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How Stem Cells Contribute to Aging and Age-Related Diseases with Rob Signer

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What challenges does aging pose to both individuals and society at large? What causes aging at the cellular and molecular level? Stem cell research is the key to finding solutions that increase our healthspan and change how we think about aging. Robert A.J. Signer, Ph.D., shares what is on the horizon.

Credit: University of California Television

Video Transcript:

[MUSIC] What I’m going to tell you about today is really as we take a closer look at aging, we’ll start by talking about what is aging. What are the challenges that aging poses to individuals and to society at large? We’re going to talk about the key solution to those challenges. To do that, we’re going to talk about what causes aging at both the cellular and molecular level. Really, the solution to this is going to require a fundamental change to our approach to research.

That is really going to be required to have the maximum impact on human health. Lastly, I’ll tell you about some of the important breakthroughs that we’re making in my laboratory to really make that fountain of youth or reality.

Let’s start by talking about what aging actually is. If you look up aging in the dictionary, you get the simple definition of it’s the process of getting older. It’s time passes and unfortunately, I can’t tell you how we can prevent time to pass.

You might have to attend a lecture in the physics department or something like that to get the answer but we really want to talk about what biological aging is. The World Health Organization defines biological aging as something that results from the impact of the accumulation of a wide variety of molecular and cellular damage over time. This leads to a gradual decrease in physical and mental capacity and a growing risk of disease and ultimately death. Doesn’t sound great, does it? This is really the crux of this major health problem, is that by the time we turn 28 years old, aging becomes the leading risk factor for disease and death.

This is all kinds of diseases. Cardiovascular disease, dementia, cancer, outcomes from COVID-19, and the list goes on and on.

Hearing loss, cataracts, back and neck pain, arthritis, osteoporosis, pulmonary disease, diabetes, depression. The incidence of all of these diseases increases exponentially with aging. Aging is a critical risk factor for our health.

But this isn’t only true for us as individuals, but really also true for us as a society. Aging is really a public health issue as well. That’s because we’re in the midst of a massive change in how our population is aging. We’re right smack in the middle of a century of change where the population in the United States is changing from an age distribution that’s shaped like a pyramid to one that’s shaped like a pillar where you have equal distribution across all of these different age groups. Within a few years, for the first time in our history, we will have more people over the age of 65 than we do children under the age of 18.

For a long time. Aging has been thought to be this challenge in the developing world. But that’s not even true anymore.

In fact, the growth of the aging population is increasing even faster in developing countries. By 2030, one in six people in the world will be over the age of 60, by 2050, the world’s population that’s over the age of 60 will double to over 2 billion.

The population of people over 80 will triple to over 400 million. By 2050, nearly two-thirds of the world’s population over the age of 60 will live in low and middle-income countries. This is going to pose immense health care challenges. Now on top of the health care issues, aging, and the changes that are happening within our population is also fundamentally changing the way our economy works. This again is impacting both individuals and society at large.

For people aged 55 and above, they represent currently about 30 percent of our population, but 56 percent of our health care spending. When you turn 65 or older, that is when you will use about half of all your health care spending throughout your life.

Now at a national level, the national health care expenditures are approaching 20 percent of our gross domestic product. By 2025, which is just around the corner, we’re going to experience a shortage of 500,000 home health aides, a 100,000 nursing assistants, and 29,000 nurse practitioners. Those labor shortages are actually going to extend beyond the health care sector.

The International Monetary Fund predicts that by 2030, we’re going to see a 10 percent drop in our labor force participation because of the aging population. If you’ve been around in the last year and you see the drop in or the effects of work shortages. This is something that we’re really going to have to address. Lots of big challenges ahead. The good thing is we know the solution that has to be reached.

The solution is that we need to increase what’s called health span. People often talk about living longer and increasing lifespan but they don’t often consider health span. What is health span? Those are the years of life where we’re healthy. Our goal needs to not just be to extend life as far as possible, but to extend the period of life spent in good health and to really compress the period of life that spent with morbidity.

When we can do this, now, people are living longer, they’re living healthier and they’re more active members of our society. How do we increase health span? Easy to say, but how do we do it? This is where I think we require a fundamental change to how we approach research. Typically, the way research happens now is in a disease-oriented manner.

You have people that work on cancer. You have people that work on Alzheimer’s disease. You have people that work on diabetes. But the idea of Geroscience is changing that approach. That is maybe what we actually need to be studying and treating are the fundamental causes of aging.

Because if we can treat what’s actually causing aging, maybe now we can prevent multiple different types of age-related diseases. In order to be able to do that, we must understand the cellular and molecular causes of aging. That’s where we’re going to turn to stem cells. I’m sure many of you have heard of stem cells. But turns out there are many different kinds of stem cells.

