— How did your journey in science start?
— I grew up in Orenburg and graduated from School No. 10 there. It all started as it usually does. When you take an interest in certain subjects, you begin to participate in science olympiads. I took part in olympiads in chemistry and won at the regional level a couple of times. We were fortunate to have an excellent chemistry teacher, Maria Kashkaryova, and we had what you could call a chemistry club or study group, where we would gather after school to conduct experiments and solve problems. Our school was nothing special, but we participated in the regional competitions and sometimes managed to secure all the top positions. After finishing school, I realized that chemistry was my strongest suit. So I decided to apply to Moscow State University.

— The chemistry department?
— Yes, the chemistry department. After graduating from MSU, I followed the conventional path to postgraduate studies. I completed MSU’s postgraduate training program and defended my PhD around the same time the Soviet Union collapsed. I needed to decide what to do next. About a third of my peers went abroad to pursue science careers, while another third ventured into business, often quite successfully. I believe one of them is actually a billionaire now. The rest chose to continue their scientific pursuits in Russia. I, in turn, decided to move to the States. It was the year 1992, and in some ways, it was easier to leave immediately after defending my thesis. Had I been younger, I would have faced challenging years ahead, and if older, I would probably have put down roots that would have held me back... As it was, I hadn’t really worked in Russia. So I defended my thesis and moved to Washington D.C. for work.

— When you say Washington, do you mean Bethesda? Also, when did you join Harvard?
— I mean the National Institutes of Health, yes. It turned out to be a highly productive biochemistry lab where many future members of the National Academy of Sciences, future Nobel laureates, and other renowned scientists had worked. After working there for a few years, I secured a professorship at the University of Nebraska-Lincoln. I spent 11 years working there, until I was offered a position at Harvard in 2009. I relocated my lab and have been there ever since.

— Has your family been accompanying you on your travels all this time? Did you start it in Russia or the States?
— We started our family in Russia, but our children were born in the USA: two of them in Washington, D.C., and our youngest daughter in Nebraska.

— Let’s move on to your area of expertise. What is your perspective on aging? Is it a programmed process of the body or a system’s wear-out? Is it pathological or physiological?
— It might seem odd that those studying aging don’t fully understand what it is, but that’s the reality.
Let me illustrate with an example. There was an aging conference in Canada before the COVID pandemic hit. The organizers handed out a questionnaire to the attendees, asking them to define aging, when it begins, and the best ways to manage it. The responses varied greatly, showing that people have very different understandings of the phenomenon. It was somewhat surprising, as aging seems like a straightforward process that we encounter daily, which has visible signs. However, when we try to pinpoint its essence, it turns out that people, including scientists, perceive it differently. Some argue that aging is the increasing probability of death with age. Indeed, in the human population, the likelihood of dying doubles every eight years. For instance, a 60-year-old is twice as likely to die in the next year than a 52-year-old and half as likely as a 68-year-old. Another perspective is that aging is the decline in function with age: our cognitive abilities decrease, we run slower, and our vision deteriorates. Others believe that it is the accumulation of damage over time: side effects of metabolism and other harmful consequences of life activities building up. Lastly, some define aging as simply the process of change with age. Those processes are all interconnected, as we observe when a person ages. But there must be a primary, most crucial process that drives all the others. So, what is that process? There is no consensus on the matter.

— Which “party” do you align with?
— I support the idea that aging is primarily defined by the accumulation of damage over time.
Why do I believe that? For instance, if we consider aging as an increase in mortality with age, there are clear contradictions. Mortality does indeed increase in people aged over 30, but the pattern at younger ages is quite ambiguous. At birth, the mortality rate is relatively high. It then gradually decreases and reaches its lowest point at the age of nine. Afterwards, it starts to grow gradually. There is also a peculiar surge around the age of 20, primarily in males, which seems to be linked to risky behavior. So, between the ages of 20 and 25, the likelihood of death doesn’t rise. It more or less levels off for men. Therefore, too many facts don’t align with that definition. I often ask my colleagues this: if we take a one-year-old child and a five-year-old child, which one of them is older?

