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Alexandra Stolzing on SENS Projects at EARD2021

SENS is making multiple inroads into the rejuvenation biotech company space.

EARD2021 SENSEARD2021 SENS
 

At our fourth annual Ending Age-Related Diseases conference, Prof. Alexandra Stolzing of SENS Research Foundation discussed what SENS is doing in terms of grants, company creation and intervention development, and programs for college students.

Script

Thank you very much for attending today’s presentation, and it’s all about the science at SENS. I will be giving an overview today about the projects that we have running internally at SENS and about the projects that we’re funding externally with partners at universities or companies.

I will be giving a quick overview about the SENS spin-off companies and where they are currently, what they’re doing, a brief summary of what education programs we have running, a summary of the grants, and very quickly just talk about future projects and what’s coming up in the future.

As it’s my duty, this is a slide about the SENS damage categories. Don’t be afraid, I will not be going into any sorts of details, I just want you to look at the right side and get a little bit of familiarity with the categories. We use them to see that we have, hopefully, one project for each of the categories.

It’s not like it’s a must we have to have, but we always try to aim to have one project for each of the categories. Unfortunately, we don’t have currently a project for the OncoSENS category. So, if someone is out there and has some great ideas about what we can do, we really would love to hear about it.

Let’s talk about the external projects first. The longest-running external project that we actually have is a project that we run with Dr. Jonathan Clark. It is about tissue cross-linking, and his job and his research is about finding tissue cross-links, non-enzymatic cross links, and long-lasting proteins of the extracellular matrix. It’s part of the glycoSENS category.

Here is where I use this kind of icons to guide you, which category is this. it has been running over five years; there have been three publications last year, so please look him up. They’re also on our website if you want to read them. We always try to keep our literature list up to date so that you can find it easily.

We also have a new, very exciting project. It’s about the functional neuron replacement to rejuvenate the neocortex. It is with Prof. Hebert, and it is basically about the idea of using transdifferentiation of microglial cells to neurons.

So he is transplanting microglia cells into mice brains and turns them into neurons in vivo to basically repopulate the neocortex with new functional neurons. He also is, I think, about to be publishing a summary of this. Look out for his new publications; hopefully, they will show this project update.

Also relatively new is a project with Prof Gudkov, and this is about the active retrobiome as an anti-aging treatment. So with aging, what is happening is that some silenced virus sequences in our genome, and we have many, many, many copies of virons in our genome. With aging, they become demethylated, they become active, and they start basically messing up the genome.

Cells that are having these activations usually show some interferon gamma activation, and he is creating a mouse model currently that should be able to genetically ablate the cells as people have done with senescent cells. It’s currently a little bit in a stall because there is some problem with creating the mouse model, but they’re still working heavily on it.

Question: Do we know what proportion of cells have activated retrobiomes at any given time in an aging tissue?

No. And that is what we exactly also part of this project. The mouse model would have also a fluorescence tracer so that we can actually get an idea of when are these cells turning up, how many of them are turning up, and also how much overlay is there between normal senescent cells and these cells that maybe have an active retrobiome and how much overlap there is. Currently, we don’t know. There is no data on this. Great question.

The last project was about lipofuscin. That’s an old target of SENS actually, I think one of our earliest project was about finding bacteria to degrade lipofuscin that accumulates in the lysosome. What is exciting this time around is that now we will be getting human heart material. so we will have real human lipofuscin to work on, and the goal is to find the composition of it and then also potential bacteria that can digest it.

What’s going on internally at SENS? Our longest-running project is with Dr. Boominathan about allotopic expression. The problem here is that mitochondrial fitness overall decreases with age. The relatively simple-sounding idea is to transfer all protein encoding mitochondrial DNA to the nucleus, which we call allotopic expression.

Amutha showed last year, in the publication that is on the screen, for all of the 13 genes that in theory, and also in practice, for the short term that this is possible. What she is currently working on is optimizing the system, getting the protein stably expressed, and also showing that there is a functional improvement, which is possible for some of the proteins but not all of the proteins.

Now to the exciting bit is that she has now started working on showing that this is also possible in vivo, and not only in cell culture. So a mouse model was created with what we call a save landing pad, basically a type of DNA that is in the mouse that has been engineered so that whatever gene we bring in, it is exactly integrated in that site and not randomly in the genome.

We’re still in the process of confirming that that has happened, but what we did was that we generated these mice and these mice were engineered in a background that came with a mitochondrial dysfunction It’s not possible to really have a mouse model that has mitochondria that don’t function at all; these mice wouldn’t be viable. So we had to look very hard for a mouse model that shows any kind of phenotypic dysfunction due to the mitochondrial mutation.

Unfortunately, what we found out was that the mouse model isn’t showing that much of a phenotype. Our outputs show that the transgene is actually there. The protein is expressed, as you can see here on the right, this is kind of a FLAG test, so our construct contains a FLAG and the target that we brought in is the ATP8. So it is present; we know it’s there. Unfortunately, there isn’t much of a phenotype to rescue.

Most of the data that will be coming up in the future will probably be all biochemical analysis of the data, but it’s super exciting. The mice are alive, it’s working, it’s expressed, it has been expressed for some while, for a couple of months, and there seems to be no problem with it. So it’s very kind of exciting work and hopefully there will be a publication coming up soon.

The next project is with Dr. Amit Sharma. It’s about the immune surveillance of senescent cells. We all know by now that senescence cells accumulate with aging and the immune system declines in its activity. Dr. Sharma is looking at how the NK cells are actually able to kill senescent cells.

Senescent cells have some different functions. One of the main bad functions of cells is the secretion of factors which can activate the immune system, specifically the NK cells, which can recognize senescent cells. The NK cells produce some enzyme like perforin that kills the senescent cells.