The stem cells that I’m going to be talking about today might not be the ones that you’ve previously heard of. These are called adult stem cells, that are sometimes also referred to as somatic stem cells or tissue stem cells. These stem cells exist in all of us. They’re present in many of our different tissues and they are, the magic cells that are enabling our tissues to regenerate on a daily basis due to normal turnover in response to different injuries and in response to different stressors. Now we have stem cells, like I said in many of our tissues, we have stem cells in our brain that help to replace brain cells.

We have stem cells in our muscle that replenish our muscles. We have stem cells in our intestine that replace the lining of our intestinal epithelium. We have stem cells in our skin, which you’ll hear about from my colleague, Dr.

Greg Cohen after this. We have stem cells in our bone marrow that make all of our blood and immune cells and we have stem cells in multiple different tissues.

Each of them are specialized to produce the cells within that tissue or organ. Now, what makes these stem cells so special? Well, I say stem cells have two superpowers. Those two superpowers are they have the capacity for self-renewal. That is, they can make more of themselves, and only stem cells can make more stem cells.

They have the capacity for what’s called multilineage differentiation. That is, those stem cells are a blank slate and they can produce any of the cell types required in that given tissue. Let’s look at this from a practical example within a tissue. At the top of this hierarchy is what’s called a hematopoietic, which is a blood forming stem cell. These hematopoietic stem cells will regenerate all of our blood and immune cells throughout life.

These cells are exceedingly rare, they represent about 0.007 percent of all the cells in our bone marrow.

That’s about 70 cells out of every million. What these cells do, as I said, is that they self-renew throughout life and they differentiate to give rise to all of the different types of blood cells. This includes things like red blood cells that carry oxygen, platelets that help with clotting, different types of immune cells like our B and T cells to fight infection, and so on.

While we have these remarkable stem cells that maintain health in our tissues, unfortunately, the function of those stem cells starts to go wrong with age, and it primarily these stem cells will malfunction in three different ways during aging. The first way a stem cell can malfunction is that it loses its ability to self-renew. When that happens, we lose that pool of stem cells and now we can no longer replace the mature cell types within our tissues that do all the work to make those tissues and organs function.

This is how stem cell dysfunction leads to degenerative disease during aging. Now the second way that stem cells can go wrong during aging is that they get too much self-renewal activity.

Or a different type of cell can hijack that self-renewal activity that stem cells normally use. When this happens, you produce too many stem cells, and this is what leads to cancer.

The third problem with stem cells with aging is that multilinear differentiation can become skewed. That stem cell that will normally produce cell Type A and cell Type B stops making cell Type A and starts making a lot more of cell Type B, and this leads to tissue dysfunction. Practically, let’s look at what that means in the blood system.

Those hematopoietic stem cells that I told you about that make all of our blood and immune cells. Well with age, sometimes they’re self-renewal activity goes away and this can lead to things like bone marrow failure in older people. Sometimes that self-renewal activity gets hyperactivated and this can lead to the development of leukemia. The differentiation potential of these stem cells also get skewed during aging. Those stem cells start producing fewer adaptive immune cells called lymphoid cells, things like B and T cells, and this is in part what makes older people more susceptible to infection.

They also stopped producing red blood cells and platelets, and this can lead to anemia or clotting disorders. Instead they’re making more of what are called myeloid cells. These are inflammatory cells, and this can lead to chronic inflammation that can have a widespread effects during aging across multiple different tissues. Now we know stem cell dysfunction happens during aging, and this is contributing to all sorts of different types of disorders. Now, the next question is, well, what’s causing stem cells to malfunction during aging?

The answer, I think is actually quite intuitive and something you all probably know, and that is that stress causes aging. I think the best example of this is when you look at before and after pictures of our presidents. This is stress on steroids, so to speak, and you really see these effects visually. But we also know how stress makes us feel. But how does a cell experience stress?

What does it mean for a stem cell to be stressed? This is where the work from my lab I think is really making key breakthroughs.

Several years ago, we adapted technology that allowed us to measure how much protein individual cells we’re making. Most people thought, well, who cares? All cells are making protein.

It must happen the same way in every cell type. Turns out not the case at all. Each cell type in our body makes protein at its own very specialized rate, and stem cells are a very unique outlier in this regard. Stem cells produce protein much more slowly than any type of cell. We were the first to show this to be the case in the blood, and now people have taken our technology and have looked in other kinds of stem cells.

As far as I know, in every single type of stem cell people have looked at, this is the same. Stem cells produce protein slowly. They don’t just produce proteins slowly, they have to produce protein slowly.

When we turn up that rate of protein production, even just a little bit in stem cells, it has catastrophic results. We really lose that stem cell self-renewal potential.

