The Future of Longevity: Telomerase, Telomeres & Reversing Cellular Ageing with Dr. Bill Andrews (Part 3)

Lisa: Well, hi everyone and welcome back into episode 3 with the amazing Dr. Bill Andrews. So today in the Curing Aging series, we're going to be talking about how we age. So Dr. Bill, can you give us a little bit of a recap of the last two sessions and then why we're going into now how we age? We talked about evolution, we talked about it from a historical point of view, why aging came about.

Dr. Bill Andrews: Yeah. We talked about what aging is, and that's a really simple explanation. That's just a decline and failure of body parts, organs and tissues. And that's all it is. The next time we talked about why we age. That's evolution. Why we age, but more importantly, why did we never evolve a way not to age? And it turns out — I'm going to turn my phone off here just a second because I just got another — I'll take these off. Okay.

Dr. Bill Andrews: So we talked about why we age and, more importantly, why have we never evolved a way not to age? You would think that evolution would be doing great things for us to overcome this dumb thing called aging. But it turns out that evolution is all about survival of the species, not survival of the individuals within the species. And it turns out that eliminating the longer lived is actually beneficial for the species, because it increases the diversity within the species by promoting the offspring interbreeding as opposed to the parents re-breeding.

Lisa: Yeah. Okay.

Dr. Bill Andrews: And so there's a lot more diversity that results, especially when you consider that mutations are always occurring. Mutations result, diversity results, and the more diversity within a species, the more likely it'll survive a rapidly changing environment — or at least some members of the species will survive the rapidly changing environment and continue to propagate the species.

Dr. Bill Andrews: I want to make a point, that everybody's looking for theories to explain why we age, or what aging is and why we age. But there is no need for theories. I think most of the people who don't really have — in fact, I know that most people that talk about evolution, why we age, and what aging is, and how we age, they actually don't have backgrounds in biology like I do. My PhD's in molecular and population genetics. Population genetics is the how and why of evolution, not the what and when that most people talk about.

Lisa: Mhm. Okay.

Dr. Bill Andrews: And I've been studying the things that I need to know to cure aging my entire life. All through high school, college, everything. It's like, what do I need to learn to be able to cure aging? And a lot of it is statistical theory, probability, logic, common sense, all this kind of stuff. Taking actual courses in common sense is something that I —

Lisa: Is there such a thing?

Dr. Bill Andrews: Yeah, there is such a thing. But it has allowed me to have the right tools to be able to look — and plus, in addition to all that, I've done a tremendous amount of biology studies. And so I understand the mechanisms that occur inside cells, how everything works. And so I can put it all together and come up with an explanation that most people can't come up with. And that's why I say there's no theories needed to explain what aging is, why we age, or how we age. It's obvious. It's inevitable, given everything about us and other species too on this planet. It's inevitable that for a species to be successful evolutionarily, it has to evolve an aging process. And that's what I explained last time in our webinar on why we age.

Lisa: And now we sort of want to get into the meat and potatoes of this course, which is really the how we age and why we can overcome that now, or to a degree. That's what you're working on and that's what you've been working on for a long, long time, and you've gotten us a fair way along on this passage. And then also we'll be able to sort of work out how long is it going to take before we actually will be able to stop aging, and you've got a very good model for that and working on that flat stick.

Lisa: So let's progress now into the "how do we age" part of the equation. So we now know why evolution did this and why it knocked us off when we got older and we brought up our offspring and then we want new genetic material brought in and so on. How does the actual process of aging work?

Dr. Bill Andrews: Okay. Well, first let me just comment that the next webinar, on how not to age, I think will be the most exciting one, when I get a chance to talk about the research that I'm doing to eliminate aging and make us all look, feel, and behave 25 again.

Lisa: Don't go anywhere anyway, everyone. You've got to stay around for that punchline, so to speak. But to understand this whole background — so how is it that we age?

Dr. Bill Andrews: Well, what are the hallmarks of aging? What do you think about the hallmarks of aging? They're all true. They're all true, but — and I'll come back to those in a second, because I was going to mention it — but I want to point out first that aging isn't just a result of random events, like random mutations to DNA or random damage. And we know that from statistical theory.

Dr. Bill Andrews: When we look at the graph of the age people are when they typically die — well, if aging and dying was totally resulting from random events, it would be a bell curve. Let's imagine first that aging is caused by, or death is caused by, one thing. And that is like running across the field with machine gun fire.

Lisa: Okay.

Dr. Bill Andrews: Well, everybody has a certain probability of making it. Some people aren't going to make it. Well, if you look at the age that people die from running across that field, it's going to be a perfect bell curve, especially when there's only one thing. Some are going to die their first time, some are going to die their 1,000th time, and most of them are going to die somewhere in between.

Lisa: Yep.

Dr. Bill Andrews: But now, we know that aging isn't caused by just one thing. It's caused by an accumulation of things. And that only shifts the bell curve to the right a little bit. So the bell curve is now going to require an accumulation of things. It's going to change the shape of the bell curve a little bit, but it's still going to be a bell curve, just shifted over a little bit.

