5 Michael Jazwinski
I’m here with Dr. Michael Jazwinski. He’s the Regent’s Chair in Aging and director of Tulane Center of Aging, a professor of medicine and biochemistry at Tulane University in New Orleans, Louisiana. I appreciate you for being here today, and I’m going to start off with a very ice-breaking question. Can you share just a little about what you do, a little bit about yourself, maybe. But really focus on how did you become interested in the study of human aging, or how did it find you?
Ok, so it’s an interesting question. So, I actually started working on aging, or got interested in aging, in 1984. In 1984 I moved from Rockville University in New York to LSU Health Sciences Center in New Orleans. And I started setting up my lab. I had been working on cell cycle control in yeast. And I was setting up my lab and I found that I had spare time because it takes time to put things together and get a lab up and running. So I had the time to cogitate a little bit about what I was doing, and I was interested in why yeast continues through a cell cycle producing a daughter cell. And what controls that?
And what I wanted to then ask is how many times can it do that? How many times can a cell do that? And I thought that was a very novel question. And I started thinking about it, reading about it, and had all kids of ideas about it. And because of that I started writing little paragraphs about what I had learned. And I saw that I had a grant application. So I said to myself “I’ll put it in and let the reviewers critique it. Maybe it will give me an idea about what I should be doing, thinking, areas that I am missing. And it’ll help me understand the project better.” I didn’t think of starting to work on it, really. I was using the study section as sort of an editorial board, you might say.
And so I submitted this thing and lo and behold, it got funded. And so I had to start working on it. So I started working on yeast aging, and was pretty successful. I introduced that model to the aging research community and it was a weird little model because it was a single cell. But it was sort of related to cell senescence, which was something the you’ve heard about. And it was sort of related to that. So it started gaining acceptance and it finally became a model that really occupies the interest of many laboratories around the world now. But anyway, around, I’d say it was 1997, I was invited to the IAGG Meeting. International Association of and Gerontology Congress, rather. And this was in Australia. And I went there and I had my own presentation but there was a session there. It was the International Centenarian Consortium. Lenny Pune and Peter Martin were there. And a bunch of other people. So I said “I’ll sit in on this and listen to it.” And it was sort of interesting. I said to myself “Well it might be interesting to see how things apply, what I’m doing, how things apply to what these people are doing.” In other words, how my work is applicable to human aging.
And so I started thinking about that a little bit when I got home from that meeting, and a few months later I sent an email to Lenny Pune and I said “Are you guys doing any genetics?” Because that’s basically what I do, genetics. And he said “Heaven forbid!” The reason for this was that this was…so there are a lot of people from Europe involved in this International Centenarian Consortium. And at this time there was a big scandal in Europe because François Shackter, who had published a very important paper in Nature Genetics, on ApoE and Longevity, Centenarians. He had gotten support from a commercial entity, and one of the things the commercial entity wanted was his samples. His human samples. And he, being…and if you have ever seen him or met him you can see he’s almost like a monk, you know? Not part of this world, in a way. So he didn’t smell a rat at all.
And so he signed over his samples to this commercial entity. And that started the commercialization of this whole thing. And that was something that people were very upset about because these are centenarians, very infrequently found, and everybody is sort of possessive of their centenarians and their samples and so on. So it was a big no-no, to do genetics. So I learned that. But I convinced the lady that maybe he should get in touch with other people in the centenarian consortium and find out if they would be interested in participating in this. And fortunately for me, I… my work in yeast genetics of aging was known among many of these individuals in Europe and so they thought there was good stuff. And so they were able to get around this concern. And in fact, at one point they started offering to send me their samples. I said “No I don’t want your samples.”
And so, but anyway. I got involved that way with [NAME] centenarian study and soon after we started putting together a program project grant application that was submitted and got funded, and we got started working on that. And that lasted for several years. In 2000, I guess it was, until 2007 we worked together. And so there’s a big database and we published a lot of work, collaborative work, with a bunch of interesting people. I think you’re an author of a few papers in that area as well. And I think I’m a coauthor with you on a couple of them. I hadn’t even met you when this happened. It just shows you. So it’s a very collaborative area, very interdisciplinary. And it really takes people who look at aging from different perspectives to begin to understand this important process. And what I’m trying to say here is that it’s not only biology it’s also psychology, sociology, it can reach into areas like architecture, in fact. Community design. So it’s a very interesting and multifaceted area. You can meet a lot of interesting people, and there are a lot of characters that I have met and I’m sure that some people think I’m a character too.
