Topics and Timestamps:
- Background and career (0:00)
- Dietary restrictions and life extension (3:35)
- Oxidative stress (7:12)
- Drugs and the aging process (13:32)
- Caloric restriction and extending life (15:44)
- Caloric restriction among animals (17:00)
- Alzheimer’s and dementia (18:17)
- Antioxidants and potential harmful side effects (19:53)
- Molecular effects of antioxidants (20:42)
- Key discovery or finding: Lack of one single key pathway (22:05)
- Cellular senescence (25:41)
- Richardson’s thoughts on successful aging (30:51)
I am honored and delighted to introduce Dr. Arlan Richardson. He is from OU College of Medicine, a professor of Geriatric Medicine. And I believe you’re the Donald Reynolds Endowed Chair of Aging Research. And also work at the VA, if I remember right. If you don’t mind sharing a little bit about yourself, and how did you… what your role is, and how did you become interested in human aging? Or, did human aging find you, in terms of your research and your career?
Ok, so to give you just a little background, I’m a native of Nebraska. I grew up on a farm, went to a small college, Peru State College, and it was there that I really got interested in science. I majored in chemistry and biology. And this was back in the late 60’s or, actually, the early 60’s. I then decided that I’d like to go on and do research about biochemistry. And one of the few places that had a biochemistry department was Oklahoma State. And so I did my graduate work, my Ph.D. work, at Oklahoma State. At that time I was working with bacteria on the ability to take up DNA. And then when I did my postdoc I got into studying liver protein synthesis in rats. And when I was looking for a job…how I got into aging, I was sure looking at what I would be more able to compete in. And so I thought “Well, I didn’t want to go on in studying the mechanism approaching synthesis,” because at that time it wasn’t known and a lot of people were doing it. I thought “I’d like to study it with respect to some process.” And I got to looking around and I thought “Well aging is a field where there’s very little going on.” This was back in 1970. And there was on protein synthesis. And so I got into aging because of that. Just feeling that this would be a field that I could be more competitive in. And, like a lot of people, the more I studied it the more interesting it got. At first it… it was interesting because back in that time, a lot of people didn’t get into aging because a lot wasn’t known about it.
So they would rather study something like cancer, something where you would go after a mechanism. And aging was just in its infancy and I like to think of it as a little bit like Meriwether and Clarke when they went to look at the Louisiana Purchase. It was kind of like studying aging at that time. We were some of the first people. Not exactly the first people, but really started to looking at molecular process. And so I got into aging and then I was able to be very successful, and then initially I was at Illinois State University where I did a lot of teaching, and had a lot of students, and research.
And then I was recruited to the University of Texas San Antonio where I would up directing the Barshop Longevity and Aging Center. And then eight years ago I was recruited to the Health Science Center at OU. And in the meantime I was also involved in the VA because the VA is very interested in aging, with respect to the aging veteran population.
Can you talk a little bit about, what’s some of the research that you’ve been doing or have done in your career specifically targeting… what aspects of aging? I know that there are a lot of persons that are interested in the molecular side, and the cellular side, and we talk about compression of morbidities and caloric restrictions and life extension, these are all terms we talk about oftentimes in the aging community.
So when I started out, one of the problems particularly with getting grant funding was that most of the people that were studying aging, particularly in human or rodent models…well we were doing this thing, comparing an old to a young [???]. And saying “OK, did this process change?” And as you said, you could say “Oh yeah, old people get gray hairs. You can see with my beard here.” But does that really have anything to do…it was always an association. And so you wanted to have some ways of really being able to manipulate aging and then see what was causing that. And I got interested in caloric restriction early on, mainly from my mentor. My postdoc mentor who said to me “Oh I read this literature, you ought to look into it.” And it had been known from the 1930’s, middle 30’s, that people kind of ignored it. And so when I got into it in the 1970’s I initially thought “Well this can’t be. This is too simple. You just feed animals less and they live longer and they age more slowly.” And then when I did it, it was rather marketable. Not only did they live longer, in other words, usually depending on the strain you’re talking about 20 to 25 percent longer. So if you talked about human lifespan you’d be talking about, instead of an average life expectancy of around 80 years you’d be talking about an average life expectancy close to 100 years. So it’s a major change in lifespan. But the other thing was, is these rats, initially I was studying rats and now mice, is if you look at them and didn’t know what age they were and you compared a normal mouse or rat that was fed unlimited amount …allowed to consume as much food as they wanted to versus the restricted ones. The restricted ones looked, you could just look at them and say they look younger. They were more active. And then you start looking at the pathology and stuff. It was amazing that it had this huge effect.