Dr. Bill Andrews: But we don't see that either when we actually look at studies. What we see is a big death rate at the beginning, from newborn babies having high mortality rates. But then it's pretty flat and level with nothing for a long time, and then it starts to increase. Let me get my finger on that. Starts to increase, and then it goes really fast, high up, and then drops like a cliff.

Lisa: Yeah.

Dr. Bill Andrews: There's studies showing that if you are very, very healthy with the best doctors in the world, a very healthy 89-year-old, you have an 11% chance of dying before you turn 90.

Lisa: Wow.

Dr. Bill Andrews: And it gets worse when you get older.

Lisa: Yeah, yeah. Well, that drop-off rate is way higher than the drop-off rate for somebody that's younger. So something is happening. There is a mechanism. It's programmed or something. There is something that is causing a limit on our lifespan.

Dr. Bill Andrews: Okay. So now, that's what all the theories are about. Like, what is that? There's a whole bunch of theories. In a lot of my talks I list about 20 of them that have existed, all the way from the size of an organism affects their aging — there's so many things. I don't want to go into them right now, but I could if you wanted me to. But the point is, there is no need for theories, because it's fully explained without any theories.

Dr. Bill Andrews: And aging all starts with wear and tear. And that's pretty much the hallmarks of aging. Almost all of the hallmarks of aging, except for one, which I'm going to be talking about at the next webinar, is a wear and tear issue. It's either mutation rates or a host of different things. I don't have the list of all the hallmarks of aging in front of me, but they all pretty much result in wear and tear.

Lisa: Yeah. Oxidative stress, and chromosomes not being read correctly, and proteins misfolding, and telomere shortening obviously, which is your thing. All of these aspects are all basically a wear and tear sort of model. So is it death by a thousand cuts? We're getting a little bit of radiation today, we're getting a bit of an environmental toxin tomorrow, and it's just accumulating.

Dr. Bill Andrews: Well, the only hallmark of aging whose mechanism of action is not wear and tear is telomere shortening. I mean, there is a mechanism of wear and tear that causes telomere shortening, but it's not very predominant and it's very easy to control by just having a healthy lifestyle. It's the wear and tear from telomere shortening that actually causes a lot of people to die young. But you don't have to, if you just lead a healthy lifestyle.

Lisa: So smoking and too much drinking and all the things we already know, lack of exercise.

Dr. Bill Andrews: Yeah. But the very first stage of all of aging is wear and tear. And there's multiple ways of having wear and tear. But now, the question that I used to ask myself even in high school was, well, so you have these cells in your body and they get destroyed by wear and tear. Well, why don't other cells in the body just divide and replace those cells? Just like a bacteria culture. And theoretically they should, and they do.

Dr. Bill Andrews: I'll go into a little more detail on that in a minute, but we do have the ability to repair all cell damage — not repair. There's a lot of talk about repairing cell damage, but that's actually not as true as you think it is. But we have the ability to replace damaged cells. And this should allow us to live forever.

Dr. Bill Andrews: So the best way for me to really get into the meat of it is to start off with the fact that all organs and tissues have some cells that are considered the front line cells, where all the action occurs. So these cells, they're doing all the work, and resulting from all their action is causing wear and tear in them. So a cell who's actively producing or doing all the fighting, the battles, and doing the work that the organ or tissue needs to do, they have wear and tear. And a typical front line cell dies on the average of once a year. None of them last longer than a year on average.

Lisa: Wow.

Dr. Bill Andrews: And that includes — when I talk, I typically show an organ as being like a ball with the cells in the front line on the

Dr. Bill Andrews: ...surface of that ball. But not all tissues and organs are like that, and especially the blood. But the blood still has its frontline cells, and they're the ones doing all the action. So if we have our frontline cells dying on the average once a year, and other cells can divide to replace those cells, we should never age.

Dr. Bill Andrews: In terms of mutations, let's say the easiest example of why wear and tear to a cell would be mutations. And there's three kinds of mutations. There's mutations that are harmful to the cell, there are mutations that are beneficial to the cell, and there are mutations that are neutral to the cell. So if the mutation is harmful to the cell, that cell is going to die quickly, because it's harmed. It's not going to be able to perform its functions. It's going to die faster, and so instead of a year, it's going to last maybe three months. And so therefore it has to be replaced faster.

Dr. Bill Andrews: Then there's the neutral ones, which mean really nothing, and especially when you consider the fact that they are not part of your germline cells or your reproductive cells. So they're not going to be passed on to your children. They're mutations that are in some cells. In fact, there's lots of mutations in our body, but every cell is different. One cell has one mutation, another cell has another mutation. It's not like we've accumulated a lot of the same mutations. And these neutral ones become pretty much irrelevant, though they accidentally can cause evolutionary changes, especially if the mutations are in our reproductive cells.

Dr. Bill Andrews: Then there's the ones that are beneficial to our cells. And the only one that we really need to worry about is the ones that cause cancer. Now, cancer is obviously not beneficial to the human, but it sure is beneficial to that cell, because that cell now can grow happy and do everything it wants and kill you. It doesn't really know it's killing you. Cancer cells, a lot of the time, sometimes they are very unhealthy and they're hard to grow and they die at a fast rate, but they still keep growing. So the cancer cells are the one concern.

