Dr. ORAWAN Medical Center


The Art of Aging Well – Longwood Seminar

Something we all need to know about – the art of aging well.

Is age just a number? How will medical and technology advances redefine biological aging? In this seminar, learn more about research led by scientists at Harvard Medical School about what healthy aging means, and explore discoveries that could help to improve the experience of aging.

The actor George Burns, who lived to be 100, humorously once said, you can’t help getting older, but you don’t have to get old.  Was he right? Our experts will tell you. Tonight, the good news is that people are living longer and enjoying a higher quality of life than a generation ago. We have a better understanding of how diet, exercise, a positive attitude, and staying socially connected can help us age well. But what does aging even mean? Why do people age differently? And why do some people we know tend to defy the aging process altogether? And what are the latest discoveries that can help keep us healthy well into our later years? Many Harvard scientists are working to answer those very questions.

Dr. David Sinclair

The future of aging

Thank you, Gina. Thank you, everybody for braving the snow here in Boston, and welcome, everybody online to this Longwood Seminar series. We have three great talks to that tonight. Well hopefully, at least two, we’ll see how mine goes.

So I’m here to start the night off to give you some good and some bad news, OK? The bad news is that we’re all born– pretty much all born in the 20th century. And that means that we may not live to see some of the amazing things I’m going to talk to you about tonight, but the good news is that scientific progress is going extremely quickly and it may actually be that we were extremely fortunate to catch just the beginning of the equivalent of human flight, but for aging. And I was just sitting here with Professor Lipsitz talking about how privileged we are to work in this age where miracles seem to happen. And so in my first slide, I posed this question to you– what will be the largest global change over the next 30 years? And if you open any magazine or the daily newspapers as we used to call them, your iPad, you will see that there’s a lot of excitement in the tech world, mainly, about how our world will be revolutionized. One day pretty soon, we’ll be able to just talk in any room and have the lights come on– we actually can do that already, what am I saying? The future is already here.

But my point to you tonight is that in 30 years, these devices will seem like a blip in history compared to what is going to happen to our biology and to changes in medicine, because I’m very fortunate as the two speakers are tonight to have a front row seat of what is coming, and I’m really excited to be able to share with you some of that view here tonight. Most members of the public have no idea how close we are to some really astounding medicines coming down the line, and I really– I get up everyday out of bed thinking, I just can’t wait to see what comes next. OK, so here’s a young boy. He happens to look a bit like me.

According to this genetic test that he did, he is related to me. Thank goodness. Or my wife would have been in a lot of trouble. So Benjamin here is a new breed of child in the developed world and increasingly across the planet that will be able to live in a world that we can barely imagine, and I hope after tonight, you will be able to imagine. So Benjamin here is taking a genetic test just by spitting into a tube, and he gets back a report that tells him where his ancestors came from, how much of the right arm of chromosome he got from his grandparents and great-grandparents.

And we’ve actually genotyped our entire family, so we can use this not just as an educational tool for our kids, but to teach them how they’re going to be able to get through this coming century. And I don’t say that lightly. Benjamin was born now 10 years ago, but there’s absolutely no doubt that he’s going to see the 22nd century unless he’s very unlucky. Most kids who are born today will be able to be healthy into the 90s and even into their 100s, and that’s if we don’t have a breakthrough. The kind of breakthrough that I’m talking about tonight could have us living even further in a healthy way, and that’s the main point. So this is a snapshot of many of my family members in 2005, OK? So we’re now going back 13 years. And just to orient you, we have my grandfather on the right, my grandmother in the middle at 80, my mother who at the time was 62, and my father who was 65. And this is my wife down at the bottom right.

I show that because out of all of the people who have numbers above their heads, only one of them is still alive. The other three lived fairly horrific moments for the last few years of their life. Now we’re talking about brain aging. Now brain aging is one of the most traumatic of any process to happen to humanity. If anybody here– and I’m sure many of you have had family members who’ve experienced some dementias, Alzheimer’s is just one of those– you know how horrible it is for not just the individual, but particularly on the families themselves.

And people can spend a decade in this state. In fact, I put it to you that actually half of the population, the adult population of the United States has at least one chronic disease, and that is what we spend 86% of our health care on. So what if you could greatly reduce the amount of chronic disease? And instead of just keeping one organ or tissue healthy, which is what we do when we go to the doctor and get a statin for your heart and pill for your blood pressure, that’s great, but what about the rest of your body? And throughout the 20th century and to this day, most researchers and clinical trials here in Boston and throughout the world are focused on treating one disease, but we now have the knowledge and clinical trials in progress where one medicine can treat potentially 20 different diseases, and as a side effect, you’ll live longer and healthier.

So we’ll get to who’s still alive in a minute. Now often I’m asked, Dr. Sinclair, Professor Sinclair, aren’t you worried that you’re dooming us all to overpopulation and who wants to be old anyway for longer? And what I’m trying to show on this slide here, hopefully it’s clear is that if we’re successful, at a minimum, what we’re going to have is that the last decade or so of life or even longer is going to be just as healthy as you felt when you were in your 20s and 30s. And I know it’s possible. There are many of us who are genetically and soon pharmacologically will do this, and we’ll hear Professor Touroutoglou talk about that.

So hopefully I’ve convinced you this is a valid pursuit. I think I’m preaching to the choir here, but often people forget that we’re not keeping people older for longer, we’re talking about keeping people younger for longer. So that you don’t have to worry about getting cancer in your 60s or heart disease and have a stroke in your 70s and 80s. And we can do this very easily in the lab. I have mice that are around this vicinity– well, my lab is upstairs– that we can keep mice alive for a lot longer and they die fairly quickly and painlessly as far as we can tell, and this is what the future offers. And when this happens, we’ll look back at today and we’ll say, wow, I would never go back to those days. The same way we look back at the early part of the last century where people would die from an infected splinter. So how is this possible, you may ask. What’s been the big breakthrough? And the biggest breakthrough has been the realization that our bodies are not just simple cars that wear out, that’s the old view of aging.

And of course, by this analogy, there’s no way anyone could develop a drug that could fix everything, because all different things break down. It would be as if we throw a wrench at this car on the right and it made everything work again– that’s impossible. But our bodies are much more complicated than a car. It’s the equivalent as if we found the body shop repair people. Our bodies are capable of immense repair. They just lose their memory on how to do that. They become less and less able to repair themselves. If you take my son, for example, he gets cut, he gets an infection, he will heal very quickly.

