By David Jay Brown
John Guerin is the founder and director of the AgelessAnimals Project—also known as the Centenarian Species and Rockfish Project.
This long-range research project involves investigators at fourteen universities around the world who study animals that don't seem to age.
There are certain species of rockfish, whales, turtles, and other animals that are known to live for hundreds of years without showing any signs of aging—a phenomenon known to biogerontologists as "negligible senescence." No one knows for sure how long these animals can live for, but we know that they can live for over two hundred years without showing any observed increase in mortality or any decrease in reproductive capacity due to age. Striking examples are a 109 year old female rockfish that was captured in the wild while swimming around with fertilized eggs, and a hundred-plus year old male whale that was harpooned while it was having sex. The purpose of the AgelessAnimals Project is to understand why these animals don't seem to age and then to apply that understanding to human longevity.
Guerin is an experienced project manager, who conceived of the AgelessAnimals project and orchestrates all of the studies. The two principal advisors to this project are Dr. Leonard Hayflick and Dr. Aubrey de Grey, both of whom were also interviewed for the Mavericks of Medicine collection. Dr. Hayflick, discoverer of the "Hayflick limit" of cellular senescence, states that "Guerin's project is not only unique, but probes an area of almost total neglect in biogerontology, yet an area with more promise to deliver valuable data than, perhaps, any other."
When I asked Dr. de Grey about the importance of studying ageless animals he said, "All organisms with organs that rely on the indefinite survival of individual non-dividing cells (such as neurons in the brain) should age, though some, including humans, age very slowly. Some species do even better—we cannot yet measure their rate of aging at all—and studying them may well reveal ways to slow our own aging."
In addition to coordinating and orchestrating the AgelessAnimals project, Guerin lectures regularly on the subject of ageless animals. To find out more about Guerin's work and the AgelessAnimals Project visit their Web site: www. agelessanimals.org.
John Guerin seemed eager and excited to discuss his project with me. We spoke about some of the latest research that's going on with long-lived animals, why this type of research has been neglected for so long, and how studying ageless animals might help us to understand the aging process better and extend the human lifespan.
John Guerin: Back in 1995, I began looking into biotech, biogerontology, and the studies of aging. I read many different books, articles, and scientific papers. The turning point came when I read Dr. Leonard Hayflick's book How and Why We Age. Dr. Hayflick had a chapter called "Some Animals Age, Some Do Not," and I thought, wow, now that's interesting. I'd heard rumors and old wive's tales about how some animals live for an extraordinarily long time, but this was the first time that I had come across that information from a scientific source. So I started doing some research on long-lived animals, and I found out that there's very little known. On my web site, I have some references available.I met Dr. Hayflick at a Gerontological Society of America meeting in November of 1995, and I told him about my project management background.
I said I'd like to join whoever is working in this area, and I asked him who is. His answer was, "Nobody is, but they should be." So I tried to get something going on my own. I did a lot of research on different animals. I spent about a year looking at koi—the fancy Japanese carp—and it's very likely that they do live quite a long time, at least over fifty years. They were reputed to live over two hundred years, but the readings were based on scales, and those are not accurate. So they didn't turn out to be a good candidate to study.
Then in 1997, I got some data from the Alaska Fish and Game. There's a chart at the bottom of my Web page with a rockfish on it that shows ages for different rockfish that were caught off the coast of Alaska, and the range is between twelve and 107 years. Now, that's a randomly caught sampling—it wasn't like they were trying to get older individuals.
Those were the ones that fishermen caught and were going to people's dinner tables that evening. So when I realized that individuals at those ages were available, I became very interested. We got samples from the Alaska Fish and Game in 1997. I say "we" because by then I had a couple of researchers at Oregon State University and the Linus Pauling Institute interested in looking at the rockfish. So the Alaska Fish and Game sent us five older rockfish. After we aged them, it turned out that the the youngest rockfish that they sent us was 79 years old, and the oldest was a 109 year old female that still had eggs.
John Guerin: Yeah, and kind of sad. It's like, how long would this fish have lived if it wasn't caught? It didn't die of old age. It was fertile and still going strong in the ocean at 109 when they caught it. So that helped us to focus the project on rockfish. We have had one study on turtles. Whales are a very fascinating subject too, because they're warm-blooded mammals like we are, and they've now been documented to be over two hundred years of age.
John Guerin: Quite simply, the goal is to understand the genetic and biochemical processes that long-lived animals use to retard aging. These long-lived animals have what's technically called "negligible senescence," as defined by Caleb Finch at the University of Southern California in Longevity, Senescence, and the Genome (1995).Q: What is negligible senescence?
John Guerin: Basically, this refers to an animal species that doesn't show any significant signs of aging as it grows older. Unlike humans and most other mammals, there's no decrease in reproduction after maturity.
