Vadim Gladyshev is a Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School, and he is one of the most prominent figures in geroscience today. We discussed various competing hypotheses on the nature of aging, the lack of the unified theory of aging and the need for one, and several fascinating papers that he has recently co-authored.
How did you end up researching aging?
It happened accidentally. We initially studied selenium, which is an essential trace element. Our lab is known for the discovery of a full set of selenium-containing proteins in humans. As we tried to understand their functions, we realized these proteins are oxidoreductases with selenocysteine in their active sites, so we ended up in the redox biology area. There have been many studies involving redox biology in the aging field, so I got exposed to that area.
As I learned more about aging, I realized just how interesting it was. There are many fundamentally important, unanswered questions in the field, and still very little is known about aging, which makes it a very attractive area for any curious scientist.
The topic of selenoproteins is a really interesting one, and you talked about it in your previous interview with us. The field of aging is exciting, no doubt, but many people think it’s also too young and under-researched. Would you agree?
Things have changed recently, and in fact, we see a huge influx of talent in the field. Even five, ten years ago, many graduate students wouldn’t consider studying aging; they would go to a more solid field, like immunology or cancer. But not anymore. Today, many students, including really strong ones, are attracted to this field, they see a potential. This is coupled with an influx of funds.
It’s both talent and resources, and this is making a huge difference. Many quantitative tools are now available. It’s not low-level science anymore. I would say we are much stronger as a field now, although many issues remain.
I think there’s a growing concern about geroscience lacking a unified theory, or even agreement on some basic, fundamental facts, like what aging is.
To me, the nature of aging is the most important question. There is no agreement whatsoever on what we study. Apparently, there is a huge diversity of opinion, which is amazing. We talk to each other, and it feels like we’re discussing the same thing, but once the question of the essence of aging comes up, suddenly we realize that we’ve been discussing completely different things.
Some think about aging in terms of damage accumulation, with our metabolism producing byproducts and other deleterious changes, which accumulate and eventually result in dysfunction, diseases, and, ultimately, death. Another school of thought is more into an evolutionary explanation. For example, it is thought that the strength of natural selection is high during development, and then at the onset of reproduction, it begins to drop, because the organism can produce offspring and therefore become less important. When the force of selection subsides, damage starts accumulating faster, organisms get diseases and die.
A third group of people think that aging is a sort of continuation of development, a trajectory that was set up during development. Yet another idea is that aging is a loss of function. I’m not fully in line with that thinking, because what exactly is function in this sense? How do we measure it? Other people think about aging in terms of mortality. They say that organisms age if they are more likely to die tomorrow than today. And yet another point of view is that aging strictly equals age-related changes. When something changes with age – that’s aging. It may be bad or good, but it’s aging.
How would you reconcile all this thinking? Yet, we need to know what aging is because we need to know our target. What is this enemy that we are trying to defeat? What should we interfere with – is it mortality, loss of function, changes in gene expression, changes in information that is transmitted from the genome, changes in damage, or something else?
Of course, these features are related to one another, especially later in life, when everything goes downhill, but they are different manifestations of aging. To develop the best approaches, strategies and interventions against aging, we need to know what is this thing that we are targeting.
This is also related to the definition and the essence of rejuvenation. If we want to make an organism younger, what does that mean exactly? Is an organism younger when it has less damage, when it’s less likely to die, or when it has improved some function? There is a complete lack of agreement.
What does this say about the field? Personally, I’ve always thought that when you have multiple “schools of thought”, this shows that the field is immature.
Certain things in biology are just hard to define. For example, what is life? It’s not an easy question. Maybe aging is just a complex phenomenon, something that is really hard to define. In fact, some people think that we shouldn’t even define aging, we don’t need a consensus on that, we just need to study it.
I’m against that idea, I think it’s important to address this fundamental question. Even if there are two, three, or several schools of thought, it’s still useful because this enables us to ask questions, design experiments according to these ideas, test them, and ultimately support some ideas and reject others.
But you do have your own favorite theory of aging, you think it’s mostly damage accumulation, right?
You may call it a theory, or a concept, or maybe a model. Yes, like many, I have certain thinking about aging, which I think is logical. I’ll try to explain it in very simple terms. Basically, to live, we have functions. We need them so that we can develop and successfully compete with other organisms. These functions depend on genes. Each gene supports a particular function, or more than one function, but as those functions are being performed, damage is also produced. Biology is not perfect because chemistry is not perfect.
