Resilience as Medicine


Luigi Ferrucci

Scientific Director at National Institute of Aging

Dr. Luigi Ferrucci is a geriatrician and an epidemiologist who conducts research on the causal pathways leading to progressive physical and cognitive decline in older persons. In September 2002, he became the Chief of the Longitudinal Studies Section at NIA and the Director of the Baltimore Longitudinal Study on Aging. Dr. Ferrucci received a Medical Degree and Board Certification in 1980, a Board Certification in Geriatrics in 1982 and Ph.D. in Biology and Pathophysiology of Aging in 1998 at the University of Florence, Italy. Between 1985 and 2002 he was Chief of Geriatric Rehabilitation at the Department of Geriatric Medicine and Director of the Laboratory of Clinical Epidemiology at the Italian National Institute of Aging. During the same period, he collaborated with the NIA Laboratory of Epidemiology, Demography, and Biometry where he spent several periods as Visiting Scientist at NIH. Dr. Ferrucci has made major contributions in the design of many epidemiological studies conducted in the U.S. and in Europe, including the AKEA study of Centenarians in Sardinia and the Women’s Health and Aging Study. He was also the Principal Investigator of the InCHIANTI study, a longitudinal study conducted in the Chianti Geographical area (Tuscany, Italy) looking at risk factors for mobility disability in older persons. In 2002, Dr. Ferrucci refined the design of the Baltimore Longitudinal Study of Aging to focus on the Geroscience Hypothesis, which states the pace of biological aging is the root cause of many age-related chronic diseases, as well as physical and cognitive disability. He has made major contributions to the literature and is one of the most cited scientists in the field of aging. Dr. Ferrucci has been Scientific Director at NIA since May 2011.


Episode Transcript


Imagine a medicine that is based on prediction where we can intervene at the time when still people have resilience. And so we’re not going against nature, but we’re going with nature, how more effective this could be. 


Aging like gravity, it pulls on each of us. Why do some of us age without illness? How do our bodies and minds experience aging at the silver and molecular level? What’s the future of aging in our society? And maybe most importantly, what can we do about it today? My name is Gordon Lithgow, and here at the Buck Institute in California, my colleagues and I are searching for and actually finding answers to these questions and many more. On this podcast, we discuss and discover the future of aging with some of the brightest scientific stars on the planet. We’re not getting any younger, yet!


Gordon: Hi, everyone! Welcome to the show. Uh, this is a special treat today- I get a chance to talk to Luigi Ferrucci. And,  he’s one of my scientific heroes for so many reasons that will emerge during the podcast today. And so I think this conversation is   going to focus a lot on translation and what’s going on with aging studies and interventions and what people can do.  

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Gordon: Luigi again, thank you for doing this today. I feel like, um, you’re someone in demand right now because you’re right at the heart of so much that people are talking about in terms of aging. But I do want to start just by going back to the fact that you’re a geriatrician and an epidemiologist. And I’m kinda wondering how you got there!


Luigi: [Laughs] I think that’s a story really. You know, I was 16 years old, and I was serving dinner at a Ronald Ross dinner. And I got a plate of spaghetti to a guy that was,  you know, at a table in the corner. And that guy looked at me and said, “It’s Saturday evening! “What the hell are you doing here? You should be out playing with your friends and going out with girls.” And I said, “Well, I want to do something that is important. You know, I want to contribute to society.” And he told me, “If you really want to contribute to society, you have to study aging because the people that will age in this world are already born and they will change everything. Aging will change a society, the family, our economy, our healthcare. You have to get into that because people are not doing it.”   and so I decided to do that [laughs].

Gordon:  That is amazing. So this was someone who was needing help?  

Luigi:  No, the person was somebody really important. You know, the person was Francesco Maria Antonini — I discovered that later — who was the first the Chair of Geriatrics in Europe.  So I decided early that studying aging was important. And then I was involved in care for a very, very, very long time. But as many of the geriatricians can tell you, you know, at that time, geriatric care was not-not very famous. You know, nobody knew what a geriatrician was.

