Steven Austad, Ph.D.

Isaac Newton once said, “If I have seen farther, it is because I have stood on the shoulders of giants.” Today’s biomedical researchers might put a modern spin on Newton’s observation by saying something like this: If they have come further in understanding the mechanisms of human biology, it is because they have stood on the shoulders of a few lowly animals.

Indeed, much of our knowledge of the aging process comes from a menagerie of creatures that would seem, at first glance, incapable of shedding any light on the subject of Homo sapiens. And yet most of what scientists know about the genetics and biochemistry of human aging comes from a relatively small number of laboratory animals.

The question remains, however, whether human aging can ever be fully understood by studying organisms that (1) are not long-lived to begin with and (2) are several hundred generations removed from life in normal wild conditions. It is this question that inspires Steven Austad, a professor at the Barshop Institute for Longevity and Aging Studies and the Department of Cellular and Structural Biology, University of Texas Health Science Center, to include a variety of non-traditional animals in his research into the aging process.

Dr. Austad participated recently in the Why We Age scientist-luncheon series organized by the American Federation for Aging Research. His presentation at the event focused on what the natural world can teach us about improving health and extending life. Here, Dr. Austad talks to Infoaging in more detail about this theme and what the near future of aging research may reveal.

Infoaging: Due to practical, clinical or regulatory issues, non-primate animal models have become one of the most important tools of aging researchers. What animals are traditionally used in aging research? Why are they chosen?

Dr. Austad: The main animals that are used include Caenorhabditis elegans, a roundworm found in soil, fruit flies, and mice. They account for more than 95 percent of papers on aging research, mainly because we know so much about their genetics and how they develop. They are also very short-lived, even for the group that they’re in. Caenorhabditis elegans, for example, is short-lived by worm standards. And fruit flies are short-lived by fly standards, and mice are short-lived by mammalian standards. This is important because in a certain type of aging research, scientists follow an animal through its whole lifetime to discover clues about the aging process.

Interestingly, the prevalence of mice in aging research is really a historical accident. In the 1920s, the fancy mice kept by hobbyists were discovered to get lots and lots of cancers, which made them ideal subjects for cancer research. As they got used more and more in biomedical research, they became extremely well characterized. Eventually, they supplanted rats as the mammal of choice in aging research. Rats were useful because they had bigger organs — bigger hearts and bigger brains — that were easier to manipulate in certain laboratory techniques. We’re now so successful at miniaturization that it’s no longer necessary to start with large tissue samples.

Infoaging: These “usual suspects” have advanced the field tremendously, but your work suggests that they have also limited what we can learn about aging. What are the limitations of using short-lived organisms, such as worms or fruit flies, in studies of the aging process?

Dr. Austad: Well, maybe nothing, but maybe a great deal. There’s a certain faith in the idea that all aging processes are the same, even across disparate species. If this is true, then understanding the mechanisms of aging in worms or flies should automatically translate into something that is informative about controlling human aging. It may be that the processes that allow you to make a worm go from living two weeks to living four weeks are completely different than the processes that would allow an animal that lives decades to live any additional days. It could be that they’re totally different. If so, none of the mechanisms that work in worms or flies or mice would be relevant to humans. It strikes me that we need at least a few animals that are already successful at aging. If they’re doing some things already that are better than what humans are doing, then that might provide a new type of approach to finding therapies that slow aging.

Infoaging: What nontraditional animals have you studied? Why did you choose them?

Dr. Austad: I have chosen a series of animals that are exceptionally long-lived for their metabolic rates and an equal number of animals that are particularly short-lived for their metabolic rates. By comparing what goes on in young adults in long- and short-lived species, we hope to get a hint about what an animal has to do to be really long-lived. The long-lived animals we’ve been focusing on are bats, which can live up to 40 years in the wild; several birds, which live a couple of decades; the naked mole-rat and squirrels, which are rodents related to rats and mice but which live eight to 10 times as long.