Each function produces some kind of a byproduct, not necessarily in the molecular sense, but in a broader sense as a negative consequence of having that function. Those are not just byproducts of metabolism, post-translational modifications, or mutations. This could be any kind of damage, that’s why we often call it “age-related deleterious changes” or the deleteriome rather than damage. There is so much diversity in these changes, and this is due to the way organisms, mammals in particular, are set up; we just cannot possibly deal with all forms of damage produced as we live.
For example, we have non-renewable, non-dividing cells like cardiomyocytes or neurons. Therefore, they necessarily age; they just cannot get rid of all the damage that accumulates. In that sense, we cannot stop aging; at least this is true for mammals, and this damage just expands and accumulates. It is important to relate this to evolutionary thinking particular to the aging theory called antagonistic pleiotropy.
This theory posits that, during evolution, species acquire certain alleles that offer advantages when the organism is young, but they lead to damage later in life. For example, there’s a gene that gives a certain advantage, such as a better visual function that helps to spot food. As a result, we may outcompete other organisms with poorer vision. That same gene, while functioning, would produce damage. Initially, there’s not a lot of that damage, so it won’t have overly serious negative consequences. What is important at that young age is improved vision, but over time, the damage accumulates, and the organism eventually develops diseases and dies.
Producing a certain amount of damage is intrinsic to having those functional alleles and genes. In a way, both the function and the production of damage are built-in in the use of genes from the very start. In other words, there is a dark side to every gene’s beneficial function. That’s antagonistic pleiotropy in a nutshell: every gene has this duality, and not just every gene, but every component that is purposely used by organisms.
For instance, we need iron for blood function, but the use of iron also contributes to the generation of reactive oxygen species. That’s antagonistic pleiotropy. Iron has not evolved; it was there already. Likewise, we do not need to invoke evolution of genes to explain whether organisms age. This means that antagonistic pleiotropy cannot really explain whether organisms age or not. This evolutionary mechanism can only contribute to changes in lifespan.
At the same time, clearly there are organisms that do not age, despite the fact that they have those antagonistically pleiotropic genes. My guess is that they are simply able to dilute and replace the damage. This can be accomplished by cell division, or asymmetric division, or replacement of cells. However, maintaining a constant level of damage isn’t possible in mammals simply because the way they are set up, biologically, as they have non-renewable cells and structures.
That’s the price we’re paying for our complexity?
You may call it complexity, but I would say it’s overall organization of the organism. For example, a decision was made some time during evolution to have a brain. We need it, among other functions, to have memories, but this demands a constant set of neurons. Eventually, neurons die one by one, and because we cannot renew them, neuronal function deteriorates, and the organism dies. This notion applies not just to neurons but to other non-renewable cells and all kinds of irreplaceable structures within the organism.
Some other organisms can replace all cells. For instance, the hydra is not a very simple organism, yet it seems to not age, as it can replace all its cells. Such a strategy would not work in mammals. That’s why when somebody discusses, for example, the naked mole rat and says, oh, its mortality doesn’t increase with age, so it’s a non-aging animal, I don’t understand that. It’s a mammal. There’s no way it does not age. It must age, as it has neurons, cardiomyocytes, and a skeleton.
This model that I’ve just described is quite logical. Until it’s validated, we cannot be sure it’s 100% correct, but it’s logical. Of course, because there is a huge diversity of opinion in the field, we have to be open-minded. We, the scientists, need to be critical first of our own models and must consider other explanations, and design experiments to test them. Then, we can ask other questions, such as when does aging begin? It’s a very instructive question.
This actually was my next question. Although the idea of aging as damage accumulation makes a lot of sense, it begs the question, when does aging begin, and how does germline reset fit into this picture?
Yes, if we consider that aging is damage accumulation, we need to ask the question, when does it begin to accumulate? We know it accumulates late in life, but what about earlier times? Does it accumulate at the age of 30? Yes. At the age of 20? Yes. At the age of 10? Again, yes. At birth? Yes! And even before birth.
That’s the topic of one of your recent papers, where you also show that a rejuvenation event occurs early into development, right?
First, we published a paper where we demonstrated that damage begins to accumulate already early in life. At that point, we didn’t know exactly if it happens at conception or a bit later. Later, I published a conceptual paper predicting that biological age decreases during early development, and the reason for that is that the germline in parents is a set of live cells. Those cells also accumulate damage over time. They age, and therefore, for the next generation to start aging at age zero, there must be a rejuvenation event. The question is when exactly it happens. Logically, we should expect it to happen after conception. As the aged parental germlines form a zygote, it must have some damage, and this damage must be cleared for the new organism to begin aging at the same low biological age.
It has to be a complete reset.