— The answer is obvious.
— It is really not! There are three possible answers. I once gave a lecture at Harvard’s systems biology department, and a professor in the front row said, “Well, it’s obvious. Who has a higher chance of dying? The one-year-old. Hence, they are older.” And I said, “That doesn’t make any sense! Are they becoming younger as they go from one to five?” And he replied, “In terms of mortality, yes. They are becoming younger.” That’s the first answer. The second answer is that we can’t really talk about aging before the age of 20. I believe that’s incorrect. I think that the body ages even then. It’s just that mortality rates don’t reflect it. And the third answer is obvious.

— I really like your metaphor about life being a river that flows from the mountains to the ocean. Please, elaborate on your aging theory.
— Let’s take a single non-dividing cell, as a cell is essentially a unit of life. As a cell lives, it accumulates damage. Of course, a cell has many defense mechanisms that can expel or break down some of the damage. But it’s inconceivable that a cell could detect all the causes of damage. Let’s say there is a chemical reaction in the cell that almost goes perfectly, but not quite, because nothing is perfect in terms of chemistry. And it generates some damage, a single molecule of something unwanted.

— A byproduct?
— Yes. And the cell has no way of knowing that this molecule exists. Given the many such molecules, it’s hard to envision, from an evolutionary standpoint, a system that could serve as a flawless molecule detector. Numerous situations like that will occur, leading to the gradual accumulation of damage in the cell. However, that damage can be mitigated. If the rate of damage accumulation doesn’t exceed the cell division rate, then the damage is weakened and, theoretically, such a life form can continue to exist.

— So, during cell division, does the new cell receive less damage than what was present in the original parent cell?
— Yes. It seems that this issue, the potential for cells to accumulate damage, has been present since life first began. From the earliest protocells, even before actual cells existed and there was just a simple membrane envelope with perhaps some RNA structures inside, damage was already occurring. Therefore, cells had to divide to dilute that damage. That’s probably the fundamental basis of life. In other words, if a cell doesn’t divide, it will inevitably age. We observe it in humans in cells that are non-renewable.

— Like in neurons?
— Yes. In neurons, cardiomyocytes, certain eye cells, some skeletal damage as well. Most importantly, the existence of such cells indicates that an evolutionary strategy has developed to utilize such innovations, which inevitably led to aging. This is true for humans, which makes it extremely challenging to completely eliminate aging as a process as we don’t yet understand how to do it. However, there are other organisms that do not age.

— I wanted to ask, what model organisms are used to study the aging process? For example, I know that your group has sequenced the genome of the naked mole rat.
— Yes. It’s called the naked mole rat, but it’s not actually naked, nor is it a mole rat per se. It’s a creature about the size of a mouse, hairless, wrinkled, and with large incisors. It lacks fur but has whisker-like structures, like that of a cat, spread all over its body. It uses those whiskers to navigate the tunnels it digs. It lives underground in Africa and may appear frightening to the uninformed due to its large teeth. However, it’s actually a very gentle creature. It never bites and can be held in hands, where it will sit calmly. But that’s not why we sequenced it. We sequenced it because it has an exceptionally long lifespan, making it the longest living rodent.

— An exceptionally long lifespan for a rodent, you mean?
— It has been confirmed to live for more than 30 years. Currently, the record is, I believe, 35 years, and that animal is still alive. So, we don’t yet know the maximum lifespan of the naked mole rat as a species. The fact that this small creature, the size of a mouse, lives ten times longer than a mouse is a remarkable phenomenon. They also rarely develop cancer. Nature is a wonder, and we are trying to understand what has changed in that organism compared to its fellow creatures to make it live so long.

— Are there other such longevity champions?
—Yes. We have also sequenced the genome of Brandt’s bat. It, too, is remarkable. It’s even tinier than the mole rat, yet it lives for more than 40 years. And the adaptations it has developed are different. Or take the bowhead whale, for example. It lives for over 200 years and probably has adaptations that are unique to it. It appears that there are two primary ways to extend lifespan. One might be unique to each animal, while the other forms some common patterns that we are also attempting to comprehend. The latter is even more intriguing because we can also apply it to humans. Naturally, it’s not a “one key to all.” There are typically numerous genes and genomic changes involved. It’s not as simple as taking one gene, expressing it, and voilà, the organism lives ten times longer.

