Part of this video is sponsored by LastPass. More about LastPass at the end of the show. This is a video about research into slowing the rate of aging and extending the human lifespan. So, before I filmed this I wanted to know: What do you guys generally think about such research? And I made a Twitter poll where I found that the majority of people were supportive and thought there should be more of it but there were some important concerns and I want to address those here at the beginning. I mean the most significant concern was: if we're looking to extend human lifespan, does that just mean we'll have more sick years where we'll be in bed with Alzheimer's? Nobody wants that, and that was clear to me.

But the professor that I was interviewing for this video, professor David Sinclair, points out that as you get older the risk of horrible diseases, things like diabetes and cancer, and arthritis, all those sorts of things... it increases exponentially. And so, if this research is successful the whole point of it will be to forestall those sorts of diseases. I mean, if you really are tackling aging, then you should also see that those age-related diseases do not set in so quickly. So, the point of slowing aging and extending human lifespan is to extend the healthy lifespan, also called the health span.

The other concerns I saw were that people were saying: "Well, this could be used only for the wealthy and increase inequality" or "It could increase the population of the Earth causing..." "...more garbage, more CO2. Where are the resources to feed all these people?". I think these are valid concerns, but they're not part of the scope of this video. So if you want to discuss them in the comments, feel free, but the point of this video is to address: can we slow aging in humans? Can we extend the lifespan and the health span? And what does that look like? How do we do it?

Okay. So for this video I traveled up to the 'Bodega Marine Lab', which is north of San Francisco and there I got to see some 'moon jellyfish'. Now what's fascinating about these 'moon jellyfishes' is that some people consider them immortal. How can that be?

So all these jellyfish have this complex life cycle where they start off as a polyp, which is basically like a small sea anemone and then they'll go through a metamorphosis and become a medusa. And the medusa stage is what we generally think of when we think about a jellyfish. And in most of these species the polyps are generally able to asexually reproduce, and they can regenerate if tissue is cut off of them or if they're damaged, and they don't have any clear evidence of senescence, which is the term for biological aging. So they appear to have some degree of immortality. No one had reported their ability to do this until... I think this was 2015. So do 'moon jellyfish' hold the key to slowing aging and extending our lifespan? Could they help us live forever?

Before I got into making this video, I would have put this sort of research in the same category as downloading your brain, your consciousness into a computer. Like, I can see how maybe that would work but I don't think we're anywhere near that. Because we don't even understand how the brain works or how memories are stored, so that seems like serious science fiction, so I would have put, say, extending the human lifespan to 120, 150, and beyond in the same category, but after reading professor Sinclair's book and doing an interview with him, I think it seems much more possible and in fact plausible that we'll make some progress over controlling aging in our lifetimes.

Now, if you want to slow aging, the first question you need to answer is: Why do we age in the first place? I mean, what really is aging? I've made a video in the past about telomeres. These are the end caps on your chromosomes. And every time a cell divides the telomere gets a bit shorter. So it was thought that these telomeres are kind of like the tips of your shoelaces and they prevent the chromosome from fraying.

But there are other signs in older bodies that you have old cells. There are an accumulation of things, they're called senescent cells. They're essentially these zombie-like cells that just go on living in your body and inflaming the cells around them. There's poor intercellular communication, there's mitochondrial dysfunction, those are the powerhouses of the cell. There are these 8 or 9 different features of older cells and they are the hallmarks of aging. But the question is: are they the cause of aging, or are they kind of the result of a deeper root cause?

In the middle of the last century, the hypothesis was that it was damage to our DNA, mutations to our DNA that happened over the course of our lives that led us to be older But, evidence since then has suggested that that is not really the case. I mean, you can take an adult cell, and you can clone it into a new organism. And that organism appears to live about as long as non-cloned organisms of the same species. Now, the first sheep, Dolly the sheep, had a short lifespan. She died early. But cloned animals; you can now clone a monkey, you can clone dogs, in fact Barbra Streisand, the actress, she cloned her dogs, and they are expected to live a normal lifespan. So in that way it seems like all the information is still there in the DNA.

So if we're not losing information in our DNA then what is the reason for aging? Well, professor Sinclair suspects that it's a loss of information, but not the information in our DNA, in our genome. No, professor Sinclair suspects that the loss of information is in our epigenome. So what is the epigenome? Every cell in your body has the same DNA, but, different cell types have different epigenomes. They have different ways of packaging that DNA, coiling up, you know, a lot of it so that it's not read, and leaving some parts of the DNA spooled out, so it's easier to transcribe and turn into proteins and run that cell.

So the epigenome is responsible for turning on or turning off different parts of the DNA. The way it does that is with proteins called 'histones' that, essentially, the DNA is wrapped on, and also things like methylation. So there's these chemical signaling markers which are placed on the DNA in certain positions. So the idea is: when your body is first forming, the epigenome is what tells your cells what type of cell to be. But as you get older, professor Sinclair's hypothesis is that we are losing information in the epigenome. And that's important because if a skin cell needs to remain a skin cell, that's the epigenome. And if you don't have the epigenome the skin cell will forget what type of cell it is and it might turn into a brain cell, which may not be that bad but if your brain turns into a skin cell you've got a problem and I think that's largely what aging is.