Dr. Bill Andrews: But it turns out that your ability to get cancer is not just because of an accumulation of damage to the cell. Your ability to get cancer increases when you get longer lived. I try to avoid using the word old because I don't like the word old. But the longer lived — and the immune system is also like an organ or tissue. It has its frontline cells. Your immune system is very effective at fighting cancers, and that's why cancer incidences are very rare when you're young. But then they get very common when you're older. And a major reason for that is that your immune system is failing. Your immune system is failing just like the other organs.

Lisa: That's such a key point, because I don't think a lot of people understand that actually, if your immune system's operating as it should do and it's firing on all cylinders, so to speak, you're much more unlikely to get cancer. And therefore supporting your immune system in whatever way you can is super crucial. Your basics, like vitamin D and zinc and vitamin C and all these sorts of things that are just basic things that are going to support your immune system, plus all the other more fancy things. But it's key.

Dr. Bill Andrews: But the bottom line that I'm going to is that damage causes cells to be lost or killed, and other cells can divide to replace them. So why aren't we immortal like a bacteria culture is? The big breakthrough came in 1961 when Leonard Hayflick showed that human cells have a limited number of times that they can divide. People thought he was an idiot at the time. They didn't believe it. But it's been reproduced a thousand times and now he's super famous, should be getting a Nobel Prize for this experiment, and hopefully he will. Human cells can only divide a certain number of times, and therefore eventually you can't replace those damaged cells.

Dr. Bill Andrews: So what I want to say is that you have your frontline cells that are on the surface of the organ, let's say. But inside the organ you have your reserve cells. I'm using a military analogy — in a battle you have your front line, and then when the frontline people start being eliminated, you bring in the reserves to fill in the spots. Well, the same thing's happening in all of our tissues. Our tissues are at war constantly. So the reserve cells are our stem cells and our progenitor cells, that really just have no trouble at all dividing and replacing by dividing and differentiating into our frontline cells. But as I said, that can only happen a certain number of times. The cells eventually, after they divide a certain number of times, they go into a phase called senescence.

Lisa: Yeah.

Dr. Bill Andrews: And they can no longer divide, and they're still alive and they can function. They actually cause other damages to neighbouring cells too.

Lisa: SASP is the abbreviation for — senescence-associated secretory phenotype.

Dr. Bill Andrews: Yeah. Yeah. And so the question really becomes, why do we have a limited number of cell divisions? Let me give you one example. Drinking alcohol kills liver cells.

Lisa: Mhm.

Dr. Bill Andrews: So people that drink a lot, their frontline cells in their liver don't last a year. It's a shorter time. And so as a result, other cells have to replace those frontline cells more often.

Lisa: And that's why you get — because you're getting to the end of that Hayflick limit quicker.

Dr. Bill Andrews: Yeah, you're getting to the Hayflick limit quicker. I didn't mention the Hayflick limit, but that's the name of this thing that we call it now, because of Leonard Hayflick. The cells eventually lose the ability to replace the damaged liver cells from the alcohol, and you get liver cirrhosis. And if you could keep those cells from reaching their Hayflick limit, you could drink all the alcohol you wanted and never get liver cirrhosis. That's probably my favourite example.

Lisa: And Dr. Bill, so when the stem cells come out of the bone marrow and they start to differentiate, they're like splitting in two, and the stem cell goes out in circulation and then gets attracted to the different tissues — which is complicated — and then becomes the tissue of that cell, that organ that's needed. So a liver cell or neuron or whatever the case is. The cells that are in the bone marrow — I've interviewed Dr. Christian Drapeau, who's a stem cell researcher, and he has a product on the market that helps produce more stem cells into circulation, helps release them out of the bone marrow into circulation. My question is, if I'm releasing more out of my bone marrow, am I then going through my stem cells quicker, or is the population just splitting and dividing but not — you know where I'm heading with this?

Dr. Bill Andrews: Oh, yeah. Yeah. So mostly the stem cells in the bone marrow are the haemopoietic stem cells. You have other stem cells even within tissues, within organs. It starts to beg the question, what is the definition of a stem cell? And I argue a stem cell is anything that can divide and produce another cell. So every cell has a stem cell. But most of the stem cells in the bone marrow are the haemopoietic, so the blood stem cells. But we do have them in lots of other places. And yes, when they divide to bring more cells, their telomeres get shorter.

Dr. Bill Andrews: It's a common misconception that stem cells don't age, but they do age. They have the same age, and they have a limited number of cell divisions just like any other cell does. The only cell that's an exception to that is called human embryonic stem cells — or if you're a mouse, it'd be mouse embryonic stem cells. And those do have an unlimited number of cell divisions, and it was through that knowledge that we discovered what I'll be talking about next time, which is how not to age.

