Arne Akbar: Well, when I was actually — did my PhD immunology wasn’t a subject in its own right. It was part of pathology. I did my PhD in the Department of Pathology in Southampton looking at immune cells, but in Hodgkin’s Disease, and I was working on humans at that time and looking at human spleen, which is a major source of white cells especially, when you have a cancer there.  I was up to my elbows in cells all the time and, and unfortunately, in those days in hindsight there were really no tools to actually investigate in-in-depth immunology like we have now. I worked on T cells just in the era of monoclonal antibodies —

Gordon Lithgow: Hmm. 

Arne Akbar: — where we could finally put handles on what the T cells were. Before we would say, “This here is a T cell, and here’s another one. They’re very similar to me.” But now, we could actually put handles on them and say, “Well, this T cell is definitely a young T cell.” And we could then pick up the older T cells as well. The ones that had matured into robust killers. And that gave me the big interest in trying to identify later on what happened to these T cells as they got even older still. 

Gordon Lithgow: 

How do you see aging now? I mean, how would you describe aging in someone who has come into the field from maybe a slightly different discipline?  

Arne Akbar: Aging was something that was always inevitable, and it’s a bad scenario. You got older, and things became bad. In the current era in the last five, 10 years it’s become more optimistic. Yes, you get old, but now, there are more and more things that you could do to alleviate the detrimental systems- the things that go wrong when you get older essentially. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: The drugs to actually block inflammation that causes a lot of problems, but now, the exciting advent of being able to clear old cells away which can then rejuvenate organ function. That’s very exciting. 

Gordon Lithgow: Super, okay. Um, so let’s go to innate and adaptive immunity.  

Arne Akbar: Well, the important thing about the immune system is that you need all parts of it to work optimally. Each part relies on the other parts that create the whole. You should think about the immune system as an army. You have the-the early soldiers that go into battle. You have the more specialized soldiers later on. You have all kinds of sophisticated machinery, but it all has to be coordinated. If the immune system is not coordinated all these dangerous soldiers could turn against you. And you have the innate side as more of early response elements of the army. Whereas, the adaptive side are the ones that come in later that are more specialized with all the heavy guns, heavy machinery and the know-how of how to actually solve the problem. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: But you need –

Gordon Lithgow: Okay. 

Arne Akbar: You need that early protection so you-you don’t succumb to the-the challenge early on by having those innate troops which protect you. Absolutely get the more specialized troops in. 

Gordon Lithgow: So the immune system, that even  exists in the tiny worms that we work on in aging. Um, when did the adaptive system evolve, and how are they connected to each other in any way?

Arne Akbar: They evolve — I think the point where you start getting an acquired system is — I’m not an expert on the — on the early changes that happen but, when you get to become a fish you can start getting adaptive immune-immune responses. 

Gordon Lithgow: I see, okay. 

Arne Akbar: That’s why the zebrafish is such an exciting model for people working on the immune system because they’re easy to grow. They grow very quickly, and they’ve got innate and also adaptive parts of the immune systems. 

 Arne Akbar: They can talk by mediators that secrete. They-they can both influence each other. They can recognize different structures on each other’s cell surfaces as well on the innate side and on the acquired side. 

Gordon Lithgow: Okay. 

Arne Akbar: So there’s a lot of communication. 

Gordon Lithgow: Hmm. Um, I’d like to talk about skin because I know that you like to talk about skin. [Laughs] Um, but before that, I’ll just get one other definition out of the way, and that’s the T cell. Tell us about the T cell.

Arne Akbar: Within the specialized troops that comprise the army, there are a couple of-of very important cell types. In the old days, the T cells was what we call the conductor of the immune orchestra. Nowadays, a lot of people who work in B cells, the other side of the acquired response, they-they think the B cells are far more important than T cells. There’s always a slight rivalry between T and B cell people. 

Gordon Lithgow: Hmm. [Laughs]

Arne Akbar: But the way to think about this is the — you know, you need them both. They’re-they’re both important. Think about antibodies. Antibodies, B cells. Think about the killer cells. The cells that can actually kill tumor cells. Those are T cells, but you need to have crosstalk between them. 

Gordon Lithgow: Um, all right, let’s get onto skin now. This is, uh, something that-that is, I guess going back quite — many years that you’ve been interested in.  And I-I guess — I heard when, uh, um, I first started thinking about aging that, “Well, the skin, we see changes in the skin with age, but it’s all a response to UV damage, you know? It — there’s nothing really happening there in the skin”, but that’s not the case, is it? The skin is an important organ, uh, for aging. 

