Kathrine

That you for joining me today. To start, would you mind introducing yourself, your field, and the main questions your research group studies?

Professor Abdulai-Saiku

Okay, my name is Dr. Samira Abdulai-Saiku. I am currently an assistant professor at Temple University where I study how the X chromosome contributes to cognitive aging and how this then drives sex differences in how people age cognitively. So we are asking questions like what genes in the X chromosomes are kind of driving these sex differences?

How do X chromosome mechanisms like the parents of X or XSCPs also influence how male brains age differently from female brains?

Kathrine

So what first interested you in studying cognitive aging?

Professor Abdulai-Saiku

So this is actually very interesting. I don't think my first interest was in cognitive aging. My first interest was in sex differences.

So I did sex differences in fear responses. As a PhD student, I asked a really basic question of does this change in fear response we are seeing in another model have okay in females at all? Because I couldn't really see any mechanistic studies in females.

So that kind of took me down a rabbit hole and I was like, there's all these sex differences nobody actually talks about. And then I read about how a big part of why a lot of drugs do not work in clinical trials is most people just study them in male cells or male animals and stuff. And then when they go into clinical trials, they all of a sudden have females in there and then it throws the data out because nothing is working the way they think it should.

And then the research gets thrown out because, well, it didn't work out. And that led to the NIH actually making people study sex differences. Now it forced, it had a policy known as the study of sex as a biological variable where people had to study both males and females unless there was a proper reason not to, like if you were studying menopause, you couldn't study males.

You know what I mean? Like it had to make sense. The problem was even though they were forced to study both males and females, a lot of it didn't force them to actually consider what that meant, like really compare them.

They just had to put them in the study to get approval. So when I finished my PhD program and I was thinking about what to do next, I came across the work of my postdoc mentor, Dr. Dina Dubao, who had also dabbled in, not dabbled actually, she'd done a lot of work in sex differences, but she'd, for also her graduate career and a lot of her postdoc in the beginning of her lab, she'd focused a lot on hormones and how they drive sex differences. But she was, she'd recently gotten, at the time recently had gotten into looking at how the X chromosome affected these things.

And we wanted to keep looking at it. So when I interviewed with her and she was like, yeah, I'm going to do sex differences with X chromosome. I was like, first of all, I didn't think X chromosomes did anything except determine sex.

So now I'm intrigued. And that's kind of how I got into it because her lab mainly studies cognitive aging. And a fun fact about the X chromosome is by size, it makes up about 5% of your genome, but it is overrepresented in cognition related genes because it has about 15% of all known cognition related genes.

That's a significant over representation. If you consider the fact that there's like 22 other chromosomes, right. Sharing the remaining 85.

So we were interested in how this affects cognition and we, we know cognition changes with aging. So that's how kind of all those things came together.

Kathrine

Oh yeah. So on that topic of cognitive aging, a lot of your research focuses on cognitive resilience and susceptibility. So what does it mean for one person's brain to be more resilient to aging than another person's?

Professor Abdulai-Saiku

Okay. So on average, normal wear and tear as you age means that, you know, things start to function less optimally than they've always done, which means you expect some degree of decline in cognitive functions. And this could be memory, decision-making.

There's a whole lot of things that change with aging. Right. But we've realized that the rate of change is not the same.

Some people decline really quickly and some people don't decline as quickly and some people don't seem to be declining at all. Right. So clearly there is a genetic component of what is happening.

Like there's a social component and people study those things too, like how your environment, your background, the way you've grown up and all those things, your ability to still socialize with people in your old age, how all those things contribute to cognitive decline is important and other people study them. But there's clearly a genetic component because what we began to see very clearly is that we could see clear differences between males and females. Right.

So that kind of pointed towards a genetic difference. So there is something inherently genetic about being male or being female that alters the way the brain declines in age and it's not uniform. So different parts of even memory, we have different types of memory and those change differently in males and females with age.

So there's a lot of nuance to it. But basically the idea is that on average, there's decline. But when you look into individuals, you realize that some people age very quickly.

Like they start to show cognitive decline really early and it doesn't stop. And some people start later, but they decline. And then some people don't.

We refer to them as super ages because they don't decline. And there are several studies now studying these people. There's a study somewhere in Europe, I forget where, I think Netherlands, of these hundred year old super ages, so hundred and above, who have the cognitive function of people in their thirties and forties.

They are not declining. They're over a hundred and they're still as mentally sharp as you can expect a normal adult to be. Actually crazy.

And we think if you can figure out what makes them so resistant to declining quickly, that could help inform how we treat cognitive decline.

Kathrine

That's really exciting. In addition, in your recent research, you found that female mice with only the maternal X chromosome active were demonstrating greater memory problems and even faster biological aging in the hippocampus. So could you walk us through how you conducted that investigation from the research questions to the methods to eventually drawing that final conclusion?