Gordon:   Yes.

Luigi: And we had very little to offer to our patients. And so I decided that if I wanted to make a difference, I needed to do research. And you know, the rest is history [laughs].

Gordon: That’s-that’s an amazing story. So you went to medical school. I guess the other way would have been to do basic biological research. Maybe there wasn’t so much around back then on biology of aging?

Luigi: No, there was very little. You know, I think that during my study of medicine,  the passion for biology. And-and that was because my professor of,  [basic] biology was an incredible woman that really infused in me this passion. But then, you know, I wanted to do something applicable. And so I wanted to see patients. And so that-that’s why I went to medicine and then to geriatric. And you know, our geriatric specialty was a little bit,  you know, was a little bit peculiar because Professor Antonini thought that in order to study aging, you need to understand human physiology. And the best way of understanding human physiology is to do acute care. So our internship was not in a nursing home. It was in an acute care unit. I stayed several years in an acute care unit.  And that was, you know, my training is really in acute care. AndI think it was important because you really — you create these automatic responses. You know, When you have, uh —

 Gordon:  Yeah.

Luigi: — acute patients. And that has remained in me and has been very, very useful.

Gordon: And-and I guess you developed a-a comfort level with dealing one to one with patients as well.

Luigi: It gives you confidence to talk to patients. It gives you confidence that if something, you know, acute happens, you know how to deal with that And so I think that that has been very important in my life.

Gordon:  So you moved into epidemiology. And was that a certain level of frustration that we simply didn’t know the factors that were driving what you saw in the clinic?

Luigi:  So I wanted to do science. And at some point, I realized that the weapons I have in my hand to fight the disease of aging were not enough. So I had an opportunity. There was an opening for a course of the epidemiology of aging in the London School of Aging and Tropical Medicine. And so I spent a month there. And I spent a month there with the best of the best epidemiologists. I mean, Richard Feachem was one of the people that were teaching, you know.

Gordon:  Yes.

Luigi:  And, you know, Dr. Geoffry Rose,  was one of the epidemiologists. And because I had very little money, I used to go for dinner in, um, this Indian restaurant. And they were passionate about Indian food as well. So we spent an evening eating Indian food and talking about aging and epidemiology. And that developed my passion completely. And I came out from that experience,  wanting to be an epidemiologist, understanding public health. And that’s when I started doing some studies in Italy, I created this study that was called the InCHIANTI study, that is still producing very very good science. And so I started doing epidemiology. Later on I became the Director of the Baltimore Longitudinal Study of Aging, which is really an amazing study. Progressively, I became more interested in, you know, in the dark side. I-I started wanting to understand mechanism.

Gordon: Laughs]

Luigi:   When you have done a lot of occupational  study, you start thinking- why?  Why is this happening? Why do people, you know, experience decline in muscle strength? Why do people lose their memory? And-and you know  that, you need to go deeper.

Gordon:  I’m not gonna forget that you called mechanism the dark side. That’s great [laughs].



Gordon:  Let’s talk about the Baltimore Longitudinal Study. So this is very famous, and-and-and —

Luigi:  Yeah.

Gordon:   — you’re synonymous with it as the Director and so on.  Just for-for those listeners that are coming to this maybe new,  describe this — the origins a bit about this study and especially the structure, you know.

Luigi:  Yeah. So-so I-I think that, um, it’s just an intuition of the titanic force,  in the field of aging, which was Nathan Shock. up to that point, people have done study of aging by correlating, you know, by comparing young and old people. For example, you know, is the liver function higher or lower in all compared to younger people.

Gordon: Yeah.