Dr. Bill Andrews: So these progenitor cells and stem cells are dividing, they reach senescence and stuff like that. And we know that in a single cell embryo, that single cell can divide 100 times. That's it. And people think that can't be right, there's got to be able to divide more than that. Okay, I've got a doorbell ringing. Hold on a sec.

Dr. Bill Andrews: So a cell of a newborn embryo, let's say a single cell embryo, can divide 100 times. And people often say, how could it only divide 100 times? That's not enough. But when you do the math, a single human cell dividing 100 times will make a mass larger than the planet Jupiter.

Lisa: Oh wow. People don't actually realise it.

Dr. Bill Andrews: Yeah, because two, four, eight, sixteen — it just turns into a tremendous mass after 100 cell divisions. So 100 is plenty to allow a person to survive for a long time. In fact, the math puts it at — when you consider that frontline cells can only last about one year, and the number of divisions, and you take into account that a single cell can divide 100 times only when it's a single cell embryo — that puts us at a theoretical maximum lifespan of 125 years. So if human cells could divide 101 times, then we would live one year longer, that kind of thing.

Dr. Bill Andrews: So they can only go that long. But from being a single cell embryo to going through all the cell divisions to become a newborn baby, you've already lost half of those. So the cells in a newborn baby can only divide 50 times. And then you still have a lot of cell division, because you're growing, you're healing wounds, you're fighting infections, there's a lot of different things going on. And eventually your cells get down to where you only have less than 10 cell divisions left, and you're pretty much 90-plus years old at that time, and you have a theoretical maximum of 125. And nobody's ever lived that long. The most common documented case of somebody living that long turned out to be a case of a daughter pretending to be the mother.

Lisa: Yeah, yeah. Who knows?

Dr. Bill Andrews: There's another case of somebody living to be longer than 120 that might end up being something similar. But nobody's ever lived to be 125 in recorded history.

Dr. Bill Andrews: So the question becomes, why is there a limit on the number of times the cells can divide? And this used to be something that we used to discuss when I was starting anti-ageing clubs in high school and college. We started thinking, how could a cell have a mechanism inside of it, a clock, to tell it how many times it had divided and how many more times it can divide? It doesn't have a calculator, it doesn't have a brain, things like that. And the analogy that I came up with, that I thought was the best explanation, is that there has to be something like ride tickets

Dr. Bill Andrews: ...at an amusement park. And every time a cell divides, it loses a ticket. At least you could imagine a biological way that that could happen, whereas other things just were too impossible to imagine.

Dr. Bill Andrews: So I spent years after that wondering, what the hell are these ride tickets? Where are they? How do they work? And then in 1992, 1993, I was attending a conference and I heard all about the fact that telomeres, the very tips of our chromosomes, shorten every time a cell divides. They're not degraded, they're not unravelled, they're not all the different words that everybody uses, they're not damaged.

Dr. Bill Andrews: When a cell divides, you have a parent cell and it makes two daughter cells. Everything inside that parent cell needs to be duplicated so that when the daughter cells are produced, each daughter cell contains the equivalent of what the parent cell had. And that includes the DNA, the DNA of the chromosomes where all of our genes are. That has to be duplicated. But it turns out that our cells, when they duplicate DNA, don't have the ability to duplicate all the way to the very end of the DNA.

Dr. Bill Andrews: The analogy I use is a bricklayer making a new row of bricks on a brick wall, and he's standing on the wall walking backward placing a brick. But when he gets to the end of the wall, he will fall off, and the new row of bricks is shorter than the previous row of bricks.

Lisa: That's a really good analogy.

Dr. Bill Andrews: That's exactly what's happening in our cells. So our telomeres get shorter not because of wear and tear. That's why I said the telomere shortening is the only hallmark of ageing whose mechanism of action is not wear and tear. It's actually the lack of the ability of the cell to reproduce the DNA all the way to the end.

Lisa: So how can we then slow down having to replicate those cells? Is that an option? Like if I live a lifestyle and I don't drink alcohol, am I going to not have to divide as many cells? So when I don't get any infections, because infections speed up the shortening because you're having to create new cells. So all of these things are going to speed it up. So that's still the wear and tear side of the telomere story, correct?

Dr. Bill Andrews: When we get to the next webinar, when I talk about how not to age, I will talk about there being two things we can do. One is decrease the rate of cell division and the other is decrease the rate of telomere shortening. There's a lot of things we can do to decrease the rate of cell division, but mostly only the things that reverse the effects caused by poor lifestyle choices. So, with drinking alcohol, we can decrease the rate of cell division to replace the cells by quitting drinking alcohol. Same thing for smoking, same thing for a lot of different things.

Dr. Bill Andrews: But there is this basal level, okay? A good example is just blood pumping through our blood vessels. The blood vessels are lined with endothelial cells, and these endothelial cells get stripped off just from the current of the blood running through the blood vessels.

Lisa: Sheer force.

Dr. Bill Andrews: We can't reduce that. So there's a turnover of endothelial cells. And it turns out, from studies that we actually did 40 years ago when I was still at Geron Corporation, we showed that the areas where there's a lot of plaque build-up have actually already gone through more cell divisions because of turbulence — because of turbulence damaging the endothelial cells and having to be replaced — than other places on the blood vessels where there's less turbulence. The study was done on the bifurcation, just around your stomach area. There are major arteries and vessels going up and down inside your body.