I've gotta say, there's some weird, hair patches, on my shoulder, that have happened as I've gotten older. Is that a cell... doing the wrong thing? Are those meant to be skin cells? Are they're screwing up or is this just some... I don't know. No, no, weird stuff happens when you get older, right? You start to get hair growing where it shouldn't: ears, nose, back. That's cells losing their identity, the cells go: "I can't remember what I'm supposed to do, I'm not reading the right genes anymore."

So, the key to this sort of breakdown in the epigenome is DNA damage? Yeah, so when you go out in the sun, not like today, but on a day where there's a lot of sun, you'll break your chromosomes. And in the effort that the cells go to to stick the chromosome back together, note: the DNA isn't just flailing around, it's actually bundled up. The cell has to unwrap it, recruit proteins to help, join it together, and then they have to go back and reset the structures. And that resetting of the epigenome happens about 99%. That 1% is the aging process. So overtime, histones are not returned to the right places and DNA methylation is added in places where it shouldn't be. We can read that methylation pattern and I could tell you how old you are, exactly, and when you're even gonna die.

How could you tell that? Well, it's a clock, we call it the Horvath clock named after my good friend Steve Horvath, and so these little chemicals that accumulate on the DNA like a plaque on the teeth, we can read that and the more you have, the older you are; biologically. So you might only be 40, you're younger than 40, of course but, you know, I'm 50 now, but I might be biologically 60, actually I was. And I changed my life and then the test said I was biologically 31.

I mean, one of the things I found really interesting was: you found a way to make mice age faster. So, how did you do that? Well, the clock of aging is due to the loss of the information in the cell, and one way to accelerate that is to go break a chromosome. Instead of going in the sun we engineered a mouse where we could break its chromosomes. Not enough to cause mutations, the cells put the DNA back together, so we didn't lose any genetic information. But if we're right about the 'epigenetic information theory of aging', those mice should get old and that's exactly what happened. It's gray, it's got a hunchback, it's got dementia, all its organs look old,

but the real test was: "what if we measured that DNA clock?" what we call the 'DNA methylation clock'. And we measured it and those mice were actually 50% older than mice that we didn't treat. So that isn't just a mouse that looks old, that mouse literally is older. What's interesting about this hypothesis is that, if it's true, if the noise accumulating the epigenome is really what's causing aging, well then there are steps we can take right now to slow the rate of aging in our bodies, by trying to better maintain our epigenomes.

So how do we do that? There's this theory, that billions of years ago early bacteria took an important evolutionary step. They actually developed two different modes of living. When times were good they used their energy to grow and reproduce. But when conditions were tough, they used their energy to protect and repair their cells. They evolved, what professor Sinclair calls: 'longevity genes'. These genes triggered by adversity create enzymes which among other things, maintain the epigenome. And today, those same longevity genes can be found in bacteria, and us.

We have these 'hormetic response' genes or 'longevity genes' that are in all of our cells, and they sense when we've run a lot, we've lost our breath or we're hungry, we are a little bit hot, or a little bit cold. These genes are turning on our general defenses against aging. So, what is that? So, parts of our cells fall apart: they can put them back together. Proteins misfold: they can get rid of them or put them back together. The ends of the chromosomes get shorter: they can lengthen them.

A lot of processes that go on but one of the most important, I think, is maintaining the information, the epigenetic information in the cell, so that our cells don't forget what to do. There are three types of longevity gene. There are the ones we work on called 'sirtuins' and they control the information in the cell. In fact, 'sir' in sirtuin stands for 'silent information regulator' number two (SIR2). There are other ones. The other group is called AMP-kinase or AMPK. This group of genes senses how much energy we're taking in... mostly in the form of sugar.

And then the third group is called mTOR. And these genes control and respond to how much amino acids we're taking in. So if you eat a giant steak, you've got a lot of amino acids coming into your body. That'll actually prevent mTOR from hunkering down and keeping you being longer lived. So the mouse experiments actually bear this out. The best way to make a mouse live longer is to reduce the amount of time it eats, so periodic fasting, intermittent fasting, to keep it a little bit cool, and to restrict its amino acids.

That's the recipe for long life for a mouse, and it's true for monkeys as well, that have been calorie restricted studies where these monkeys for 15 years didn't eat as much food as the ones that gorged themselves whenever they wanted. And they were protected. They didn't just age slower. They didn't get as much diabetes and heart disease, they were actually fit and healthy, when the control group, eating whatever they wanted, aged and became sick quicker.

When some people think about eating less, like, calorie restriction as a way to extend their life. That doesn't seem like a very pleasant way to extend life. I mean, to be hungry for longer... So are there other ways to... you know, mimic that effect? Or to simulate that? There are these molecules that turn on the sirtuin pathway, and trick the body. And so, for example, in the lab if I give some of our mice a molecule called 'NMN', which raises the level of a chemical called 'NAD', you get hyperactive defenses in the body.