Why are you talking about protein production? What does this have to do with aging? Let me tell you where the light bulb moment really came from. But before I do that, let’s make sure we all understand exactly what a protein is and what protein production is. Really the central dogma in biology is that we have DNA that is broken up into about 20,000 genes.

Now what each one of those genes is, is actually an instruction for how our cells can build a specific protein. It’s the protein that actually is the function, it is what is doing something. Consider your phone. Inside your phone, someone has written a bunch of computer code, and that’s all stored as zeros and ones. That’s our DNA, it’s the instruction for how to do something.

For the most part, that’s not practical, doesn’t impact us. What impacts us is that, that code is the instruction for how to use an app or how an app works, and our proteins are our apps.

They are what actually does something within ourselves. The key moment now comes from studies that were done in various model organisms, where they found that when protein production is slowed down either genetically or through environmental interventions, that organism will actually live longer. This has been shown to be true in yeast, in flies, in worms, in mice.

Less protein synthesis, longer life. This really led us to a key hypothesis. We said, if turning down protein synthesis promotes lifespan and longevity at the organismal level of the organism, then maybe the same is true for long-lived stem cells that they have low protein synthesis to really enable their long life. The next step here is to understand, well, why does having low protein synthesis promote long life? It goes back to that question of stress.

It’s that reducing protein synthesis alleviates stress. Again, what is stress at the molecular level? Well, I told you that each of these proteins that built has to have function. But you don’t just have to assemble the protein piece-by-piece. It actually has to fold and enter a very specific shape and confirmation in order to work well.

Now, sometimes that protein does not fold properly or is built incorrectly, and it turns out that protein production is a highly error-prone process. What happens if a protein folds in the wrong way? Well, not only is it not going to work properly, it can actually be toxic to the cells, and this is stress. Again, an analogy if we think about building, I dump out a Lego set on the table, I can put all the pieces together and build something. [NOISE] But if I don’t build it the right way, it’s not going to look at all like the front of the box tells me it is, and this is what happens with protein production.

When it goes fast, it makes mistakes. When it makes mistakes, proteins misfold, this causes stress. Do stem cells have less of these misfolded or stressful proteins? The way that we looked at that is by using a technique called western blotting, which is shown here. The way that this works for those of you that are unfamiliar is will basically take cells, crack them open, and look at all their protein.

In this case we’re looking at all the protein that is tied with a molecule called ubiquitin. Ubiquitin ties all the misfolded proteins in our cells. It says, “I’m labeling you as misfolded as trash.” This is essentially a measurement of trash. When we look at this in stem cells, as compared to other kinds of cells, you can see stem cells have less trash.

The stem cells are under less stress than these other types of cells. Through a series of experiments, we went on to show that when we increase how fast stem cells make protein, we increase the trash in those stem cells. Then separately, we could show, even if we didn’t increase that speed, if we just increased the trash, we were impairing stem cell function. Stem cells do not like to accumulate trash that comes from their stress. Most cells in our body are short-lived.

They synthesize protein quickly, they have lots of stress, they live fast, they die young.

Stem cells though are in it for the long haul. They need to make sure that every protein they produce is as pristine as possible because they don’t want to accumulate this trash. We actually know a lot about protein misfolding and how it can cause disease from neurodegenerative disorders. Because these misfolded proteins when they accumulate in cells, what will actually start to happen is that they’ll clump together.

We know that this is a feature of many different types of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and so on. We know this because you can actually see them. When they do pathology on the brains of people, you can actually see these clumps of protein that are essentially forming plaque-like structures in the brain.

Well, easy to see this in the brain, a large organ, lots of cells. Stem cells though, remember, 0.

007 percent. How are we going to see these accumulate within stem cells? Well, lucky for us, the stem cells have an alarm system that just tell us that this is happening. This alarm system involves a gene that we study called heat shock factor 1, or HSLF1 for short. The way that this alarm system gene works is that normally it’s sequestered in a part of the cell called the cytoplasm.

Now HSLF1 binds to other proteins that are called chaperone proteins. Those chaperones help proteins fold properly. Now under conditions of stress where you start to have lots of misfolded proteins, well, those chaperone say, we’ve got work to do. They leave HSLF1 alone, they bind up all those misfolded proteins and this allows HSLF1 to move through the cell to enter what’s called the nucleus, where we have all of our genetic material and to activate a program to help restore normal function and fitness in those cells. We know if there’s a problem in these cells by looking at where this HSLF1 protein is, is it in the cytoplasm or is it in the nucleus?

When we look at stem cells in young adults, we don’t really see much HSLF1 present in the nucleus, which is stained in this blue region here.

But by middle age, you can start to see all this HSLF1 present within these stem cells. HSLF1 is shown in these green fluorescent dots here. Aging stem cells are sounding the stress alarm. What is HSLF1 doing in those stem cells?