And so we were really after what about dietary restriction…what was the molecular process that made them live longer? And so for about a decade or two we were looking at various processes: DNA repair, repair of oxidative damage, and all of these things. And the research, I don’t want to say, didn’t go anywhere because we found a lot of interesting data. But the problem was is almost everything that went wrong, caloric restriction reversed. It was hard to say oxidative damage was improved, hormonal changes were improved, and so it was very difficult to ferret out exactly what was happening.
And so, as a scientist you want to go and try to figure out… This was about in the 1990’s, I suddenly, because at that time a big shift in technology occurred. Where we were able to genetically manipulate mouse models. So that you could basically put in a specific gene that would affect the pathway, and then you could see what’s happening. And so that’s where I changed my research dramatically. And said “Ok,” and we focused primarily on oxidative stress. If we manipulate, put in genes that would reduce oxidative damage or we knock out genes that would cause more oxidative damage, are we showing an effect on aging and age-related pathology and healthspan of the animals? Because that was a popular theory
at that time. And there was a lot of evidence for it. And, interestingly, when we did this we found that, particularly in mice, when we manipulated and reduced oxidative damage or increased oxidative damage, in most of our animal models they didn’t have much of an effect on aging or lifespan.
And so, our studies kind of…which was unfortunate, in a sense for us, because it would have been nice to show it the other way, but one of the things I always tell my students is lots of times negative data is as important as positive data. And so our negative data really suggested that oxidative stress in lifespan itself, and I should say, in mouse models, doesn’t have much of an effect on aging. With respect to age-related disease such as neuro-degeneration, heart disease, I still think oxidative stress has or could play a role in this. But from the standpoint of simple aging in mouse models, it didn’t. Now, this kind of comes back to what you were thinking about, Alex. We haven’t done anything with humans. Our studies have all been around mouse models. And so, the question that always comes up is, how well what we see in a mouse model mimics human aging.
And one of the problems with the mouse models is that in almost all strains of mice, the major cause of death is cancer. And so, we’re thinking that maybe oxidative stress has very little role in cancer and that’s why it doesn’t have an effect in mice. And so, some people have looked at other models and there may be a chance that it happened on that. And so, then the next turn in my career was, which was kind of exciting, was I was part of a group at San Antonio that discovered the compound rapamycin increased the lifespan of mice. And this was in 2009. And this discovery was a real big deal. And the reason it was a real big deal is that up to that time, I always like to tell folks that when I would go to meetings, and reporters would be there, and they would come up with their microphone and say “Ok, talk about your research.” And they would always say “Well, when are you guys going to have a cure for aging?” And you know that you don’t want to tell the truth totally. I’m not as bad as some of the politicians, but you know you don’t want to say, which I felt at the time, “I doubt we’ll find something in my lifetime.” You don’t want to say that.
So I always say “Well, probably in about 10 years.” And I always figured 10 years was long, but it wasn’t too long. And it was a long enough time that nobody would remember what I said 10 years ago and so I would be safe. But I honestly felt, at the time, that probably there wouldn’t be a drug or a pill you could take to slow down aging. And the interesting thing was, is that rapamycin, a compound that was used in treating cancer and for other diseases, actually had an effect on the lifespan of mice. And that study has been replicated a dozen times. So it’s really hard and robust. And it wasn’t just that a drug…it’s interesting, because it was a drug that was FDA Approved to humans. It wasn’t something that you had to spend a lot of time to figure out whether is toxic or not in humans. And the other thing that was really probably more important to the aging community is that the study by accident started at rather late in life. In other words the mice were about 19 months in age which would be, in human parlance, probably around 50 or 60. Probably 60 years of age. And the reason that was important is that caloric restriction and other manipulations, we always thought that you had to start them fairly early in life. Not real early, but as soon as the animals got to be adults, we would be like a 20 or 30 year old, that you would have to have them on this to basically slow down the progression of aging. This suggested that you could wait until later in life, and people have done this now so it would be more like 70 year-olds, where they treated it with rapamycin, and still had a beneficial effect. In fact, it seems like it’s adding it earlier in life had no additional effect. So, this study was important for two reasons. It basically showed that, one, you could, with one drug, affect lifespan and aging. And so these animals are aging more slowly and they appear to be healthier and have better health conditions. It’s not quite as dramatic as caloric restriction, but it still is there. And the other thing is, that you can start it later in life.