Yeah, really coming at it from a bio-psychosocial framework, and we talk quite a bit about that. From the biological side, you talked about senescence and often times we talk about senescence in class and this whole idea of the timing, the biological timing, of life. We use terms like biological age, and biology of human aging. Can you speak to that? What’s your perspective on these types of terms: senescence and biology of aging, or biological age? What’s their connection?
Ok, let’s start with that. So, of course as you know the best predictor of longevity is calendar age. Chronological age. The older you get, the older you are. It’s a nonsensical statement. It’s a circular argument, but it’s true. It is a strong predictor of mortality, your age. Actually, that’s what Benjamin Gompers discovered in the early 19th century. He found that mortality rate increases exponentially with calendar age. And this was important because all of a sudden now the insurance industry started making money because they could predict how long people would live. On average, of course. It’s a probabilistic thing.
So, this was sort of an important finding and it is the basis for a lot of work in the biology of aging. So, but what you an observe is that, and this is observed by many people, that if you look at the observed mortality of a population and compare it to the predicted mortality based on an extrapolation of the curve you see there’s a departure from that, that begins right around the age of 80. And around the age of 90 it’s very obvious. And some people believe that at greater ages like 105 there’s a plateau in mortality rate. It’s a little bit difficult to be
absolutely certain of that, and so it’s a little bit controversial. And the reason it’s difficult is there are not that many people who reach the age of 110, 115, 120. So it’s hard to populate the database with those individuals. But it looks definitely like there’s a departure, there’s no doubt about that. But whether there’s a plateau is a little bit controversial. I think there probably is a plateau. And I’ll give you some reasons why I think that is. But anyway. So this tells you that it’s not only calendar or chronological age that defines how long a person will survive. There’s something else, especially at later ages. And of course the other observation is that if you look at individuals of any given age, they’re going to live a different length of time. So that’s why you have a life expectancy. It’s not that everybody…it’s not like the mayfly. It’s born, it lives for 24 hours, and they all die. Right? That’s not how it works in the human population. People die at different ages.
And it’s not only accidents, which is the major cause of death in people up to the age of, probably, late twenties, but it’s all kinds of other causes. So that means that there’s something else that explains the variation in lifespan that is not contained, not explained, by chronological age itself. And so that’s where the biological age concept comes in. There’s a biological age that characterizes the individual more accurately, in terms of what their expected lifespan will be. What the mortality rate will be. And so, we want to find out what that is. And people who study biology of aging believe it’s the biological aging process. And I’m sure that’s the case. At least some of it is. I’m sure there are other factors: environment plays a role too. But anyway. So that’s where that comes from. And so the issue is how do you quantitate that? And that’s been a very interesting area that’s been studied very intensively. There have been measures like Fried’s Frailty. It’s a very useful one. Apparently there are variations of that that are applied in the clinic, which clinicians can use, for example, before they operate on an older person they can determine their level of frailty which determines what their probability for survival post-surgery will be. So it informs clinical decisions. But I’m not a clinician, even though I’m in the department of medicine at Tulane. I’m not a clinician.
My interest, really, is the basic understanding of the process. So to understand better, biological aging, you have to have a more objective quantifiable measure of that process. And so we’ve been interested in that for a long time, actually. Since 2010. And we use what’s called the Frailty Index, which is sort of a misnomer, in a way, for us because we’re not interested in frailty per se. We should probably be using deficit index. But I’ll tell you, when we published our first paper on this, the reviewers liked it but they said “You have to call,” we called it a deficit index in the title, they said “You have to call it a Frailty Index.” And I argued, but I had a hard time convincing them. I said “I’ll call it a Frailty Index since we want to get it published and move on.” So it became the Frailty Index. But we’re not the first to devise it.
The Frailty Index was first devised by Rockwood and Mitnisky in Canada. At Dalhousie University. And they published many papers on it, and we even published quite a few now too. Our way of deriving it has evolved a little bit. But it’s a very simple way of categorizing the state of an aging organism. A human. And that’s because you look at different deficits that represent different body systems. And you can assemble 20 to 100 of them, and then you score them in an individual. You add them up and divide them by the total of the items that you considered. You have an index that goes from zero to one.