Using many different animals is important because it allows scientists to ferret out what’s general and what’s specific. In other words, it’s very likely that there are going to be processes that are common across species and others that are idiosyncratic.

Infoaging: What generalities have aging researchers discovered?

Dr. Austad: The one thing that seems to hold across species is that animals that are long-lived are better at repairing their DNA. That seems to be something that’s pretty general because we find it across a whole range of species.

One generality — that animals with high metabolic rates live shorter lives — has actually turned out to be untrue. It was a reasonable assumption because the very processes that make energy in an organism’s cells produce free radicals that can cause damage. If those internal processes occur at a faster rate, it seemed logical to assume that they caused more damage. It was really quite a surprise — and exciting — to find animals with high metabolic rates that are such dramatic exceptions.

Infoaging: Some of your most notable work involved studying aging at the organism level, yet your recent work focuses on cellular and molecular mechanisms. Will aging researchers continue to learn from organism-based studies, or will all of the action in the future be concentrated on cellular and sub-cellular activity?

Dr. Austad: I think it’s going to require both. Let’s imagine that we clarify a specific kind of DNA damage that, when repaired quickly, is always associated with long life. In order to really demonstrate the impact of that DNA repair mechanism, you’re going to have to do some kind of experiment to see how long an animal lives. The various cellular and molecular processes scientists study are just tools. They still have to go back to the whole organism and see how well the tools work.

Infoaging: What about experiments with animals in their natural habitats versus animals in a highly controlled environment?

Dr. Austad: There have been two studies that show mice taken from calorically restricted colonies die at a higher rate if they get exposed to certain infectious organisms — certain bacteria or viruses. If that turns out to be an inevitable consequence of living longer by caloric restriction, then we might want to rethink developing drugs that mimic this effect. In fact, it’s always good to remember that living conditions for laboratory animals are quite different than those encountered by animals in the wild. The longest-lived mice are dwarf mice that live 75 percent longer when given a calorie-restricted diet in a controlled environment. If you put those same mice out in the fields around my building, they wouldn’t last a day. In laboratory conditions, they live longer, but in the real world, they wouldn’t stand a chance.

That’s why we’re so excited about the bats and the birds we study. We know they live a very, very long time in the wild. These are not animals that are crippled in some respect that just happen to live a long time in ideal conditions. These are animals that live a really long time under real conditions.

With all of that said, it’s important that we find out what’s happening in the cells of these animals. They have a certain design that makes them live longer, and we need to know the details of that design. Those details can only be revealed using tools and techniques available in the controlled environment of a laboratory.

Infoaging: One of those tools is genome sequencing. What is genome sequencing, and what is it telling us about aging?

Dr. Austad: It’s the process by which scientists determine the gene sequences for the entire genome of a particular organism. The rate at which a genome can be sequenced is increasing because scientists are getting so good at it. In fact, there’s a contest, known as the X PRIZE, for the first team that can build a device and use it to sequence 100 human genomes in 10 days or less. Many predict that this will happen in the next decade, making research for people like me even easier. If I want to inhibit the activity of a certain gene to see the effect, I need to know what the nucleotide sequence of that gene is. I would also need to know specific gene sequences to conduct DNA micro-arrays, which are tests that enable scientists to look at which genes are active or inactive at the same time.

Infoaging: Are scientists working to sequence the genomes of other animals?

Dr. Austad: There are 40 species being sequenced. There’s a group in Boston that is sequencing the little brown bat genome and another doing the marmoset. We’re going to be getting at variation in the marmoset sequence, which represents the next level of genome sequencing — to identify variants of genes and try to associate those with different processes. For example, we already have the dog genome. Now we want to know why small dogs live twice as long as big dogs. They have the same genes, so the difference must be related to variations in the genes. That’s a problem that’s not being attacked right now. But we should be able to figure that out in a reasonable amount of time with the appropriate funding and motivation to do it.

Infoaging: Where do you think genomic sequencing will take aging research in the next five or 10 years? What sort of things do we hope to learn?

Published: November 2006

Read More Ask the Experts