Luigi: And,  there-there-there is nothing wrong with that. We still do a lot of cross-sectional studies. But there is a problem that people that are old also have experienced, you know, different things in their life. Somebody that is one hundred years old now was born, you know,  during the war. And so imagine, you know, what kind of nutritional status of stress they went through. So they’re different to — from younger people, not only because they’re old. It might be because their experience in life has been so different. The only way to really study aging was to follow people over time, you know, and study them multiple times, and so that you can study aging at the single individual level and so you don’t have that bias. So the Baltimore Longitudinal Study of Aging was really the first study of aging that was done with this in mind. In 1958, the Baltimore Longitudinal Study started. So people were enrolled in the study, and they were enrolled in the study when they were extremely healthy. They had to be healthy because Nathan Shock wanted to study the difference between aging and disease. He said that one of the ways we can better cure for disease is to extract from disease the effect of aging. And we know now that was the wrong question, you know, because now we know that there is not really a solution of continuity between aging and disease. But we had to discover that. When our technology improved over time, we discovered that it was almost impossible to dissociate aging from disease, from chronic disease. At that time, that was the construct and the idea. So in the Baltimore Longitudinal Study of Aging, people are coming to our unit every four years if they are less than 60 years old, every two years between the ages of 60 and 80, and every year after the age of 80.  And we host them. We host them for three days, and we measure the measure [laughs]– I think that any measure that comes to your mind, you’re probably doing – including a dedicated MRI that we have in our unit only for the BLSA. Two actually! Now we’ll be using a 3 TMRI, but now we’ll be using an even stronger, a 7 TMRI. And that is a really new emerging technology. And I think that that allows us to really understand a lot better, not only how people age but how the different dimensions are correlated to the chatter. And we found that the people that lose muscle strength faster are also those that tend to lose their kidney function faster or health function. So there’s some sort of homogeneity in the way we age. And that really convinced me of the geroscience hypothesis, that there is an underlying force that is driving these changes that we can call aging or biological aging or whatever we call it. It is there.


Gordon:  Thank you.  There was a couple of interesting points you made along the line there. So first of all, Nathan Shock, I guess, was the-the Founding Director of the National Institutes of Aging, uh —

Luigi: Yeah.

Gordon: — which is kind of an important development in, you know, the federal government’s commitment to all of this, along with the —

Luigi: Yeah.

Gordon:  — the Baltimore-Baltimore study itself. And then you mentioned the fact that Shock was, um, interested in this if you want separation of disease and aging. And I mean, I guess this was important at the time, right?  

Luigi: Uh, yeah, absolutely.  I-I think that  Nathan Shock was certainly a visionary, you know. He conceptualized the idea of longitudinal study before anybody else. But remember that at that time, medicine was organized by organs. You know, you studied myocardial function. You studied, you know cirrhosis . You studied, you know, hip fracture. And those were supposed to be disease. And diseases are more likely to occur with aging. But they’re not aging because some people do not develop them. You know, some people get to age 100 without having a hip fracture. So people thought that they were not connected. Well, I-I-I — the-the problem is that when you start doing longitudinal studies, you find that the same — that there are sclerotic severity that,  eventually lead to myocardial function, occurs with aging in everybody- almost in everybody.

Gordon: Mm-hmm.

Luigi: And the same necrotic process that eventually leads to hip fracture almost, uh-uh, you know, develops in almost everybody. So the cleavage between the disease and the fact of aging is very — become very artificial, especially now that we have the technology to look at the data. And that — and then by looking at the longitudinal trajectory of these functional organs, we realized that aging is pervasive across different organs you know. And the fact that, you know, aging is manifested differently in different individuals is probably due to genetic predisposition and also to the fact that we have different environments of exposure. You know, somebody exercises. Somebody doesn’t. And so the same aging process, you know, will have a different effect in somebody who exercises than somebody who does not exercise. And this is so true that now that we are playing with biomarkers —

Gordon: Uh-huh, yes.

Luigi: — we see that the secret of aging- it is universal. You know, we find that some of the proteins that change with aging in the blood, change in the same direction for everybody, and when this changes more in others, they are predictive of the development of disease. So we read indirectly the biology of aging through biomarkers. So that’s where we are at the verge of transforming the science into clinical application.


