Dr. Vera Gorbunova is a famous geroscientist who, for the last several years, has worked mostly on uncovering the amazing biological mechanisms that are responsible for the enviable longevity and resilience of long-lived species such as the naked mole rat. We talked about those feats of evolution and how they can be harnessed to increase human longevity.
How did you end up studying the biology of aging and long-lived species in particular?
It was a serendipitous occurrence. I wanted to study biology from very early on, probably from some time in middle school. I remember when I was at St. Petersburg University, we had a guest lecture dedicated to cell aging and the Hayflick limit. That concept seemed so fascinating to me, that there’s some kind of regulation of the aging process, and that it can be studied using cells and organisms. From that moment on, I was hooked.
I wanted to understand it. It was more of a scientific question for me: how does this work? I wasn’t able to start working on it right away because, at the time, there weren’t many groups working on aging. Even when I was looking for a group to pursue my PhD at the Weitzmann Institute, there was no one there who worked on aging, so I had to work on something else. But for my postdoc, I made a promise to myself to finally dive into aging. I joined the laboratory of Olivia Pereira-Smith, where we were studying senescence. Later, I worked with John Wilson on DNA repair and aging.
These were very interesting topics but more on the conventional side of things. Those groups didn’t study long-lived organisms. Somewhere in the second half of my postdoc, I started thinking about how to really address this question head-on, how to understand longevity.
I was somewhat disappointed with the existing models based on very short-lived creatures like worms, flies, mice and so on. Whatever we are trying to learn from them would be limited. We might be able to understand something but maybe not the mechanisms that we really want to find.
That’s when I got this idea to study long-lived organisms. We started with long-lived rodents because I thought, well, there’s the mouse, which is very well-studied. There are many tools available for it. What if we work with an animal that is similar, but long-lived?
Actually, the first rodent that we dissected in the lab was a beaver. Beavers live over 20 years. The official record is 24, but anecdotal evidence suggests they can live up to 50 years. From there, we moved to the naked mole rat, and I realized that it contains a treasure trove of information about the biology of longevity. This is what I have been doing until this day.
We don’t really know the actual maximum lifespan of long-lived species, right?
Yes, the definition of a maximum lifespan is the longest lifespan documented for any individual of the species, so it’s difficult to say whether we know with certainty that this really is their maximum lifespan. This could be said with confidence for species where many individuals were followed from birth to death. Hence, this is something that we know for humans and mice, even though, for humans, there’s still some debate. But for most less-studied species, we probably underestimate their maximum lifespan.
For the naked mole rat, this is currently 41 years. Those numbers come mostly from the colony of Shelley Buffenstein, because she studied those animals for a very long time, and that’s how long she kept them. However, most lifespan figures for other species come from zoo records.
Which traits or abilities of long-lived species do you personally find most fascinating?
I think the most important one is that all these species are not just chronologically long-lived, but they also stay very healthy, because to live for a long time, and especially to survive in the wild, species must be able to avoid getting sick. Their longevity comes with resistance to most age-related diseases.
This is really important, because whatever mechanisms we find there will be associated with better health. When people perform screens on short-lived organisms and find something that allows these organisms to live longer, this perturbation often comes with negative side effects. But whatever we find in naturally long-lived species comes hand in hand with better health, because it was optimized by millions of years of evolution.
What do you think are the evolutionary reasons for some species developing those superior anti-aging mechanisms, but not other species? Why can’t we humans have nice things like superior double-strand break repair or antioxidant protection?
In a nutshell, longer lifespan evolves in the conditions where it’s beneficial. Many long-lived species have particular traits that protect them from accidental death due to predators or other environmental factors. If an animal lives in a certain ecological niche where it can live longer, it will evolve molecular mechanisms to support this long life.
For example, for a mouse, there’s no point in evolving longevity mechanisms, because it just can’t live very long, it has too many predators. But many long-lived species will either occupy particular ecological niches where it’s difficult for predators to get them, or they are very large, or they have a hard shell, etc.
This is, in general, where longevity evolves. What particular mechanisms start to be regulated in any given species is a more difficult question, and maybe there’s some level of randomness here. It’s whatever is available. For instance, in naked mole rats, we discovered hyaluronan that seems to protect them from cancer. Recently, it dawned on us that it’s a common trait for subterranean animals. It seems important for those living in subterranean tunnels, probably because hyaluronan makes the skin stronger and more flexible.
So, it’s sort of a side effect?
Yes, you might say so. Animals already had this upregulated, and it came with an opportunity to evolve a longer lifespan, so this trait became co-opted. You mentioned double-strand break repair, which is quite interesting, because this seems to be a conserved feature of long-lived organisms. Basically, any organism that is long-lived would have very good double-strand break repair.
