If we’re going to find robust solutions for aging, we may need more than mouse models — argues the University of Alabama at Birmingham’s Dr Steven Austad.
So a New York City cab driver, a newspaper reporter and a big cat trainer walk into an interview with Longevity.Technology…
From a UCLA English Literature grad, to a taxi driver, reporter, then onto a wild animal trainer for TV and film, the arc of Dr Steven Austad’s picaresque career trajectory eventually finds its inflection point at a PhD in Biological Sciences at Purdue University.
After earning his PhD, Austad began a three-decade career in evolutionary and zoological research. It was in the late 1980s, while conducting field-work on opossums near Sapelo Island, that he discovered marked differences (of 25%) in the forest-dwelling marsupial’s lifespan depending on its exposure to predators.
This, and the fact that opossums lived aberrantly shorter lives in comparison to animals of a similar size (up to a slender two years of age in the wild and four in captivity) drove Austad to investigate the various evolutionary strategies animal biologies have adapted to fend off the symptoms of age-related decline. As examples, Quahog clams (whose ingenious ability to prevent their proteins unfolding can see them living for more than 500 years) and freshwater creatures called hydra (who, given the right environment, can express genes that make them effectively immortal) feature prominently in Austad’s research.
Just as many anti-aging therapies are, for the first time, attempting the translational leap from mice to humans there is a growing awareness in the aging community of the need for other models. With this in mind we spoke to Austad — now a distinguished professor and department chair at the University of Alabama at Birmingham’s Department of Biology, as well as the scientific director of the American Federation for Aging Research (AFAR) — about his insights into new and old animal models for aging, rapamycin, the TAME trial, and his ‘lifespan bet’ with fellow gerontologist Stuart Olshanky.
Longevity.Technology: What motivated you to study aging through the lens of comparative biology? Why not, like so many other researchers, just study it using mouse models?
Steven Austad: It’s because I come at it from a different background. I didn’t come from a laboratory-based background, but from one in evolutionary biology.
And, in fact, I got started in aging research because of some of the things that I discovered, quite accidentally, about opossums. They age so quickly for an animal of their body size. So I’ve always been thinking about that from a comparative background.
It’s led me to feeling quite doubtful about our current mouse/worm/fly approach to aging research. Simply because they all are demonstrably unsuccessful at aging. And all that we’re doing in our various studies is making them slightly less unsuccessful. Humans are one of the longest living mammals, so we’re already pretty good at aging. I have serious concerns that what we’re finding in mice will have limited relevance when translating it to people.
Longevity.Technology: This is a problem a few researchers are picking up on now. We’ve been told that mouse models are good for other areas of research, but for aging they can be ineffective. This could even bias the current crop of aging therapeutics to be predominantly metabolic in their roots — because the lab mice suffer from metabolic problems. What’s your take?
Steven Austad: What we’ve done is we’ve taken all mammals and we’ve represented them with the, uniquely, short-lived, fast-breeding mouse. And, from a comparative perspective, the mouse couldn’t be more different from a human being.
I’m currently working with people who advocate bringing back the rat. There are observations made from studying rats that raise lot of questions for our mouse findings, and they should because the two species are so closely-related.
One of the most robust age-related findings in mice is that if you activate the growth hormone, it will lengthen life and improve health. But the one study that’s been done in rats shows exactly the opposite result. That’s the kind of thing that concerns me. And not only is the result the opposite, but everybody ignores the result!
Longevity.Technology: There are a lot of exciting results in the mouse models about to enter human trials. With people ignoring contradictory results as you say, do you think we’re going to see a lot of failures?
Steven Austad: That’s where we are right now. There are a whole bunch of things that are primed to be tested in humans. I don’t know if they will fail, but my concern is that if a bunch of them do, just like the many Alzheimer’s trials that failed, then people won’t take a lesson from that — they’ll just keep doing more and more. The Alzheimers field tells a cautionary tale, they’ve had 400 successes for Alzheimer’s treatments in mice, and none of them have worked with people. Yet they keep doing the same thing. It’s strange.
Longevity.Technology: So let’s look into this. What would you say mouse models are good at investigating in aging? And what are they bad at?
Steven Austad: I think mouse models are quite good at studying fundamental cellular and metabolic processes. I don’t think they’re good at other things. It’s questionable how good they are at predicting therapies that are going to translate to humans. In the cancer field, the translational success rate is about 1/10. What about for Alzheimer’s? More like 0/300. So where does that leave us in aging? I’m hoping it’s going to be more like cancer, because at least mice get cancer. Mice don’t get anything like Alzheimer’s disease; unless we modify them genetically a great deal and create a very crude caricature of the disease.
Longevity.Technology: You’ve said before that animals larger than us would be more suited to studying cancer. Why?
Steven Austad: If I were to pick an animal to study cancer resistance in, then I would choose a large one, like a whale or an elephant. They have thousands more cells than us, and each one is at risk from cancerous mutations for a long lifespan. Elephants get around that with extra copies of the TP53 gene, that seems to be their trick. But that doesn’t seem to be what whales do.
We simply don’t know if there’s one, two, six or hundreds of ways to slow aging in nature; so there could be as many undiscovered ways of doing it in people. Elephants, whales, even clams, have all developed their own unique tricks and strategies for this. There are many things to learn in the natural world. Evolution has had several billion years, and trillions and trillions of opportunities, to experiment.
Longevity.Technology: So why is the rest of the field not following your advice? Is it the time it would take to study other models? The costs involved? Or are we seeing the field shift?