 Gordon: That-that-that’s super important. I actually want to talk a little bit more about technologies because, as you said when your subjects come in for study, you measure everything you can! And everything you can is-is,  an ever-increasing universe of potential techniques. And I’m wondering just thinking about — I guess genetics was a major factor for a long time in terms of association studies and trying to find genes with main effects. And then we had the omics have kicked in in a big way. We’re talking a lot about clocks, which is related to biomarkers, of course. But let’s go back to the genetics for a minute because this is — I think this is fascinating because we’ve talked a lot about the effects of genes on aging in this series, and especially in model organisms that the effects can be absolutely massive. And then we come to the human populations, and things are a bit more complex. And I guess this could be summarized by the missing heritability question. Talk a little bit about-about how you study the effects of-of genetics on life expectancy and on individual diseases and-and-and whether you think that we’ve, um — that  sort of well is drying now or-or-or there’s still things to be discovered.

Luigi: Well, you’re-you’re-you’re making a really strong point of the missing heritability where, you know, we all started doing genetics   you know, making the assumption that studying genetics will solve everything. We will find what are the genes associated with different projections of aging. And then we will find things on genetic characteristics- what are the interventions that are, you know, perfect for the certain individual instead of another. There-there was a concept that I was really into. I do remember, you know, doing the-the first GWAS that we did in the BLSA where we found that there was a peak on APOE4 that was – APOE is the strongest — the-the variant 4 of APOE. The strongest part of Alzheimer’s disease. And we found that even in the LSA, the preliminary study, that in this figure, you know, where each gene is represented by some sort of a tower, what we call the Manhattan Plot, you know, the APOE4 was on top of everything else. And so that gave us a lot of hope that will happen. At the beginning, you know, happened — what has been happening always inside. So people kept their results    separate, they wanted to do their, you know, GWAS.

Gordon: Yes, yes. 

Luigi: Then we realized that nobody had enough data.  The only way to  really explore genetics was to get consortia, you know, to have a big group that, um, you know, the group many, many different institutions so that the number was sufficient. But even when we did that, the association studies were many. There were many traits associated with genetic variation. But the amount of variance explained, the amount of association explained was minimal.   And that is a  problem because when we started  , you know, monogenetic and polygenetic,  it means, we find that some traits are very, very genetically connected.  You know, 30 percent, 40 percent. In GWAS you’re lucky if you find the one percent of the variances explained by genetics.  So this discrepancy between the two that  we still — I don’t think we understand completely. I mean, I think epigenetic is part of it and is becoming more important. But still, I don’t think we have the key to understand that. 


Gordon: So going back to GWAS — the GWAS stands for the Genome-Wide Association Studies, 

Luigi: Yeah, in order to do that, you collect blood, you [extract] the DNA, the-the nucleic acid that comes from the blood —

Gordon:  \ Yeah.

Luigi: \ — to count white blood cells. And then you use, you know, a chip that looks at, you know, genetic variation and different parts of the DNA. In the beginning we were using chips, uh. So we were using, uh — we were measuring 450,000 locations. And then we got to a million, to 20 million. Currently, we’re doing,  what we call whole genome sequencing that allows us to really study the entire DNA in-in high detail. And then when you have that, you say, okay, who of these people is developing myocardial infarction? You know, the genetics do not change.

Gordon: Yeah.

Luigi: And so you see what is the difference of the DNA of people that develop myocardial infarction and those who do not.

Gordon: Well, the big picture here, I guess, is that — you said it. You said that the effect of genes is less than you might have expected. You mentioned one percent at one point. That’s unbelievable! Just to sort of translate that for a particular condition, only one percent can be assigned to differences between genes between people. And then so for life expectancy itself, so the big picture — I know you’re not the only person doing this, but for life expectancy at birth, you know, which I guess is the big, big picture of what’s the effect of genes on aging, what do you think heritabilities are, the effects of genes?