Arne Akbar: To be totally honest, the reason I got into skin was because I wanted to investigate human immunity. And if you want to work on human immune responses the most accessible place you can look at apart from the blood is actually in the skin. If you look in the blood you look to see what happens well-well after an immune response has been initiated. Whereas, we wanted to look at an in vivo immune response in humans, and it’s actually, very difficult —

Gordon Lithgow: Mm-hmm. 

Arne Akbar: — [but] where we started the response of and then, be able to follow the progression of that response and how different cell types come in at different times. How they interact with each other at different times. And ultimately, what goes wrong in older people in the skin. Older people get more skin cancer, more skin infections —

Gordon Lithgow: Yeah. 

Arne Akbar: — and decreased barrier function. All these things contribute towards dysfunction, and the skin, it’s very interesting, but it’s the most accessible part of the body in a human that we can actually investigate. 

Gordon Lithgow: Got it. Um, so you mentioned zebrafish as a potential model system that’s exciting. Where are you on — and you’ve always been, I think, human-centric in your research, and that-that-that’s fantastic. You were way ahead of your time in that regard, but, uh, you know, coming back to other models where-where does the mouse stand, for example? Which is where most of us are focusing our attention in interventions, and so on. 

Arne Akbar: I was still, uh, a young postdoc in the days where the initial genetic models for mice,  and knockouts, and knock-ins came into being. And everyone was totally overwhelmed: all the things you could do with genetic experiments. And yes, there — a lot of good work was done, and in certain systems the mouse and the human are very similar. If you look at all the death genes, for example, even the nematodes, as you know, the death genes are actually very similar. And so, working on early organisms is great for certain pathways, but not for others. For example, you can’t look at the acquired immune system in those — in those — the lower organisms. 

Gordon Lithgow: Yes.

Arne Akbar: And so, I think the important thing to understand is where you can extrapolate and where you can’t. And so, working in humans we could get to a certain point where we could follow the kinetics of, uh, of an immune response. But then, if you want to follow a mechanism to see what changed we have to go back into a mouse again. But we have to find a defined system where what we’re looking at is actually relevant back again to the human. So it has to be cross-informative. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: Which meant that you’ve got to — you have to define very clearly what you could extrapolate and what you couldn’t. 

Gordon Lithgow: Yeah. 

Arne Akbar: Luckily, in the last five years or so we’ve found mouse systems that very closely resemble what we’re looking at in terms of mechanisms.  So we’re looking at a molecule called a sestrins, and they regulate a new complex of proteins that can  actually inhibit the function of T cells. There’s sestrin knockout mice, and the sestrin knockout mice work in exactly the same way as the humans in this kind of context. And these molecules —

Gordon Lithgow: So sorry, they inhibit the T cell development?

Arne Akbar: They inhibit the T cell proliferation. 

Gordon Lithgow: Okay, so does that mean that the knockout mouse is a healthier mouse?

Arne Akbar: It seems to be, funnily enough, but if you look at time to boost an immune response so you could vaccinate, um, young mice, and old mice, and old mice don’t respond very well. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: But if you look at vaccine responses in old and young sestrin knockout mice  they work a lot better. 

Gordon Lithgow: I see, um, wow. 

Arne Akbar: And you get up to 20-month-old sestrin knockout mice who look totally healthy compared to wild type mice. That’s anecdotal, but, you know, you didn’t —

Gordon Lithgow: Wow. 

Arne Akbar: — you didn’t lose them early-they’re there. 

Gordon Lithgow: That’s incredible. I mean, it does obviously, pose the question, “What are they there for?” I mean, there must be a positive benefit to these proteins.

Arne Akbar: Yeah, so you touched on a very important point which is looking at signaling pathways in cells. Everyone investigates pathways and isolation from all the other pathways that are going on. 

Gordon Lithgow: Hmm. 

Arne Akbar: The interesting-interesting thing about the sestrins is that you can turn them on by senescence.  Aging in a cell will turn on the sestrins, in a T cell, that is. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: But also, nutrient deprivation will also turn on the sestrins. And once we get to the point where the sestrins are turned on the downstream pathways are very similar. This means that you can have convergence of different signals upstream that lead to the same downstream effect, which is blocking functions of the cell, but —

Gordon Lithgow: Mm-hmm. 