Lisa: The aorta, yeah.

Dr. Bill Andrews: There's a bifurcation that essentially takes one leg and the other leg. Well, at that bifurcation there's a lot of turbulence. And so we were able to study and find out that the rate of loss of endothelial cells is much higher at that bifurcation than other places.

Lisa: That's why people like my father died from an aortic aneurysm — he died from the sepsis following on from the aortic aneurysm. But that aortic aneurysm would have been because he had damage in that bifurcation area that would have caused a blowout and then the aneurysm at that point.

Dr. Bill Andrews: Well, he probably also had high blood pressure too, and other things.

Lisa: Yeah, he did. And he smoked. Dad smoked.

Dr. Bill Andrews: Yeah, smoking is going to increase aneurysms and things like that. The poor lifestyle choices, because those all cause high blood pressure. They all cause conditions in your blood that increase the wear and tear of those cells at the high turbulence areas.

Lisa: Yeah. And there's a genetic factor too. We all have in our family a genetic — the 9p21 gene — that makes it weak. So we've got to take extra special care of our endothelial cells, if you like. Otherwise that's our weak point.

Dr. Bill Andrews: I keep scratching my neck because I was at my cabin yesterday and went out for a run and I got bit by 50 mosquitoes, on my legs. I'm just itching.

Lisa: You're causing inflammation and the speeding up of telomere shortening in the neck area right now.

Dr. Bill Andrews: Maybe. But so, the telomeres — every time a cell divides, the telomeres get a little shorter. And we know that from in vitro, from growing human cells in a petri dish, that as soon as the telomeres... So, telomeres, you're conceived at 15,000 bases. When you're a single-cell embryo, your telomeres are 15,000 bases. Bases are units of DNA and you can count them to measure the length of the DNA. So you've got 15,000 bases of telomere sequence when you're first conceived. When you're finally born, you only have 10,000 bases of telomere.

Lisa: A third already.

Dr. Bill Andrews: Yes, you've lost a third. But actually, you've lost half, because you die of old age when your telomeres get to 5,000 bases. And the cells go into senescence when their telomeres get down to 5,000.

Lisa: Senescence.

Dr. Bill Andrews: So the first 5,000 bases at the inside of the chromosome — I don't know why they're there. They're just pointless, because you have to have a minimum length of at least 5,000 bases to keep the cell functioning normally. Otherwise, it goes into senescence. So you've lost half by the time you're born and the other half for the rest of your life. And it turns out that when you do the math, the maximum number of years that you can live is 125, just like from previous studies before we'd learned about telomere shortening. And this has been verified by every lab in the world that works with human cells in petri dishes.

Lisa: And so this is the crux of ageing then. This is — we can do all the other hallmarks of ageing and improve the immune system and reading of the chromosomes and the protein folding and all of that and have that optimised, but we're still going to die before 125 if we don't solve this problem.

Dr. Bill Andrews: I always say, no matter what else we do to solve the ageing process, nothing is ever going to allow us to live longer and healthy for longer than 125 years if we don't also solve the telomere shortening problem. So that's why I say that telomere shortening problem is the number one problem we have to solve. And in the next webinar I'll spend a lot of time talking about everything we're doing to solve that problem.

Dr. Bill Andrews: And I'll also talk about the fact that there are things that you can do to decrease accelerated cell death. And that's like antioxidants, anti-inflammatories, meditation, yoga, quit smoking, quit being obese. And one of the peculiar ones, which is a really hard one to explain, but there's two studies supporting it, and that's pessimism. Pessimism has been shown to accelerate cell division and therefore accelerate telomere shortening. And so if you don't think you're going to live to be 100, you won't. And if you do think you'll live to be 100, you're more likely to.

Dr. Bill Andrews: But there's a few other things you can do, and this will broach a little bit on my next webinar, but you can take antioxidants, you can take anti-inflammatories, you can find out what foods and lifestyle choices cause inflammation. Exercise is one of the things that I think is a good way to decrease inflammation, but only if you do it right.

Lisa: You have a good point there. Inflammation —

Dr. Bill Andrews: No exercise is going to increase inflammation. Too much tough exercise is going to increase inflammation. You and I, as ultramarathon runners, we should therefore be having tremendous accelerated ageing. But it turns out that when you are consistent in exercise, especially endurance exercise, when you're consistent, your body never recognises the pain or the stuff going on with your joints as injuries. So it doesn't do anything about it. But if you're an occasional exerciser, you're the type of person that runs once every two weeks and then you go run a marathon, your body is going to have a tremendous inflammatory response.

Lisa: Yeah, and you're going to be in pain, and you're going to be suffering, and you'll be weeks to recover.

Dr. Bill Andrews: And that's accelerated ageing. But I'm sure you, from running all your races, and same with me, we've noticed that sometimes we can go out and run a 100-mile race and the next day run a 10K, without any trouble. Well, maybe a little trouble.