Maybe we can classify all those longevity mechanisms into something more “private” that evolved only in certain lineages and something that is more conserved, that we keep finding again and again. DNA repair would be in that second group.
That’s what you are mostly working on, right?
We are interested in both types of mechanisms. It’s really fascinating to find conserved mechanisms, and it also means that if we manage to tweak it, it should probably work across species, including in humans. Although, a word of caution would be that if it’s already upregulated in all long-lived species, and humans are quite long-lived as we are, it would be difficult to make it work even better, because we already have it quite optimized.
Right, we tend to forget that we humans already are a long-lived species.
Yes, we are quite privileged in this regard.
Still, many species have far superior mechanisms, such as a more effective SIRT6, which is something that you study as well.
Yes, while our SIRT6 is already quite good, we probably can make it work even better. We are currently studying what probably is the longest-lived animal, the bowhead whale, and we find that in many respects, it outperforms humans.
There are many factors that correlate with longevity across species, such as body size, the rate of mutations, epigenetic drift, retrotransposons. Do you think all those might be somehow related?
Those are definitely related. Let’s take double-strand break repair and epigenetic drift. Some enzymes that we study, such as SIRT6 that you mentioned, are involved in both, because to repair double-strand breaks, you need to rearrange the chromatin. These processes are happening at the same space and time. Aberrant double-strand break repair accelerates epigenetic drift, and recent work from Sinclair Lab reinforces this idea. This is something we keep seeing, because when we compare different types of DNA repair, double-strand break repair always seems to be the most critical for the aging process.
Retrotransposons are a part of the same epigenetic drift situation because they make up the majority of DNA in the cell. When they become activated, things really begin drifting away, because it disrupts transcription patterns in the cell and probably drives many age-related dysfunctions downstream, because when cells don’t express what they are supposed to express in each tissue, it leads to loss of function.
These three processes are very much related to each other, and this might be the most fundamental underlying mechanism of aging, when the epigenome gets disrupted because of double-strand breaks or because of retrotransposon activation. That’s when all other problems begin.
I was actually going to ask you about your thoughts on Sinclair’s paper where they claim that aging is caused by the loss of epigenetic information.
I really like it. I wholeheartedly agree with that. That loss of epigenetic information is probably what drives other hallmarks of aging. Which of the hallmarks are causal is a good question, and I’d say that epigenetic drift is probably the causal one, and it drives other dysfunctions downstream.
Can you think of a process of aging that’s unrelated to this?
People tend to assign a lot of importance to the accumulation of protein aggregates in some tissues, especially in the brain. Everyone who’s working on proteostasis would probably say – wait, but what about proteins? Damaged proteins have a very profound impact on aging. You can view it as an aging process that is separate from epigenetic drift, but people find more and more relationship between DNA damage, inflammation, and neurodegenerative diseases.
It’s difficult to say whether there are processes of aging that are completely uncoupled from epigenetic drift. It’s speculation at that point, but it seems to me that this is the causal one, and the rest can be linked to it.
Some evidence for this is provided by the fact that you can rejuvenate the cell completely by rejuvenating its epigenome. That happens repeatedly when a new life is conceived. You put the cell through the zygote, and everything gets restored to its youthful state.
Let’s move on to translation. All those superpowers that long-lived species possess look very tempting, but how can they actually be translated into humans?
There are many different avenues that are being explored. That’s what makes our field so exciting, because once we find and understand the mechanism, we can look for ways to target it. Right now, we are pursuing several of these directions, and maybe the most translatable is the one we found in the naked mole rat. People already use hyaluronan in the beauty industry for skin rejuvenation, or at least to make the skin look better, but we also see its anti-inflammatory effect. We generated mice with the naked mole rat’s hyaluronan synthase, and they live longer. Right now, we are looking for pharmacological ways to increase hyaluronan in human tissues, and this is a very straightforward path to translation.
Epigenome, DNA repair: how can we make it better? This is a bit more difficult, because hyaluronan is just one molecule. You increase its level, and things get better. DNA repair, on the other hand, is a process that involves multiple enzymes.
Looking at various ways to improve DNA repair, we found that among different enzymes involved in DNA repair, SIRT2 and SIRT6 can activate it very effectively. That was quite unexpected, because most other enzymes we tried just made things worse; after all, this is a process where exact balance is very important.
We found that SIRT6 can stimulate DNA repair, and then we found that long-lived species’ SIRT6 is more active. Even in human centenarians, we found a variant that was more active in certain ways, and it was improving DNA repair. Now, we are looking for chemical activators of SIRT6, and we actually found one, which is exciting. It’s a natural product called fucoidan, and it comes from brown seaweed.