— There are things like age-related diseases and chronic illnesses. How do you define them in relation to humans, not naked mole rats?
— Age-related diseases are chronic illnesses whose likelihood increases with age. Cancer and diabetes are the most typical examples. The chance of developing cancer roughly parallels the probability of dying. Meaning, on average, your chances of getting cancer approximately double every eight years. But naturally, it varies slightly for different types of cancer. Some cancers, for instance, are common in young people, but those events are typically rare in the population.

— There was a popular notion that sooner or later everyone would live long enough to develop their own cancer, if they didn’t die before that.
— Not everyone, but roughly 20% of the population, I’d say. But cancer isn’t the only age-related disease. There are also heart disease and diabetes. In fact, the list is quite extensive. Most of the diseases we know are chronic illnesses that affect older people. Those are what we call age-related diseases. They are typically studied as diseases with their own distinct risk factors. But actually, age is the primary risk factor here. That’s precisely why we do research in our field. We’re trying to understand what aging is and how it can be influenced. Because if we could influence it and slow it down just a little, we could delay the age at which age-related diseases occur. That would be wonderful. It would revolutionize medicine and our lives. Regrettably, they would still emerge later, or perhaps if we overcame them, different ones would appear...

— So, when exactly does aging start? Is there no consensus among experts on this either?
— It’s a broad topic. We published an article a month ago where we pinpointed what we believe is the onset of aging. In the 19th century, there was a scientist named August Weismann. He suggested that an organism could be split into what’s known as the soma and the germline. The germline consists of spermatozoids and oocytes, in other words, the gametes that will form a zygote upon fertilization, from which the organism will subsequently develop. The soma refers to everything else. Weismann further posited that the soma is mortal while the germline is immortal and doesn’t age. That seems logical because if the germline aged even slightly towards the end of life, then the next generation would start life at an older age, and so on, leading to the eventual extinction of the entire population. But it doesn’t happen, which means the starting age in every generation remains consistently low.
So far, it sounds logical. But consider oocytes. How can they not age? They are living cells, so they produce byproducts, accumulate mutations and epimutations, generate metabolites and damaged proteins, and undergo other modifications. Clearly, they must age. This creates a contradiction because when an egg is fertilized, it should be older than at the time of conception. We then proposed that the germline does age, but is rejuvenated within the embryo after fertilization, not instantly, but gradually. I published the first article on that topic earlier this year.

— Is it a theoretical study?
— Yes, the first one is theoretical. But now we have an experimental paper being published in Science Advances, which I mentioned earlier. In that paper, we determined the biological age during embryogenesis. We found that age decreases from the fertilized egg stage to a stage called gastrulation, when the three primary cell types – the three germ layers – are formed within the embryo. Around this time, we detect the organism’s lowest biological age. We suggest that this is when the biological aging of the organism begins.
So, the organism begins to age after gastrulation, along with the germline, but when an embryo forms in the next generation, rejuvenation occurs. That stage of the lowest biological age is what we refer to as ground zero, the starting point. In essence, it could represent not only the onset of aging but also, in a way, the beginning of an organism’s life.

— Are there other aging theories besides what you’ve described?
— We sometimes joke that in our field, we have more aging theories than scientists studying the aging process. This is because aging appears to be a simple process on the surface, and every newcomer to the field proposes their own ideas. If we group these ideas, we can identify the main trends. One trend suggests that aging is a programmed process. The assumption is that there is a necessity for an organism to live and then to vacate resources and space for the next generation.

— If I’m not mistaken, Dr. Skulachev supports this theory.
— Yes, he does. There are also numerous other scientists who share this belief. This idea is quite attractive from a general standpoint, as we do observe elements that suggest programmability. For instance, the average human lifespan currently hovers around 80 years. Organisms age in a similar manner, with many developing the same diseases such as cancer, diabetes, or heart disease. While there are similarities, it doesn’t necessarily mean that the process is programmed, in my view. It merely appears to be programmed because we possess a genetic life program. We have a life program, but there is no aging program. For example, there are no genes that, if turned off, would halt the aging program, but there are plenty of genes that would stop the life program if turned off.
Another concept is the so-called “disposable soma theory of aging,” championed by scientist Tom Kirkwood, who is based in England. He argues that organisms always exist in environments with limited resources. Those resources must be allocated to reproduction – a process that requires energy – and to supporting the organism itself. However, due to resource scarcity, resources have to be diverted from support to reproduction, resulting in less than perfect support, and this is why it’s impossible to eliminate all the damage we discussed earlier. As damage accumulates, the organism eventually dies. Yet, one could imagine a scenario where a species has unlimited resources: abundant food, no predators for many generations, no threats. But we never observe aging suddenly halting in such organisms.