Arne Akbar: — initiated by different means. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: Either aging can do this or so, lack of nutrients can do this, and you block the-the cell from dividing which is very energy consumptive. 

Gordon Lithgow: And you mentioned senescence, and we should go there actually and think about this because it’s clear that senescent cells are both beneficial and detrimental at different points in our lives. And, in surprising ways actually, and it also speaks to the challenge of targeting an aging process like senescence that you have potentially beneficial and detrimental effects. Just unpack senescence for us, if you would. 

Arne Akbar: Yep, senescence is thought to be an anti-cancer mechanism. So if a cell divides too much eventually, there will be mutations in the DNA that could make it very bad for you because these cells can grow out of hand and become a tumor. And senescence is a process whereby you actually stop a cell with damaged DNA from dividing so it’s thought to be an anti-cancer mechanism. But the conundrum for the immune system is that you have challenges all through your life from the same bugs over and over again. And each time you have a challenge you actually expand the cells that are specific for that organism. You don’t maintain large numbers. Otherwise, your body would blow up the new cells each time you have a new infection. 

Gordon Lithgow: Oh, okay. 

Arne Akbar: And so, at the end of a response you actually cull most of the cells, the memory cells, the ones that remember the infection, but you have a few there that can actually recognize and respond more quickly. That’s the whole concept of immune memory. That’s what vaccinations are all about , you remember the response and respond more quickly to boost the response. And so, the conundrum is that you have to get cells to divide when you meet the infective agent.  But there’s this limit to how often a cell can divide because of the anti-cancer properties of senescence. And so, if you’re looking at senescence, yes, it’s-it’s good for you to stop cells growing too much, but from the perspective of the immune system, and the cells can’t grow too much, you have potentially decreased immunity.  And how can you overcome that? And that’s been one of the challenges that we’ve faced. 

MUSIC INTERLUDE

Gordon Lithgow: So then, there’s this concept of sterile inflammation, that, my office is right next to Judy Campisi’s office so I’ve heard that phrase a few times in my life! So,how does this interact here, right here because you’re telling me about the yin and the yang about cancer and infection, but there’s also this idea that you don’t necessarily need to have an infection to see inflammatory processes take off —

Arne Akbar: Mm-hmm. 

Gordon Lithgow: — and then, drive, uh, uh, other aging pathologies. Is that –?

Arne Akbar: Yeah. 

Gordon Lithgow: Is that right?

Arne Akbar: Yeah, I think it’s been known for a long time that as you get older there are more inflammatory mediators floating around in your — in your blood anyway. The question is, where do those inflammatory mediators come from, and are those mediators actually bad for you as they accumulate with aging? These mediators can come from a variety of sources. One being defective barrier function. So the gut is a barrier keeping the bugs — most of the bugs out —

Gordon Lithgow: Mm-hmm. 

Arne Akbar: — from-from the inside of your body. That barrier breaks down a bit so you’ve got leaky gut syndrome. Another barrier is the skin. The skin works very well at keeping things out, but when you get older, that barrier breaks down. You might get other things coming in as well.  If you put on too much weight the fat cells that you accumulate, they’re actually very inflammatory so there’s another source of this sterile inflammation. 

Gordon Lithgow: Hmm. 

 Arne Akbar: An there’s also, the inability of your clearance systems in the body to get rid of misfolded proteins, get rid of debris,  you get kind of clogged up with all this — it’s like — looks like all the people do all the garbage collection going on strike essentially, when you get older, and that all creates inflammation as well.  And also, senescent cells and your neighbor in your office, Judy, is one of the perpetrators of this concept, senescent cells that accumulate when you get older also secrete a lot of inflammatory mediators,  And this is called a senescence-associated se-secretory phenotype, SASP, but no one really knows whether the SASP or this inflammation is bad for you. 

I’ll tell you very briefly about how we addressed this. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: We found that in the skin of older people if you just challenge it just with a bit of an injection, not even the antigen that causes the immune response, just the —

Gordon Lithgow: Yeah. 

Arne Akbar: — just a bit of perturbation gives you a lot of inflammation in the skin in older people, not in younger people. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: And this was correlated to their ability to respond to an immune challenge you gave in the skin. And the immune challenge to which the older people should be already immune to like the chicken pox virus, for example. 

Gordon Lithgow: Hmm. 

Arne Akbar: So we gave them a little chicken pox-like stimulus, and they couldn’t respond even though they’d had chicken pox in the past. 