Fucoidan is very safe, people consume it as food, especially in Japan and South Korea, two of the countries with the longest life expectancies. In preclinical studies, where we gave fucoidan to aged mice, it improved their frailty scores. So, we are very excited about this safe way to activate SIRT6, but we’re also pursuing other strategies, for example, gene therapies that may provide a much stronger SIRT6 activation and also can be targeted to particular tissues. It is ongoing research, but as you can see, it is possible to translate those mechanisms.
I didn’t know that you were also working on gene therapies for SIRT6 activation. Do you have any preliminary results or insights?
Like I said, this is ongoing, so I don’t have a lot of results, but we’re exploring this using different models and targeting different organs. Hopefully, we’ll have the results soon, but just based on genetic models of SIRT6 overexpression, we expect to see a rejuvenating effect, because if we simply overexpress SIRT6, mice live longer.
It’s not an easily translatable system, but if we can deliver SIRT6 and even express it transiently, we hope to see improvement. I can share one type of results, which is in cell culture, not in animals. When we overexpress SIRT6 briefly in cultured human cells, we see epigenetic age going down.
You have found that exposure to cold also improves DNA repair. So, should we all start taking ice baths?
Maybe. Of course, we have to be careful about it, because ice baths for someone who’s in less than perfect health might actually be detrimental. But there’s a lot of evidence that a brief cold exposure can have beneficial effects. We can see it in traditional folk medicines, such as cold-water swims that are very popular in Russia and in Scandinavian countries. It hasn’t made it into the mainstream, but right now, there are many scientific works, especially in sports medicine, that show cold exposure having a potent anti-inflammatory effect. The mechanisms were not very well understood.
We found that this protein called CIRBP, cold-inducible RNA-binding protein, which is induced by cold as its name suggests, also improves DNA repair. This is a very exciting connection, and cold exposure is something that many people can easily practice without any major complications.
Do you have human data to back it up?
No, the human data that we have comes not from our lab but mostly from observational studies. There have been small trials of swimmers versus non-swimmers where cold exposure was found to have generally beneficial effects, but nobody has measured its effect specifically on DNA repair. The DNA repair work comes from our cell culture studies, where we expose cells to cold and then we see an improvement in DNA repair.
In one of your talks, you said that calorie restriction works in both directions, upregulating both pro- and anti-longevity genes. We know that CR is a potent anti-aging intervention, so how does this square with this finding of yours?
You’re referring to a result from our transcriptomic study, where we established a signature of longevity based on about 30 species of animals, short-lived to long-lived, and we identified which pathways were more highly expressed in the long-lived species. Then, we used this transcription signature to evaluate interventions such as calorie restriction.
This way, we can identify interventions that can move our transcriptome towards those of more long-lived species. This doesn’t necessarily mean that this is how every intervention should work. For instance, you can tweak certain processes that make a mouse live longer but don’t necessarily make every other species live longer.
This signature is not absolute: it only tells us whether this particular intervention works in the same direction as the evolutionary process of evolving a longer lifespan. For instance, we found that rapamycin worked exactly the way we wanted it to work, meaning that it upregulated and downregulated the same genes that are upregulated or downregulated in long-lived species.
With calorie restriction, we saw that it worked both ways, which perhaps tells us that it has a more mixed effect. We know from mouse studies that, yes, it definitely extends lifespan, although even in mice, it works in some strains but not in others. Perhaps this reflects the complexity of this intervention. It may shape the transcriptome in some ways that are similar to what’s going on in long-lived animals, but there may be some detrimental effects as well.
Of course, the question is, does calorie restriction really work for lifespan extension in humans? Clinical data up to now seems positive, although less dramatic than what’s been observed in mice. It could be that for humans, the effect is less pronounced.
My explanation of it is that mice have a very fast pace of life. They live fast, they eat a lot, they reproduce copiously. We are somewhat slower creatures. So, maybe for mice, just slowing them down a bit with calorie restriction can increase their lifespan by a lot, while for us humans, the effect might be smaller. There probably is some benefit, clinical studies support this, but it may not be as dramatic as in mice.
Obviously, it’s not easy to work on long-lived species in a lab, but some prominent figures such as Steven Austad think that we really should be expanding our repertoire of lab animals with long-lived ones. Where do you stand on this?
First, Steve Austad is a great inspiration to all of us. I remember reading his review when I was just starting my lab, and I thought, this is exactly how I should address all the questions to convince people that this is the right way to go.
This process of introducing long-lived species to labs is already happening. I’m happy to say that my group contributed to that, because we demonstrated that by using long-lived species, we can actually identify molecular mechanisms. We’re not just doing some descriptive zoological work. We can drill down to mechanisms! This encouraged the field, and now, many more groups are moving in this direction.