Why is it that as we get older, that declines? And eventually it becomes so bad that you can die from an infection when you’re old? We believe as a field– not just my lab, but a whole group of hundreds of labs around the world– that we finally understand how it is that the body when it’s young can fight disease but cannot when we’re older. Not only that, not just disease, but how do we feel– why do we have more energy when we’re young than when we’re older? Why do we groan when we get up out of a chair or out of bed as we get older? We take it for granted. It’s almost so common that we don’t even ask the question, why does this happen? So the good news is that there are sets of genes that researchers throughout the world have discovered that control our bodies’ health.

Now there are some ways to make them more active. Now we know that exercise and being lean and dieting, eating a good diet are good for you. Even eating a Mediterranean diet and eating these molecules from stressed-out plants is good for you. Why is that? And I don’t believe that it has anything to do– or not very much to do, I should say, with antioxident activity. What’s going on is that you’re activating the genes that repair the body and tell the body to be in a fitter state and try to survive during these times of adversity when we’re running and we’re hungry.

Some of those genes are called the sirtuin. There are seven of them in your bodies. Everybody has them. Without them, you’d be in real trouble. But we can engineer mice to have more of these genes, and in many cases, the mice are healthy. And in a couple of cases, a couple of the genes, the mice lived longer, and they lived longer because they didn’t get the diseases of old age. Now we can’t genetically engineer ourselves, at least not yet. There are certainly some people here at Harvard who are working on some genetic therapies to help people have a better genetic repertoire, particularly to repair what’s lost over time in terms of genetic disease. But let’s just say within our lifetimes, most likely what’s going to be beneficial to us are drugs that are developed through the traditional route.

And what’s exciting is that we now know how to do this. It is no longer surprising to anybody in my field that within the next five years, somebody is going to make a drug that doesn’t just treat heart disease, but treats almost every disease that we get when we get older. And I’m not the only one doing this anymore. I used to be one of the few people– there’s almost every month there’s a new big discovery and/or a new company that started to make this come true. So in my research, what we’re looking for is a molecule that activates these sirtuin pathways that I just mentioned, the genes that we believe make you fitter when you exercise and when you diet. Now this is quite a remarkable molecule. This is called NMN. Don’t confuse it with M&M’s.  M&M’s are not as good for you. NMN is what the body uses to make a molecule called NAD.

Now NAD turns out to be a remarkable molecule. It’s very small, it’s just a chemical. It’s related to vitamin B3. And what we used to think in– when I was back in high school, was that NAD was just important to keep chemical reactions going in the body. All it did was housekeeping, not that housekeeping is a bad job, it’s just that it’s not particularly exciting. What was discovered about 20 years ago is that NAD also controls the body’s defenses against disease by activating those sirtuin enzymes that I told you about. So now what we can do is we can feed cells and even animals and even people in clinical trials molecules like NMN and get their NAD levels up, boost their NAD– these are called NAD boosters. And what we see is really quite remarkable in the animal studies. And very soon, we’ll know if this works in people as well. Now you might ask, Dave, why you boosting NAD if we already have a lot of it? Well first of all, NAD is extremely important. Without it, you’re dead in about 30 seconds, so you want NAD.

But do we have enough? Well, we definitely have enough, I think, when we’re in our 20s. My son has enough. If you took his blood and measured it, he’d have abundant amounts of NAD. The problem is, that by the age of 50, you have half the levels that you had when you were 20. And as a result, your chemical reactions aren’t just slower, more importantly, your body doesn’t fight against diseases anymore the way it used to.

So when we give old mice this NMN, what we do is we just put it in the water supply and they drink it for a few weeks, and then we ask, what happens to those old mice? Let me show you what happens to these mice. Now I admit that these are black mice on a black treadmill, but hopefully you can focus on their tails and their ears. Now one of these mice has been drinking NMN for a few weeks and one of them has not. And this is fairly a typical result.

We are about to tell the world in a publication that we are able to greatly increase the endurance of old mice back to the levels when they were young again. And the way this works is it actually builds new blood vessels in the muscle– and we think in the brain as well– to be able to get rid of toxins in the body up as they build up during exercise and during aging. So this is great. What this means is if this could be done for humans, for us, we could take a pill every morning and get the benefits of exercise without having to necessarily exercise.

OK? It sounds too good to be true. And I agree, it does sound too good to be true, except so far, it is true. This is cutting-edge science, this is in the world’s best scientific journals, so hopefully it will translate to people. You might ask, is this an excuse just to sit around and pop a pill and eat chips? The answer is no, it’s not an excuse, because if you’re fit and you take this molecule, if you run while you’re drinking this molecule or you drink it and then you go for a run, these mice now can run more than twice as far than they did. We are developing super mice here. Now we just had the Olympics, I’m not sure what’s going to happen at the next Olympics if this turns out to be true, but what it means is that we’re finally potentially able to reach the best that our bodies can give, not just when we’re young, but even into our older age, so that we don’t groan when we get out of bed in the morning.

And in fact, if we start to lose our mobility and we’re stuck in a wheelchair or bedridden, it’s those people that would absolutely need exercise in a pill– for those people. And imagine if they could start walking again or exercising again and get the benefits of that, that would be a beautiful positive cycle that doesn’t just allow them to exercise, but to get the rest of their body up and active and their brain– more blood flow as well, which we’ll hear later, I’m sure, about the importance of that. So this molecule, others as well have worked on it for years. For the last five years, we’ve seen that NMN and a molecule related to it called NR, when given to old animals, protects them against a whole variety of diseases– diabetes, memory loss, hearing loss, eye sight loss, inflammation, it even improves wound healing. This is, as far as I can tell, the closest thing to a reversal of aging. So we’ll see how far we can go and whether this will actually turn out to be true in people.