Yes, a complete reset. Then, we consider what we know about early development, for example, about the length of telomeres. After conception, telomeres begin to extend, and only later, they begin to shorten again. So, there’s a reset there. Also, during early embryogenesis, DNA methylation is stripped, and the DNA is subsequently remethylated, that’s another reset. That’s when you realize that there’s something special about a certain phase of development.
It seems like there are many different lines of evidence pointing to a possible rejuvenation effect during embryogenesis. Again, we have to be critical of our own models, and it’s important for other labs to validate this concept before it is accepted. We just report what we find. From the perspective of damage accumulation, it makes sense that aging would start at that developmental stage – approximately at the stage of gastrulation.
How does this reset even happen? Is there any hope that eventually, we may be able to use the mechanisms of germline reset to reverse organismal aging?
I don’t know yet whether it will be possible, but I sure hope so. We also know little about the mechanisms involved. We need to better understand the timing, and what exactly happens. What does it mean to be rejuvenated? What happens to the cells? Is it activation of particular genes, or maybe cells divide so actively during this time that the damage gets diluted, or maybe they export damage by asymmetric division?
There are various possibilities here, and if it does involve activation of certain genes, then maybe we could activate the expression of these genes in somatic cells later in life. But, at this point, it’s too early to say. We simply don’t know.
Do you think cellular reprogramming has anything to do with this germline reset?
We know very little about reprogramming as well. Clearly, when cells are reprogrammed, they become younger, but the exact mechanism is not known. In the same way, it could be activation of certain genes, or it could be dilution of damage by massive cell division, or maybe some other mechanisms. Therefore, we cannot really compare it directly with embryonic rejuvenation. We don’t know whether they represent the same process or not.
Intuitively, I think they are not identical. Maybe there are some common features, but they seem to be different. I think it’s important to study both and also identify other examples of rejuvenation so that we can uncover common as well as unique features of different rejuvenation strategies. Perhaps, just like we consider different models of aging, we need to consider different models of rejuvenation.
We obviously have mechanisms that repair damage, so why do they fail us?
It’s impossible to deal with the entirety of damage. Of course, we have many protective systems, but they cannot remove damage in its entirety. The diversity of damage is too high. Nature solved this problem by building new organisms from within the old ones rather than by maintaining organisms indefinitely. There are various damage control systems: for example, the germline seems to accumulate damage very slowly.
When somatic cells are quite old, germline cells are older than they were in the beginning, but not as old as somatic cells, which makes it easier to reset their age during embryonic development. We also have many repair systems that deal with damage in somatic cells, like the renal system or the hepatic detoxification system, or systems that remove damage from the brain.
Let’s go back to the naked mole rat and this decoupling of mortality and aging that you demonstrated. Naked mole rats are thought not to age demographically, but your paper proves that they still age epigenetically, as measured by methylation clocks. How would you interpret these important findings?
In this particular project, we wanted to address the relationship between aging and mortality, because for many people, mortality is the manifestation of aging, a key feature of aging. According to this view, an organism ages if it’s more likely to die tomorrow than today. All demographic aging models are based on mortality.
The Gompertz equation is the most famous quantitative model in the aging field, which has been used for many years. However, it does not explain certain features of mortality. For example, starting from about 40 years old, we see an exponential increase in the mortality rate in human populations. But when we look earlier – for example, between the ages of 20 and 25 – there’s no increase in mortality. Do humans age during that period?
Moreover, during early childhood, mortality actually decreases. That means that people who think aging is measured by mortality do not even consider childhood, or the period between the ages of 20 and 25.
The constant mortality of the naked mole rat is another observation that they must somehow explain. They say that since mortality doesn’t increase during adult ages, the naked mole rat doesn’t age, but this is in clear contradiction with what we know about mammals. Naked mole rats have neurons, they have cardiomyocytes. We predict that those cells must age.
To address this issue, we built an epigenetic aging clock, and we proved that at least epigenetically, these animals age, even if demographically, they do not. So, do they age after all? Our interpretation is that they do, it’s just that mortality is not a good measure of aging in this species, it’s simply not representative of aging.
In certain species of fish and some other animals, mortality actually decreases with age, which puzzles evolutionary biologists. They say it’s negative senescence! I am not sure what negative senescence is.
I think those organisms still age, they accumulate damage over time, it’s just that their mortality does not increase with age because mortality is an integrative measure of not just organismal aging but also of organismal development and interaction of the organism with the environment. This includes features like predation, how well an organism can withstand certain stresses, and so on. Or simply becoming bigger, which happens in turtles and fishes. Maybe these organisms are less likely to be eaten as they grow, which is why we observe this pattern of reduced mortality, even though they age at the molecular level.