Professor Abdulai-Saiku

We took females and then we said, well, we usually hear that part of the reason why we see discrepancy in X-related genes is that females have two Xs and males have one. But female cells, because they have two Xs and males have one, undergo a process known as X chromosome inactivation. What this means is that each female cell in the body will silence one of the two Xs.

So functionally, they also only express one X. The difference is that because the two Xs, they obtain one from their mom and one from their dad. And there is randomness, which means each cell makes its own decision about which X to silence.

What happens is that some cells will end up silencing the X from mom and some cells will silence the X from dad. And so it means that you have cells now in the female body where some express mom's X and some express dad's X. But in males, they get one X always from mom.

So they only express mom's X. So in females, for example, if there's a mutation somewhere on the X chromosome, you're going to, and it causes like very severe disease. If it's from the X inherited from mom, the males are always going to get it and it's always going to be serious.

But in females, because of random X, you are less likely to have it very serious because, you know, randomness means not all the cells will have mom's X active. And then somebody in like the early 2000s made a very interesting discovery. There are these individuals that don't actually, they are essentially females because they don't have a Y chromosome, but they only have one X.

They don't have a second sex chromosome. So is it weird? Yeah.

So it's one of the diseases of X chromosome where they somehow do not inherit a second X and they do have some impairments, but they function, look, act like normal females. Yeah. But we realized that they do have some cognitive impairments when you compare them to females that have two Xs, right.

However, somebody decided to study that and realize that those who got their single X from their mom showed more cognitive impairment than those that got their single X from their dad. And in order, it's this condition, by the way, is known as Turner's syndrome. And in order to study it, people made a mouse model to kind of mimic it.

So they also created a mouse model where it didn't have a second X and they saw the same thing, right? The mouse where the single X was coming from dad was better cognitively than when it was coming from mom. And this was not even an aging study.

This was just random young mice, right? So it got us thinking, could the parent of X be important, right? Which X is active, where your active X is coming, which parent you inherited from, could that be important in driving kind of the cognitive trajectory of individuals?

And it's important to note that in these mice, we use inbred mice. And what this means is that there's no genetic variability within the mice, right? So unlike humans, where individual humans, even within the same family, have genetic variation, you don't see that in these inbred mice.

They are genetically identical. But we did something interesting where rather than allow the cells to make their own choice about which X to choose, we forced, we made the decision for them, right? And this has a lot to do with understanding how X chromosome inactivation occurs, which is a whole other one hour of talking.

But essentially, we deleted X's because if an X chromosome cannot express an X's, it cannot be silenced. So if we delete X's of mom's X, that means that that X automatically gets silenced. It's forced into that process.

And then we compare these mice. And right from when we compare them in young, we could see that there was some memory impairments, right? Let me take a step back.

I want to mention that another reason why we really wanted to look at this is that because males have only one X from their mom, but females have the, like the dual, some X from their mom, some from their dad. We wanted to see whether we could mimic a male-female comparison sort of without the baseline of testosterone versus estrogen hormones, right? If we normalize X expression, then we could do that because we know about sex differences.

And typically, at least for a majority of cognitive tests, males do worse than females do. So when we saw the data in the young, we were like, well, we are a cognitive aging lab. We should see where this goes as far as aging.

So we aged them out, but we kept testing them. And each time we would test them as they grew, while both were declining, the mice that were only mom's X were declining faster, right? So by the time they were like really old, and really old in mouse years is about 22, 24 months, we were like, oh, these guys are still really terrible.

And they are much worse than the females that have both. And this is important because there were very, there was one very different thing about our approach versus the people who were studying it for turners, aside the aging. See in turners, they deleted the X they didn't want.

In our situation, we kept the X there. And that's important because even though we refer to that X as silent, it's not completely silent. There are still a few genes that get expressed of it.

And a lot of them, and we call them X-escaping genes, because we are very original as a scientific community. But these X-escaping genes typically tend to contribute to cognition, like not having them usually leads to one syndrome or another, but all those syndromes have a cognitive impairment component, or like an intellectual disability component, something that affects cognitive performance. So we wanted to use a model that kept X-escaping so that you couldn't blame them for the impairment.

And still we saw the impairment happening, right? So that told us that there's something inherently different about which parent you inherited from, even if everything is similar, like the genetic components are similar, which made us think it has to be something epigenetic. So that's kind of how we came.

And then we said, well, if it's epigenetic, is it affecting what we call epigenetic age or biological age? And what that is, if I asked you how old you are right now, you would say 16 or 17, right? That's your chronological age.