Lisa: Maybe a little trouble. It's a lot easier when you're fit. We're bedridden for weeks sometimes.

Dr. Bill Andrews: But that's because our joints didn't — because we didn't get inflammation. And swelling is usually a result of inflammatory cells migrating to the injuries and causing the swelling.

Lisa: And I think this is a really important point. You've got to build up. I'm really against people going and doing an ultramarathon when they haven't done the hard yards to build up to it, for example, because then they are going to cause themselves damage and do their body a real disservice. When you've built yourself up over a long period of time, then you're more likely to be able to cope with that stressor, and you won't have that inflammatory over-response. And doing the extreme stuff that you and I did — maybe you less, but I certainly did have inflammation after running in the Himalayas or whatever. And it did do harm, in the fact that I wasn't trained to that degree properly perhaps, but I pushed through on the day. And pushing through is probably not the best way to do it. You should probably back off just before there. I mean, this is apart from the whole psychological benefits that you have from it. But just from a physical perspective, you really do have to prepare for those races.

Dr. Bill Andrews: I regret to say that you and I both accelerated our ageing by demanding that of ourselves, finishing that race in the Himalayas.

Lisa: Yeah, it would really speed up the ageing process.

Dr. Bill Andrews: And the worst that happened to me was the intense blisters on the bottom of my feet, and it took weeks for those to heal.

Lisa: But again, I always say — you mentioned the word cope, cope with...

Dr. Bill Andrews: It everything — and the way to cope is to keep it fun, okay? As long as you keep endurance exercise fun and quit when it quits being fun, then you're okay. And therefore, when you do that, you end up getting — you can go longer and longer distances by keeping it fun. That's why you and I can do these races. But still, when you enter a race like that, you still push yourself because you don't want to be a "did not finish".

Lisa: Yeah, yeah, you go beyond the fun part of those races, to be fair. You've got to finish. You can't go home saying you dropped out of the race.

Dr. Bill Andrews: Yeah, you try not to. You give it everything that you don't — yeah, for sure. That probably wasn't the best thing to do, but I would never regret having done that race.

Lisa: No, because you've got to live, too, don't you, Dr Bill? At the end of the day, if we got to the end of life and we'd lived it perfectly and we hadn't done anything that was going to cause any harm — and we were still going to die — and we hadn't had the experiences that we've had, then that would be a shame, too, right? So we've got to do this trade-off between what we actually want to achieve, and sometimes that's pushing beyond what would be healthy, so to speak.

Dr. Bill Andrews: I always say, what's the point of living a long time if you're not living? So we can't be so bored with life that we live to be 125. We've got to have some things that shorten it.

Lisa: Yeah, I agree. So, coming full circle as we round out this section on how we age, is there anything else from the other hallmarks of ageing that you would say — okay, besides the telomere limit that we've established as our major, major issue in the whole ageing game, and how we can't get at the moment beyond that 125, which is what you're working on and what you'll talk about next week, what lengthens telomeres and all of that — from the other hallmarks of ageing, is there anything that you find really valuable that would help us understand how we age, from all the other 12 things that they've got, or 11 things besides the telomeres?

Dr. Bill Andrews: I think they're all important. There's not a single hallmark of ageing that I don't believe in. They're correct in their theories. But I am hoping that when we figure out a way to prevent telomere shortening, they become less relevant. Until then, the best thing you can be doing is to prevent the damage that is caused by all the hallmarks of ageing. I don't have the list of the hallmarks of ageing in front of me, but if you wanted a list of a particular few, I can tell you.

Lisa: Yeah, like protein misfolding — what's going on in that hallmark of ageing? This is one that I've struggled a little bit to understand. So we produce proteins in the endoplasmic reticulum, we're making proteins, and these are sometimes getting misfolded. These are 3D structures, basically, that the body is putting together. What happens there?

Dr. Bill Andrews: They're just clogging up the system. It's like accumulation of junk. That would fall under the accumulation of junk. Not everybody has it as bad as everybody else. The protein misfolding is sometimes a genetic result, is sometimes a lifestyle choice that's making certain proteins not work correctly — proteins that are involved in folding other proteins, let's say, are not correct, or proteins that are responsible for eliminating or removing improperly folded proteins aren't working enough or working correctly. But the net result is that it causes damage to the cell, and it causes the cell to die sooner than it would have if there wasn't this accumulation of improperly folded proteins that are junking up the system.

Lisa: Yeah. And if we look at some of the other things, like our immune system is another sort of area that I've been focusing on. How do we support our immune system? And I suppose this is an example of telomere shortening: our thymus gland calcifies, or becomes like a fatty sort of thing by the time we're 60, and it's not functioning anymore, and so that's where our immune system has learned to recognise what a pathogen is, which is a bacterium, which is something that's bad for us — and then that function starts to decline as we get older. Is that telomere shortening again at play?

Dr. Bill Andrews: Yeah, it is. But in the case of the thymus, I believe that the frontline cells in the thymus are so overworked that even under normal conditions they do not survive a year, okay? And so the thymus is gone by the time you're 60 or something like that. Probably the best person I know on the thymus is Greg Fahy.

