Dr. Gordon Lithgow on the future of geroscience (part III)

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Photo Credit: Rick Goldwaser [CC BY 2.0], via Wikimedia Commons

Dr. Gordon Lithgow of the Buck Institute for Research on Aging spoke to us recently about the Caenorhabditis Intervention Testing program (part I) and the past and present of the anti-aging field (part II). Finally, we talk about the future of geroscience research, and learn the origin of one very special word.

What drew you to the aging field originally?

Curiosity. I think that’s where most of us start. Some people at the Buck are driven by the desire to not age, maybe about 5-10% of people come into biology research because of aging. I was into biology first. I was curious about life and especially molecular and cellular processes.

It was odd that I ended up studying aging, because in many ways aging is non-biology. Aging is not really an output of evolution, it’s kind of the garbage that’s left over after biology’s been in action. I got into it not really knowing that, just seeing a profoundly mysterious process that there was no papers on, as far as I could tell. There were specialist journals and you could get papers – back then, to read a paper you went to a library, or you got some inter-library loan and a photocopy sent to you from somewhere else in Europe, so getting access to things was difficult enough. But it was very obvious that there was no papers on aging in regular journals. The first one I saw was Tom Johnson’s paper in Science in 1990, which was just like a gee whiz moment – oh my god, there are mutations for aging? This is it, this is how we’re gonna study aging. So the self-same curiosity I had then is still here today.

In the last 25 years, we’ve got textbooks on worm aging, we have signaling pathways and hormones and so, so much, it’s great. But I still struggle to tell people what aging is. I tell them narratives about protein and protein insolubility during aging and how that could be driving dysfunction, but it’s still hard to really say to someone, “This is what aging is”. And now more than ever, beyond curiosity it’s this idea that while it’s been a great privilege to just be able to mess around and do science and find stuff out, actually what we’ve found out could be useful for people. And I didn’t turn my lab into a preclinical science lab or anything like that, although people in my lab are definitely interested in translation, but that’s definitely a motivating feature. It motivates the research somewhat, but also how I talk about the research, and my willingness to go off and do public stuff to try and turn people’s heads to thinking about this.

And it drives me crazy that we’re training a group of scientists who are very comfortable with the biology of aging and the idea that it causes multiple diseases, who are very comfortable moving from discipline to discipline as you have to do in aging research, working on Alzheimer’s one week and thinking about cancer the next, and unfortunately there’s no jobs for these people. So we have lots and lots of very talented postdocs who could do a way better job than me in running a lab and making new discoveries, and they can’t get jobs. And that’s a resource question, that’s federal funding. And it’s also philanthropy in this area and foundations, and all of it has to do better so that we can grow the field. Funding has been flat for 15 years in aging research. We had foundations like the Ellison Foundation that did a great job of funding aging research that went away, and they changed their priorities and they didn’t fund aging research anymore. They really did a great job of bringing people into the field. I don’t want sound too negative. We’re still here, the institute’s growing. It wasn’t for a while, but we’re gonna be hiring again and creating some new jobs, so it’s not like nothing’s happening, but compared to what should be happening, and what the science is telling us we should be doing, it can be a little frustrating.

Is industry a viable path for some of these scientists that aren’t going to be able to get a federally funded lab?

Definitely, definitely. We’ve seen our own people go to Calico and Unity, which is a spinout biotech from the Buck that’s doing very well. There’s been many false dawns of aging companies and aging biotechnology going back 15 or more years, but with Calico and Unity it feels different. It feels like they’re serious about finding cures to diseases based on aging technologies. And I hope they’re going to be big employers. They certainly have the capacity to be, and hopefully there will be a whole raft of new companies. Each of those 100 compounds in the freezers downstairs could be a company. That’s definitely one cause for optimism right now.

What do you thing the biggest obstacles are right now in the field more generally?