Gordon Lithgow: Yeah. 

Arne Akbar: And so, we had a hypothesis that if maybe we could block inflammation in the older people we could reconstitute the immune response. So saying that, there’s baseline inflammation that increases with aging. Is it good or bad?

Gordon Lithgow: Mm-hmm. 

Arne Akbar: If it was bad, and we blocked it maybe you could actually reconstitute the immune response. 

Gordon Lithgow: Yeah, yeah. 

Arne Akbar: So we did exactly that. We used —- an anti-inflammatory drug that was-was donated to us by-by GSK so there wasn’t any conflict of interest there. 

Gordon Lithgow: Yeah. 

Arne Akbar: And we carried out the study. And so, we treated all the people with this anti-inflammatory drug just for four days. Just tablets. Two tablets a day for four days —

Gordon Lithgow: Hmm. 

Arne Akbar: — as an oral inhibitor. And we found that if we blocked inflammation in older  people and the inflammation wasn’t just in the skin, it was everywhere,

Gordon Lithgow: Mm-hmm. 

Arne Akbar: — we could actually boost the skin response in those individuals. 

Gordon Lithgow: Hmm. 

Arne Akbar: The proof of principle that in a human you could temporarily block this high baseline inflammation to actually enhance the immune response. And in our studies, a lot of that inflammation that lives in the skin was coming from the senescent cells. 

Gordon Lithgow: That’s fantastic. Uh, that’s really — that’s really amazing. Uh, does that also say that, you know, that the senolytic drugs that are being developed with something like over 100 companies now targeting senescence, uh, are you optimistic then, that-that these things could be really beneficial?

Arne Akbar: I’m optimistic. You have to be. As a scientist, you have to be optimistic. Otherwise, we wouldn’t be getting out of bed and going to work. 

Gordon Lithgow: [Laughs]

Arne Akbar: I’m optimistic that there’s an avenue ahead that could be beneficial. There’s still lots of things to know like how long do you have to block the senescent cells for before they come back again?

Gordon Lithgow: Yeah. 

Arne Akbar: It’s probably the same as with any drug you use. You could use say, the same thing from an anti-inflammatory drug perspective. How long do you need to do it before the problems start again? What we haven’t explored yet are what the long term side effects might be because at the beginning you said yourself that senescent cells could be bad for you, but also, they can be good for you in certain contexts. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: What happens if you block it for too long? 

Gordon Lithgow: Yeah. 

Arne Akbar: And so, you could get rid of senescent cells as one strategy. You could also block the detrimental substances that those cells secrete. That the inflammatory mediators which has been done, and this treatment didn’t kill the senescent cells. It just blocked what they secreted for a while. And what is good about blocking temporarily the inflammatory mediators, is that you open up a window to allow the immune system to work. So the way —

Gordon Lithgow: Hmm. 

Arne Akbar: — you should think about this is maybe you can let the immune system work in an older person during cancer therapy. Maybe you can get the immune system to work better by blocking inflammation before you vaccinate someone. But you don’t want to block forever in case it’s bad. You can just open up a window of opportunity to let it work. 

Gordon Lithgow: Uh-huh. You know, we’re seeing like parallel situations even in nematodes  where, you know, we’re ramping up the autophagy, for example. This is work from Julie Anderson’s lab.  And again, it’s one of those things where you-you don’t want to chronically be doing this, uh, because there’s downsides. It’s going to be toxic eventually because it starts to interfere with normal processes.  But if you ramp up autophagy for a short period at a time you see all these phenomenal benefits in 

Arne Akbar: Mm-hmm. 

Gordon Lithgow: — neurological disease models, and proteostasis, and everything else. 

Arne Akbar: Mm-hmm. 

Gordon Lithgow: So it seems to be an emerging theme in aging that you want to go in, fix the damage, get rid of certain cells and then, get out again.  

Arne Akbar: Like having a bad knee and having a steroid injection. It lasts for a little while, but then, you need to get another one at some point. 

MUSIC INTERLUDE 

Gordon Lithgow: Could we get back to, um, let’s go back to the cell biology a bit and some of the work you’ve done? So you’ve looked at intracellular molecular pathways that are, you know, involved in processes like senescence so maybe you could talk about that? 

