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John Guerin

it won’t select against longevity.

David: So we don’t know if these animals are simply aging more slowly or not at all? Since we have haven’t found any rockfish or whales that live for three or four hundred years, that might suggest that there is a certain limit on how long they can live.

John: 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. Ecologists then assume 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 optimum nutrients and 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 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.

David: How might studying ageless animals help us to understand human aging better?

John: 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’s two major problems with studying long-lived animals. One is that nobody knows what causes aging. If we were able to say what causes aging, then we could target that same factor in animals that are living a very long time–whales, rockfish, sturgeon, lobsters, and several other animals–and then study it. If you looked on our Web site you’ve seen that we did studies in everything from lysosomes to microarrays to telomerase activity, because you just don’t know what to look for. 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 longevity, so we were going to do a knockout gene. Then instead of living two hundred years a rockfish lives seventy-five years.

David: It would take quite awhile to run the experiment.

John: 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 approach 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 to 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’s 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 doesn’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. Actually there is perhaps one other instance–the naked mole rat. In the last few years it’s gotten a lot of 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 small mammals, and birds, of course, are their own interesting exception.

So comparing long-lived and short-lived rockfish is 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.

David: Could you talk about some of the principal investigators for the AgelessAnimal project, and can you summarize some of the latest research that’s going on with long-lived animals?

John: There’s fourteen principal investigators at fourteen different universities, 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 one 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 lysosomes and proteolytic activity, and she actually has done more than is posted 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 so that she intends to publish her manuscript. So that would be the most extensive study. Also, there’s Glenn Gerhard, an M.D. who was at Dartmouth who then 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.
David: Why do you think that the study of long-lived animals has been neglected for so long?

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 got 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 do not have cultures available. 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.

David: Has anybody done any studies to see if whale cells, rockfish cells, or turtle cells reach a Hayflick limit in the number of times that they can divide? Are their telomeres growing shorter with each cell division?

John: 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 the enzyme telomerase that allows cells to keep dividing.

David: When I interviewed Michael Fossel for this collection he thought differently.

John: I would have to say that the majority of gerontologists don’t believe telomere length is important in aging. 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 they are. The telomerase limit and the Hayflick limit doesn’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

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