Luigi: The interesting thing is that the genes associated with extreme longevity are not many.

Gordon:  Yeah.

Luigi: And,  you know, the most constant found in all the studies APOE two, which is the — you know, the protective variant against dementia is also the most associated with longevity. And then OXO 3a is the other one that everybody is finding. Um, many others that I found in some populations but not in others, much more inyou know, not very constant and not very, you know, replicable across the different populations.

Gordon:  Yeah. No, it seems surprising considering the-the genetic effects on flies and worms and so that-that are massive —

Luigi:  Yeah.


 Gordon:  — um, although it’s a different question in a way. You’re asking about the differences between individuals and those other big genetic studies that are really talking about effects on  populations that have variants at a single locus or a, you know, single gene. So I guess this may be a bit apples and oranges. But doesn’t this all come back to what you mentioned originally about life experience and really an appreciation that  that is — that is the overwhelming force that’s driving our aging as individuals?

Luigi: Yeah, I mean, I think that, um, why we all understand, you know, genetics because genetics bear all the information to build our body and make it function is there. So that why the DNA does not change over our lifetime and so we are fixed machinery, we can moderate the way this machinery works. And the modulation occurs through a mechanism that we call epigenetics. We don’t change the DNA sequence. But we chemically modify the DNA in a way that responds through gene expression different to different stimuli. For example, you know, especially — this is especially in studies in the early part of life where if you have, you know — if you don’t have enough nutrients, you change your gene expression to slow down your metabolism. So you need less nutrients to maintain life. And then we strongly hypothesize, and there is some strong evidence that this occurring in early life, is a determinant of some of the metabolic diseases that we see in late life. But then in late life, you get in a period where you can have enough nutrition, but your body has slowed down the use of those nutrients. And so those nutrients accumulate without being utilized. And that is one of the reasons why people develop diabetes or metabolic syndrome or other metabolic disease. So the experience, the exposure to the environment, your behavior, you know, the smoking, uh  – the-the type of nutrition change,  these epigenetic modifications and so make us completely different, in reality.

Gordon: I’ve been trying to think of a metaphor for this. It’s a bit like moving into a new house, and there’s a garden there. Uh, and the garden has a certain structure that always will be. There’ll always be a hill there, or probably there’s gonna be a path there. But you can decorate that garden and change it in ways where it looks completely different despite the structure being the same.

Luigi:  You know, (scientist’s name) did a study comparing in collaboration with the BLSA. And he said, “Well, let’s take a mouse that is genetically identical. You take mice that are genetically identical, and then in midlife, I look at the variability of something like, you know, weight —

Gordon: Yes.

Luigi: — or height or walking speed.” And what he found is that,  the variability of these traits is similar to the variability of humans in midlife.

Gordon:  Mm-hmm.

Luigi:  So that shows you that genetics is a primer. Then on top of the genetic, epigenetic modification make us, each one of us, a different individual. So you don’t — even when your iden — genetic identity —


Luigi: — you don’t have identity in aging. 

Gordon:– this is an incredibly important result when we think about interventions, which,  I want to come to very soon. The-the-the natural variability between individuals that has the same genes is enormous. It’s amazing and something I  guess we don’t quite understand. I mean, all these animals are living in the same place, right? It’s not like a human population at all.  

Luigi: Same diet, the same everything.


Gordon: So-so we’re at a point where we’ve got all these technologies. And-and just to summarize, what do you think’s the best way to measure [aging] right now?

Luigi: [Laughs] Um, you know, I-I think that, before we started with methylation, I think that,  that’s the best way to study aging at this point.

 Gordon: This is a modification of the DNA.

Luigi:  By adding a methyl group. Traditionally we think that, when you add this methyl group,  you kind of block,  you know, gene expression —

Gordon: Okay.

Luigi: — that-that-that because you interfere with the binding of the transcription factor. And so that modulates,  you know, your gene expression.

Gordon: Yeah.