That's how much time has passed since you were born in human years. But your epigenetic age is kind of how well your cells are functioning, right? So if you do things like have a terrible diet, you don't exercise, smoke all the time, drink all the time, your epigenetic age is usually really high because your cells are functioning like they are older than, like they are aging faster, basically, right?

If you take very good care of your body, your cells act more like they are younger. And when we looked, the cells from the mom only expressing mice were much older than those from the wild type mice, right? And these were the same age.

And so we use another transgenic mouse, which is really cool. We didn't make it in another lab, but it's so cool. They attached fluorescent proteins, so a GFP and a TD tomato to the X chromosome on two separate mouse lines.

So when you breed them together, the babies that are born have these fluorescent proteins. And so because of where they put it on the X chromosome, if a particular cell expresses mom's X, it shows up as GFP, so green. And if it expresses that side, it shows up as red.

So you can take cells from the same brain, kidney, liver, whatever, and you can separate them based on which X they are expressing using a special machine called a flow cytometer. And that allowed us to compare mom's X-expressing neurons to dad's X-expressing neurons. And what we saw was that even when they are coming from the same brain, mom's X-expressing neurons are still older.

So it was pretty cool. And because we thought it might be epigenetic, and we know epigenetics affect gene expression, we looked at that. We looked at how the two populations were different in their epigenetic, in their gene expressions, and pretty different, very significantly different.

So that's how we kind of, all these things helped us come to this conclusion that something is inherently different about the X you inherit from your mom and the X you inherit from your dad. And it could be completely based on how they are epigenetically marked and identified by the cells. And so part of my ongoing work is figuring out, part one is figuring out what are those epigenetic marks.

And then also trying to find the mechanisms, the different genes we identify from the X-chromosome, how they, then what is actually the mechanism of action? How are they acting in the brain to induce these differences in cognitive performance? And this time we are going to include the males.

So there'll be a little bit more variability because now we have to kind of think about how to account for the hormones, but we'll make it happen. It'll be fine.

Kathrine

That sounds like a really exciting project and I definitely would love to see where your research continues to go.

Professor Abdulai-Saiku

I mean, we're really excited about it. We think it will be great to kind of begin to understand what makes males different from females in the brain. And then, because if we can figure out what it is, we can help people.

If something about one group is better, then you can take that thing and help everybody with it, right? So that's what we're trying to do.

Kathrine

Absolutely. So how exactly do researchers measure memory in mice and how must scientists be cautious when connecting those results to human cognitive aging?

Professor Abdulai-Saiku

Okay. So we have some very interesting cognitive behaviors. We have behaviors for everything.

We can measure anxiety in mice. We can measure what people refer to as autistic behavior in mice. But in cognition, we have a few well-validated tests we use.

We have what is known as the paper that you saw the data from, the Morris Water Maze, the Large Wild Maze, the novel place preference. Repeated testing in the open field. We have novel object recognition.

All of these typically kind of depend on certain inherent characteristics of mice. For example, mice, because they are prey animals, right? They constantly have to figure out where they are, map out the environment so that they know what is going on and they don't end up being eaten.

And even though these are inbred mice and they have been essentially domesticated for research for decades and centuries, they retain certain instincts, right? They need to know where they are, which means that mice and rodents are more likely to explore a place they do not know, an object they do not know. Anything that is new to them, they are more likely to explore it and make sure they've kind of characterized it in their head so they know what that is.

And they are less likely to explore stuff they already know. So this is the basis for both the novel place and the novel object test, right? The Large Wild Maze is kind of the same thing where we allow them to get to know a place very well and we introduce a new environment.

And if they explore the new environment more than the old environment they know, then they have a good memory because they can remember that they already know the old environment, right? The Morris Water Maze is kind of a more interesting one. We teach them to find something in a pool of water.

The water is meant to be motivation because they hate being wet. So it's a little sadistic, but it's also motivation. They hate being wet.

So typically they try to learn quickly where to go to end the experiment so they can get out of the water and stop being wet, right? So that's how we do that. So we teach them, you need to get to this part of the water because there's a little platform there.

And if you stand on the platform, that ends the experiment and they learn how to do it. And then we measure if they remember it by removing the platform and seeing how long they hang out in that area, looking for it. Or how many times they keep coming back because in their head, they're like, no, I know it's supposed to be there.

Why is it not there? Right? So that's what the Morris Water Maze is.

And it's one of the few tests, we call it a gold standard because it's one of the few tests where we can actually measure how well they are learning and how well they remember in one experiment. And there's a non-water version of the water maze known as Barnes Maze, which is a similar concept, but without the water. So we use these tests.

And in recent years, I would like to say maybe in the last five years to a decade, people have started basically making virtual reality for these mice, which is very funny because you would see them with these funny looking goggles over their eyes and they're running tests. What that does is allow scientists to put very different scenarios in there and see how these mice behave. And this is usually done while they have electrodes recording from neurons in the brain in real time to see how different situations affect neuronal firing and neuronal activity.

