David Sinclair TEDxBoston on the Science of Aging Reversal

So I stand here as a representative of a field called Aging Science, Longevity Science. Some people call it anti-aging. We don’t use that as scientists. But what has happened in the last 25 years is nothing short of revolutionary. And thank goodness, I come from Harvard Medical School, or what I’m going to tell you tonight you would find extremely difficult to believe is true. I’m on record saying that the first person to live to 150 years has already been born and I already said that about five years ago, and in the last five years, something extraordinary has happened since making me think that it’s not just 150 years. All bets are off. And that’s not just for somebody who’s born today who will live definitely into the 22nd century, where the technologies that they’ll have, we can barely even imagine. Even 10 years from now, we can barely imagine. But those of us who were born in the 1960s, like I was, 1970s, 80s and even those who are now just in their 20s will benefit from this real major advance that I’m going to tell you about today. This is also personal, it’s not just about technology. In my family, I was raised by my grandmother predominantly. My mother, also helped. She was working. But my grandmother escaped Europe in the 1950s, having lived through, as a young girl, the depression World War II. She was from Hungary. It was a brutal time. She escaped to Australia, where I got my accent; and I came to MIT in my 20s. But she raised me to believe that humans can do better than we’ve done in the 20th century And she said it’s partly my role to show humanity can be better than they are and that’s what drives me every day I get up, and my goal since I was really four years old was to try and leave the world a better place. And in my teens, late teens in college, I thought: “Well, there’s this thing that happens to everybody called aging, and it's 90 percent of all the sickness and suffering in the world. But no one seems to care about it” You go to your doctor and they say “That’s normal. You’re old. You should be getting sick.” And I said: “That’s not right.” At any age, we should apply the same technology, the same effort to make people live as long as they possibly can. We fought against cancer, we fought against heart disease, we’re fighting against Alzheimer’s disease. What about aging? And I refuse to believe that just because this is natural and common, that we should regard it as something different from a disease. In my view, in my world, aging is a medical condition. You see behind me an image of my father, who, of course, is the son of my grandmother who raised me. My grandmother lived a very different life than my father. My grandmother smoked, drank, did pretty much everything that was not going to slow down the aging process. She died like a lot of people do, who lived through the 20th century in a frail state, demented in a slow decline. It was very painful for her and certainly painful for us as a family to watch. My father, on the other hand, has watched the science come out of this field and done the right things that we’ll talk about later. So at 82, he started a new career. He’s thriving. He’s looking forward to the next 20 years of his life, if not longer. This is what I want for everybody. We can all do this if we just know the facts and don’t pay attention to 99% of what’s out there on the internet because it’s all wrong. Speaking of wrong, we have a new theory of aging. We used to think that antioxidants were the cure to aging, and if you go to the supermarket, you’ll still get a lot of that bull. It’s not true. Antioxidants have been really unsuccessful at lengthening the lifespan of anything, even a worm. It doesn’t work that well. The reason is that there’s much more going on than just free radical damage. What we need to do is to tap into our body’s natural defenses against aging. We have three main sets of defenses. One is called MTOR, responds to fasting, one called AMPK, responds to low energy and lack of sugar. You want to keep your blood sugar levels low as possible without fainting. And the group of genes that I work on are called the sirtuins, they respond to all of the things that we do: the adversity, the exercise, the fasting. And this group of genes and these proteins that the genes make, sense the environment. And when times are thought to be tough and could threaten us, they fight harder to keep our body safe, protected and ultimately healthier and longer lived, even late in life. And what they’re doing, these sirtuins, is controlling this structure here. They’re doing a lot of things, but the main thing I believe they’re doing to make us live longer is controlling what we call the epigenome. If you haven’t heard of epigenome, think of it like this: we have DNA. I’m showing you as a blue strand. It’s digital information, ATCG. There’s four bases. It’s base four. It’s not base two or binary. The epigenome is not digital, it’s mostly analog. And anyone who’s old enough to have had an analog device, whether it’s a tape recorder, a record player or record, these things get disrupted. They get scratched. It’s very bad, very poor at copying information. And that’s true for the epigenome as well. Copying epigenetic information doesn’t work that well. What is the epigenome? It’s the structures that wrap up the DNA and say that this gene A should be on in a brain cell, but in the liver cells should be off. And this gene B should be off in a skin cell, but should be on in a kidney. That’s the epigenome. And largely it’s due to the three dimensional structures of the folding of DNA and these sirtuins that defend us are called silent information regulators. That’s what sirtuins actually stand for: SIR. And “tu” is the number two for the first gene in yeast that we showed extended lifespan, way back in Lenny Guarente’s lab at MIT in the 1990s. But here’s the analogy that the DNA is the digital information on a compact disc. Those of us who are old enough know what that is. For the youngsters, this is what we used to store 20 songs on. It was great technology. That’s your genome, the digital information. The epigenome is the reader. It can read different songs depending on different parts of the body in different cell types. But what I believe is causing aging is the skipping of those songs, skipping of the reader. And what makes songs skip? Scratches. So aging is essentially scratches on a compact disc that makes the music skip and eventually cells, by reading the wrong genes, skipping the wrong genes, lose their ability to fight against disease. They lose their function. We get dementia, we get heart disease, we get cancer, we get frailty. That is aging. So with this new theory of what I call the Information Theory of Aging, we can perhaps test this by testing if epigenetic changes cause aging. And if that’s true, is it possible to reset these structures back to being young? Is there a backup copy of the epigenome? In other words, can you polish that CD and get back the original music of our youth? Before I go on I want to point out something really important in this structure. It’s not just the proteins that wrap up the DNA but the modifications that are on the DNA itself. Chemical additions