This issue directly relates to the essence of aging. What is it? We have tried to expose these contradictions. I’m not claiming that I’m correct, I’m just saying that there are contradictions. Let’s discuss them, debate, plan experiments, and solve this puzzle.
If we could only solve mortality and not aging, I’d take that. Looks like a good goal.
Yes, but that would be a slightly different goal, in my mind. This is what advances in medicine have done, especially in the last 150 years.
Your lab works on several directions of research. Could you tell us about them?
We are interested broadly in aging and rejuvenation; we try to understand the nature of these processes. We also would like to better quantify them, so we develop tools to do that. Our specific projects are designed to address these big questions from multiple angles. For example, we have projects on cross-species analysis. We examine many species, trying to understand how nature changes lifespan. This is a way for us to identify new interventions and develop approaches to both extend lifespan and rejuvenate organisms in response to those interventions.
It’s a bit hard to discuss specific projects because some of them are in progress, and for some we don’t have much data yet. I guess I could mention some random projects. For example, we are studying parabiosis in collaboration with Jim White. We find that the young mouse parabiont gets older and the old parabiont gets younger when they get connected, but what does it mean? Do certain organs get rejuvenated or become older? Is it reversible or not?
In another example, if we transplant a young organ to an old mouse, or an old organ to a young mouse, how is aging of the animal affected and of the transplanted organ too? If you have an organism of a certain age, and it has an organ with a widely different age, what is the age of that organism? Those are some of the questions that we address.
We are also interested to know how stress is related to aging. We find that severe stress seems to increase the epigenetic age of organisms, but once the stress is relieved, the age is decreased too. We’re trying to understand, is it just an epigenetic age, or is it “real” aging, meaning that an animal, when placed under severe stress, literally becomes old, and when the stress is relieved, it actually becomes younger? This would mean that the biological age is not a feature that only increases but that it can fluctuate.
This would also mean that some kind of a local rejuvenation event happens. Yes, it’s a great paper.
It also opens many other questions, because if we look at the organism under severe stress, we see more damage, a higher epigenetic age, and also an increased risk of death and disease. And when the stress is relieved, we observe a drop in all those features. Some might say that it’s just inflammation, or just stress or another transient feature that we cannot call aging.
Then again, what is aging? How is it affected by this extra stress? Perhaps severe stress brings extra damage. This would make the organism slightly older, and once the damage is cleared, whether it was due to inflammation or some other challenge, perhaps the organism becomes younger. Therefore, it may also be possible to consider rejuvenation on short time scales.
Yet, some scientists might consider that going back to a normal level of damage shouldn’t be called rejuvenation, that rejuvenation is when an organism becomes younger than in the absence of stress. This discussion brings us again back to the core definitions: how do we define aging and rejuvenation? I hope our studies can help address, consider, and debate these issues, which ultimately will bring clarity to the field.
Going back to heterochronic parabiosis, I was wondering if you have any new insights on this. There are still many things we don’t know.
We have a couple of papers on parabiosis in BioRxiv in collaboration with Jim White and Steve Horvath. We attach animals for three months and then detach and follow them. For example, we found that old animals, after being attached to young animals, live longer and are younger than those attached to old animals. After separation of the animals, the rejuvenation effect was sustained. We also have another BioRxiv paper where we subjected mice to rapamycin only during early development, and this treatment extended lifespan. Apparently, it may be possible to interfere with early development of mice, affecting aging for the rest of the animal’s life.
Yes, this is another very interesting paper, but there seems to be a certain trade-off in terms of growth, right?
Yes, growth is definitely suppressed in these animals. They are smaller, and they never reach the full body weight of untreated mice.
Interestingly, rapamycin is also the only molecule that was found to extend lifespan similarly when the treatment started in early adulthood or much later in life.
Yes, it’s a nice discovery, and rapamycin is a very promising molecule, for sure.
As one of the central figures in the field of geroscience, how would you describe the current state of affairs?
I think, in general, the field is in a better shape than ever before. We may discuss the fact that, unfortunately, there’s no consensus on the nature of aging or rejuvenation, on causes of aging and on the best approaches to target it, we may disagree on many issues, but at the same time, there’s clearly an improved quality of research and more and more recognition of the field. This research is now taken very seriously, which brings more resources and talent to the field.
These resources and talent will be instrumental in moving the field forward in the next 5, 10, 15 years. I expect a lot of progress. The field may be completely different by then. It may reject the current models or support certain ideas; it’s hard to predict. It’s very exciting to be in this field today and hopefully will be even more exciting in the coming years.
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