The good news is is that so far, a very safe molecule or group of molecules. I mentioned that it’s basically a super vitamin. The other good news is that this is a naturally-occurring molecule, we all have NMN in our bodies and NAD, we just lose it over time, and all we’re talking about is replenishing those levels. So there’s a clinical trial that’s ongoing here at Harvard Medical School and at the Brigham and Women’s Hospital, and it’s a very exciting time for my colleagues and I to see whether we can translate the last 20 or so years of amazing discoveries in animals finally through to people. Now I’m under no illusions that this is going to be easy or that it’s going to be quick. Most clinical trials are in the hundreds of millions of dollars, and they also cost, in terms of time, it’s at least five years.

But how long has humanity waited for something like this? And how big is the payoff? It’s in the trillions of dollars in the economy. That’s money that can be put back into other things such as education and the environment. And we will not have a greater GDP, we’ll actually– or loss of money in the economy, we’ll actually have a lot more money to spend if we’re able to keep people healthier for longer towards the end of their life. And I’m not an economist, but all economists that study this say, this is the best bang for the buck in terms of the health care system, and if we don’t do something, we’re in trouble anyway.

So let me just finish now by highlighting the member of our family that has survived. My father is now 78. He’s in Sydney, Australia, where he landed after escaping Hungary in 1956 with my grandmother. Now out of all the people that I’ve mentioned here in my family who had numbers above their head, my father was very interested in our research and started taking some of the natural molecules that we were discovering about a decade ago.

Now for those of you who say, Dr. Sinclair, you know, a science experiment needs more than one person, I’m absolutely aware of that. I’m not going to publish this result any time soon. But it is interesting. He’s certainly not dead yet. In fact, he’s gone from a person who was not looking forward to the next 10 years of his life– he had retired, he was slowing down, he didn’t expect to live a lot longer than another 10 or 15 years. So what’s happened to him? This is what he did last year. That should say 2017. So the top left is he’s climbing trees in Germany and putting on skis up on the ziplining. Top right is he’s going up to the tallest mountain in Tasmania in Australia. The lady on the left with the red t-shirt is my ex-girlfriend. Go figure. I have nothing– I have no problem with that. It’s my wife who feels it’s strange. He’s climbing in Montana. He was doing abseiling or rappelling down a mountain. He’s gone caving, he’s riding these bikes, he went whitewater rafting.

And just about everywhere he goes, people say, we haven’t had somebody your age do this before. So again, it’s just one anecdote, but what I would like to make the point, if nothing else, is that this is the way the future will be. This is what we’re aiming for. The people in their 70s, 80s, and beyond will be able to have a life that isn’t just pain and sorrow for them and their families. And you know what? My father started a new career. He was so optimistic about the future, he started working for a nonprofit at the University of Sydney, he now actually oversees clinical trials. But at his age, when I first showed you him, if I had said, you’re going to start a new career when you’re 77, he would have said, tell me another one. So he’s got a new lease on life, I’m really looking forward to seeing how he does over the next decade or so– and so is he, by the way.

So finally, I just want to finish up by giving you a little insight into how far some of this can happen. Again, I did an experiment– I like to experiment. And sometimes we experiment on ourselves. Now I hope you can see that– this is a line from a local company called Inside Tracker, and in full disclosure, I advise that company. But they’re the only group that I’m aware of that has a true scientifically-based algorithm to be able to estimate what your biological age is. And so I said, sure, analyze my blood. They’ve analyzed thousands of people now. And so they took blood samples, and you can see, I hope, that although I’m only– at the time I was 46 or so, I was about 10 years older based on their algorithms. And they measure five things– glucose, testosterone, and a few other things that basically correlate with longevity. And I was not looking very healthy and I thought, this would be really bad if I died young.  So I decided to do something about it. And what I did was– first thing I did was, I was more conscious of what I ate.

And I lost some weight, I lost about seven pounds, which didn’t hurt, OK? Full disclosure, that’s one of the best things you can do if you have a little bit of overweightness. But also what I did was, I tried some of this NMN molecule. We had some that was safe in mice and I was prepared to try it. And what you can see over the next few months is that this company came back with– they didn’t even know what I was expecting, they just came back and they said, your blood test now predicts that you’re 31.4 years of age. So I jumped for joy. This is fantastic. Now I put on a little bit of weight since, but the point being is that if this is true, then it is fairly easy to give yourself some extra life, and that’s really what we’re talking about today. And I’m very excited to hear the next two speakers that will tell us even more exciting things about their work in the species we call human beings.

So thank you very much. I appreciate that.  So now without further ado, I want to invite Alex. Alex Touroutoglou is a worldwide and renowned expert in human aging and I can’t wait to hear what she says.

Alex Touroutoglou – superagers

Thank you. Thank you very much. So it’s a pleasure to be here. I’m going to present SuperAgers to you, and I think David’s father is probably a SuperAger. Let’s look at the SuperAgers. Let’s see what are the SuperAgers. We all know that the memory and cognitive decline usually with aging. For example, with the young adults, scores about a 13 on a memory test. Typical older adults usually perform much worse. But there are some people around 60 to 70 years old that continue to perform equally or even better than young adults 40 years their junior.

This unique group has resisted the cognitive decline that is typical in aging. We call this group the SuperAgers. We will start out by describing what is a SuperAger. And I would like also to show you today how their brains are different. As neuroscientists, we had to gather the SuperAgers to come into the scanner, look inside their brains to uncover their secrets. There are several ways you can look at the brain using MRI.

You can look at the brain structure, you can look at the brain networks, the brain activity, and you can look at what parts of the brain become activated when people perform a task. So I’m going to present today three studies to understand the superaging brain. Study one will look at the brain structure, study two will look at the brain connectivity in SuperAgers, and study three will look at what parts of their brains activate when they’re performing a memory task.

Let’s begin by describing the definition of SuperAgers. One of the reasons why I believe our studies are exciting is because we are focusing on people around or just about– just after their retirement date, mostly in their 60s and their 70s. And we’re interested to see who perform– what older adult is it that performs as well as young adults in their 20s. Based on the laboratory testing, we give them a memory test, a memory test that includes 16 unrelated words. The challenge is that older adults who will have to memorize this list and later on recall– repeat this list after 20 minutes.