And if you look at a of individuals who are aging they will show different values of this Frailty Index. But overall in a population you see that there’s an exponential increase with calendar age in the index. It means that as you get older it gets more intensified, this increase. The increase becomes greater over time. There’s an acceleration of this increase in the Frailty Index. The other thing we found was that we found that it was heritable, and this was in studies with twins. It’s heritable, and therefore it can be used to understand the genetics underlying aging. Biological aging. And so we’ve used that fact to look for genes as well as epigenetic marks. DNA methylation. We’ve looked at various phenotypic manifestations of biological aging. We’ve looked at energy expenditure. Energy expenditure is composed of three things, basically: resting metabolic rate, active physical activity energy expenditure, and there’s also a small component which is thermogenic activity. Energy generated through the act of eating and digesting food. That’s a very small amount of it. But the major part is resting metabolic rate, which makes up 60-70% of your total daily energy expenditure. And this is just sitting there, relaxed. You’re using more energy than for any other thing. And that’s the energy that’s needed to maintain basic body functions: your heart, your brain, everything just to keep them going.
And so, we know that, and we show that (many people have showed that) resting metabolic rate, total daily expenditure, physical activity expenditure, they all decrease with chronological age. However, if we look at the people who are oldest of old, 90 and older, and we look at their biological age, or their frailty index, we see that as the Frailty Index goes up, the resting metabolic rate also increases. So it’s contrary to the overall trend that you see. And that suggests to us that with the loss of health in older individuals there’s a greater need for energy to maintain the body. And so this conjures up the notion that you have energy input just to maintain the integrated function of the body. And when you think of this, you can think of a network. So you have all the different components at various levels: cells, tissues, organs, in the whole body, that are interconnected. And they connect with each other and they exchange information. And as different elements, these deficits occur, and different elements drive out you lose connections.
And so the organism is less well integrated and therefore has a more difficult time maintaining homeostasis. And there’s an extra energy requirement to be able to deal with that. So it’s sort of like when you have granny, and she’s got difficulty walking. She takes a walker with her to help her. So that’s the extra thing that she needs to keep going. And we, as organisms, need extra energy to keep us going as we lose our health in old age. And males and females differ in how this plays itself out. In females, there’s a loss of lean body mass, in other words muscle mass, that’s associated with this. In males it’s not the loss of body mass, it’s the loss of quality of the muscle because there’s association with cell death. And we found genes that are associated with these processes that all involve mitochondrial function. In other words, energy metabolism.
Yeah one of the questions I was thinking of was how much of this process is due to genetics. And how much is due to lifestyle choices, behaviors, the things that people do in their life: smoking, exercising, all those types of behaviors we engage in as human beings.
We found that the Harable portion of the Frailty Index is .39, plus/minus a good bit. So I would say it ranges anywhere from .15 to .4 or .45, maybe. So it’s not the major component in terms of explaining the variation in health and age. There’s a major environmental component…when I say environmental I mean lifestyle, of course, because it depends on your diet, exercise, social activity, and productive pursuits. These are all important for maintaining health in old age. We want to be able to function later in life, and so we should apply various environmental interventions. So it’s interesting that the worse off you are, and this is not in terms of aging, necessarily, but in terms of many complex traits. The worse the hand you get dealt with, genetically, the more effective the interventions, that are lifestyle and environmental interventions, are in helping you get by. So there’s always, you got to be optimistic. Because you can make up for a lot of the genetic deficits that you might inherit with environmental lifestyle changes. And so, that’s an optimistic message.
But the other thing about this deficit index, or Frailty Index, or measure of biological aging, is its importance is not only for basic science, and I already alluded to clinical applications, right now there’s a big push for so-called anti-aging therapeutics. There are all kinds of interventions. You’ve heard of Rapimicin I’m sure. Then there’s Metraformen, there’s a big trial that’s beginning to get going. And then there are these cenalytics and cenomorphics. They affect senescent cells in our body because it’s been shown that this phenomenon, in vitro of cell senescence, actually has some application in vivo. This process occurs in vivo, inside the body, and accumulation of these cells and what they do to the surrounding environment, is detrimental and can result in various age manifestations like osteoarthritis and cardiac problems. Brain health. And so, it’s been shown in the laboratory with animals that if you eliminate these cells you can actually extend lifespan.
And not only lifespan, but function. Including cognitive function in these animals. And so now there are human studies that are being carried out with various disorders because we can’t really measure lifespan, effect on lifespan in humans, because you’d have to have a lot of time on your hands to be able to measure lifespan in humans. Although you could probably start with 80-year-olds and if you start with 80-year-olds and you were a 30-year-old maybe you could live longer than the individuals who are in that cohort that’s aging. But the idea is maybe if you measure biological aging and look at the effect that these interventions have on that trajectory of biological aging, you can demonstrate an effect on…that’s an anti-aging effect. A bona-fide anti-aging effect. So anti-aging therapeutics, as you probably know, was a dirty word for a long time. And in some circles it still is. But now it’s coming back again because there are actual real treatments that may have that effect. You can make up a word for it rather than anti-aging, but anti-aging is good enough.