called methyls, Methyls are carbons with three hydrogen. They’re very simple. And cells add them as we’re developing in the womb to say, all right, that cell that’s come from stem cells should be a neuron for 80, 90, 100 years in the brain. And this one should be a skin cell. These marks, called methyls, dictate the production of 26 billion cells. Many of them have different functions in the body, even though they have the same set of instructions encoded in the DNA. What’s been found since 2013, Steven Horvath and his colleagues discovered that by reading the changes over time of these DNA methylation marks on the DNA that are attached to the letter C in the DNA, not the A, T or G, you can estimate somebody’s biological age, because it’s reproducible. We’re all aging due to the same mechanisms and that there’s a pattern that occurs from conception very rapidly until we’re born and then slows down, and then is linear throughout our lifespan. We can measure that clock. I can take your blood, I can take your skin, any part of your body, and I can run that through a DNA sequencer to measure the methylation, there’s thousands of them. And putting that into a machine learning derived algorithm, I can tell you your actual real age, not your chronological age. I mean, birthdays? Who cares? Number of times the Earth went around the Sun. That’s not your real age. What your real age is, is these changes to the epigenome, that determine how old you really are. So the question is if we tweak the epigenome, if we scratch that CD, if I’m right about the Information Theory of Aging, what do we get? We’ll get accelerated aging. This is a mouse. That’s the control in my lab. So we tweak this mouse in every other way, except scratch its CD. At the same time, we took a sibling born at the same time, and we for three weeks accelerated the scratches on the CD. We disrupted its epigenome and the cells started to lose their identity. The mouse didn’t feel it. It’s like getting an X-ray, you don’t feel that, but what happened 10 months later was we got an old mouse. This isn’t just a mouse that looks old. This mouse is 50% older than its sibling, even though it’s genetically identical. These are twins born at the same time. One is old and one is not. We can drive aging as fast as we want forwards. Then the question is, if you can give something, can you take it away? And if I’m right, the answer is yes. First of all, let me show you about a minor tweak to age reversal. We found these sirtuins can defend against aging, but they can also reverse aspects if we activate them, either giving them molecules from the plant world, that plants produce when they want to slow down their aging process and survive. We call these xenohormetins. We have drugs that have been in development. We have more that are coming. We have one in particular that’s of interest and it’s called NAD booster. NAD is a fuel for the sirtuins, whereas resveratrol is the accelerator pedal. So giving the fuel to these mice, I’ll show you what happens. One of these mice has been on the sirtuin activating molecule called NMN: Nicotinamide Mono Nucleotide. Hopefully you can guess which of them has been rejuvenated from an old state. These are really old mice. They are almost two years of age, and only one of them has been drinking NMN in the water. If you pick the mouse on the right, you’d be wrong. (Laughter) It’s the mouse on the left, obviously. And we published in the Journal Cell in 2018 that this is possible, to rejuvenate the cardiovascular system of mice and make it younger, through the sirtuins. We know it works for this sirtuins because, if we delete those genes, you don’t get this effect on these mice here. But that was just the beginning, that’s 2018. We’re now in a world where our technology makes this pale by comparison. We now have the ability to reset the age of an entire animal, leading to one day being able to reset the entire age of our bodies. What did we do? We really stood on the shoulders of a scientist, Shinya Yamanaka, who won the Nobel Prize in 2016 for discovering a set of embryonic genes that could take an adult skin cell from any of you, and turn it into a pluripotent stem cell that could be made into any other type of tissue, and we can do that in the lab. High school students can do this by putting in the six Yamanaka genes. Now we found that if you put in a subset of three of them Oct4, Sox2 and Klf4 short for OSK, we could take the age of the body of a mouse backwards, but not so far that it would become a stem cell or a tumor. This was published in December 2020. It made the cover of Nature Magazine, and the title on the magazine was Turning Back Time. This is one of the pieces of data from that paper. We did three things. The first was to damage an optic nerve in a mouse, and you can see on the top image that the crushed nerve is dying. That orange stain should extend all the way to the brain on the left. But in the reprogrammed eye where we injected those three genes and turn them on for three weeks, we could make those neurons grow back. We measured those neurons and they were literally half the age that they were three weeks ago. And young nerves, as you might know, grow back. Adult nerves do not. So this was the first indication that we were on the right track. We also could see that those structures, the epigenome, those scratches on the CD, they went away. We can also grow human tissue in the lab. We don’t know yet if this works in humans, but we can model it in the dish. These are human pluripotent stem cells that have been engineered into little mini brains. On the left of this image, you can see these are little organoids. These are quite similar to human brains. They have electrical activity, and on the right is the electrodes that we put the brains on. We can measure that. We think they dream. They have thoughts, and we can also age them using our technology of disrupting the epigenome. And now we’ve shown that if you reset the age of those little brains, they get their ability to think again. The electrical activity comes back. Does this mean one day if we reverse the age of the brain, you’ll get your memory back? Possibly. We’ve done this now in old mice. We can rejuvenate their brains, take their brains back to half their age, and they get their ability to learn again. So you might say, well, sounds great, but how long is this going to be before we have it? And my hope is that we’re at a turning point in human history as important as flight and Silicon Valley and energy and crypto. The 22nd century is going to be about biology and the ability to control your age and the rate of aging and slow down not just body aging and heart aging, but even brain aging. With these tools and age reversal tools that are just coming along will radically change the arc of our lives in a way that we can barely even imagine, and where we can reset our age by a couple of years, which is now being published, that’s been done by Greg Fahy and colleagues. If we do that every year, even just set your age back one year every year, what happens? Things then get really interesting. And that’s the world that we have to stay alive to be able to witness. And if we all do the right things, we will witness that. Thank you very much.