Most older adults will recall after a delay between eight and 10 of those words. Young adults will remember 13 or more words. SuperAgers will also remember 13 or more words, and in some cases, they will remember as many as all 16. So it is really remarkable for SuperAgers, for this group that is around 70 years old to have a memory, sharp memory, the same memory as someone four or five decades younger. So based on our laboratory testing, we define SuperAgers as those older adults who perform equally or even better than younger adults 40 years their junior. First we looked at the their gender and education and we found no difference. There was no difference in neither gender nor education between SuperAgers and typical older adults. In our study, it turns out that we had 17 SuperAgers and 23 typical older adults who did not meet the superior memory criteria. So next we asked, what makes a SuperAger a SuperAger? So we looked at the structure of the brain in study one.

We used MRI. Mass General Hospital is the first US hospital to establish a diagnostic and research program specific to MRI. MRI uses strong magnetic fields to create images of biological tissue– in our case, the brain. I present here a schematic organization of the scanner and the control systems that we are using. In addition to the scanner, we are using a series of amplifiers and transmitters that are responsible for recording the data and for sending the MRI signal into the powerful computers where we analyze our data in our laboratory.

In study one, we measured the thickness and the size, the volume of gray matter. Gray matter is the part of the brain where all the thinking and sensing is actually happening. There are several ways that you can display the MRI data on structural MRI scans. One way is to use a volume template. Another one is a folded brain or an inflated brain. I will be using both volume and inflated brain to present– to show you the data. OK, so let’s look at the data.

Let’s look what study one showed about SuperAgers. We looked at their cortex. The cortex is the outer layer of brain cells that is really important for our critical thinking abilities. We knew from previous studies that the cortex as well as other parts of the brain typically shrink with aging. We compared the brain scans for SuperAgers, typical older adults, and younger adults. And what we found is that as you see here, the red blobs, we found all of these regions were thicker in SuperAgers than in typical older adults. These are the areas where there was more gray matter in SuperAgers. And it’s not just a few regions, it’s distributed all throughout the cortex. I group them based on their function, and as you can see, those that are included in the blue outline are important regions for attention, and those that are included in the yellow outline are regions that are important for memory.

Remarkably, some of these regions were truly youthful. And when I say youthful, I mean they were statistically indistinguishable from young adults, as we will see in the next slide. You can see here, the bar graph shows the cortical thickness in these two example regions, the medial prefrontal cortex and the mid-cingulate cortex. The thickness in SuperAgers was the same as in young adults. It was thicker in this region than typical older adults, but it was about the same with the young adult. Same here in the medial prefrontal cortex, this region showed full preservation. It was noticeably thicker in SuperAgers than in the typical older adult, but it was statistically indistinguishable– comparable in size with young adults.

As Hippocrates once said, “It is far more important to know what person the disease has than what disease the person has.” So we looked inside each individual brain to better understand the brain of SuperAgers. And here we are. Looking inside the brain, we realized that if we measure the size of brain regions, we can predict how the individual is going to perform on the memory task. We measure the brain size before the task, we’re able to predict how that individual will perform on the task. You can see here that this individual, who had the largest hippocampal volume, performed among the best in memory. And this individual, who have the smallest hippocampal volume, perform among the worst in memory. Hippocampus is a deep brain region which is really important for memory. So the larger the hippocampus, the better the memory. Summarizing the data from study one, we saw that although memory decline may be the rule, there are exceptions.

SuperAgers show youthful brain structure in important regions for attention and memory. The thicker the brain regions, the better their memory performance. But in order to understand the brain, it’s not enough to focus on the brain structure. The brain structure is not the whole story. You need to understand its wiring as well. Brain activity is important for understanding the brain because no brain region is an island. Brain regions are connected with each other, they communicate with each other, and they are part of a network.

And when regions are part of a network, they ordinarily talk to each other and they function together. A growing number of studies have looked at the aging brain from the perspective of networks and brain connectivity, and there are several theories that have suggested that cognitive decline in aging may be the result of disruptions in brain connectivity. So we looked at the brain connectivity and we wanted to compare the SuperAgers to typical older adults, and again, to young adults. And here are the data. As you can see here in red-yellow, these are the regions where the SuperAger were more strongly connected than the typical older adults. There was no region in typical older adults that had higher or stronger brain connectivity than SuperAgers.

So the SuperAgers were more networked. Their brains were more networked. Again, as we saw in the anatomical data, you can see here that the strength of connectivity in SuperAgers were noticeably stronger than typical older adults, but it was actually comparable in magnitude with young adults. We also looked for another clue in the individual brain. Here, we measured the connectivity in the region deep inside the brain, the hippocampus and in the cortex, the posterior cingulate cortex. And we found that SuperAgers had stronger connectivity in these areas, and the stronger the connectivity, the preserved connectivity also predicted their memory performance. Stronger hippocampal connectivity, better memory performance for older adults. Taken together, the data from study one and study two, we’ve established that SuperAgers show youthful structure and youthful brain activity. They do not have only preserved neuroanatomy, their brain networks are also preserved. But if you think of SuperAgers as an extreme group from typical older adults, it’s not enough to simply show preserved anatomy and preserved connectivity, you need to see how these groups are prone to memory problem differently if there is a difference.

You need to see what is the difference between them when they are actually performing the task. And that’s what study three sought to do. So in study three, we measured the brain activity in response to a task. We looked at what parts of their brain light up, activate when they are performing the memory task. So we put them into the scanner, we give them a memory task, and we were watching their brains. fMRI is the first fMRI technique was discovered by Jack Belliveau in 1990 at Mass General Hospital and the research facilities where we are actually conducting our imaging studies. In 1991, the prestigious journal Science published his paper and they also got his image of the first scan on their cover. After that, the fMRI became widely available and allows scientists now to study the brain in a noninvasive way. The basic idea is that you look at the brain and you try to identify hotspots of brain activation in response to tasks.

And here are the data. The brain maps here show the hotspot– the regions of hotspots of activation in SuperAgers versus typically older adults. Before I talk about what we do see here, the hotspots of activation, let me just focus for a moment on what we don’t see. And notably, these are the regions that are traditionally involved in memory. SuperAgers and typical older adults performed the memory task in the same way in terms of memory regions. They activated equally at the same degree their traditional memory regions. The difference lied in another region. The difference lied in mid-cingulate cortex, a region that is implicated in many functions, but importantly, for motivation. When this region is being stimulated, it elicits the will to persevere. So this means that SuperAgers approach the problem differently than typical older adults. They were more motivated, they did not quit. And not surprisingly, when we extracted the signal from this area, we found that those individuals who activated the mid-cingulate cortex more, they did better on memory performance. So taken together, the data from studies three, we found no differences in the memory regions when SuperAgers and typical older adults performing a memory task.