Now in your career studying human aging, and this is a big question, what is one of the key discoveries or findings that has intrigued you the most out of your work or perhaps, do you feel, has advanced the field of aging? In ways that you didn’t really anticipate.
Gosh… Well OK, if you’re talking about aging in general, I think that what the biggest findings for me were the findings that demonstrated that genes play a role in the entire lifespan. And the reason I’m saying that is because until then you had a plethora of theories of why people age. And they’re all answers to the question of how you age. In other words everybody and their friend were studying aging, and were looking at some aspect of it. So you can imagine the elephant and the old blind men touching that elephant. There’s a trunk, “Oh, it’s a snake. It’s like a snake.” They’re seeing part of the problem and and they were devising theories based on that part of the problem. And it was very unsatisfying because it was not very rational and wasn’t a very hypothesis-driven [method to] describe how the whole organism ages. And with the advent of genetics of aging, and the ability to show that age, in model organisms, that genes actually can determine lifespan and now healthspan. That was a major, major boost because now we could talk about cause and effect, and really talk about mechanisms. But now we’ve come to the point where we’re again getting back to this thing where there are all these different mechanisms. So you’ve heard of the hallmarks of aging, right? It’s illemeres, it’s stem cells, it’s mitochondria, it’s senescence cells, and so on. It’s inter-cellular signaling, and chromatin stability, etc.
So it’s again beginning to multiply but it has some rationality behind it. Because the idea is that cell damage contributes to aging and because, and this is my interpretation, because we have a system that’s composed of networks at various levels: the cell, the tissue, the organ, the whole organism. And they communicate. Then that’s what the determines lifespan and healthspan. So I think that, for me, it’s the understanding that genetics, that genes, contribute to lifespan and healthspan. That it was a major discovery and really contributed to rationalization of the aging field. And that actually led to, and I’m speaking of, biology of aging of course. Because if you’re talking about psychology that’s a different field. But in biology of aging that was a turning point because it resulted in more people entering the study, the field of, biology of aging. All of a sudden people who had no interest before were studying aging.
And I can give you an example. When I was…in the early 90’s I was a member of a study section at NIH. And when you go to a study section meeting every introduces themselves. You go around the table and you say what you’re working on. And I said “I’m working on genetics of aging.” And during the first coffee break one of the scientists who was in the study section approached me and said “You’re studying aging?” I said “Yeah.” [They said] “You can’t study aging, it just happens.” So I was sort of perplexed. I said “What do you mean it just happens?” [They said] “Well it just happens! You can’t study something that just happens.” So I thought that’s ridiculous. And I wrote, I was asked to write a review article in Science, and it starts out by quoting this person. But not by name, I didn’t name this person. But this is a very well-known person, now. Ok? Who is a Nobel Prize winner, by the way. And I say that this person told me that aging just happens. Well, everything in nature just happens. Sunspots just happen, too, but there’s an explanation to it. And now this person studies aging! That’s the ridiculous thing about it. So people then…when genetics became important for aging studies and to the field. And then of course human genetics of aging is a little bit different. Because it’s not as easy to show cause and effect. In fact you can’t really directly because, whereas in studies in lower organisms you can form a hypothesis, then postulate that there will be a certain phenotype that will appear when you make a certain genetic manipulation, isolate a certain mutant, or make a certain genetic cross, and when you find that you can say “Well there’s a cause and effect here.” And it’s proof. In human genetics that’s not possible because human genetics are the archival analysis of chance encounters. Archival analysis because you don’t formulate a hypothesis, really, before you collect the information. Right? You’d have to first collect the information. And chance encounters because you can’t determine what you mate. You can’t determine the two male and female that mate like you can with model organisms like mice. You can mate a certain mouse with another mouse. You know what their phenotypes are, their genotypes are, and mate them. You can’t do that with humans. And humans are an outbred population too. And most studies with laboratory animals are on inbred strains. That makes it more difficult. There’s more variability. And that’s the key.
So if we could understand the variability better, we will be able to then tailor our interventions, whether they be lifestyle interventions or actually drugs, therapeutics of that sort, to individuals to affect their health span. This is what’s being done now in cancer treatment. You don’t treat the cancer by just scribing it, anatomically or pathologically. You now take biopsies and determine what the mutations are in the tumor that are driving that cancer and you adjust the drugs, the chemotherapeutics, that you apply based on that. It’s really rationalized…made it a precision medicine application. So we’d like to be able to do that with aging. as well.
