Welcome to the Life Span podcast where we discuss the science of aging and how to be healthier at any stage of life.
I'm David Sinclair. I'm a professor of genetics at Harvard Medical School and I'm co-director of the Polish, Glenn Center for biology of Aging research. This podcast series is about why we age and while we may not have two things you can do today and going forward to increase your wellness and to potentially live a much longer healthier life. We've talked about biology Beijing. We've talked about things that you can do at home. Preferably under the supervision of your doctor. And today, we're going
Talk about things that you definitely will be talking to and requiring a doctor's supervision to do and even things that your doctor is unable to do, but potentially in the future may be able to I'm joined today by my co-host and my co-author the lovely Matthew Laplante. Hey,
maybe we're back. We're doing it
again. We are definitely doing it. Today. We're doing a deep dive into some, you know, somewhat controversial stuff. This is scary episode.
Well, I don't know if it's scary but we have to do a disclaimer. I think we have to say that what we're going to talk about today. A lot of it isn't approved by the FDA but maybe in the future and some things that were available until recently and were banned by the FDA and are currently available only offshore.
And just as was the case when we have the conversation about drugs and supplements and maybe even more. So in this case, there's a lot of misinformation out there about a lot of things that we're going to be talking.
Thing about today, these potential avenues for let addressing longevity. We're going to try to cut through that but we are not doctors of the physician
type. That's right. I'm a PhD in genetics. I'm not a physician. And so the things we've talked about in this series should always be done with the supervision and advice from your
physician. Yeah, podcast is no substitute for a
physician. That's right, but I'm a scientist. I can read the scientific. Literature can distill that down your science communicator, and we're
Here to be able to distill the wealth of information that's out there and distinguish. What's fact from fiction and give people a starting point as to really, how do they figure out what's best for their wellness? And what's actual complete bull out there?
And so, today we're going to be talking about stem cell therapy peptides exosomes testosterone growth hormone. And then we're going to spend a little time talking about one of your favorite subjects, epigenetic reprogramming, but we can't do that until we do something else
first. Well, we
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by starting today with testosterone, super popular subject.
Lots and lots of growth in testosterone replacement right now because of the fact that testosterone decreases as we age and that's disconcerting to a lot of people.
Well, for sure, after the age of 30 to 40, we lose about 1% about testosterone levels men and women. It's important for both sexes, but the market is growing so trt or testosterone replacement therapy has grown from a few hundred million ten years ago to multi-billion Dollars. Now, it's widely used
Just to supplement for sexual dysfunction, which is a common side, effect of low testosterone, but for other things, that include mental health, building, muscle overall, Fitness
vitality, and people swear by this. And a lot of people did they do this? They say they feel younger, they say, they feel more. Vigorous. They want to have sex again. They want to have sex all the time. There's an important distinction to make here though, which is just because you feel younger does not necessarily mean, you are reversing your biological.
Cool aging,
right. Let's make a clear distinction. We've talked about adversity, memetics and the last episode, we talked about the supplements and the kind of things you can do in your life to mimic that. We want our bodies to be in a state of fear. The times are tough and they need to hunker down and survive. There are other types of things that we're going to talk about which are abundance. Memetics testosterone is one, we're going to get to growth hormone as well. These tell the body the times a good to build your muscle to reproduce, go forth.
And that's what testosterone is doing. We get to start our own replacement therapy. We are putting a substance back into our body that has been reduced. But which signals our body that times are good enough. It's okay to build muscle. It's okay to run around chasing woolly. Mammoths. Yeah. Well chasing the cave women
around. Exactly. Yes that for sure. And that benefited our ancestors very well, but it didn't help them. Long-term. What we now are appreciate is the body has cycles of want and need and adversity, which is
Good for the long-term health of the body and times where things are abundant times to grow reproduce, which are great short term, but probably not great for long-term Health, and Longevity either. Okay. So
let's talk about what actually happens when our testosterone lowers and what happens importantly, when we put it back, because this is helping a lot of people with a lot of problems that are coinciding with aging.
Oh, for sure. They're being a lot of studies millions of dollars and many
Thousands of people treated with trt as it's called Shelly Basin. Who's a colleague of mine at Harvard has done a lot of these studies and he's found some improvements short-term improvements. So of course improvements in libido, but also he shows a dose-dependent increase in skeletal muscle mass. She a bigger muscles. You got more power, you can climb stairs. You can walk further in six minutes, improves aerobic capacity. These are all good things that he sees, but but actually, it's not all good news. There were some side effects and may actually
The impact longevity. So, some of the risks of trt. There's worse, sleep. Apnea. You can actually get larger breasts. Little known fact, is your testosterone can be turned into estrogen, which is a risk for men. And particularly our, you can have what's called benign prostatic hyperplasia. So big, a prostate need to go to the bathroom at night shrinking. Testicles not something. I think many of us would want and increasing red blood cell protection, which could lead to blood clots.
And if you're already predisposed to prostate cancer, you have
Source growth already. This could actually aggravate the
tumors. Yes. And actually, the opposite is true. If you if you look at the history of Unix they live longer and so it may actually be that supplementing with Tesla's testosterone is not conducive to longer life.