But we did find a difference in a region that is really important for motivation, in what I call tenacity. This region is important to push forward when you face difficulties and you face a challenge. Summarizing the three studies together, all of our superaging work, I wanted to show you today what makes a SuperAgers a SuperAger? Well for starters, a young brain in an older body. We’re trying to piece together the puzzle of the superaging brain. It’s a puzzle that is far from complete. We’ve seen that SuperAgers have avoided that memory and cognitive decline. They show sharp memory despite their age. They have youthful structure, useful brain connectivity, and when they are faced with a difficult task, they become tenacious. We believe that understanding SuperAgers is the first step towards understanding successful aging. If we can understand what makes them SuperAgers and what makes them to remain youthful memory abilities, then we are one step ahead understanding what healthy aging might mean for all of us. I’d like to close by asking one important question– can you make a person a SuperAger or are you born with it? And with that, I’d like to thank you, and introduce Dr. Lipsitz to hear about all the interesting data about healthy aging.

Dr. Lewis Lipsitz – geriatrics

Thank you, Alex. Well thank you, Alex. I’m just going to take a second to pull up my slides here. Well great, good evening, everyone. I am a geriatrician, which means I’m a physician who cares for older patients, as well as a clinical researcher. So what I’d like to do is speak from the perspective of a geriatric doctor– that doesn’t mean that I’m old, but that I study old– and share with you some of the new developments in clinical research and aging. Curiously, aging is a young field. A century ago, very few people lived to old age.

In fact, the average life expectancy in 1900 over 100 years ago was only 47 years. And as you’ve probably heard in the media, now 10,000 members of the baby boom generation, which includes me, are turning 65 every day. In fact, that was old news– now it’s 10,000 people turning 70 every day. This means that older people over age 65 will soon comprise 20% of our population, and as a result, as you’ve heard, there are enormous social, medical, economic, and ethical challenges that will be facing us. But there’s a lot of optimism, because there are a number of opportunities, which I’ll share with you, to apply advances in science and engineering to improve the health and well-being of older adults. This just illustrates the fact that the world is rapidly aging. You can see a variety of different societies here, and Japan leads the list in having the most rapid growth of the older population. But this is occurring in the United States as well, and the estimates are that by 2030, the number of people over age 65 will double from about 35 million today to 72 million.

And those over 85 are one of the fastest growing segments of the population, and that will double from about four million to nine million by 2030. So this is a huge change in our society. Currently we have about 13% of the population over 65, but they account for about a third of all hospital stays, and almost 50% of the days in the hospital that a patient might spend, and 50% of the hours a physician spends with a patient, costing Medicare $26 billion. So as you can see, aging is us and aging is expensive. That’s illustrated here by this story that says, I’m sorry, we’re bombarded with aging boomers, so come back in about 20 years for your health care system. Unfortunately, our health care system has been slow in adapting to this baby boom population. But the good news is that life expectancy is increasing.

The yellow line here illustrates the life expectancy or the survival pattern of people in 1900. And you can see, there was a big drop-off actually before the age of 10 due to early childhood diseases, which we’ve now conquered, pretty much. And as time has gone on, more and more people are living to older age. We generally speak of life expectancy as the number of years a baby born today can expect to live. And you can see here in these successive curves that life expectancy is increasing over the years from 1900 to 2000. But another concept is lifespan, and lifespan is considered the maximum number of years a given species can live. And it used to be thought that our lifespan really was capped at about 100 years of age. But as you’ve heard from Dr. Sinclair, there have been some very exciting advances that suggest that maybe we are going to be able to increase the lifespan as well as life expectancy. In fact, it seems also the older you are, the longer you live. These are actuarial tables that some of our actuaries used to decide how much insurance we should pay, but you can see here that today, a person about five years old can expect to live to about 82 if they’re a man or 86 if they’re a female.

Curiously, women have always lived longer than men. They are the stronger sex, I must admit, this is true until very late in life. So the older you are, the longer you might expect to live. So an 85-year-old today might expect to live to 93 if they’re a male and the same age if they’re a female. So the key to this is live to 85 and you’ll have a good chance of living even longer. But that’s not enough.

We don’t want to just live to a ripe old age, we want to live to that age without disability. And I think Dr. Sinclair demonstrated this quite nicely in his slide, but the goal of us in geriatric medicine and researchers in the field are to decrease the duration of disability. So this top line really shows the situation today. At about 55 years of age or so, people begin to accumulate illnesses that eventually result in more and more morbidity or disability, and ultimately, perhaps at age 76 or so, they might experience death.

One goal is to extend the life maybe to 80, 90, 100 years of age, but if we didn’t do anything about disability, all that would do is extend to the number of years, increase the number of years in which we had to suffer with disease and disability, and of course, that’s no good. So what we need to do is shift to the right the time at which we might develop disability, and as well as increase our lifespan. Ultimately, what we hope to do is shrink morbidity– in other words, delay any kind of illness, any kind of morbidity or disability until the day we die, and then suddenly drop off with a healthy life the entire time. And that’s what Dr. Sinclair and other scientists are now beginning to show us that we might be able to do with some of the new innovations in aging research.

Well this lists some of the challenges, though, that we all experience in the cycle of aging. As you know, at age one, the challenge is walking. By age two, it’s keeping dry, you know? At age 16, it’s driving; at age 20, the challenge is having sex; age 30, having kids; age 40, working; age 65, retiring. And then the cycle begins to repeat itself. At age 70, having grandkids; age 80, having sex; age 85 driving; age 90, keeping dry; and age 95, walking.

So this is the cycle that I think we’re all familiar with. But as we age, there are two problems that worry us all, and certainly, I think it’s true that most of us worry about the loss of memory and mobility, these are major, major problems that we in clinical research need to tackle while we wait for Dr. Sinclair and his colleagues to find a way of curing all illness so that we can live a long life. So let’s look at these. Memory loss, of course, is a very prevalent problem. Currently, about five million Americans have Alzheimer’s disease, and about a third of older adults ultimately die of Alzheimer’s disease or other dementias. This is the sixth leading cause of death in the United States, and for the first time, our government is actually putting a lot of money into studies to try to tackle this problem.