Funding at every level. Translation. We’ve got a lot of information and compounds that we need to move forward. Obviously those two things are tightly related. Funding also is at the heart of the inability to grow the field with these new scientists. It’s just so sad, people with fantastic skillsets leaving science or going into industry, and not in an aging context at all. That’s pretty disappointing, because we work hard to train people, and people work hard to get their papers and develop these skillsets.

I don’t think conceptually that there’s a problem. In past years we could have said that there’s a big problem because people don’t understand the evolutionary origins of aging, or problems in the past where people were very dogmatic about it being down to one mechanism or another. And there was literally a time when many people in the field thought cellular senescence was an artefact of the culture dish and couldn’t really be important in aging, because it didn’t happen frequently enough in animals. And now we’re at a point where we’re thinking no, chances are it’s really important. So a lot of the factions are melting away and you’re seeing much more unity in this paradigm of what aging is.

How did that come about?

Just evidence, just discoveries. It’s mainly animal work that’s broken down these things. There’s very little human data that’s really been helpful in that regard. If you think about the human population, clearly we’re not optimizing ourselves for health. If we were to pay strict attention to our diet, if we were to exercise, then as a population we would have some sort of squaring of the survival curve. We would obviously have less obesity and obesity-associated disease, and generally nutrition and especially exercise seem to be protective in just about every sphere of human aging and disease. I mean, what’s the recommendation of a neurologist for someone they’ve just diagnosed with Alzheimer’s? Exercise. So it’s true that we’re not optimizing ourselves, but it’s also true that laboratory animals are not optimized either. It’s not like we’ve systematically spent a long time working out the best possible conditions to maintain a colony of worms on a dish or a colony of flies or whatever.

One possibility is that most of the modifications that we’ve made or interventions that we’ve made are really just optimizing interventions. That they’re not really affecting the underlying biology of aging. It’s hard to draw a hard distinction between optimization and changing the underlying biology, but essentially all the models that we use, flies, yeast and worms, they all come from the same ecological niche of rotting fruit. They all have laboratory drift and we use lab strains that aren’t the same as wild strains, and during that process we may have been creating problems and shortening lifespan for years, and now all we’re doing is fixing some of those laboratory-based problems. That’s one view of a lot of what we’ve done.

If that were true, it would be a bit of a crisis. It’s certainly the case that we seem to be hitting some sort of upper limit with things. We don’t see lifespan being extended in mice by two- or threefold, like we’ve seen in worms. Even in flies we haven’t seen twofold life extension. It’s possible that we’re hitting limits in our ability to extend lifespan. I don’t know. We’ll have to look back and see if that’s the case. I hope not, I hope all these ideas of combination therapies will work out. There are some really nice genetic combinations in the worm that really do show that you can go further than individual mutations by combining mutations.

Do you think there’s an upper limit on lifespan?

You know, this is a funny argument, this one, because biologically no. There are clearly examples of animals that are aging much more slowly than us. We have clams living over 500 years, bristlecone pines that are living hundreds of years and things. In theory, we could all live to 122, because one human has done that. So in theory we can at least do that well, which is amazing in itself. In theory, there are mammals that live even longer than that, so we should be able to live longer than the oldest human. Clams have a circulatory system, there’s a beating heart, so if there are hearts on earth that have been beating for 500 years, why not our hearts? Well, maybe we could attain that, but maybe we need to be clams to do it. Maybe you make all the genetic changes required to live for hundreds of years and you become a bristlecone pine, you know?

So yes, I don’t believe in biological limits, because even in human life expectancy, every time someone says there’s an upper limit, someone breaks it. I don’t believe in limits of that sort, but how much you have to change the human condition to attain greatly extended longevity, I don’t think we know. And that’s why I don’t tend to make predictions about how long people could live if X, Y and Z happens, because I don’t know if we’d even call the result of those manipulations humans.

So it sounds like it’s harder to produce strong effects in more complex animals.