Luigi:  So we know that [probably] is a lot more complex than that. It’s probably true in different small part of DNA, but not-not, it’s not the general mechanism. But the bottom line is that, you know, Steve Horvath, the first [was the first], maybe not the first, but the first, you know, well known that discovered that,  if you study the methylation of the,  limited number of these binding sites in-in the DNA, you can create a score of 353. You can create a score that is associated with chronological age. Uh, I-I want to stop for a moment here – and I say something that I always say. You know, if you find a drop of blood on the floor in your corridor, and you study the methylation in that drop of blood, you can say the age of a person that lost that drop of blood with the precision of three years  [one oh point five], plus or minus. This was not possible before.

Gordon: Yeah.

Luigi: We didn’t have any biological markers that will allow us to know from the drop of blood the age of that person. This is an extraordinary discovery because, since then, we only were chronological age. And we knew that people in their 70s — some of them are in bed and they can’t really walk. Some of them still run half marathons, like me. I’m almost 70, and I still, every year, run half a marathon. So chronological age doesn’t tell you, you know, very much. Well, it tells you something, but not enough about the health of an individual. And-and we hope that by studying this, aging clock methylation is one of them, we can understand more about biological aging. And I think that,  that,  you know, think the first [methylation] clock from Steve the others were created, some of them based on longitudinal data-data, such as the pace of aging from Dan Belsky and,  you know, GrimAge from Ake Lu. And-and they seem to be more powerful.  Again, they’re not powerful enough to be applied to clinical practice and mostly because these has been applied to a single population. We need to study them in many, many different populations. And then the other problem with this is that, why we know they predict outcomes, such as mortality, we don’t know why. We have absolutely no idea of what is the underlying mechanism of the epigenetic clock. So the new clocks that we’re now creating and people are creating, that they’re based on proteins, are probably mu-much more likely to be applicable in the clinic because we know what proteins do. And I’ll give you an example. You know, I-I think that,  you know, I became a physician in 1980. And in 1980 we measured — we were measuring the same 32 proteins when any patient was coming to the hospital. You know —

Gordon: Yeah.

Luigi: — you studied the list. You know, [unintelligible], globulin, and then,  you know, the same markers. And-and-and we still study them. But our technology allows us to study 10,000 proteins in less than a cc of blood. 10,000 in a very, very small amount of blood.

Gordon: Yes.

Luigi: And we-we to leverage on that clinically because those — there’s so much information in there. And in order to extract that information, we will need to do this measure in many large studies,across different diverse types of population. And-and-and that is the medicine of the future. I mean, I want to make a dream. I think that, for any patient coming to the hospital, we will measure them and then say, yes, you’re coming here because you have a shoulder that is painful. I can see from your biomarkers that you’re having occlusion of the left artery of the [unintelligible], and you need to do something about that now because now our treatment will be effective. In the future, it will be a lot more difficult. Imagine a medicine that is based on prediction where we can intervene at the time when still people have resilience. And so we’re not going against nature, but we’re going with it, helping the normal properties of a healthy measure, how much more effective this could be.



Gordon: So I guess another measure is-is functional outcomes, things like,  frailty measures. What’s your thoughts on those?

 Luigi: My conceptualization of aging,  as you know is a ratio between damage accumulation and resilient strategies. So the stochastic ports that create damage accumulation in molecules and in cells. And then there are evolutionary selected decision strategies that prevent this damage. To me, frailty is when the effort of life is too much for the residual resilience that has remained. Even living is too much of a stress because you have exhausted your resilience strategies. So everything that you do determines an accumulation of damage, very rapidly. And that’s why people, when they become frail, have a very short survival. Now walking speed is another important measure. And to me, and you know, we know that it’s incredibly powerful in terms of, you know, prediction of mortality. It’s more powerful than any other medical measure we know about.

Gordon: Yes.  