If everything works well, then the body would actually clear up the apoptotic cells and everything would be good. He has set up an in vitro system where he actually can show the cytotoxicit, so the killing of senescent cells. here on the left, that’s non-senescent cells, and on the right, these are senescent cells. We can nicely see how the NK cells are killing it. He now works on ways of improving this and tricks on how to make it happen in an old environment.

The last project for today is with Dr. Tesfahun Admasu. He is looking at how senescent cells are spreading. There has always been the idea that the SASP potentially can generate more senescent cells, and that would be a way of how senescent cells are very quickly spread in the body.

He is interested in isolating these secondary senescent cells and analyzing how they are different and how we could also kill them very efficiently. This is the concept, and any kind of insult that creates primary senescent cells, they would produce the SASP and turn other cells into secondary senescent cells.

He has analyzed the gene expression profile of these cells, and as you can see, there are many places where there are distinct differences between them. He is currently looking more deeply in it and will be looking to find ways to kill the secondary senescent cells as efficiently as the primary senescent cells.

That’s what is internally going on. I will later talk about upcoming projects, but very quickly, usually what we are trying to do is to incubate projects at SENS because a lot of our projects are very fundamental and far, far away from translation, but we always have an eye on making the translation happen.

What has happened in the past is that ideas have spun out into companies. Our very first spin-out was Lysoclear. That was actually on lysosomal lipofuscin of the eye and degrading it, and they are looking at doing this in macular degeneration. The same person also spun out another company that is more focused on clearing senescent cells.

We have Covalent Biosciences; it is interested in clearing a form of amyloid, and they have catalytic antibodies. There is Revel; that is interested in breaking advanced glycation end products, the non-enzymatic crosslinks we talked about earlier, of the extracellular matrix. They’re looking for compounds that can break these bad crosslinks.

Very recently, Underdog Pharmaceuticals was spun out, and they are retooling a cyclodextrin against oxidized cholesterol. To be specific, it’s 7KC that they are targeting.

So, that’s all very exciting. We also love to bring people on board and excite them with our projects, and for that we have summer school, a program where students can come into the labs or in partnering labs and get a couple of weeks of hands-on education. Down here, you see a couple of the institutes that we have collaborated with in the past.

We also have a postbac fellowship program, where slightly more mature students are coming to us or our partners, and it is for roughly nine months that they are spending in the labs, mostly together with more senior scientists working on a project.

You can also apply for grants for us. You can send us a letter of intent any time basically during the year. I summarized what we had coming in last year. We got 49 grants submitted. Four of them were what we call full proposals, and two grants were funded: one internal project and one external.

For 2021, it has been slightly slower. We only got 14 grants so far. Again, two full proposals and two rounds were funded. Again, one internally and one externally. If you want to have more information, just go to our website. Look up the details, and please contact us with more of your projects.

That’s where I don’t say thank you yet but give a brief glimpse of what the future might bring and what are these new projects. One of the projects will be about the catalytic antibodies with Covalent Biosciences. It will be spearheaded by Dr. Sharma internally with SENS. We don’t have yet an initiative to show, but we wanted to let you know this is a project that is coming up.

Also, Amutha has a new project coming up. When it’s ripe, we will be updating our website with more information. There will be a third one that we’ll be looking at combining some senolytic treatments with stem cell treatments in mouse models. That, over time, will hopefully show the world that it’s very important that we are looking at combining interventions, because that is traditionally not done very much neither in academia nor in companies.

Most companies have one target they’re interested in, and they’re going after that target, but they’re not much interested in combining some other company’s target with their own one, for obvious reasons. So we think at SENS that this is a project that lies within our duty as a service to the community where we combine these targets and see how much they would actually synergize and bring additional lifespan extension.

For everything else, please visit our website, send us an email, our [email protected] email address is always there for you. Please do get in contact with us, ask questions, get information. Please all, come visit our website, we have plenty of jobs that are out there, and we would love to have you join us. So yes, we are currently expanding. Please look out, there will be more announcements in the future.

Question: When you said you will consider grant applications from outside, do you have a cap on the scale of the project? What monies do you generally fund?

We usually fund projects in the size from 50k to, let’s say, 350k; there isn’t really a top budget line. We always say it needs to fit the project, but naturally, we can’t fund something for millions and millions. So that is usually the range, but it can be shifted. For the length of the project, we’re usually looking for projects that are one to three years; that’s mostly what we see.

The application or the grant schedule, however, is always on a yearly basis. So if you write a project, make sure you create your project in one-year bits because you only get funding approval for one year. But if you submit a project for three years, we usually expect you to progress and then get approval for the upcoming years.

Question: What’s the deadline for the grant submission?

We really don’t have deadlines. In most years when we don’t have COVID, we have four meetings a year where we look at the grants and make decisions, so usually, the deadlines or the upcoming meeting is being advertised on our website. So just look at the current website; that date is always updated. Generally, just consider like there is no deadline, just send us your LOI and it will be considered for the next meeting.

Question: I just want to highlight our education program and how we may expand it. What other ideas do you have to engage the upcoming generations into rejuvenation therapy? So in addition to summer scholars or postbac fellows, do you have any other choices for them? If they wanted to do a PhD in the field, would you be willing to entertain that?

It’s not official yet, but there will be a reworking of the education project or the education part of the organization. It’s not publicized yet, but most likely, it will contain changes like this, that also PhD projects are being considered. Please stand by and wait for the announcement; it hopefully is not far away. Great, then I hope you all enjoyed it, and please do get in contact.

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CategoryNews, Talks
  1. jimofoz
    October 2, 2021

    I really like their little damage icons for each class of damage at 1:02 in the video.

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