But the problem is not just in the person who suffers from this disease, it is also a problem for the 15 million caregivers who provide more than 18 billion hours of unpaid care to help manage their relatives and friends who have Alzheimer’s or other dementias. In 2017, Alzheimer’s disease cost the nation $259 billion, and this is expected to rise to $1.1 trillion by 2050– huge problem. So what causes Alzheimer’s disease? Well, we don’t really know yet, but we do know that if you look at the brains of people who have died of Alzheimer’s disease, there are two proteins that gather in the brain and cause damage.

One of them on the left here is the amyloid plaque, shown as this yellow schmutz here. And on the– technical term, that is. And the right here is neurofibrillary tangles, which are these dead neurons that have in them a protein called tau. So one of the challenges is, if these are truly the cause of Alzheimer’s disease, we need to get rid of these toxic proteins. So much of the work that’s being done in laboratories around the world is to try to think of new drugs that can actually sop up these or prevent them from being deposited so that we do not develop Alzheimer’s disease. But one of the challenges is, you know, we can’t look at the brains of individuals to try to see whether we’ve been successful or whether they have Alzheimer’s disease, because that would require a brain biopsy, which we’re not going to do in living people. So we’ve been very fortunate over the last decade or so to have scans, like the MRIs you’ve heard about, but special scans in which we can actually image these toxic proteins.

And one of them is on the left here, this was a PET scan for Alzheimer’s disease that injected a Pittsburgh agent it was called, because it was invented in Pittsburgh, that can actually light up amyloid in the brain shown here in these yellow and orange MRI scans. In people with Alzheimer’s, you can see a lot of this amyloid, but in controls who are normal, you do not see it. So now, having this scan, we’re able to actually look whether new drugs can get rid of these amyloid deposits, and much of the research going on today is trying to get rid of these amyloid deposits earlier in life before people develop the disease.

And on the right is just another scan that looks at the ability of the brain to use sugar or glucose, and you can see, a normal person on the right has lots of activity, lots of red and yellow, while the Alzheimer’s patient loses that ability. We’ve been working on many therapies for Alzheimer’s disease, and I wish I could tell you we have a cure, but we don’t. In the meantime, though, we need to be able to treat the disease. So there are many therapies that might slow the progression of the disease that are listed here. Some of them increase a transmitter in the brain called acetylcholine, and you’ve probably heard of drugs called Aricept, Exelon, Reminyl that can do that. And they might slow the progression– they’re not dramatic, but they have some effect. And the same is true of a drug called Memantine which can prevent some of the damage in the brain. But something you all can do is reduce your cardiovascular risk factors. Because we know that the same factors that cause heart attacks and strokes are also related to Alzheimer’s disease and other dementias, particularly vascular dementia.

So we need to treat hypertension, treat high cholesterol, and treat diabetes or prevent it in the first place earlier in life to prevent these diseases. Dr. Sinclair mentioned oxidative stress, we used to think that if reduced oxidative stress in the brain, that might reduce this disease, that has not been met with much success. We also are aiming to prevent the inflammation that these toxic proteins cause. And also, as I mentioned, we are trying to develop drugs to reduce amyloid or tau deposition in the brain, and there are many drugs being tested and many scientists are looking for vaccines to sop up these abnormal proteins. But another thing that we can all do is become involved in mental and physical exercises.

Do those brain tests that the SuperAgers are doing. That might, in fact, enable you to become a SuperAger. We know that the aphorism, “we use it or lose it” is true. People who have remained active throughout their lives are engaged in cognitive activity tend to have less risk of Alzheimer’s and other dementias, so it’s very, very important to engage in activity. And one study I always like to refer to is one that actually took a group of older people from a community and invited them to volunteer teaching children in elementary school classrooms in Baltimore, this was called the Experience Corps.

These people who came to the classroom and taught these young children had brain scans actually similar to what you just heard to look at the brain activation before and after this activity. And they were compared to a group of people just like them who did not participate in teaching these children. And you can see, in the blue areas are parts of the brain, using this functional MRI, that were activated more in the volunteers than those controls. And you can see on the right in the blue lines that the activation during a number of cognitive tests was actually increased in these people who simply volunteered to work with children in the classroom compared to the red, who were the controls. So remember, use it or lose it. What you’re doing today, sitting here and thinking, is really going to help you give you a couple of extra years hopefully without Alzheimer’s disease. So the second worry that we all have, of course, are mobility problems, and these are quite prevalent.

About 30% of community-dwelling older people fall each year, 50% of nursing home residents fall, and this is associated with lots of injury and costs of as much as $31 billion. This is not a hambone, but a human thighbone here– this is the cross-section of a thigh of a healthy young person. And you can see the bone up here with the marrow in the middle. And you know what this yellow is? It’s muscle, and the fat is red. Keep that image in your head, because this is the same cross-section of a thigh in an 80-year-old. And what’s happened? They’ve lost muscle and they’ve developed fat.

Now we used to think this was inevitable, that all of us develop this as we age. We used to think, shown here, that muscle mass declines with age in all of us. But in fact, activity level also declines with age, we all sit in rooms like this all day long, and it is the activity level, the sedentary lifestyle that is actually responsible for much of the muscle loss– not all of it, but much of it that occurs in older age. And the good news is that resistance training can actually improve muscle strength and muscle size at any age. We took a group of 100 frail nursing home residents who were as old as 98 years of age and had them go through 10 weeks of progressive quadriceps resistance training, just lifting weights with their legs. And we found a 113% increase in muscle strength, a 12% increase in walking speed, a 28% increase in their ability to climb stairs, but only a 3% increase in the muscle area, so we got a big bang for the buck.

For that small amount of muscle size increase, we got a lot of strength increase. So it’s never too late. We should continue exercising or take that pill David’s been talking about. [LAUGHTER] I won’t go there. So a common cause of falls that we’re all interested in is multitasking. You know, you’re all– probably some of you are probably doing it– taking pictures, walk– looking at your cell phone, driving while texting– we multitask all the time.