Lisa: Yeah, I'm interviewing him.

Dr. Bill Andrews: You can interview him. He's studying, trying to figure out how to get the thymus to survive longer, and one of the things he's looking at is ways of keeping the telomeres longer. But it's still the same thing. Even under normal conditions it's not going to last as long as the other organs, but you can accelerate its decline by poor lifestyle choices and diet, things like that. But do whatever you can to decrease the chance that the immune system has to be fighting things all the time. So, don't get infected with flu all the time, things like that. And just stay away from COVID. COVID has shown a tremendous amount of accelerated ageing. There are several — numerous — publications now on it. And lengthening telomeres would allow people that had suffered from COVID and had accelerated ageing to make that accelerated ageing irrelevant. They could live a normal life. So there are a lot of people looking at the idea of lengthening telomeres as a way to solve the long COVID problems.

Lisa: Yeah, it would make sense. And then we've got things like epigenetic alterations and mitochondrial dysfunction. Mitochondrial dysfunction is another major player, isn't it? The mitochondria are the little energy factories in your cells that make the energy for that cell to function, and they're actually a bacteria from a non-human origin originally, way back in the day — and Dr Bill, you know better how this works. But these are the little factories that are making energy, and they seem to be one of the major hallmarks of ageing, or a cause of a lot of diseases when the mitochondria start malfunctioning or become dysfunctional. What's your take on that?

Dr. Bill Andrews: Mitochondrial dysfunction is a major cause of ageing. What a lot of people don't understand is that most of the proteins that make up the mitochondria are actually encoded by the chromosome itself, the human chromosome. There are a few proteins in the mitochondrial DNA that play a role. But keeping your chromosomes healthy by keeping telomeres long is also a way of keeping your mitochondria healthy.

Lisa: Wow, I didn't know that.

Dr. Bill Andrews: And mitochondria produce a lot of free radicals and they damage things, and they also damage their own DNA. They damage their own tissues, their own membranes.

Lisa: These are easy to damage, aren't they? The mitochondrial DNA is actually easier to damage than our DNA.

Dr. Bill Andrews: It's probably harder to repair the damage, but I would say the damage is probably not more. I'm not an expert on that. I would have to say that DNA damage is going to happen no matter where the DNA is. But we do have repair mechanisms that are really good at repairing. So if there's a higher increase of mutation generation in mitochondria, it's going to be probably due to the fact that the repair mechanisms are actually incorrectly repairing the DNA, not the actual mutations occurring to begin with. So one of the things that you can do is decrease your glucose intake.

Lisa: Yeah, makes sense.

Dr. Bill Andrews: Because it goes through the — what is it? — the electron transport chain. But before then, it's the first steps of converting into lactate that goes into the Krebs cycle.

Lisa: Before pyruvate, what's that part called?

Dr. Bill Andrews: Glycolysis.

Lisa: Glycolysis, yes.

Dr. Bill Andrews: Glycolysis, Krebs cycle, oxidative phosphorylation — those are the major three steps of glucose metabolism. And the result is that a lot of free radicals get produced from that. So a healthy diet again can play a role. But it's very important that we fix the mitochondria, and I do believe that lengthening telomeres is going to be a major factor in doing that as well.

Lisa: So it seems like it touches so many of the things. If you think about stem cell exhaustion, that's telomeres really, isn't it? At its core it's telomere shortening as well. And genomic instability is also part of the telomere story. When telomeres get really short, mutation rates and chromosome rearrangements skyrocket.

Dr. Bill Andrews: Skyrocket because of telomere shortening. Once those base pairs get below that 5,000, that's when you really start to see it.

Lisa: And things like cellular senescence are also related to telomere shortening.

Dr. Bill Andrews: Yes, we were the ones that first showed that, okay? Because before we discovered a way of lengthening telomeres, which is the enzyme telomerase, which I discussed last time, nobody knew exactly what caused senescence. There were theories on what caused senescence, but everybody said senescence was irreversible. Once you went into senescence, you cannot come out of senescence, and you can't prevent senescence. But when we discovered the enzyme telomerase that lengthens telomeres, we were able to show in — I think it was a 1998 paper, or maybe it was a 2000 paper; the first author is Bodnar, B-O-D-N-A-R — we were able to show in that paper that we actually abolished senescence. Again, the first time ever. And so now nobody says you can't reverse it and you can't prevent it, because we now know that in humans it is totally caused by — well, let's say senescence is totally caused by telomere shortening, but quiescence, which is a very similar thing to senescence, is caused by other things, and quiescence is reversible.

Lisa: Wow. So at the early stage it can be reversed, but once it gets to the full senescent stage it can't be?

Dr. Bill Andrews: With lengthening telomeres, yes. You can take cells — you can put the telomerase gene into cells and you can have an on-off switch where you can turn it on or off. And you can let the cells get into senescence, turn the telomerase gene on to lengthen telomeres, and that'll bring the cells out of senescence.

Lisa: Wow.