And the other thing would be that maybe drugs that are being used to treat cancer or diabetes might have an effect on aging. And so that, in my mind, was kind of a big breakthrough. As I wrote in an article, what I’ve seen happening with aging from the standpoint of the biology of aging, has been enormous in the past 50 years. Where we have gone from “We have no idea what we could do to stop aging.” We now know that there are dozens of genes that you can manipulate and slow down aging. And so one of the things that I always like to tell people is that when I started out the concept was aging is inevitable. It happens to everybody. It happens to all organisms, almost. There’s a few exceptions. But it’s universal, it’s something that you can’t mess with. It’s just there. And the interesting thing is that from the biology standpoint, we now know, as I said, dozens of genes and ways of manipulating aging. And I don’t know if you’ve talked to Steve Austed, but Steve would be a great person to talk with because if you look at, from a standpoint of evolution, and you look at in nature, the lifespans of individual animals is enormous. In other words, dogs live usually around 10-15 years. They go through the same process that we do. But they’re much shorter in lifespan than we are. And other animals like whales live a lot longer and this sort of thing, so it’s very interesting how…and birds tend to live much longer than animals that cannot fly. And so manipulating the aging process, while complex, is not something I thought, and a lot of people thought 50 years ago, that why study this? This is so difficult. You’re not going to be able to manipulate it.
Now, talking about going back to caloric restriction aspects, that seems to be a very, for lack of a better term, for a lot of people, low-hanging fruit. A way that they can extend their life. But we often talk about compress, caloric restriction in the concept of compression of morbidity. How does caloric restriction help human beings extend their life, but especially extend the quality of their lives?
So I would just like to take a little bit of exception with you Alex. Yes, dietary restriction is low-hanging fruit and is relatively easy for all of us to implement. Having said that, and having wrestled with a weight problem myself, this is one of the most difficult things…I always joke with my students that if I had a choice of having a drug that would cure cancer or a drug that you could lose weight on, I would take the one that you could lose weight on because there’s a lot more money in that than in the other one.
But I think that the interesting thing is you could go in to the doctor and say, particularly when you get my age, and say “What do I need to do to get better?” or “What should I do” they’ll say “Eat less, and exercise.” And so I think that there’s a lot of data that shows that eating less is very important and can improve the quality of life. It’s interesting, when you were talking about the compression of morbidity, is if you look at caloric restriction it doesn’t really compress it. The animals that are fed caloric restriction, it’s actually, they start dying a little bit earlier and then live a lot longer. And so, it’s not one of those things. Now, keeping in mind, is we’re studying in inbred strain mice. So we have very sharp curves. We don’t have any lifespan curves looking like humans. But in most mice it doesn’t appear that you’ve gotten sharper compress the morbidity.
But certainly, all of those animals… you don’t have to be a pathologist. You can look up in the tissues and the tissues look much better in the caloric-restricted animals than the other animals.
Does it apply also to…I don’t know if you’ve expanded and looked at Alzheimer’s and dementia? Does it play into that too?
Yeah, it does have an effect on that as well. Right. It’s… there is some question about whether it will preserve memory or not. As I remember, some studies would suggest that it does, some suggest that it doesn’t. The interesting thing about rapamycin that I’ve talked about, one of the first studies that we did once we saw the animal live longer was we wanted to ask “Did it have any age-related diseases?” So we looked at cardiovascular disease, cancer, both of those were improved. It wasn’t surprising because there were some studies out there that suggested that rapamycin might be effective. But the interesting thing is we had two junior investigators that were studying Alzheimers in different mouse models. And they showed that it improved, or reduced…improved cognition and reduced the [???] and this sort of thing. And that’s been reported. The other thing is that, giving rapamycin appears to improve memory in older animals too. So, from a standpoint of comparing rapamycin to caloric restriction on brain and Alzheimer’s, I would say I would give it to rapamycin. If you look at overall quality of life I would say caloric restriction would have a bigger effect than rapamycin from that standpoint.