This man is walking across the street while he’s reading the newspaper, not a good idea. Multitasking we can actually test in the laboratory by having somebody stand on a balanced platform and measuring their actual balance shown here, and this is what happens, these are all the movements that you make when you’re standing presumably still on a balance platform. We then ask that person to do what’s called a dual task. They can stand here and count backwards from 500 by threes, and when they’re standing, and counting, look what happens to their balance. They’re now swaying all over the place. And what we can do with that is draw a circle around this and look at the degree of sway. We can then compare those two circles and compute what’s called a dual task cost. So this is the cost of doing two things at once– so texting while driving. And we can use that cost as a measure to look at how bad your balance is when you’re doing too many things at once, when your brain has to control many things simultaneously. So we can actually improve dual-task costs with a number of different interventions, but one we’re using is electricity and magnets to stimulate the brain.

This is one of our subjects. You’ve all heard about brain stimulation. This is deep brain stimulation that’s used for Parkinson’s disease, but we’re actually using transcranial magnetic stimulation to try to enhance the activity of the brain, or what’s called transcranial direct current stimulation, just a little C-cell battery, you know, attached to your head can actually stimulate certain areas of the brain. When we do that, we could look at a given individual– in this case, it’s just a 72-year-old woman– and we can look at their dual-task cost of standing or their increase in sway during the balance test. We can then give them some electrical stimulation of the brain and measure the reduction in that cost. So this is a very exciting, non-invasive intervention that people can do at home that will hopefully eventually lead to a reduction in falls and many older people. And I expect also to do this when I’m slumping over my desk about 1:00 in the afternoon feeling tired, just put a little C-cell to my forehead.

We did 10 daily sessions of this transcranial current stimulation and showed that it could actually improve the dual-task costs to balance. Well one final intervention I’d like to share with you is about vibratory shoe insoles to improve gait and balance. We developed a little insole that can go into the shoe and it vibrates a little bit– you can’t even feel that vibration– and showed that it was able to improve walking and balance in older people.

And this is based on a physical principle called stochastic residents that says that a little bit of noise can improve your ability to sense things. Here, you can see what the ground does on the bottom of your foot. You can see that here. This is just the sensation of the foot as it stands on the ground. But when we superimpose a little bit of noise, that sensation is enhanced. And by doing so, we can actually improve gait and balance. Here is a picture of the insole, it can fit inside your shoe and a little battery can sit right on the laces here. And we can actually test your walking on a little gait platform shown here. So as we walk somebody on a little gait mat while they’re subtracting 7’s, you can see, here’s what their walking pattern looks like, and it’s a bit irregular, they stumble a little bit, take short steps, long steps.

Later when we do it again with the insoles turned on, you can begin to see a more regular pattern, and here, we now have improvement in the gait pattern, and hopefully these will be developed in such a way that we can prevent falls. So the good news is, there’s a lot of positive interventions that might improve our experience of aging. We hope to be able to reduce disease and disability in old age, hopefully find a vaccine for Alzheimer’s disease. I believe we will all be seeing an increase in the retirement age and working to ripe old age of 70 or 75.

We’re developing elder-friendly cities and housing options within cities that have health care and services in the home so we can age in place and don’t need to go to nursing homes, hopefully not go to hospitals, and use personalized medicine to really emphasize our own personal goals of care so that we can live a healthy, happy life. It’s never too old for anything. Here’s a woman who’s skydiving for her 92nd birthday. This, I’m sure, will be David’s father in another few years. [LAUGHTER] So thank you all for your attention and interest.

[APPLAUSE] Do we have time for this? Yeah. All right, we have about 15 minutes of questions, thank you for sending those in, those in the audience. And also, we have some questions from around the world, our online audience. So we’ll see how far we get, we’re going to try and keep our answers brief given the time. So I have a question at the top, and this could be for either of you, tell me who wants to take it. The question comes in from Bangalore, India. Wow. Would this research help people who are already experiencing the onset of neurodegenerative diseases such as Alzheimer’s? Or would it only healthy individuals? Well, I’ll just say quickly that much of the research with people who already have later Alzheimer’s disease has not been that successful, so many of the new studies are looking at earlier disease. But it is very hopeful that we’ll be able to perhaps develop some ways of getting rid of these toxic proteins and other causes of diseases even in late life.

And much of our research, though, while that’s going on is trying to nevertheless improve the quality of life of people who already have Alzheimer’s and other neurodegenerative diseases. So I think while the research is going on, we need to really focus on the quality of life, even if people have Alzheimer’s disease. OK, this one’s for Alex. What are the age ranges and categories of SuperAgers, and what impact is there of exercise and blood flow? Nice question. Well, SuperAgers in our study were around their retirement– SuperAgers in our study were around their retirement age. About 62 to 80 years old.

They came from all different walks of life. There was no difference in education, no difference in gender as we said. Can we hear me now? Might have to hold it up. OK. Maybe– That’s good. Sorry. I was saying that they can– SuperAgers come from all different walks of life. There was no difference in SuperAgers and typical older adults in their education or their gender.

Exercise, exercise has been shown to improve cognitive function in older adults, and although we don’t know yet whether SuperAgers are involved in more exercise, we can predict is that SuperAgers are more active in their lives. Future studies will need to systematically examine and follow older adults longitudinally, and those that have developed to SuperAgers and those that do not to see their exercise pattern. All right. This is a question for me, I think. How long before you see NMN molecule becoming available to the public, and are there any downsides? Well, we’re in phase one clinical trials across the road here, and what that means is that we’re just observing the safety.

And then there’s phase two and phase three and these take a few years to get through at best. At worst, something will crop up and we’ll be slowed down. So it’s not going to be available as a medicine any time soon. A few years, maybe? If we are successful and lucky. That said, there are related molecules that are available, being sold. And I can’t vouch for those because they haven’t been fully tested in humans, but there have been a few clinical trials with supplements, and so far, they seem to raise NAD levels, which is what we see in the mice. But are there any downsides? Basically, is there a risk? Of course, there’s always a risk when you introduce a molecule into your diet. I mean, don’t quote me, I’m certainly not recommending you do this, but I can tell you for a fact that we haven’t seen any serious downsides or even anything to worry about in mouse studies. There’s a study at Washington University in St.