Okay. So this is an important principle here and we're going to come back to this a couple of times on this episode which is just because something makes you feel good today and just because it might even be medically beneficial to you today. That does not necessarily mean it is
Is do, it is addressing the causes of biological aging. It may be fixing something that you have a problem with and maybe improving even your quality of life right now. Long-term. That's not the same thing as, as reducing or eliminating biological
aging. Yeah. Let's go back to the main concept here today, which are that adversity of adversity. Memetics are great things that mimic like a food and a lot of exercise but these abundance memetics are
Probably a problem long-term, even though they make you feel great short-term.
Okay, and that sort of giving away the punch line for HDH, but we need to talk about HGH as well. Human growth hormone. Also. Something that is really popular right now. People supplementing with human growth hormone to address things like decreased Exercise capacity, decreased bone density, decreased muscle mass and increased body fat. This works right? For those things is
HGH is
helpful. Well, no question short time. You'll feel better. You'll grow muscle. You'll have less fat on growth hormone therapy. The science says that this may not be good for long-term health and wellness. Going back to the original studies of Cynthia, Kenyon, which we talked about in episode 1. Those mutant worms had low levels of growth hormone and Insulin like growth hormone signaling and they live longer twice as long and this has been reproduced also in mice and even in humans, there are the LaRon dwarfs were talking about earlier.
A smaller people that have low levels of growth hormone actually, igf-1. One of the versions of this pathway. They are relatively resistant against cancer and heart disease and may even live longer. Conversely. If you're supplementing with growth hormone, long-term the chances that you're having the opposite that you feel great, but long term, you might have even greater risk of cancer and heart
disease. And, you know, people who are on HGH for various reasons, one of the immediate side effects, even before we get to the sort of, like the
Longevity. Implications is sore joints. Carpal. Tunnel
syndrome, right? This is the kind of thing that that does happen. Now. I just want to be clear that there are some benefits to bringing the levels back up to normal. Okay, but going too high, which a lot of people do, if they want additional benefits. That's where I think the main risk comes from
another risk. Immediate is increased insulin resistance.
That's true. We get high levels of blood sugar. We get high cholesterol carpal tunnel. Adiemus a buildup of fluid.
Joint
pain. Okay. So soreness in your joints insulin resistance. Another one is an increase in the likelihood of type 2 diabetes because of that, insulin resistance. All of this actually kind of sounds like symptoms of
Aging, right? And that's the risk that the animal studies are telling us that growth hormone will tell your body that times a good abundance. Mimetic and that's not good for long-term effects of health and probably what's going on is some acceleration of Aging,
okay, but this isn't to say again, I think I
I think this really we don't want to say human growth, hormone is bad, testosterone is bad. People need to have a naturally healthy level of these hormones in their body
and there are ways to do that naturally. So for testosterone, you can work out the bigger muscles in your body and that also help with growth hormones. So I work out my thighs, and my back, particularly keep those nice and strong. And I found my natural testosterone levels. Go up to normal levels with that so that that's the way to do it with growth hormone.
It's all about eating at the right time and sleeping. So if you eat not too close to sleep time, and then you rest through the night and have a good night's sleep. That's the best way to improve your growth hormone levels.
And if you're doing all of that, and you're still struggling to keep these levels up, that's the time to talk to your doctor about supplementation, but that supplementation needs to be aimed not at hyper increasing, the levels of these in your bodies, but just keeping them at that sort of like that Natural Healthy
level. Well, exactly.
Italy. But I would encourage everyone to try it naturally
first. So so far this sort of feels like bad news. Is these are things that a lot of people have gotten it in, their heads might be beneficial to anti-aging and what you're saying and what the evidence suggests is that there is no anti-aging benefit. There might be a short-term gain, not a long-term anti-aging benefit, but these aren't the only things that are sort of like,
Hot on the market right now. Another thing that's really popular to talk about, really popular to try where it is legal. Is peptide supplementation.
Yeah. So pip ties, just like hormones and made of him strings of amino acids, but typically smaller about 100 amino acids. You can synthesize them on a machine or extract them from tissues and they're used by cells to communicate between each other. So your brain will put out peptides to Signal the body, your liver and your muscle. And some of these are really good. Some are really bad.
We don't know what they all do. There are probably a thousand made by the body. We've probably only know about what 20 of them do in great detail.
But what we do know is as a class, the the helps us communicate to one another, right? And so just sort of like holistically speaking to go. That's really good because in part aging is loss of cellular communication and so, peptides help increase that cellular communication. Voila.
They must be great for aging.