Now the general public…you’ve talked about oxidative stress and that’s great because we talk about that with students quite a bit. And we often refer to, eat your fruits and veggies, right? Is there… you know, there’s been some debate or there’s been some evidence that too much of a good thing can be harmful. Can you explain how that operates a little bit, or what you know about… you’re eating all these fruits and vegetables, you’re just focusing on “I’ve gotta get my antioxidants, I’ve got to eat properly,” How is that harmful to you?
Let me use the example of Vitamin C, because Vitamin C is a very good antioxidant. In other words it will trap the free radicals and that sort of thing.
Everybody knows about it.
Right. The thing is that most of these antioxidants, because they can trap free radicals, they have the ability to generate free radicals too. And so if you get too much of these things, instead of gobbling up free radicals they can kind of initiate the process. And the reason oxidative stress is believed to be a problem is that you, if you just have kind of one trigger it’s a little bit like an atom bomb. You have one free radical, it basically attacks another molecule. And it sets off two more, and it just mushrooms. And so what an antioxidant does is that when it hits the antioxidant, because it’s less reactive when it’s a free radical, it kind of traps that radical so it is not there damaging something else. And so that’s how the free radicals and the antioxidants work. And so you only need a small amount of it. So if you eat a lot amount, and you have a lot of it, you have the potential that you can essentially, because this thing can generate free radicals, it can generate free radicals and they can kind of take off. So that’s kind of the concept behind having too much could be harmful from the standpoint of free radicals.
Now in your research you’ve done in your career when you think about the totality of your career, scientists often talk about serendipity… a discovery that they didn’t expect. And you might have highlighted this already, but are there any one particular discovery or finding that surprised you? That you didn’t expect to find it and it somehow helped you re-shift your thinking or at least, maybe even moved the field in a way or a direction, the field of aging, that was unexpected.
Yeah, so I can give you an example right now that I confronted. Because, generally, as I said, is when we were looking at dietary restriction hoping that we would find the key pathway, we found that there wasn’t one key pathway. When we were doing the studies with our transgenic and knockout mice to prove oxidative stress we didn’t see it. So, and that’s what usually happens with research. Usually your hypothesis doesn’t pan out. And as I said, that’s still a good thing because negative results tells you “Don’t go that direction. Go to another.” So I’ll tell you about a study that we’re doing now. As I said, I was involved in oxidative stress thinking that as important, and one of the things that, as you probably talk to your students about, one of the areas that’s believed to be important in aging is inflammation. In other words, we know that there is an increase in chronic sterile inflammation.
And this is inflammation that is not induced by a bug or a virus or something. It’s just that as you get older you have more inflammation. And it’s believed that this…and we know that inflammation is associated with a lot of age-related diseases: cancer, diabetes, Alzheimer’s is neural inflammation, and so inflammation has become really big. And I avoided this with a passion initially, because I hate immunology. And immunologists, they just have so many abbreviations, you know. And so I was avoiding it but I decided you know, we were studying a model that was accelerated aging and we were trying to figure out why it was…and we knew it had increased oxidative damage, but we said “Well, is there something else?” And we found these animals had a dramatic increase in inflammation. And so I said “Hey,” you know. And I got interested. And even though we know that there is an increase in inflammation in humans, rodents, non-human primates, everybody kind of thinks that this increase in inflammation, which is called inflamm-aging, is partially responsible for aging and certainly responsible for age-related diseases and maybe even reduced function.
And so, but nobody knows exactly why inflammation is occurring. And so I initially did a study, and we have looked at the fact that these animals that had increased inflammation had increased cell senescence in some of the tissues. I don’t know, have you talked to your folks about cellular senscence?
We scratched the surface on it.