Louis, and they fed a molecule called NR, which is a relative of our NMN molecule– no, actually they also gave NMN for a year, and the mice– side effect was that they had slower aging and there was no physical downside. But of course, a mouse is not a human, and that’s why we’re taking the time to do these clinical trials to be sure that they are safe, because if we’re going to be taking these molecules, you probably have to take them for many, many years to have the long-lasting benefits. All right, I’m asking questions, OK. Are there any genetic signatures for SuperAgers? That’s a very interesting question. Perhaps we can collaborate, David, to see what’s happening. There are no studies that have linked genes to SuperAgers. This is really innovative research, there’s a lot more to be learned. I might just make a comment that sometimes SuperAgers are confused with centenarians, who are SuperAgers by the fact they’ve made it to age 100.

And there are many genetic studies now looking at a variety of genes, and there is no one gene, but there are some interesting possibilities of genes related in cholesterol metabolism, and depends on your culture and your background. But it’s not just the genes, it’s also the environment and the lifestyle and behavior that influences whether you’re going to make it to 100. Yeah, absolutely. Which leads us to our next question which has come in from Facebook, no country listed here– what is the correlation– if any– between weight gain and longevity? That one’s a simple one, I’ll take that one. Avoid weight gain. [LAUGHTER] In human studies and in mouse studies, it’s very clear that having excess weight accelerates aging– not just physically, but even at the molecular level, we see those changes accelerate. Obesity will lead to increased inflammation and a lot of chronic diseases that come. All right, I think that that one’s pretty clear. Is mitochondrial damage associated with aging? Yeah, the answer is yes, but we’re not sure yet if it’s a driver of aging or not.

Probably it is because if you damage mitochondria either in mice or unfortunately, there’s genetic diseases, mitochondrial damage, there are aspects of aging that you see happen to those individuals. And so it’s probably a part of aging, but it’s not the whole answer. And we don’t actually fully understand why we lose our mitochondrial function as we get older, but we are working on reversing that in my life. Ah, so this is for one of you two. Is brain activity related to brain plasticity? That’s also another great question. There are studies that have shown that when you perform a task and they measure brain connectivity right after you perform a task, brain connectivity changes. The strength of connections between the regions that were involved in the task increases, which suggests that yes, brain connectivity can be changed through neuroplasticity, through experience.

All right. A question from the audience– why is it so difficult to prevent aging in the brain? We don’t know if it’s difficult to prevent aging in the brain. There certainly are changes, we’ve seen that in the normals. It’s only recently been studied to see how plastic or how much plasticity, but we know the brain can change– that’s what this word plasticity is all about. That’s why when we use our brain, we can actually see improvements in many of the functions that we perform.

So I do think– I’m pretty optimistic about the fact that we can affect the brain, that we can change connections, we can improve it. But Alzheimer’s, when that occurs, that’s a disease. So I think in normal aging, yes, you can do a lot to keep our brains healthy, but when we get a disease superimposed on that, that’s when degeneration begins to take place. And to date, we haven’t found a cure, but an awful lot of work is going on to try to do that, and a lot of money is being put into research in this field. Also, just to add to that, I agree with Dr. Lipsitz that this is an area that is new and we don’t know if reversing brain aging is difficult or not. Very few people have tried this. I can tell you is that reversing aging in other tissues is extremely easy, and it’s quite surprising how you can reverse aging in just a week. One of the things that we’re now learning is that it’s relatively easy to improve blood flow in the brain, and that could be a large part of early stage dementia, vascular dementia is a huge problem.

And you know, whenever we make a great breakthrough in science, what we end up realizing is, it wasn’t as difficult as we thought, all we needed to know is the answer, and that’s really what we’re– the reason we have a place like Harvard Medical School. And I can tell you as well that SuperAgers at least seem to have avoided the fate of aging. They are not affected by the typical patterns of aging that other older adults have been affected. So it is a live example. Yeah. All right, this one might be a little controversial. Does taking human growth hormone help reverse aging? No controversy at all. No.  There’s been studies in the past about human growth hormone. A lot of work was done after surgery, for example, to see if it helped people overcome the stress of surgery, and that showed that it had more toxic effects than beneficial effects.

Although we do lose growth hormone, replenishing it has not been proven to reverse aging. Well those are all the questions that I have. I think– Grab some more. We have more? Barbara? Excellent. All right, OK. One member of the audience wanted to know, is there any link between Lyme disease and Alzheimer’s? Do we know? I am not aware– now Lyme disease causes neural disease. It can cause peripheral nerve problems, it could cause problems in the brain, but those problems are not Alzheimer’s disease. So to my knowledge, there has been no link between Lyme disease and Alzheimer’s disease. OK, I’m just going to read this one literally, don’t blame me. All right. And Barbara, you gave it to me. All right, who wants to tackle this one? Some loss of sexual function in men as we age is not just age, but boredom. New stimuli, et cetera, et cetera, may help reverse the loss of function, yes or no? Yes.

I don’t know. OK. That actually is true. OK. Some things do get a little slower, but sexual function still is maintained in older age, but it sometimes takes a little more stimulation. Let me just leave it at that. [LAUGHTER] We have a question– what influences the pathophysiology changes in the human body in order to trigger the loss of NAD? Good question. Why does NAD go down with age? We don’t know for sure. Now what we do know is that there are enzymes in the body that destroy NAD, which seems like a silly thing to be doing, but often in biology, when you want to alter the levels of a certain molecule, you have some enzymes that make it and others that destroy it and that gives you fidelity.

Also, what I didn’t mention that’s interesting about NAD is, it goes up and down with the time of day, and the likely reason that you jet lag is because your NAD cycles are out. And so the answer to that is, we don’t know, but these enzymes that destroy NAD are a likely culprit, and perhaps we can also develop drugs that would inhibit that degradation and keep the levels higher. That was a good question. This is for Lou again. At what age group do we visualize higher accumulation of amyloid plaques and tangles? Yeah, there is no specific age, but there is a couple of points. One is, Alzheimer’s disease can occur earlier in life, sometimes as early as the 50s and 60s. This is early onset disease, it’s a different disease, perhaps, that does have some genetic predisposition. But we usually see in our practice and in our field is late onset of disease, and that can occur any time– late 60s all through the rest of life. So there are the– highest prevalence is probably in the 70s and early 80s, but there is no specific age for late onset disease.