Regarding the difficulties, it may not be that difficult, depending on what type of questions you ask. Because if you envision a naked mole rat or, if we go for an extreme example, a bowhead whale, used in the same way we use mice, it’s not going to work. You can’t do a lifespan study on a creature that lives 40 years, let alone 200 years.
You cannot breed transgenic whales or naked mole rats, but this may not be necessary, because the strategy we adopted is to use these long-lived animals as a discovery platform. We study them from the -omics perspective, we do cell culture experiments. We can also do some limited in vivo experiments in naked mole rats, which we can keep in a vivarium, but any further genetic characterization and manipulation is done back in mice. Once we find a candidate gene, we just move it into mice, where we can manipulate it. Then we can test whether it extends lifespan in a short-lived organism.
So, you still have to go through mice, with all their limitations as a model animal?
Yes, and that actually makes it convenient. Of course, we can try using different models, which is what Steve Austad advocates for. That’s something we’re always considering. But as of now, mice are still the most useful model with the largest toolbox available for them.
We do collaborate with people who use zebra fish or killifish, which is another vertebrate that is easy to manipulate, and you can keep a lot of fish in one tank, which makes large studies affordable. But if the whole idea is to find a longevity intervention and then test whether it can be used to increase lifespan in a short-lived organism, mice are the ideal way of doing it. Then, if it works in mice or in killifish, we can start thinking about doing the same in humans.
Neurodegeneration is one of the most important processes of aging in humans. Do long-lived animals experience it too?
We don’t know a lot about that, because to study neurodegeneration, you must have access to aged animals. Especially when you’re studying wild animals, aged animals are very rare. We mostly deal with young adult animals.
For naked mole rats, because they are kept in research colonies, people observe that they do not develop similar signs of neurodegeneration as we humans do. Their brains don’t seem to form similar plaques and tangles. Although their amyloid-beta sequence is such that it should be prone to aggregation, it is not. That means they have some mechanism that helps them avoid it.
Right now, we’re doing something quite interesting: we’re developing a new model of neurodegeneration using a rodent that’s somewhere in the middle in terms of lifespan. It’s called the degu. Some people keep them as pets because they are cute and smart, but at a fairly early age, around five, they begin to develop dementia. They come from South America, Argentina. So, researchers in Argentina were the first to notice that these animals develop Alzheimer’s-like dementia.
We acquired several degus and we’ve been breeding them for the past four years, because they may be a great model of sporadic Alzheimer’s disease. All mouse models don’t reflect sporadic Alzheimer’s, which is a big reason why interventions are so slow in coming. We just don’t have good models to test them on. Whatever works in these mice doesn’t translate into humans, because the disease etiology is different.
Do you have any preliminary data from your fucoidan trial?
The human trial is ongoing, we’re recruiting patients, so there’s not a lot of data as of now. In the mouse trial, we observed a quite significant reduction in frailty scores in aged mice. We started at 14 months of age, and the effect still was impressive.
Do you or will you have data on lifespan from these mice?
There is a trend towards a longer lifespan, but I’m careful to say that, because we’re not powered enough for a proper lifespan study. But we’ll have data, and I hope it will reach significance. We started with only 20 animals of each sex, so that might not be enough, but we do see a trend.
As a veteran of geroscience, what do you think about its current state? What do you find exciting or maybe disheartening?
Right now, the field is growing so fast. It’s just blooming. Ten, twenty years ago, we started with some foundational discoveries showing that aging can be genetically controlled and manipulated. Then, there was this era of model organisms. Now, it’s moving towards long-lived species that are becoming generally accepted as models for longevity studies.
There are also many interventions in development. We see new startups popping up very quickly. Finally, I see that society as a whole has realized how important aging research is, and that this is the proper strategy to address many health issues instead of going after individual diseases.
This is a great time. It excites me a lot. Those epigenetic therapies that we just discussed are very promising, because if we can find a way to address the underlying cause of aging, there’s huge potential there. I think we’re coming close to that.
I remember that at our conference last year, Ending Age-Related Diseases 2022, when answering a question from the audience, you said, and I hope I’m not misstating, that we will have anti-aging therapies in about 20 years from now.
Frankly, I don’t remember what I said back then, but I think 20 years actually sounds too long. I would say therapies may be available in the next five years. The question, of course, is the magnitude of life extension they will provide. After all, interventions that can give a small but significant lifespan extension are perhaps already available, such as certain lifestyle modifications that are based on large epidemiological data. If we are talking about pharmacological interventions, I would say, we should have something broadly available in five to ten years from now.