Well, we’ve studied that and we found that HSLF1 is helping to keep our stem cells fit as we age. Unfortunately, they’re doing their best, but it’s not always good enough. Now, using some newer technology, we actually see that aging stem cells, just like those aging brain cells, are really accumulating aggregated proteins. These data are hot off the press in our lab, we just generated them where we’re now seeing about 20-30 percent increase in the amount of aggregated protein within old stem cells. Now, it’s great that nature has figured out a way to help stem cells reduce stress.

Doesn’t seem to be good enough as we really progress into the later stages of life, but there’s another downside, and that’s this adaptive response is a little bit of a double-edged sword. When HSLF1 gets turned on, it’s not only helping stem cells cope with stress, it can also help cancer cells cope with stress.

When we look in acute myeloid leukemia we also see HSLF1 turned on, and turns out that HSLF1 is really important for helping these cancer cells grow. What I’m showing you here are human leukemia cells injected into mice. This signal that you’re seeing here represents the burden of leukemia cells that’s there.

Now we’ve taken those exact same leukemia cells and we’ve deleted the HSLF1 gene.

We’ve taken it out of the system, and you can see the cancer grows much more slowly in that case and these mice survive much more than the normal leukemia cells. To show you exactly how this double-edged sword works, again, is that normally young stem cells, they’re in good shape, they work normally. As they age, they start to accumulate these misfolded and aggregated proteins. This can impair stem cell self-renewal and lead to tissue dysfunction.

But we can turn on this alarm gene that’s responding to this stress and that’s helping to eliminate some of those misfolded proteins and to maintain normal stem cell function. But when HSLF1 turns on, well, it can cause stem cells to go a little haywire and that can lead to the development of cancer. What’s the answer here? It feels like we’re in a catch-22, we can either keep our stem cells fit and risk cancer or we can avoid the risk of cancer at the expense of having proper tissue regeneration and function. We think that the key is to limit the biogenesis of these misfolded proteins to keep our stem cells fit so that they never even have to activate these pathways that can later prevent cancer.

If we look at these old stem cells, if we can prevent them from getting those misfolded proteins, well, they’ll never activate HSLF1, they’ll never get cancer and the tissue function will be normal. Sounds easy, how do we do it? We’re taking lots of approaches to do it, looking at multiple different pathways but I’m going to just briefly tell you about the one that I’m most excited about.

Again, it sounds easy. Our strategy is to make the process of protein synthesis less error-prone.

It sounds reasonable? Well, this is a process that is conserved all through life. Protein synthesis is one of the most required processes, how are we going to just change it? Oh, here’s the good news, we’ve already done it. We’ve introduced the tiniest mutation in a single base pair of DNA that can alter how the machinery that builds proteins has errors and we can improve the quality of proteins that are produced with this single mutation.

This single mutation is permissible for life in mice, we have made mice that contain just this tiny mutation. They produce less errors when they make protein and in our very early studies, we see that their stem cells are aging at a slower rate. We are super excited to continue to pursue these studies and are really empowered to see how minimizing this stress from protein errors and protein misfolding can not only affect stem cell function, but can affect multiple tissues and overall health span and lifespan.

On top of that, we’ve engineered a system where we can actually screen drugs now to do the exact same thing and we’re really excited to launch that. Let me now summarize by telling you how we plan to keep stem cells fit to extend human health span.

Today we’ve talked about what aging was and how it’s a primary risk factor for disease and death. We talked about how aging poses immense health and economic challenges for individuals and society at large. Our goal is to extend health span by treating the underlying causes of aging with the hope of preventing multiple types of age-related diseases. We’re targeting stem cells because stem cell function declines during aging, contributing to degenerative disorders, tissue dysfunction, and cancer. We believe that by preventing the accumulation of misfolded proteins and stress will be the key to keeping our stem cells fit and preventing these diseases.

Let me just take this opportunity to thank all the people that contributed to the work. I feel so fortunate to work with just an incredible group of scientists in my lab that range from undergraduate students and even this summer high school students through graduate students, post-docs, clinical fellows, we really have an amazing team that embraces our collaborative nature, our kindness and respect, and our desire to make big impact on human health.

Let me also thank my many collaborators both here in the local at UCSD and in San Diego and across the country and the world. Of course, none of this work is possible without funding and that’s really what drives our ability to do more and more of this work. I really given you a little bit of a surface level of the science we do, but my door is open.

If you’re interested and you want to learn more, please come get in touch with me. Come, happy to meet, happy to teach you, happy to talk to you, happy to answer questions, happy to let you tour the lab and that’s what we’re here for.

Thank you to everyone for your attention. [MUSIC].

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