And what did you see in these... 'senescent mice' that you gave NMN to? Well, we had a bit of an incident. These mice that we gave NMN to ran 50% further, but actually some of them ran so far that the machine, the little treadmill, stopped working. And we had to reprogram the software because this program had never seen a mouse that ran more than three kilometers. Three kilometers for a mouse? For an old mouse. They outran the young mice. And that's like an ultramarathon for us? That would be probably like taking a 70 year-old and making them run faster than a 20 year-old; further. Yes, so these are ultra marathoners, and if we did that to humans I imagine you could have 90 year-olds winning Olympic medals.

So to sum up, there are six things that you can do right now to slow the rate of your aging. Starting with zero: avoid DNA damage. Wear sunscreen, avoid x-rays and all that sort of stuff. Number one: eat less. Caloric restriction. Number two: eat less protein, because your body has ways of detecting how much of that you're taking in. Number three: do some exercise. 'High-intensity interval training' (HIIT). Get your heart rate up to 85%, make your body feel like you're running from a lion or something. Number four: be uncomfortably cold, or number five: be uncomfortably hot. All of these things will trigger your body's 'longevity genes' into maintaining your epigenome. Going into 'repair and protect mode' rather than 'grow and reproduce', and if you think about those things, those are generally all the things that we don't do.

But what if slowing aging isn't enough for you? Well, this is where my interview with professor Sinclair took an interesting turn, because he's actually done some research on reversing aging. So how would you do that? Well, effectively, you would need to take the epigenome and reset it back to an earlier time. But how is that possible? Back in 2012, a scientist named Yamanaka received the Nobel Prize for discovering four factors, which when applied in a gene therapy to an adult cell, would reset the whole epigenome back to how that cell was when it was an embryo. So it is what is called a 'pluripotent stem cell'.

Now, you wouldn't want to apply that to your entire body because, well, then you would turn into a giant tumor because your cells wouldn't know how to differentiate. But it does suggest that there are ways of resetting your epigenome, and they could be the key to reversing aging. The big breakthrough that we just had in my lab, finally, you know, about a year or so ago, was to reprogram the eye of a mouse. And the eye, we chose the eye because that's a very hard thing to fix, right? If you go blind when you're older, we think that's a one-way thing, you're never going to recover your vision, but we decided: let's try it anyway, let's go for broke.

So we put our gene therapy in the eye of old mice, turn their retinas to be young again, reversed aging in their retinas. So those one-year old mice went back to about two months, And guess what? Those mice could see again, just like they were young again. How do you reset one of these eye cells without resetting it to just a stem cell? Well, we have to be very careful not to reset these cells to be basically a stem cell, otherwise, we wouldn't have mice that can see, we'd have mice with a giant tumor in the back of their eyes.

So what we do is a couple of things: we didn't use all of the four reprogramming factors that won the Nobel Prize, we use just three, we leave off one called 'cMyc', which causes cancer, and those three seem to be just the right recipe for taking the age of the eye backwards, but not too far. Then, the second thing we do is: we turn it off. We can actually turn this system 'on' when we want, and 'off' again, so that we don't take them too far back in age.

Can you do that with any cell? We think we can do this in any tissue. We've now given it to the whole mouse and those mice are fine. No evidence of cancer. They seem to be really quite healthy. So the big question is: can you take a mouse way back, the whole body, and be totally younger? Maybe back from two years, back to two months. And that's what we're doing right now. That's pretty exciting! It's freakishly exciting, actually! I thought we'd just slow down aging, now we're talking about an aging reset. You know what? We've only reset the age of the eye once, But how many times can we do this? Maybe it's twice. Maybe it's a hundred times.

So, professor Sinclair claims that his gene therapy reversed aging in the mouse's eye and allowed it to see again. But applying a gene therapy to every one of your trillion cells is pretty impossible. So in order for this to actually work and reset an entire body, you would need another way, and this is where the jellyfish come in, because 'moon jellyfish'—any cell in an adult jellyfish can actually be reset into an earlier stage of its life cycle. It can become a polyp again.

So it seems like the jellyfish are actually capable of activating something like the Yamanaka factors and resetting their epigenomes to an earlier time in their lives. If we were able to figure out how they do that, well, then maybe we could do the same with our own cells. We do have the ability to reset our epigenomes, but that is typically only used when we're in the embryonic stage, when we need to maintain all our cells as stem cells.

As we age, most mammals including humans, we lose stem cells over time. And the stem cells we do have become more and more restricted over time to the types of cells they can make. So if we can understand how the 'moon jellyfish' can take, presumably, many different kinds of cells, and reverse-engineer them into the cells it needs during regeneration, that might give us an idea of how to do it in ourselves, as well.

So, I still think we're a fair ways off from reversing aging in the entire human body. But what I found interesting from talking to professor Sinclair was that there's at least a roadmap. At least a path ahead where you can see that it could be possible to slow and even reverse aging.

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