— There is also the concept of reducing calorie intake to extend lifespan, correct?
— Well, it’s more a method than a theory. It is a somewhat different matter, and there are various ways to extend one’s lifespan. We discussed the metaphor of aging being like a river. In that metaphor, the gravitational pull represents aging, while the duration of the river’s flow symbolizes lifespan. Indeed, there are numerous ways to alter one’s lifespan. However, it doesn’t mean that we can halt the aging process. Those are two different things.

— Shall we then discuss extending life expectancy?
— To begin with, our scientific field has seen substantial progress, even a revolution in the past decade in terms of determining biological age. Before, we could only know the chronological or passport age, while determining the biological age was challenging. However, new methods have now made it possible. Currently, we restrict the calorie intake of mice and then use biomarker analysis methods to determine their biological age. We observe that mice of the same chronological age who consume less food are biologically younger. We compare a ten-month-old control mouse with a mouse that has consumed less food. The latter is also ten months old according to its passport, but in reality it is, for instance, only nine months old.

— Let’s backtrack a bit. How do you determine biological age? If I were to visit your lab, could you determine it for me?
— Yes, we certainly could. We use a method known as the epigenetic clock. Now, DNA has four different types of nucleotides. One of them, cytosine, can undergo methylation, a process of attaching methyl groups. There are millions such sites in the genome. We can sequence the genome and ascertain the likelihood of each of those cytosines being methylated. Next, using machine learning techniques, we can identify a specific group out of millions of cytosines and create a mathematical model that can predict age based on their methylation patterns.
Such epigenetic clocks have been developed for certain tissues, such as for analyzing the aging of blood, liver, or brain. This method was initially devised by a scientist named Steve Horvath in Los Angeles, leading to a surge in similar research. Numerous versions of those clocks have been created, and thousands of people use them. There are even companies that specialize in determining biological age. Currently, we are collaborating with Steve on a project involving “clocks” for 200 different animal species. I believe it to be a unique study, even though it hasn’t been published yet. We also use those clocks in our work. In my lab, mice are the primary model organism because we can quickly test how they age and how that process can be manipulated.

— Do people also age at varying rates, meaning their biological clocks function differently?
— Clocks function uniformly, but the biological age of an organism can change at different speeds. It’s important to understand that a clock is merely a biomarker, an indicator. That is, the causal relationship isn’t exactly straightforward. If we disrupt the biological aging clock, it won’t alter the aging process. By using such clocks, we observe that people age at slightly varying rates. Different organs within the body age at slightly varying rates, and even within each organ, different cells can age at varying rates – that’s why the process is so complex.
This is linked to one of the groundbreaking areas of my lab’s work: we currently have a paper under review in a journal where we outline the first clock that specifically determines the aging of single cells. It appears that it will also be a crucial method in the future.

— How does it work?
— In contrast to other aging clocks, our method offers a probabilistic approach to determining the biological age of single cells. For instance, the primary cell of the liver is the hepatocyte. In a four-month-old mouse, the majority of hepatocytes are also four months old. But as we observe, some cells are older, and we suspect that something is amiss with them, causing them to age more rapidly. If we examine a 26-month-old mouse, we find that most of its liver cells are also approximately 26 months old. And if we examine embryonic cells, we find that their age is virtually zero. But there are more complex scenarios. For example, muscles contain stem cells (i.e., cells that have not yet differentiated), and it turns out that even in old mice, those cells remain relatively young. They too age, but at a slower pace.
This diversity leads us to a specific model. Each tissue ages at a certain rate, and within a tissue, cells age at slightly varying rates. For instance, some senescent cells age more rapidly, while some stem cells, conversely, age more slowly.