Arne Akbar: There’s one pathway we’ve been very interested in which is looking to see how nutrition and senescence signaling — so senescence comes from DNA damage essentially. How these pathways can converge to give you the outcome of decreased proliferation.  And the reason that that’s important is that you need proliferation in the immune system each time you see the bug — the same bug over and over again — you have to increase the number of your cells that are responsive to that organism. One thing we were very interested in is an enzyme called telomerase. So if a cell can upregulate its enzyme, you can extend its ability to proliferate. Otherwise, you’d just stop proliferating because you shortened your telomeres, and that’s what telomerase does. It extends your telomeres. And we know that in T cells that are towards the end stage of their life, they shut down the ability to make telomerase. My group was involved with —

Gordon Lithgow: Mm-hmm. 

Arne Akbar: — a lot of this work for many years, and one question we asked is whether a cell could inherently turn on telomerase again or is it shut down forever?  What we learned about the sestrins and this pathway was that if you were to block this sestrins-signaling pathway, you could actually turn telomerase on again. And you could  turn on proliferation again in the cells. And you can turn on other functions of the cell as well like cytokine production, et cetera. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: This implied that in at least T cells the senescence or the aging process is something that’s reversible. 

Gordon Lithgow: And-and could — what’s the connection to the-the p38 MAP kinase, um, function that you-you’ve also studied extensively?

Arne Akbar: Uh, the sestrins are unique in that they organize a complex of three MAP kinases. So the three MAP kinases people normally work on, p38 Map kinase is one, which we mentioned, 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: There’s ERK MAP kinase, and there’s also, JNK MAP kinase. They do different things that are all very important, but we showed for the first time and at one single cell type in a human which is the T cell the sestrins coordinate the activation of all three MAP kinases. And this new molecular complex that we’ve discovered,  

It showed the sestrins are bound together in a complex of all three MAP kinases. And within that complex if you want to boost proliferation ERK, JNK and p38 can be involved at proliferative reconstitution. But only p38 is involved with the telomerase. So it’s a sestrin complex but through p38 that turns off the telomerase. So if you block telomerase– say, if-if you block, um, um, either the sestrins or block p38 it you can turn telomerase back on again in those cells. 

Gordon Lithgow: Historically, I guess there’s always been this idea that turning on telomerase was not necessarily a good thing because it was just also associated with cancers…is that not the case in T cells?

Arne Akbar: Yeah, I think it’s a situation that we mentioned earlier that you don’t want to block anything for too long, especially if it’s a defense pathway- you’re defending against cancer. But if you want the cells to respond and increase in number maybe during vaccination this could be something very useful temporarily- let the cell go. But I think if you then take away the inhibition, the cell will go back to its default state with just no new proliferation which is — which is key. 

Gordon Lithgow: Yes. 

Arne Akbar: You just need to open up that window to let it respond for a little while. But there’s one thing that we haven’t actually talked about which is very important from the immune perspective- which is the immune system is thought to be there to react against infection. We talked about that. It’s there to react against cancer cells and to clear them, kill them off, et cetera, but the immune system can also recognize senescent cells in the body. Which means that if you’ve got old cells in every tissue your immune system has the capacity to recognize them and kill them so you have your own anti-aging mechanism inbuilt in your immune system. The question is, why do senescent cells increase when you get older?

Gordon Lithgow: Yes. 

Arne Akbar: What happens in the immune part that stops it doing what it’s supposed to do which is clear away all the old cells?

Gordon Lithgow: Right! [Laughs]

Arne Akbar: Which means that — and this is a paper we published recently, and Judy Campisi was a co-author of this paper, is that senescent cells have evasion strategies. And one of the evasion strategies is they can increase their expression of an inhibitory receptor that stops killer T cells from actually working. Interestingly —

Gordon Lithgow: Mm-hmm, hmm. 

Arne Akbar: — that same pathway is used by cancer cells.  And so, there’s a drug called, uh, Monalizumab that’s out there. It’s been used for anti-cancer therapy, and what that drug does is it blocks the interaction — I won’t go into details, just tell you the names, but it’s an inhibitory pathway.  You have the receptor which is the inhibitory receptor on the T cell, and it’s called NKG 28. You’ve got the ligand called HLA which is on the target cell. It could be a senescent cell. It could be a tumor cell. The drug is designed to actually block the interaction to allow the immune system to then recognize the target cell to kill it. It’s an anti-cancer drug.  But the same pathway operates in senescent cells. So when you use this drug as an anticancer drug you can actually get rid of senescent cells without the need to kill them directly by senolytics,

Gordon Lithgow: Mm-hmm. 