Yes, that’s certainly the empirical observation so far. And it could be because it’s just that the experiments in more complex animals are more expensive, so a tiny fraction of the experiments we’ve done in worms have been done in mice. It may be that we just haven’t hit on it yet. A really good example of this is the insulin receptor. In mice there are a couple of studies showing that if you hit the growth hormone axis you can extend lifespan. Now in worms you can double lifespan by hitting that same axis. But in worms we have looked at dozens of allelic variants of the insulin receptor gene, the DAF2 gene, and some of them aren’t very good for the worms, some of them shorten life. So maybe if we’d looked at as many allelic variants in mice as we looked at in worms we’d see the same thing, I don’t know.

It was argued years ago by Judy and Jan in a Nature piece that complexity itself is a reason to believe we will not be able to obtain large, significant differences in more complex animals. I appreciated the argument, but I felt that we have to do the experiment, you actually have to look at lots of the variants to know the answer.

And what is up next for you?

More of the same. I enjoy my job, which, as I say, is an incredible privilege. What I enjoy most is when I’m talking with my postdocs and my grad students and we’re poring over data and trying to work out what on earth is going on in aging. Sometimes when we do something, when we find an intervention, we don’t really know what we’ve done. We’ve got a compound that extends lifespan, and if only we knew what we had done there, we might be able to convince someone else that it’s worth following up on. We had no idea we were going to publish a paper on vitamin D, that came out of nowhere, and we said, “Well, we’re not gonna study that, because everybody studies vitamin D.” But we were curious about the mechanism in the worm, and the first thing you think is, well, vitamin D, bone health. Well, it’s not that. So we followed the mechanism in the worm, and it turned out to be really novel. It was affecting protein homeostasis, and that was novel to the vitamin D crowd, who looked at this work and went wow, that’s incredible, now they can think about what it means for human clinical trials with vitamin D and so on. So again, doing more of the same, finding additional interventions and explaining the mechanism, and going as deep as possible.

One of the biggest remaining mysteries is why aging causes disease, really diverse disease. And I think there’s a lot to do at the interface of disease and longevity. While I still want to push out lifespan, and I still want to find novel mechanisms of lifespan extension for its own sake because I think that’s telling us about aging, honestly the most important thing we could do is to take what we know and apply it understanding the connections with disease. There are a bunch of people I work with and people who work in my lab who are more seriously thinking about disease. And stress as well. I see aging as a long stress, and so the way that environmental change and fluctuations and stressful events impact aging is also a story of disease. So we’ve got a lot to do there.

Is there any advice you might give to a young scientist who is thinking about aging?

I think it’s great that there would be young scientists who are thinking about aging. There are still profound mysteries in this area, and I think that’s what you need when you’re embarking on a career. You want to be doing it for one of two reasons: either you want to help people, and that will get you up in the morning and get you to go look at worms and flies down a microscope for hours and hours and hours; or you’re just fundamentally very curious, and you just see a biological problem and you think, “We really don’t know what’s going on there,” and you want to know. And it could be that you want to understand cognitive problems during aging, or why cancer arises, or why young people don’t get Parkinson’s disease or any of those really strange questions. Why do clams live 500 years? What secret have they got? And can I be the person who finds that secret, and goes to a cardiology conference and gives a presentation on how it’s done, and finds out if we can augment human hearts in this way? So if they’re coming at it like that and asking big questions, I think that’s the way to go.

There are a bunch of people I know who are saying we should not be training any more graduate students, because there aren’t jobs for them. That we should be fundamentally downsizing labs to be doing science in a different way because of funding crises. But I think if someone is genuinely curious or genuinely wants to help people, they’ll find a way. They’ll find a way to have a career. There’s a whole generation of people running labs that will eventually, if our work fails, retire and die.