Dr. Bill Andrews: That experiment that I just mentioned was done by Jerry Shay and Woody Wright at University of Texas Southwestern.

Lisa: And you've got drugs and things that are in supplements that are on the market now, like fisetin, and rapamycin being a drug that does it, that

Lisa: ...gets rid of senescent cells, or starts to get rid of some of the senescent cells. As you rightly pointed out, if you got rid of too many senescent cells in the elderly population, they'd disintegrate into dust because there's nothing left.

Dr. Bill Andrews: Sort of like that, yes. There are a lot of senescent cells. I'm worried about, let's say, a 110-year-old person using a — what do you call it? — a drug...

Lisa: Rapamycin. Or senolytics.

Dr. Bill Andrews: Senolytics, yeah. A drug, senolytics, that actually kills senescent cells. Because let's say the majority of the cells in the skin might be senescent. And if you kill them all, that would kill the person.

Lisa: Yeah. We don't know.

Dr. Bill Andrews: Nobody's ever done that, so I don't know. I'm worried about it, but I think that combining senolytics with telomere lengthening would be the solution.

Lisa: Yeah. Now you're talking.

Dr. Bill Andrews: When you kill some senescent cells with a senolytic, still another cell has to divide to replace that cell, which is actually now going to cause accelerated telomere shortening.

Lisa: Yeah.

Dr. Bill Andrews: So senolytics, I think, is a short-term solution to the problem, but it's going to cause some major problems in the future.

Lisa: And that's all the more reason why I want you to do your job and fix the telomere stuff, so that we can use our senolytics and use all these things that actually — like even skin resurfacing and lasering and all of that, microdermabrasion, all of that. That actually speeds up — you get younger-looking skin, and it is younger for a while, but you've actually created new cells, which means you've caused more cell division, which has caused more problems. So there's a lot of things that fall into that category, right? That are actually beneficial but are causing shortening of telomeres. So if Dr. Bill can fix the telomere problem, then we can go and use our microdermabrasion and our exercise to extremes and do all of these things that could cause shortening of the telomeres, and then you can fix the telomeres for us. That would be great.

Dr. Bill Andrews: Anything you do that increases the rate of cell division is going to accelerate ageing. So microdermabrasion, like you just mentioned, but also immune boosters — those are going to cause accelerated ageing in the immune system. And even something like human growth hormone, which a lot of people are taking to build up muscle, that is causing cell division, which is going to accelerate telomere shortening.

Lisa: And this is not to say — because this is a balance, right? If you don't have any human growth hormone, you're going to have a lot of other problems and you're going to die of other problems. So there's always this balancing act of, how do you have enough IGF-1 and enough human growth hormone and enough testosterone and enough human optimisation so that you live a functional, vital life, but on the other hand, you're speeding up the ageing process? It's just this terrible damned-if-you-do, damned-if-you-don't scenario.

Dr. Bill Andrews: A lot of my talks — a lot of my talks show a scale, and it shows how much it can go up and down either way. And you're right. Another analogy I use is a tug-of-war. It's always a tug-of-war back and forth between different things going on. Life is a tug-of-war. Everything about it is a tug-of-war.

Lisa: So it's not that microdermabrasion is bad and you should never do it, but understand what's happening and then you better balance out the other side, and pick and choose. IGF-1 is one of those really difficult ones. It has so many benefits. I'm trying to increase Mum's IGF-1 levels at the moment for her brain cognition, for her bone density and all of that sort of stuff. But am I speeding up the telomere shortening process in the meantime? But is it too low that she won't survive if I don't do that? You sort of are in this damned-if-you-do, damned-if-you-don't scenario.

Lisa: And so this is why I think that the next webinar is just going to be absolutely fascinating. Because the telomere story — we've shown today how many of the hallmarks of ageing it actually influences and is a part of. It's sort of a linchpin. So we can then be able to have this vital, strong life, have our optimised testosterone and human growth hormone and IGF-1 and all of those mTOR sort of pathways going, build muscle, be better, but not shorten our lifespan with it.

Dr. Bill Andrews: As I always say in my talks, microdermabrasion, human growth hormone, things like that are good. Okay? Because what's the point of living a long time if you're not living?

Lisa: And you feel like you're half dead because you've got no energy and you've got no muscles and you've got no functionality.

Dr. Bill Andrews: You don't want to miss out on all the great things about life, because living is the greatest thing that ever happened to us. You don't want to miss out on all that just to be able to live as long as possible.

Lisa: I mean, just to have the long-term effects...

Dr. Bill Andrews: I will fix the problem. I will fix the problem before most people have to worry about it.

Lisa: And on that point, I think we wrap it up for the day, Dr. Bill. I think that was actually a really good jumping-off point for our very important webinar, which is the next one, on how not to age and what Dr. Bill is doing and working on. So make sure you stay tuned for that one. Now you've got the history, the background, the why, the how, the what, and now it's how not to, which is the key point of this. So thanks, Dr. Bill, for sharing your insights today, and really appreciate you.

Dr. Bill Andrews: All right, thank you.

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