Arne Akbar: — without the need to just block their inflammatory mediators. We could license —

Gordon Lithgow: Really?

Arne Akbar: — the killing by blocking the inhibition. 

Gordon Lithgow: Fantastic. That’s-that’s really interesting. Um, it makes me wonder… if you had, uh, a 100 million dollar grant, uh, issued tomorrow, um, where-where would you — where would you focus your research fund with that?  And I presume that you’re obviously someone who collaborates a lot with other people, and gets ideas and watches other people. What sort of team would you build or what project would you go after? Is this one —

Arne Akbar: Mm-hmm. 

Gordon Lithgow: — of the areas, for example, that you would be interested in?

Arne Akbar: Yeah, it just — as a subtext to that, I’m involved with a — I’m involved as the coordinator of a UK-wide grant to look at aging of the immune system. And we’re bringing in people from all walks of-of science. Not just —

Gordon Lithgow: Mm-hmm. 

Arne Akbar: — immunologists, but people working on circadian rhythms. You know, people working on nutrition. You know, people working on the, you know, the-the physical aspects, and everything is linked to — we’re trying to link everything to frailty. Frailty being the —

Gordon Lithgow: Yes. 

Arne Akbar: — inability of an older person to walk very well or to-to just, you know, live a nice, good life. We’re trying to understand how the immune system takes part in the frailty response because ultimately, what you want is not just to boost your immune response. We want to actually live better and live in a healthier, more productive way as we get older. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: Get rid of frailty, that’s what we need. We know that the immune system is involved with that because there are various studies out there saying that T cells which are old, so senescent T cells, will actually affect many, many different tissues in a negative way. 

Gordon Lithgow: Aha, okay.  

Arne Akbar: And if you get rid of those T cells then, the — everything gets better in-in an older animal. 

Gordon Lithgow: This is really fascinating because we know that something like frailty which is measured in, uh, quite simple, straightforward ways in humans, and people are doing it in mice now, and so on.  We tend to think of frailty as the integrated, um, function of, like neuronal function, skeletal/muscle function, all these things. And what you’re saying is that, uh, T cells could be at the nexus of some of that dysfunction. 

Arne Akbar: So T cells may be at the nexus of some of those functions, but here’s the challenge that I think we all face. It’s a lot of money, and here’s what we should look at. We should look at the common mechanisms that lead to dysfunction in many different systems in the body.  So what links muscle frailty with, um, Alzheimer’s? With other things that could go wrong? Lack of responses to  vaccination, for example. And, uh, do-do dif — individual things. We can’t have polypharmacy. We all know that. 

Gordon Lithgow: Yeah, yeah. 

Arne Akbar: But what are the common things that link all these dysfunctional elements together? And that’s what we should target. And so, the money should be put towards trying to integrate the information to find out where they all join up and target that one thing that can affect many different things ultimately. And  a perfect site for that is the sestrins. Nutrition and senescence linked up by one pathway.  

Gordon Lithgow: We talked earlier about sterile inflammation and the sources of that. And you-you mentioned, for example, fat cells and-and the inflammatory processes that come from fat.  And I occasionally wonder if we just have an incomplete knowledge of our microbiome. The kind of issues I’m thinking about here is the fact that there’s now  this, uh, incredible interest in the idea that Parkinson’s Disease, for example, originates in the gut. And, you know, we’ve been looking at neurological disease essentially, in a silo, if you like. I know we’re seeing a much more wide, you know, fuller-body view of what diseases like this are. 

Arne Akbar: Mm-hmm. 

Gordon Lithgow: Do you see that as well? Do you think that we have a-an incomplete knowledge of the viruses that are probably there? That are inducing inflammation that we don’t know about right now?

Arne Akbar: Yeah, yeah. It won’t just be viruses. It will be — it will be microorganisms. It will be bacteria. There will be other things as well. Everything outside is trying to get in and eat us up essentially, and they all — and we’re fending these things off through our life, but where does the time come where we can’t fend them off as well as we could before?

Gordon Lithgow: Mm-hmm. 

Arne Akbar: And it could lead to many, many different things. You mentioned the link between the gut, and organisms there, and the brain. I’ve just spent, uh, a short sabbatical in Cambridge working with Menna Clatworthy’s lab. And she actually wa-wa-was one of the first people to-to show that link between the brain and the gut. And something else we haven’t touched on which was actually crucial in all this. No point getting a better body that fights infection better if your brain is not working. 