And if you look at it another way, if you say, what do we need? With the demographic change that’s happened, and the incidence of chronic disease that’s happening, and the expense it’s causing not just developed countries but countries across the entire world, what do we need? We need the biomedical world to embrace the necessity of studying aging, and there should be phenomenal career opportunities in this area. Forget today and the miserable things I’m talking about, just look at the need, and you realize that eventually governments and foundations and everyone else is going to go, “Oh my god”. The British government did this. Many years ago they prioritized aging at the highest levels for the research institutions, and they did it because the British government pays for healthcare, and they saw the numbers. Jack Rowe, the geriatrician, was giving a talk here a few weeks ago and he used the phrase “smell the demographics”. People will have to smell the demographics, and when they do they’ll make the appropriate investments. So I’m very optimistic for people beginning their careers now and thinking about aging. I think it’s going to be amazing because they’re going to see the entire biomedical world change in response to this research. So that’s the bigger picture, never mind that we’re struggling right now.

Is under-prioritization a problem in particular for the American biomedical field?

No, I think it’s true worldwide. I mean, the British government made that adjustment, but that’s not to say the British medical profession suddenly embraced a new worldview. No, I think this will happen worldwide. I’ve given a talk in the past where I describe someone in medical school, and the old professor is in the front of the room talking about diseases that she had to diagnose and treat when she was a younger doctor. And the students are like, “We don’t need to know about this stuff, I’m never gonna see Alzheimer’s disease.” And that world will come.

The profound change that will happen between now and then, it’s the same as what’s happened with infectious disease. If you go back a hundred years and you think about what we were obsessed with as a society in terms of medicine, it was tuberculosis, polio, german measles, mumps, syphilis. And there was an entire industry of infrastructure supporting those diseases, so you had people building iron lungs for polio, you had sanatoriums built all over the whole western world treating tuberculosis with nothing but sunshine. So you had an industry supporting the symptoms or the outcomes of the diseases, and it’s all gone now. The sanatoriums are all closed and demolished along with all the rest of it.

And it’s gone because of the realization that all of the diseases were caused by one thing, microbes. Once you make that discovery, you’ve got a general strategy: kill the microbes, or develop immunity to the microbes, and then it’s gone. Doctors still are taught about those diseases, but not in any great detail. It’s not like they’re actually going to have to diagnose small pox. So that’s the kind of change we’re going to see for chronic disease and aging as well, where these diseases will be taught as part of the history of medicine, not as something doctors are going to have to be faced with on a daily basis.

One last question – you coined a pretty important piece of terminology, and one we at Geroscience.com like a lot. Where did it come from?

I came up with the word ‘geroscience’ to describe the research that was going on between the biology of aging and age-related disease, because the words that we were using at that point didn’t seem to cover it. We weren’t doing geriatrics medicine. We hoped to impact it, but we weren’t doing it. We weren’t simply doing longevity biology. We were kind of doing gerontology, but gerontology is quite a wide view that encompasses social gerontology, care of the elderly and the insurance people, and we weren’t doing that either. And so we were applying for an interdisciplinary consortium grant, and I thought, how can we describe what we do here? And the idea was based on the word ‘neuroscience’. So the ‘neuroscience’ didn’t exist 20 or 25 years ago, and it was a coming together of neurology and neurophysiology, and then all the molecular biologists came into the field and suddenly it was molecular biology of neuronal function. And then they came up with an umbrella term, and then they all went to the same society and the same meetings. We didn’t have that, so we thought, “Let’s start with geroscience, we’ll use that as a shorthand,” but it’s been picked up by so many people, it’s been picked up by textbooks, by university departments, the Geroscience Institute at the NIA. It’s great, I absolutely love that it’s been picked up. We actually had a conversation about whether we should patent the word or trademark it. And we thought, no, don’t do that, let it go out there. If it’s actually going to be used by people, if it maintains its meaning as a concept encompassing all of this science and biology between diseases and aging, that’s fantastic.

Tegan McCaslin

Tegan has an eclectic academic background and writes about science and people here and elsewhere on the web.