— Being a journalist, I’ve got a tricky question for you. In your opinion, does a human being have a maximum lifespan?
—Yes, they do.
We have conducted a study where we calculated the maximum lifespan of human beings. But we are not the only ones to have done it. There is also a company called Gero that independently calculated the same thing using a different method. Interestingly, the figure that emerged was roughly the same, somewhere around 130–140 years.
This is likely the maximum lifespan of our species, humans, even if we influence the body with simple methods like environmental factors, physical activity, and diet. But that doesn’t mean that it’s a limit that can never be surpassed. Life expectancy is currently on the rise. The average lifespan is nearing 80 years and will likely continue to increase, up to 90 years of decent, quality life.
But to go beyond that, science is exploring other methods where we can have a more radical impact, at least on parts of the body. This is precisely about enabling the body to breach that 130–140-year barrier and live even longer than that.

— Can induced pluripotent stem cells help with that?
— That’s an excellent question. The discovery of such cells is tied to Shinya Yamanaka’s name, the scientist who was awarded the Nobel Prize for his work. Yamanaka’s factors are four genes that he expressed in adult human cells, effectively reverting those cells to an embryonic state. It is an extraordinary discovery, arguably the most significant one in biology in this century.
From an aging perspective, this tells us that it’s fundamentally possible to rejuvenate a cell – to take an adult cell and make it young again. However, when we do that, the cell loses its function – it becomes embryonic and undifferentiated.
Our goal is to rejuvenate the cell in a way that it remains functional. For instance, if the cell is a hepatocyte in the liver, we want it to stay a hepatocyte and continue detoxifying harmful substances rather than becoming a stem cell.
Currently, numerous labs are focusing their efforts on that issue. The idea is to slightly stimulate the cell, transitioning it partially into an intermediate state where it has somewhat rejuvenated, and then remove that stimulation so it reverts back to its functional state. In the case of a hepatocyte, it would transition into an intermediate state, rejuvenate, and then revert back to being a hepatocyte, but a younger one. Although, that’s a very delicate and challenging process.

— Has there been any success?
— Yes, there has been progress indeed. At the end of last year, a paper we co-authored, led by David Sinclair who heads a neighboring lab, was published in Nature. We used mice as model organisms and studied their optic nerve. If it’s severed, the mouse loses its ability to see. However, if you express three out of the four Yamanaka factors, regeneration occurs, including the rejuvenation of neurons, and the mouse’s vision is somewhat restored.
Thus, we were able to slightly rejuvenate the cells of the optic nerve using those factors. There are several similar studies from other labs. There is a study on a progeroid mouse where all four Yamanaka factors were expressed, but in a restricted manner. The scheme was as follows: you express factors during one whole day, then let the mouse rest for six days, then express again for a day, followed by another six days of rest, and so on. That way, they managed to rejuvenate the mouse, which then lived longer. However, this hasn’t been done on mice with a normal lifespan yet.
Such studies are ongoing. In that context, I’d like to mention what I said before about the onset of aging. If you remember, rejuvenation occurs during embryogenesis. But how does it happen? Is it the same process as rejuvenation through Yamanaka factors, or is it a completely different method? If we can find a commonality between the two rejuvenation methods, perhaps we can induce the same changes in regular human cells and thereby rejuvenate them. But that’s a prospect for the future.
That’s why it is crucial to comprehend the process of rejuvenation, but we haven’t been able to do that yet. Still, there are numerous labs now eagerly pursuing that subject, because if they succeed, it would be a significant scientific breakthrough.

— If there is considerable scientific interest, there should also be interest among journalists and popular science authors, right?
— In the U.S., I get interviewed whenever significant articles are released. However, I feel that in the States, there is a larger gap between scientists and the general public than in Russia. In Russia, there seems to be a higher number of journalists and individuals involved in communicating science. Maybe it’s because I’m originally from Russia, so they interact with me more. It seems like there is a smooth transition between scientists and non-scientists without any huge gap.
I believe that Russian journalists are doing an excellent job covering this subject. In terms of books, David Sinclair has written a book titled Lifespan: Why We Age – and Why We Don’t Have To. In it, he discusses aging in popular science language, detailing his journey in aging research.
In Russia, I was particularly impressed by Polina Loseva’s book. It turned out to be very good.