Yeah. You know one of these days it might be around the corner.
It may be, because there, like I said, there are clinical trials out there now. There are also other interesting things. So, vampires. You know why vampires live so long? Thousands of years? Well because they suck blood out of people. So there are these experiments that now go back over a decade that are in heterochronic parabiosis. So parabiosis is when you take two animals and you stitch together their circulatory system. Heterochronic means that one is young and one is old, of the two. And the observation was made that when you do that the old animal becomes younger in terms of its health and function, and the young animal becomes older. There are factors that are positive that the young animal has that can help the old animal behave like a young animal, and vice versa. There’s negative factors that are produced by the old animal that do the opposite to the young animal. And so there are a lot of these studies that were done and we now are in the position to identify some of the factors. And there are proteins that are circulating in the blood that can have really remarkable effects on aging, of cardiac muscle, brain, and in fact you can rejuvenate people just by providing these things. I jokingly say that that’s why vampires live a long time because the typical picture is Dracula biting the neck of a young lady, right? And so he becomes, he’s immortal.
Well in the interest of your time, one last question, and one of the key topics of this class is successful aging. So when you think about, and I’m asking everyone this question, when you think about Rowe and Khan’s concept of successful aging, how do you define successful aging and what advice might you give individuals to age well?
Well I think their definition is very good because it’s general enough, it talks about being physically and mentally, cognitively, healthy, and being engaged in life. And that’s really what you want.
So I remember Gene Cohen who was the interim director of NIA at one time, National Institute on Aging, at one time, was asked “How would you like to die?” And he said “Well what I’d like to do is come home, sit in my easy chair in front of the fireplace, take off my shoes, put on my slippers, pour myself a snifter of brandy, light up a cigar, and check out.” So the idea is to lead a quality life, and a quality life means different things for different people. Some people think a quality life is one that’s physically active, others think that it’s cognitively, mentally active, intellectually active. But anyway, the quality of life for that person, what they think is quality of life, is as long as possible and not to suffer a long time before you die. And there are various trajectories of disability in the last year of life. There’s a very interesting paper published by Thomas Gill, New England Journal of Medicine, it was the April 1st issue, in 2010, on the trajectories of disability in the last year of life. 12 months of life. And so one trajectory was no disability… that would be perfect, right? Another one was, for example, an accelerated disability. One where it accelerated in the last couple months. That one’s pretty tolerable, only a couple months of disability at the end of your life. And it would also save a lot of money because you’d be spending less money as a society on care for elderly people. So there are all sorts of advantages.
So this biological aspect now gets into the psychological and societal areas, and can lead to policy changes. So biology, psychology, sociology all come together when you study aging which makes it exciting. Makes it fun, I think. And the interesting thing is that, so, getting back to these deficits, in the the Frailty Index. So, our face is a system, ok? Many people say that we wear our age on our face. Ok? We have so many features here, and the fact is that there really are a lot of features there to quantify. And facial identification has really blossomed in terms of identifying individuals, and this is used by governments as well as the private sector. So, the face is a good example of a system, and there is numerous studies, one that really fascinates me is one by Gore Christensen, was published in 2004, I think, in Epidemiology. They had these elderly twins, centenarian twins, and they had pictures of them and they gave them to a panel of nurses to classify how old these individuals are. And they found that it was very accurate, what they were able to say.
However, they found that even if you had an identical twin one looked older than the other. And this actually let them quantify how much of the variation in biological age, they didn’t call it that then, but biological age is due to genetics. And this genetic contribution becomes larger as you reach older ages. So that also coincides with the plateau in mortality that I was talking about. And so you’re as old as you look, is basically what the answer is. However, there’s another study where they looked at the mortality of individuals, a cohort of individuals, whom they rated as to their overall health, by self-rating survey. So the individual rated themself. And they found that it was very well correlated with survival. Those who rated themselves as healthy survived longer than those who did not. So that means that you’re as old as you look and you’re as young as you feel. So I like to think of it that way. So there you go. You have biological and you have the psychological.
That’s a great way to end the interview. I appreciate it.
also referred to as “replicative senescence which suggest that normal human fetal cells have the ability to divide and replicate approximately 40-60 time before death
Discipline of study or approach that views aging as a “disease” that can be can be “prevented,” “delayed,” or “cured” through medical means of intervention(s)”
collectively and socially shared experiences with those born at or around the same birth year.