Luigi: But I’m not surprised by that because, um, you know, walking and bipedal walking has been the characteristic that allows a human to survive in spite of,  you know, the aggression of other species. You-you are bipedal, and then you free up your hands that allow you to do other things. So because of that, walking is incredibly physiologically redundant. You have many, many compensatory strategies that may allow you to keep mobility in spite of a lot of damage. And so because of that, when you lose mobility, when your walking speed is going down, that means that all those strategies are gone, and we could spend another hour, you know, to explain what those strategies are because it’s one of the wonders of the physiology of life. But imagine that when you lose that, that means that all the redundancy that was in your body is no longer there. So that’s why it’s so predictive of mortality.

Gordon: Do you believe in blue zones?   

Luigi: [Laughs] I-I think so. I don’t know whether the blue zones are the ones that have been identified.

Gordon: Ah!

Luigi: You know, I was involved, uh — I was involved in one of them. I was a — when I was a young geriatrician, I was an interviewer in Sardinia, you know, where  we identified — in fact, I-I was part of the first paper describing it. The area close to Nuoro (IT), where there was a concentration of centenarians and especially male centenarians that is a really very, very peculiar characteristic. I think that, yeah, you live in a certain area where you have certain constraints of exposure. And those concentration of exposure and behavior can enhance your capacity to live longer and healthier. So I-I-I think that can support — I don’t exclude that there are, you know, blue zones, and probably there are many more than those that have been identified.

Gordon: Okay.

Luigi: But, you know , if  that is true, that means that we can — we should be able to develop drugs that do the same thing.

Gordon: Yeah. Yeah.

Luigi: You know, that-that’s our hope.

Gordon:  Well-well —

Luigi:   And  there’s always metformin. Perhaps. I don’t want to sell, you know, these certain things because they work in animal models. We don’t have the results of the trials. You know, the senolytics, all these drugs, you know, seem to have a good effect in model organisms. And then now, many of them are in randomized clinical trials,  that will give us the unbiased answer about if we can use them, you know, to really  enhance our ability to age well. And I hope they will work.

Gordon:  Oh, but —

Luigi:  But-but,  but they may not work at the beginning. We-we-we need to be aware that some of them — some of this trials will fail and we will keep trying, and we’ll find — we will refine them. And eventually, I’m sure we will find them.

Gordon: It’s nice to hear that level of optimism from someone who is such a careful and-and conservative commentator on-on-on the field. What is the standard that we-we need to establish that a nutritional intervention, say, or-or a drug-like molecule is really slowing the measures of aging? I mean, what — do we need new populations? Do we need new study designs? I know people are talking about, you know, Mendelian inheritance…  

Luigi: That is a great, uh — that is a great, great,  you know, question. I will respond in two ways. One is,  you know, hopefully the biomarkers of aging will become so strong and predictive that we can consider them as proxy outcomes. You know, in order to study the effect of a drug on longevity, If you are studying somebody that is 40 years of age, you will have to wait 45 to 50 years. And that’s not practical. But if we are confident that those biomarkers of aging truly follow, you know, the pace of aging, then we can see whether within a couple of years or three they’re slowing down the pace of aging. And you can imagine that those proxy measures will predict longer survival.  But I think that, our ability to test what we call the the gerotherapeutics uh —

Gordon: Yeah.

Luigi: — is strongly binded to our ability to develop strong biomarkers.

Gordon: Okay. Okay.

Luigi: That is absolutely true. So I talk about randomized controlled trials because they are the gold standard. So what is a randomized controlled trial? We come very conceptually. That’s to say, I take a group of homogeneous individuals, you know, people that are between the age of 40 to 60. And then I say I select the half of them by chance, by pure chance. I become blind. I put their name in a hat. And then I put my hand in the hat, and I put them in two groups, just by taking that from the hat.

Gordon: Yes.

 Luigi: And then I say I treat the — I ask those in Group A to take a certain drug-a certain intervention, drug, whatever intervention I’m talking about. And Group B I give them a placebo. You know, a placebo could be, you know, the same pill of color and shape but doesn’t have the compound that I’ve given to Group A. Why is this important? This is important because health is a lot in our mind.

