CellAge – the best of AMA

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. This downward spiral of increasingly negative signalling is one of the processes of aging.

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.  

The CellAge team has a diverse range of skills and experience on board. Apart from Mantas, the core team includes Azuolas Ciukas and Eryk Jan Grzeszkowiak. Azuolas is finishing his degree in Economics and brings financial experience and business acumen to the team. He has worked in an M&A advisory boutique, Porta Finance (Rothschild’s exclusive partner in the Baltics), and KPMG’s Deal Advisory division. Eryk holds a BA degree in Philosophy, Politics and Economics (University of York) and is currently studying for a MSc in Human Complex Trait Genetics (University of Edinburgh). He is the author of the first Polish blog dedicated to genetic genealogy and speaks regularly on the genealogical applications of genotyping and DNA sequencing at regional and national conferences. Trying to take well-grounded decisions, CellAge involved several renowned scientists, such as Alexandra Stolzing and Dr. Juan Carlos Acosta who are providing scientific guidance to the CellAge R&D program.

Right now CellAge is running a crowdfunding campaign at Lifespan.IO to finance the first part of their research aimed at developing a universal assay to accurately identify senescent cells of different types and at different stages of senescence. It is worth noting that this assay is going to be offered to the academic community for free, as the CellAge team is willing to foster the progress in the field of aging research and senolytic therapies in particular. Being able to identify all senescent cells and evaluate their quantity is important to make senolytic therapies safer. The next goal is to develop a gene therapy to remove senescent cells.

Recently CellAge held an AMA at Reddit Futurology so we have collected some of the best questions and answers here. You can also check out the full AMA here.

JoeDerivative: Hello, thanks for the AMA! Are there any short-term benefits of senescent cells that we would be losing with senescent cell clearance and that we would have to make up for?

It really depends how are you removing senescent cells. For example, you definitely don’t want to prevent senescence from happening. Senescence plays a number of positive (and even essential roles). It prevents some cells from becoming cancerous, it helps in wound healing and development. So preventing cells from becoming senescent is not a solution. However, what might be a solution is periodical senescent cell removal – basically removing them every couple months or years for example. This would avoid interfering with their positive effects (preventing tumours by driving bad cells to senescence instead of cancerous state or assisting in wound healing by stimulating immune system) while giving therapeutic benefit of not having these cells sitting in tissues. Also, these cells do not make large proportion of all cells, so tissue atrophy (due to large amount of cell lysis) would unlikely be a problem. And even if it would, our system could adjust to that and target only proportion of senescent cells – something that would be very hard to achieve by using small molecules or antibodies.

Jansen1975: If we consider the SENS damage model of aging. What order do you think damages will be solved in?

I believe the SENS model covers many important aspects, and obviously some are dealing with intracellular (IC) and some extracellular (EC) damages. In my opinion, EC (like aggregates and issues arising from the extracellular matrix) will be much harder to solve and therefore will be (properly) solved later in time. This is because most of the current approaches when we are looking for new medicine are focused on modifying or interfering with some pathway within the cell and we don’t have much expertise in drug pathways which would result in efficient remodelling. From the IC damage areas, I think dealing with cancer will be hardest (due to heterogeneity of the disease and its progression) while cell replacement will come into existence very soon. All that being said, I think we can create synthetic circuits which we computing within living cells to solve many of problems identified by SENS. This is the long term vision I have for CellAge.

Jimofoz: If we use the SENS damages of aging, do you think your technology of synthetic promoters/biology can be applied to one of the other 6 categories of damage? If so, which one and how?

I do believe it can! Synthetic biology is broad field but in this case we are talking about artificial (synthetic) computing within the cell and you really (potentially) can target many aspects of biology to be modified. I personally do think we can actually target all aspects of SENS (and this is why I have chosen to do synthetic biology) as you are basically creating new commands within the cell. So just imagine a situation, where for example you create a synthetic circuit which senses (looks for) different signs (biomarkers) within the cells and if correct markers become present, cell is removed (OncoSENS and ApoptoSENS) or is forced to perform asymmetric division to remove some junk (LysoSENS and MitoSENS) and so on. So yes, I believe there is promising and bright future for both synthetic biology and ageing research

Elgrano: Hello and thank you for working on this important issue. I have a tangential question. In the comments section of the Youtube video introducing your project, someone wrote the following :

“They can’t do it without us, yet they operate with proprietary technology. Sort of like give us money so we can make more money and not share it with you.”

How do you respond to this criticism ? One could indeed argue that sending free assays to scientists may not be enough, seeing as you are a for-profit company and in comparison with other Lifespan.io campaigners such as MMTP which are not-for-profit and make their research open access.

“Thanks for asking this question. For us it is very important to be transparent and honest – this is how we want to lead our science and startup. Firstly, we have access to the technology but we do not own it – its like you would have a bike frame but you still need wheels and you ask someone else to borrow them for a bit to make a full bike. And then that full bike will help people be healthier. Also, as it has been mentioned, the reason why we are for-profit is that it would be extremely hard to raise fund needed to develop such tools and therapies otherwise (preclinical and clinical trials etc.). Like it or not, investors are looking for returns and this is main source of money to most translational research. For example, many initiatives like SENS help develop technologies to proof of concept (POC) stage which then require injection of a lot of cash and that usually comes only from investors who are looking for profit. That being said, we will be making our first tools available free of charge to academia to facilitate the process.

But I would like to assure you that the main thing that we care about most is helping people and I will personally fight tooth and nail to keep this our main mission.”

Oliver06: You have mentioned about wanting to develop therapies to target some of the diseases of ageing, but you also want to target general aging itself, yes? How much of a problem do you think it is that generally speaking ‘aging’ isn’t acknowledged to be a disease?

Interesting question (and philosophical one). I think ageing is a combination of diseases and dysfunctions. You can target all of them or some of them and we are hoping to target only few initially and then move on to more broad therapy. Regarding the problem of misconception, I think it is very good question. I believe this will change (and is changing rapidly) with time as long as we are not afraid to talk and give evidence-based answers why we think so.

Reasonattlm: The current situation for clinical testing of senescent cell presence is subpar, something that any of the people here can verify for themselves by investigating the websites for larger test companies like LabCorp.

The existing tests established over the last few decades are poorly available, somewhat time-consuming to carry out, and automation is lacking. Is the work you are doing potentially a path to a cheaper, better set of senescence assays for clinical testing?

We fully agree that robust and versatile assays are missing. B-SA-Gal only works in specific pH, telomeres are hard to detect and sometimes identify non-senescent cells and so on. Therefore, one of the early CellAge milestones is to develop more robust assays and we will offer these for free to academics because our main mission is to push field forward. After this, we will be working with CROs and screening centres to further validate and perfect our assays (add specificity for example). Hopefully, this will also be used in clinical settings assessing efficacy of different treatments etc. So in short, yes – that is one of the pathways we are taking.

We at LEAF congratulate CellAge team with an interesting discussion at Reddit and wish them good luck with the crowdfunding campaign.

If you are a rejuvenation biotechnologies supporter, the power to change the way we age is in your hands. By supporting CellAge with an affordable donation you are contributing to an important research which will benefit the whole field of aging biology and gerontology. If you want to see a world free from age-related diseases, please visit the campaign page at Lifespan.io, donate and share the campaign with your friends!

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