Steven Austad: I think the reasons that the mouse, the worm and the fly dominate the field is that the biology you can do with them is really neat. They’re well understood, so the stuff you can do with them is a lot sexier than, say, bashing the genome, or the cells, of these long-lived animals and trying to understand what’s going on.
Longevity.Technology: So what would force researchers away from the exciting stuff and back to the fundamental biology?
Steven Austad: What will really change this, is if we have a series of high profile failures. A good example might be something like rapamycin, which has had these dramatic effects in mice, not just for longevity, but all kinds of beneficial effects. And if we did a trial like that in humans and it was a complete bust, and then more busts followed from other therapeutics, that would really open up Pandora’s Box. I think people would be forced to rethink the fundamentals of how they do research, just like what’s going on in the Alzheimer’s field now.
And if the mouse models turn out to be very predictable, that’d be great! I’m just concerned that we’re betting everything on them right now.
Longevity.Technology: Would you say that a bust like that is is around the corner? You talk about rapamycin, but it seems to be performing fairly well in people. Is there something we’re missing?
Steven Austad: I agree. The rapamycin vaccine trials have been very promising. If I had to predict the one thing that would be quite different between us and mice, it might be the immune system. But at least at the level of vaccine response, it seems to be translating very well. I’m not dogmatic that mice are not going to work out. I’m just concerned, that if we put all this effort into it, and it doesn’t work out that we’ll have lost a lot of valuable time.
Longevity.Technology: You started out with opossums in Venezuela and you’ve looked at protein-folding that fights cancer in elephants. What other models are there out there?
Steven Austad: One of the most interesting is the naked mole rat. It lives 10 times as long as a mouse, and 1/3 or 1/4 as long as a person. And yet they’re the size of a mouse! So there’s something really interesting going on there, and a lot of interesting research coming out of them.
I think the mouse lemur, and a lot of other short-lived primates, are going to make for interesting intermediate ways to test therapies that have been first developed elsewhere. Because with them you can test in just a few years, but in humans it’s really going to be much longer.
Longevity.Technology: Do you see the development of intermediate models as a way of avoiding translational crashes, like we’ve seen with Alzheimer’s?
Steven Austad: I’m a big fan of the TAME trial for this reason, simply because the most promising results come from human work, not from mouse work. The effects of metformin in mice are marginal, at best. But the way the TAME trial is going to work is we’re going to give it to people who’re already old and reasonably sick. What a lot of people are more interested in is giving these drugs to healthy people and keeping them healthy for longer.
But you can’t get the permission to give drugs to healthy people, so that’s where these intermediate models come into play. If you could take a healthy mouse lemur, marmoset or companion dog and show that you can keep a healthy animal healthy for 50% longer, I think you’re much closer to being able to persuade regulatory bodies that we can safely attempt the same thing in people.
Longevity.Technology: How developed are these intermediary models? Do we know enough about them yet to use them clinically?
Steven Austad: They’re still developing. The mouse lemur and the marmoset have been around for years, but they haven’t been used for aging research.
Using something for aging research is a lot different. Suddenly, the husbandry (the way you take care of the animals) becomes extremely important. If you’re using animals to test a cancer drug or a stroke drug, then you don’t really need to care how healthy they are as you’re probably working with relatively young individuals.
I think the most promising animals are dogs if we’re looking to develop something straight away. We know so much about dogs. I would argue we can do health exams for dogs almost as well as we can for people. The current rapamycin trial in dogs is the way of the future. And that’s not to say we’d use them to develop new things, but as a basis for intermediate testing.
Longevity.Technology: In an interview with the Buck Institute’s Kris Rebillot, you spoke about antagonistic pleiotropy in aging. In mammals, for instance, we observe a balancing act between fertility and longevity. Being as we don’t fully understand this, how do we design interventions that make us all live longer without making us, say, infertile?
Steven Austad: I think the answer is to begin the therapies when people are no longer interested in reproducing.
One of the real revelations to come out of mouse model trials is that a lot of our therapies have more powerful later life effects than any of us ever suspected. We’ve always assumed that the sooner things start the the bigger the effect will be, but for rapamycin that’s not the case. If you start rapamycin on a mouse of advanced age you get the same effect as you would on a younger mouse.
My biggest concern is not the reproductive side effects, those are easily managed, but that there may be other antagonistically pleiotropic effects. We don’t know, for instance, if these drugs could make you more susceptible to infectious diseases. That would be a really serious side effect. Your muscles, your lungs and your brain and stay healthy for longer, but when the next flu outbreak comes around — you die. That’s more what concerns me.
Longevity.Technology: Is there anyone doing any serious studies of pleiotropic effects?
Steven Austad: No! People really like to ignore these things. Just like they ignore that mice may not be the best model. When in doubt, just ignore the potentially disturbing complication. I’d say this is pretty much completely ignored.
Again, it’s a great reason to look into dogs. With dogs we can assess this really well, we can very precisely monitor their health. We’d see them being more exposed to infectious diseases and we’d be able to stop it. Dog studies are really great for staying alert to, identifying, and then catching early, any detrimental side effects.
Longevity.Technology: And finally, what about your bet with Stuart Olshansky, is that still on?
Steven Austad: Oh yeah, it doubled in 2014, so its $1bn now. I’m confident I’ll still win it. Even if we say that average human life expectancy is 100 years by then, it will still happen because it still only needs to happen for one person. As skeptical as I can sound, what makes me a bit more optimistic are the sheer number of promising leads. Sure, 90% may not work out, but that still leaves us with some real possibilities.