There's also no notable increase in mortality rate with age, but that's a little harder to prove. I've been talking with a statistician and he's asking, how do you know? To do a study of this type would take a couple of hundred years to complete. But compared to us there's no noted increase in mortality rate. I mean, if you are ninety years old, you're much more likely to die next year then you are if you're only twenty years old. But we don't seem to see any increase in mortality with rockfish and several of these other animals over time.
John Guerin: The purpose of the project is to understand why, and how to apply it to extending the health and lifespan of humans. My background is in business project management; I have a project management professional certification. I'm not a bioresearcher, a biochemist, or a biogerontologist—but I'm the one who organizes it all, and gets everyone involved. I get the researchers the samples and all that.
Actually, I thought I had a better idea about why these animals have negligible senescence when I started this project ten years ago. But it's hard to say. Back then we didn't know whales lived that long. That whales can live for over two hundred years was just discovered in the last five years. Up until then we thought that humans lived longer than any other mammal. So why certain animals would live much longer than others, and much longer than we do as a matter of fact—pretty much double what we've known humans to live—we don't understand.
There are some people who think that this can't be so, that this would violate the evolutionary theory of senescence, because nature doesn't select for longevity. But that's not necessarily true, because what's commonly seen is that there's just such a high mortality rate in nature.
Even for humans, probably before two thousand years ago, we didn't live very long. We were hunted by tigers and wild animals, and traits of longevity, presumably, weren't selected for. But if these animals, like the rockfish, can be 109 years old and still be reproductive, nature is going to allow those genes to keep contributing to the gene pool, so that it won't select against longevity.
John Guerin: Well, we just do not know. We honestly do not know. It really is unfortunate that there is so little known in this field. Ecologists have never thought of this in the terms that gerontologists are now thinking of it in. To give you an idea, let's say you have a sample of a species, and you see they live to twenty years. That's the oldest you sample out of several hundred. Then that's their maximum longevity. That's really the basis of their thinking in most cases. Mice, as you probably well know, don't live for more than a couple years, even in the best laboratory environment, with all the best nutrients and all the best food. They don't live very long. They just can't. They'll start having all sorts of age-related pathological functions, and they'll die of old age.
But this other group of organisms, those that possess what Finch termed "negligible senescence," they don't seem to be showing the classical signs of aging that we're used to. So, who is to say the longest they could live? As an example, in Finch's book that was published in 1990, at that time the longest lived whale was—I believe it was a Blue Whale—something like 108 years old. That's like, okay, well that's not so startling. Humans live longer than that. We're mammals. They're mammals. We live longer. Then a study was done on bowhead whales, and they found that out of forty whales sampled, four of them were over a hundred years old, and one of them was over two hundred years old. And they didn't die of old age either—they were harpooned. I have a reference on the web site.
John Guerin: By understanding how other animals are naturally able to live a lot longer than we are, we can ask: What is genetically different? What is biochemically different? There are two major problems with studying long-lived animals. One is that nobody knows what causes aging. If you're able to say what causes aging, that'd be really easy then to target that same factor in animals that are living a very long time—whales, rockfish, sturgeon, lobsters, and several other animals—and then you could study it. If you looked on our web site you've seen that we did studies in everything from lisosones to microarrays to telomere-telomerase activity, because you just don't know. That's one problem. The other is that these animals live so long that you have to ask: How do you do an experiment? Let's say we think a certain gene's involved in aging, so we were going to do a knockout.
Then instead of living two hundred years a rockfish lives seventy-five years.
John Guerin: Yeah, it would be somebody else finishing it up, and it certainly wouldn't be of much practical benefit. So the direction we're taking in the project is we're looking at the difference between long-lived rockfish and short-lived rockfish. The other thing is basically identifying genetic differences, and going at it that way, because there's no practical way you could run an experiment that would go on for decades.
At first rockfish just seemed to be a good model, or a handily available model. They're commercially caught, go on the dinner table, and we were able to get lots of samples of them. Then, of course, the news about whales came out, which is very intriguing, and there are lots of other animals that are either known or suspected to live a very long time. But the really intriguing thing about rockfish is that in the same genus—which is sebastes—there are rockfish that have not been noted more than about twelve to twenty years maximum longevity, and these are essentially cousins. They are rockfish, and some of these at least have been caught in thousands of samples, so it's not just an aberration of a small sample size.
One of the key issues people have raised to me at meetings is that you have to have something to compare these long-lived animals to in order to try and understand why they're successfully retarding aging. So what better model can you have than another species within the same genus that don't live a very long time? In all the meetings I've gone to I haven't had anybody come up and say, oh here's another species that has a really diverse longevity. There is one kind of similar one—the naked mole rat. It's just in the last few years that it's gotten more publicity. It's a rodent, and most rodents—like mice and rats—live maybe two to five years maximum. The naked mole rat has been documented to live at least into its twenties. So it's on quite another order of magnitude different than other rodents. The bat is another exception that lives way longer than other mammals, and birds, of course, are their own interesting exception.