Gordon: Mm-hmm.

Luigi: So if you feel that you have been treated or not treated, that is going to influence your health.

Gordon: Yes.

Luigi: And so everybody needs to feel the same way. Everybody should have the feeling that,  they have been treated with something that is good, although half of them don’t know that they’re taking a pill of sugar. And then, you know, then you follow them for a certain outcome and see whether those who are taking the intervention or the drug do better than the other. In this way, you have an unbiased response to tell you that something is working or not working.

Gordon: I — the-the — first of all, it must be — must be difficult to think about a placebo for your Southern Italian cooking, but, uh —

Luigi: [Laughs]

Gordon: — maybe you can work on that. Um, but-but the placebo effect is absolutely massive, right? I mean, it can be 40 percent of the benefits you see in-in most studies. So — and-and that’s something that I think we need to be very cautious about. There are study designs alternatives, like the N-of-1 type study. Do-do you have any feelings about this?

Luigi: Yeah.

Gordon: This is where really you’re studying individuals, and you’re making changes, and you’re following those changes, I guess is the way to summarize it.

Luigi:  Over time, yes. I think that they’re becoming very popular under the idea that each individual is different from the other. The only real way to understand the effect of intervention is to follow individuals over time. I-I-I think that-that why I-I like them, I think that the regulatory agencies still don’t recognize them as rigid enough. And so I think that, it’s important that we stick in this stage, you know, with the traditional approach. And I think that-that for research purposes, certainly the N of 1,  very, very interesting, you know, design, that needs to be explored.


Gordon: What are you really excited about right now?

Luigi: [Laughs] Um, I’m-I’m excited about the study of aging. you know, Why? Because I think that we have made a massive effort to understand the mechanism of aging. But if you think about it, what we’ve found are not the mechanisms of aging. They’re focal [old marks] of aging. The old mechanisms oppose aging.

Gordon: Yeah.

Luigi: You know, my [unintelligible], mitochondrial function. And so what we have discovered are the mechanics of life —

Gordon: Ah.

Luigi: — the roots of the mechanics of life. And only [unintelligible] the mechanics of life, we can enhance the health of an individual. I call them the mechanics of intrinsic prevention. We have a classic mechanism of intrinsic prevention within us. And if we could enhance them, there will be much more powerful than any [amount] of prevention that we have done so far. To me, that is the future of medicine because I think that the prevention that we have done so far is kind of hitting a ceiling. We’re not seeing in the population very much more improvement. And so I think that changing the direction and acting on announcing the mechanics of intrinsic prevention, it’s very hopeful for a better future where, you know, we compress morbidity. I don’t think that,  stem longevity is something that,  we care very much for. But compression of morbidity, where everybody lives their life fully, and then in a short period of time, they get sick and die. I think  that’s the ideal situation that we want to accomplish. And I think we can. There is some evidence that we can.

Gordon: Thank you. That-that’s-that’s a-a really thoughtful and thought-provoking summary. Luigi, it’s delightful to talk to you. I could talk to you all day. Um,  but maybe we can — we can share a-a-a meal sometime soon.  

Luigi: I’m very happy to do that. Absolutely. It will be great.  


Thank you so much for listening. Please subscribe, share and give us a five star review on Apple, Spotify or wherever you get your podcasts. We’re Not Getting Any Younger, Yet! is produced by Vital Mind Media: the Buck Institute’s very own Robin Snyder as the executive producer, Wellington Bowler is right next to me here directing the recordings, Stella B is behind the scenes ready to debrief when we wrap, and the esteemed Sharif Ezzat weaves the show together for you. 

If you’re listening to this podcast, you know that there’s never been a more exciting time in the research on aging. Discoveries from our labs or moving into the clinic to help us all live better, longer. The Buck Institute depends on the support of people like you to carry on our breakthrough research. Please visit us at Buck Institute dot org to learn more and to donate.

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