and we took it!
Yes there are multiple companies working towards same or similar goal and I am very happy of their efforts. First and foremost, I am scientists and I lead CellAge as a scientist - we just want to see this technology coming to existence, be it us or someone else who does it. That being said, at this stage it's really hard to see which approach will be best and it's likely (considering examples in oncology field) that combination of therapies will need to be taken (e.g. immunotherapy together with gene therapy or small molecules together with gene therapy). Moreover, some approaches might be more suitable for some applications and some patient groups. So its good we have multiple shots at the same goal to maximize our success chances and not have all the eggs in the same basket. But of course this all only make sense if we have an unique angle and I strongly believe we do! At CellAge, we are focusing on using synthetic biology tools to construct promoters which will be only active in senescent cells. Early on, this will help scientists working on aging research to better identify senescent cells and push field forward faster, and later this might become a key or supportive technology used in the therapies. Lastly and most importantly, I just want to stress out that for me science is key thing here and I do not see other groups working the the field as competition but rather as a potential source of collaboration.
There seems to be a growing contingent who want to treat cellular senescence by tinkering with or shutting down the senescence-associated secretory phenotype (SASP). What is your take on this as an approach versus cell destruction?
I think this is a very potent strategy, which probably is also technically easier to achieve because of regulatory burdens and the fact that small molecules might be more potent in this front. That being said, there might be couple of downsides with this approach and so different approaches, like ours at CellAge, should still be investigated. Firstly, different cells have different SASP and so there might not be a single bullet to cure it all. Secondly, although SASP is one of the key mechanisms how senescent cells harm our body but it's not the only one. Senescent cells can also escape senescence and become cancerous. Lastly, unless you take "SASP inhibitors" for the rest of your life, this will be only temporary solution if cells remain in the tissues. Also, I just would like to add that senescent cell destruction is only a first step for us. Here at CellAge we believe that eventually we will go beyond just killing cells and will be able to repair cells before they become damaged or senescent.
You're looking at crowdfunding; what made you choose this path for the initial development of your work?
Crowdfunding is not the only path we are taking, but it is one we are counting on most. We are also applying for grants and various competitions in addition to this crowdfunding campaign. We believe that for the stage of our company, this is most appropriate path. Importantly, we want to make our tools available to academics free of charge and investors might have a problem with that.
You are clearly energized by the goal of healthy life extension, making the human life span longer. What is your vision for the broader future of SENS-like rejuvenation medicine over the coming decades?
As a scientists I would like to be a bit more skeptic and rather advocate that CellAge is working on healthspan, rather than lifespan extension. I think that although we had glimpses of how lifespan can be expanded in mice, but we are still relatively far from translating that into humans. Instead, CellAge is focusing on age-related diseases and their prevention - a field in which role of senescent cells has much more of scientific proof. I personally am a big fan of SENS and their work. I think they are taking a correct way forward and I would even dare to predict, or hope, that many things they are aiming to achieve will reach the daylight soon enough. For the future, CellAge vision is to construct even more elaborate genetic circuits and gene therapies which will allow to fix cells instead of killing them. We are big believers in using biological logical gates and circuits to construct novel computing processes in the cells in the form of gene therapy.