So that's our focus, which is almost out of necessity, because how do you design an experiment to test for longevity when you've got such long-lived animals? Whatever tests we're going to do to the long-lived rockfish in the future, like a micro-array, we want to do with the short-lived ones too.
John Guerin: There's fourteen principal investigators at fourteen different universities. There are some co-PIs involved as well, such as Dr. Judd Aiken at the University of Wisconsin, Madison. He's very well-known and respected in the field. He does mitochondrial mutation studies, and this could be one of the more important areas because of what we know about free radical damage. The oxidative theory seems to be of the more important theories of aging, so I'm encouraged, even though at this point he hasn't gotten results yet. His lab is working on amplifying the primers. So that could be a very important study. I think the microarray study is an important one too.
Dr. Ana Maria Cuervo, who's at Albert Einstein College of Medicine in New York City, did the most complete study. Her study was on lisosomes and proteolytic activity, and she actually has done more than is on the web site. She added some more tests that she didn't have available a couple of years ago, and she told me about a month ago that she was getting her manuscript ready to publish. So that would be the most extensive study. Also, there's Glenn Gerhard, M.D., who was at Dartmouth and then he took a full-time research position at a research institute in Pennsylvania. He did a SOD (superoxide dismutase) study and then also the microarray study.
John: I have thought about it, and partly I have to say I don't understand why. I think that's why somebody like me would get involved, because I have a project management background and I can see the big picture. There's more than one reason I can see as to why people in the field wouldn't have gotten involved. It's risky to put your career on the line to look at animals that haven't been studied very well and that there's no cultures available of. Whereas with other species strains are easily available. For instance, with any mouse you want you could get a strain, and you could have it under the identical conditions you need.
But this hasn't been done with any of these long-lived animals. For me, the biggest question really is: Why hasn't the National Institute of Aging taken a lead? This is a perfect opportunity for government to get involved, where there is no profit motive. This is basic research that we're doing with these animals, and basic research doesn't necessarily have a pay-back. Now, let's say we find something like we did with the SOD study. We had a very interesting finding that SOD went up with age in rockfish, and as you may be aware, SOD is the strongest antioxidant in our bodies, and in most animals. So that it goes up with age is a very intriguing finding. That's something we hope to look into more, but in general all of the things we've done are just basic science. We're just laying the groundwork.
John Guerin: In terms of the Hayflick limit, you very well may be aware that most gerontologists don't consider that to be a limitation of aging. At some point, maybe about ten years ago, it was a much bigger topic.
Nowadays, telomeres and telomerase is much more of a cancer issue, because most cancer cells keep producing that enzyme that allows cells to keep dividing.
John Guerin: I would have to say that the majority of gerontologists don't believe it that way. I remember at a meeting a couple of years ago, somebody just making an offhand remark that we used to think telomerase and telomeres were important. I think if you do a survey you would find that that the majority of gerontologists don't believe it that way. The telomerase limit and the Hayflick limit don't seem to necessarily be what it once was thought to be, because even older people have continued replication of the cells that do divide. There's a bunch of reasons that it doesn't seem as important now as at one point when they thought it was.
John Guerin: We have fourteen studies—twelve in the U.S. and two in Europe. One of the European studies is in Germany by someone named Guido Krupp, who looked at telomerase levels in nine different rockfish. He looked at three samples—one of heart, one of liver, and one of brain—all the way from teenage years up to a 93 year old rockfish. All of the three tissues showed expression of telomerase, and there was no age-dependent change of expression of telomerase in the tissues. There was individual differences. Some were higher and some were lower. One of the higher levels of telomerase was found in the 93 year old, but the primary finding was that there was no trend.
As far as whales go, the only other person I know outside our group and Caleb Finch at USC, who actually is studying these long-lived animals is a guy at the University of Texas in Dallas named Jerry Shay. He got some samples of bowhead whale, and he's basically doing these cell replications to see how many replications he gets out of them.
Apparently, it's pretty hard to get the samples, because they had to go through the Canadian government, and it was quite an ordeal. Jerry Shay is the only one I know of who's done bowhead whale studies. But in this one study four of the whales out of forty were documented to be over a hundred years old, and one of them was over two hundred years old. And that's without doctors. Although this was not in the paper, we know that at least one of those hundred-plus year old male whales was reproductive, because when he was harpooned he was caught in the act.
John Guerin: Yes, and it was over a hundred. There were three that were between a hundred and two hundred. One was 211 years old. When I talked to the researcher, who is an ecologist, I said, "Gerontologists want to know, how do you know that the whales weren't about to keel over, that they were on their last leg?" And then he has an example like this. I'm like, were they reproductive? And he goes, well, one of the males sure was.