Or it's done like imaging whilst they're doing it. So it's pretty cool. Yeah.

I also like, I have a, I know it's a crazy irrational fear, but I'm like, what if they like lose the electrodes of their head? But people have been doing this for years. It's pretty safe.

And the mice are okay. I just have an irrational fear of having a mouse running around with a tiny microscope on their head. Right.

And I think the question is how, how is this different from humans? Yeah. So we measure really like we, as part of cognitive tests, we will measure something like language, for example, which is kind of hard to measure in a rodent.

We would measure verbal reasoning, which you can also not measure in a rodent. So there are definitely existing differences, which is why people do human research as well. But the reason why animal research has existed for so long is that there's a lot of like genetic, structural, and even physiological similarities between mice and humans and even other animals and humans.

And because we cannot do causative studies in humans, we do correlational studies in humans. So you would say, I don't know, all the humans that have good cognitive performance, maybe eat 30 grams of fiber because you ask, eat like at least 30 grams of fiber every day. Because you ask them and they all eat 30 grams of fiber, at least 30 grams of fiber a day.

And the other guys, most of them don't. Right. So we would say, oh, eating more fiber correlates with X, Y, Z.

But there's really a way to test it the way we would do in mice. Does that make sense? In mice, I would go in and feed them.

Okay. One group gets five grams of fiber a day, another gets maybe 20 grams of fiber a day, another gets 30. But what happens if I kick it up to 50 grams of fiber?

We can do causative studies. We can keep everything else constant and just switch these very specific things in mice. And so that's how we get to not this occurs at the same time as this, but this actually causes this.

Kathrine

So your group finds animal behavior, cell culture experiments, and omics approaches. What does each method reveal and how do you connect them to support a cohesive conclusion?

Professor Abdulai-Saiku

So the behavior is actually where we take the gene or whatever we are interested in, put it in the animal and see how it actually acts. So that's a phenotypic output that we can see. Yes, it does.

No, it doesn't. Because things can change in the brain, but the brain is an organ like other organs. It has compensatory mechanisms.

So sometimes things changing don't always elicit a behavior. An animal behavior confirms to us that the behavior actually changes or is maintained. Omics experiments allow us to see how different substances in the body are changing in response to our treatments and give us a big picture place to start from.

We see how the genes are changing, how the proteins are changing, how metabolites are changing, how even epigenetic marks are changing, and then we can begin to construct a cohesive kind of analysis of how our different groups or our different treatments alter physiology in the body. Cell culture experiments is actually where we understand mechanism in my lab, because we can take a culture of neurons or a culture of astrocytes or whatever we want, and we can add a gene and see how it changes function of the cells. Does it increase neuronal firing?

Does it decrease neuronal firing? And stuff like that. Are the neurons healthier because of this?

Are they more resistant to apoptosis because we increased... If we increase oxidative stress, which increases in aging, do the genes we've modified in these neurons make them survive better? This is where we actually do mechanistic work.

So that’s how we put all of those approaches together. Omics gives us the biggest-picture sense of what has happened. We can see, “Hey, I am seeing these changes between this group and this group.” We can then put that back into the brain and ask, “Does it improve? Does it not improve our phenotype?” Then we can work from that broad regional picture, break it down, and use cell culture to understand how a particular gene or pathway is interacting. That’s how we put them together.

Kathrine

So finally, what is one realistic step that a high school student could take this summer to begin exploring neuroscience or cognitive aging?

Professor Abdulai-Saiku

So I think there are a lot of really good online resources. YouTube videos and things like that can give you an introduction to whatever topic you are trying to learn, and there are interactive sites you can go to and see some of these things in action.

I think you can also start to read review papers. A review paper is when somebody sits down, looks at the literature published over the last five or ten years, puts it together, and says, “This is what we know, and these are the questions that remain to be answered.” So read. I know scientific jargon can sometimes be difficult to understand when you are young, but there are resources that can help you work through it.

Another thing you can do is talk to people. If there is somebody whose work you are really interested in and you have questions, email them. Nine times out of ten, people are happy to have a conversation with you and talk to you about the topic. Especially in academia, scientists are always trying to get more people interested in what they do, so they are usually happy to talk to people about it.

And many of us, especially as women in STEM, want to encourage more young people to become interested in research and in becoming scientists. So talk to people. You may be surprised by how happy they are to talk to you. People are often very kind and willing to share.

Kathrine

Yeah. I really enjoyed learning about sex differences and their impact on cognitive aging, and I really appreciate your time. I think students will learn a lot from hearing your perspective.

Professor Abdulai-Saiku

Thank you. This has been really fun. Forty minutes really flew by.