Gordon Lithgow: Yeah! 

Arne Akbar: How do all the things that we’ve talked about — how does the immune system link in with the brain? And there’s now a lot of interest in the neuroimmune access. How do brain cells interact with the immune system? We know that there are lots of innate-like cells that look after the neurons. They’re always associated with neurons. They’re also in the brain as well, but how — what is that interaction? Who is the shepherd, and who is the orchestrator of what’s actually happening?

Gordon Lithgow: Hmm. 

Arne Akbar: What-what are these cells doing, and how do they go wrong? And how could we change that access of interaction between those cells and make things better?

Gordon Lithgow: Uh, super! If our audience was to tune back in, in five years’ time, and we were still talking like this, uh, what do you think you’d be saying then about the advances that we’re about to make?

Arne Akbar: Mm-hmm. A lot of our advances at the moment are linked to two things; mainly, technology. The better the technology you’ve got the more you can actually do which makes me wonder how, when I started off my PhD, going way back to my earlier parts of the conversation, how we did anything at all. We had so little —

Gordon Lithgow: [Laughs]

Arne Akbar: — so little technology to do anything. 

Gordon Lithgow: Right, right. 

Arne Akbar: The other thing is you need to have conceptual leaps. And, you know, in the senescence field, in the aging field that there have been a lot of conceptual leaps quite recently. A very exciting field for that reason. The whole idea of senolytic therapy, the whole idea of, you know, the immune system being able to attack senescent cells, that’s all new. And that’s conceptual leaps together with technology. We can do single-cell RNA seq now. We can look at individual cells and see what they’re doing within a tissue, and that’s fantastic. 

Gordon Lithgow: Mm-hmm. 

Arne Akbar: We need to better organize the relationships between mouse and human systems, but also, other in vitro systems. Risk coordinate,coordinate, coordinate. That’s what we need to do.  And if you gave me the grant money that you promised earlier, and I’ll be looking for that in my bank account soon —

Gordon Lithgow: [Laughs] Of course!

Arne Akbar: — I would just like to coordinate and get people to coordinate interactions between people to find out how an area of research can actually go, and set its tendrils into many different areas as well, and with the interactions that go on.  Microbiota, important in the brain and interestingly, important in the gut and the brain. You know, the other things as well. Nutrition. What happened to somebody who is starving somewhere and getting old?

Gordon Lithgow: Mm-hmm. 

Arne Akbar: You know? They could have had double whammies, triple whammies in all kinds of different ways. 

Gordon Lithgow: So what do you say to your young scientists at UCL? I mean, this is not the world we grew up in. We were stuck in our own disciplines and as you say, with relatively little technology to work with. What do you say? What are the skillsets that people need to acquire now?

Arne Akbar: I think — a-and I say this to my groups, I’m not just saying this to you, I try to instill courage that you need to be able to think outside the box. And because we think that no one will think — believe you, it’s not a good reason to think about new ideas. The excitement as a new scientist, as any scientist is the new idea and the what if. “What if that was true? What if that, around the corner, we’ve got that instead?” If you’ve never had the courage to think about that possibility you’re never going to find it, and you’re never going to be excited. 

Gordon Lithgow: I think that’s an inspiring way to end this conversation. Arne, thank you so much! Again, I learned a lot. I didn’t pick up enough immunology when I was at university and so, I’m always scrambling, but, uh, that was absolutely fascinating — thank you so much. 

Arne Akbar: Been my pleasure to talk to you, Gordon. 

SHOW OUTRO

Thank you so much for listening. If you’ve enjoyed this podcast, please subscribe, share and give us a five star review on Apple, Spotify or wherever you get your podcasts. 

 “We’re not getting any younger, yet!” is made possible by a generous grant from the Navigage Foundation. The Navigage Foundation is enhancing the lives of older people through the support of housing, health, education and human services. Our podcast is produced by Vital Mind Media: Wellington Bowler is here with me using sign language to keep me on course and recording the podcast. Stella, who I love spending time with talking about science, as you know, is our editor with the Creative Direction of Sharif Ezzat and the Buck Institute’s very own Robin Snyder as the executive producer. 

If you’re listening to this podcast, you know that there’s never been a more exciting time in research on aging. Discoveries from our labs or moving into the clinic to help us all live better, longer. 

The Buck Institute depends on the support of people like you to carry on our breakthrough research. Please visit us at Buck Institute dot org to learn more and to donate.