Ok, and so this was found back in 1963. What happens is that when cells, we now know that when cells have primarily DNA damage, is they basically cannot reproduce. They go into a senescence state. And this has been known for a great deal of time. And the question is, does that have anything to do with aging? Initially I thought this was a bunch of hooey, you know. It was an interesting study but whether it had anything to do with aging. And then Judy Campiese showed that these senescent cells, they are resistant to cell death. They don’t divide, but they start producing compounds, and secreting these compounds, and even though you have a small number of senescent cells they can produce these compounds and they can activate various pathways. And one of the pathways they activated was inflammation. And so I was thinking “Oh, cell senescence may be important in that.” And so I started thinking about it. And then I happened to give a talk at University of Alabama at Birmingham. And one of my former colleagues at San Antonio said to me at the end, “You should be studying necroptosis.” And you know, you don’t act like an idiot and say “I’ve never heard of that,” but I basically said “Oh, could you tell me a little bit more about it.” And so what this is, is at one time they thought that cell death occurred through apoptosis which was programmed cell death. Where the cell kind of shrivels up.
The other way was necrosis where the cells burst, and that’s considered bad because when they burst they release a lot of compounds. These can activate the immune system and turn on inflammation. Necroptosis is a program. It does the same thing but it’s a program. And the beauty of it is you have three genes that are involved in it. And so we started, we did the first studies and said, “Lo and behold, necroptosis is up with age, and dietary restriction reduces necroptosis. It reduces inflammation.” And so I thought “Oh,” because I’ve never been a strong…I shouldn’t say strong, but I’ve always thought that maybe cell senescence was overplayed and I thought “Ah! We have a system here that’s more important than cell senescence and inflammation.” And so we basically had methods, drugs where we could specifically reduce necroptosis and we said “Ok, if we reduce necroptosis what happens to inflammation.” It went down! And if we knocked out genes for necroptosis it went down and I was saying to my student, I said “We got it! We’re showing that necroptosis is more important than cell senescence.” And we discussed, and I said “Well maybe we should, just for the hell of it, measure cell senescence when we inhibit necroptosis.”
And what did we find? Cell senescence was reduced. And this was totally against what I would have predicted. I would have said there was no evidence that necroptosis had anything to do with cell senescence. So it blew my mind. But I always believe in those experiments that go against what you propose. I listen to those quite a bit, because I always think when everything works the way you have, maybe we’ve just done something to cause it. We haven’t, but you always have that thing. That feeling. And so we did it again. We looked at different models, and we did it again and then what we found is that we said “Well what happens if we inhibit cell senescence?” We inhibit cell senescence and we inhibit necroptosis. And so all of a sudden, and this is just…I don’t know how this will shift the field because we just submitted a couple papers on this. But we’re seeing here that there is some interaction between cell senescence and necroptosis. And we think that they basically, cell senescence will activate…push cells to undergo necroptosis. The compounds they produce will push cells to go to cell senescence, so you have this vicious cycle that increases with age and is underlying inflammation. And so as I said that’s a totally unexpected discovery that we made. And it’s really kind of exciting. And so it’s kind of new to the area. And I’ll give the cell senescence people credit for it: they’re very interested in this.
So we’ve got a grant and hoping that it will get funded so that we can look at this more. And actually, we are working with one of your colleagues over at OSU on this process.
Yeah, it’s very interesting. It’s amazing how science just kind of unfolds, really. Well a final question for you, and an important part of our course is considering successful aging and that concept of successful aging. And I want to know, how do you define successful aging? What is it? Rowe and Khan talked about it a couple of years ago and then they revisited again, but what’s your take on that term, the concept of successful aging?
I think a colleague of mine at San Antonio, Mike Lichtenstein, who is a geriatrician, I remember talking to him about his patients. And I remember him talking about how he was not excited, but he felt very positive when one of his patients passed away. He said “It was a success because she was able to stay at home all her life.” And to me, successful aging is being able to be independent up to the end of life. In other words, and I’m getting there, you know? I’m 80. And so, you’re kind of thinking of all of the things that can happen and one of the things is to not be in a nursing home. And it’s really, I think, Alzheimer’s is particularly devastating in the sense that my mother had Alzheimer’s where you can have an individual be essentially in a position where the quality of life is so poor. And so I would say, from a simple standpoint, is being able to be independent up until you die.
Interesting. Yeah, that makes sense. Well I appreciate your time in the interview.
It’s been great talking to you Alex.
also known as the Free Radical Theory which involves the loss of an electron which creates a molecular imbalance and chain reaction leading to the erosion of the cell membrane and process of oxidative damage
also known a pro-oxidants which rob cells of energy and contribute to the deterioration and eroding of the cell membrane