Well again, it's whether you're in a versary adversity, mimetic or an abundance mimetic. That's the difference and really you have to make a distinction between those two things. One of the best studied peptides of all time is insulin and clearly that's important. If you're deficient in it, we've known this. Since the
1920s do we actually have 100 years now is a 1921 which was when insulin was first discovered,
right Banting and Best in the was a 1921 found. They could extract this insulin extract from the
Pancreas of a dog and injected into a dog that had diabetes and cured, within
hours and within months, they were trying this on human beings because that's how things worked back
then. Yeah, and they even won Nobel prizes quicker. There was only one or two years afterwards that they won, the Nobel Prize for
that. So, they went from this works and dogs to. Let's try this out in a 14 year old boy to Nobel Prize in the span of, like two years
who always worth it. Because in those days, particularly type 1 diabetics, which are the is
The childhood version of this, the lack of insulin meant that they would have to go into the kids, would have to go on a starvation diet and even then they would die within a year or so. It was horrific and suddenly people were living for decades that first patient lived for another 13
years. And so this set is down the road of studying peptides and their health benefits. And then a really big thing happened in the 60s, which is we figured out how to synthesize
peptides, right? That was a big deal. And then in 1978, they started to be made.
Using recombinant, DNA technology. And that's why if we find ourselves today is that most of these hormones and peptides that are available on the market are made using recombinant, DNA technology, though. These very small peptides are unique, because you can synthesize them on machine which makes them very cheap. Didn't you
say like there is like some people have these machines at their homes.
Yeah. I'm aware of some people that have them and they're making them at home and injecting themselves. I don't recommend that that's currently
That's off-label use of drugs and you don't want to do that. But that gives you an idea how it possible it is to make a drug these days, especially these peptides because
these are at this point, so easy to synthesize and because a relatively cheap and because they are relatively non-toxic there's been lots and lots of clinical studies on on the use of peptides,
right? Thousands of human studies and it's interesting. Why are they
Save, well, they're not foreign that typically already found in the body and they're small. So they don't typically have an immune reaction though. The risk is not 0,
then metabolize quickly.
They're also metabolized quickly. And so that the risk is relatively low. And for that reason, there are a number of doctors who have been, okay, giving these peptides to
patients, and what we're looking for, when we give peptides to people, specifically for the cause of the anti-aging is a boost of regenerative
signaling, right? So what you're looking for is
the ability to recover from damage, increase wound, healing, lower blood sugar levels, increase mitochondrial activity. Those are examples for signatures of an adversity memetic, not an abundance
mimetic. Okay, let's talk about some of these. We have discussed in the past
matze, right, matze matze. So I'm OTS d.c., That's a really interesting peptide and unusual class. That actually doesn't come from the nucleus that normal chromosomes that we talked about, but from the
Bill DNA in mitochondria, and up until about 10 years ago. We thought that there were only 13 genes encoded in the mitochondrial genome. And there are now about 100 known and matze is probably the best characterized of those. There's another one called human and as well matze, when injected into mice, lowers blood sugar levels, increases mitochondrial activity, gives you the signatures of long life, probably promotes life. There's some evidence of that and has been in humans. In fact, there's a clinical trial that was just released the results of which show
showed that it reduces fat in the body and improves fatty liver, which are again, signatures of potential
longevity. And so, to your belief at this point is that there are likely peptides that are valuable when it comes to addressing the causes of biological aging. Unlike these other things, we talked about today
will almost certainly but we don't know enough yet to say for sure if that these are perfectly safe or will increase lifespan. They lot less is known about these peptides then
Dosterone or growth
hormone and to that end, the FDA agrees. They're nervous.
Well, yeah, because they became so popular. Typically on the west coast. L.a. There's there was a real megatrend and and still is to try these out and they've variety of properties, that seem to be beneficial anecdotally. Improving memory muscle mass, lowering inflammation, the FDA looked at this and said, whoa, hold on. We don't know enough, and they sent a letter to accompany.
Saying stop making this and then that sent shockwaves. This was March of 2020 and and so since then, it's been impossible to get some of these peptides in the United
States because they've stopped compounding
them, right? So even though they have been some promising results with peptides. The FDA has said some of these need to be regulated and many of them now, are you cannot get in the United States?
So they're still in clinical studies. Researchers are still examining them, but the Avenues for getting these in the United States have become more limited.
Are so people getting them overseas compounding them in their own machines at home?
Right? But still, we have to be careful because they they're not all perfectly safe. And one of the reasons the FDA was nervous about this and been banned. Many of them is that there are some side effects. It's not just that they can be redness whether injected but actually it seems like you can induce arthritis type effects when the immune system recognizes these peptides as foreign and that would be something you definitely wouldn't want to have is an immunological
reaction. A lot of these have me.
Names that are like Star Wars droids. And so, people have heard these heard of these, they might wonder what they're doing. One. That's really popular in conversation right now is BP 157.
Yeah, BP 157 is one of the more popular ones. It's been used to increase blood flow, lower inflammation and even regenerate neurons for cognitive ability, but there are lots of others. There's one called SS 31, which targets the mitochondria and improves mitochondrial function, could seem to be good for the heart, Maybe.
Longevity. There's another popular one called ghk copper. It's part of a couple. Complex was first identified in human plasma later, which is found in saliva and urine. And it's been used to help wound, healing attract immune cells and it's an antioxidant stimulates collagen protects tissues against inflammation can even be used apparently, to reduce Fine Lines wrinkles and grow here again.
There's a bunch of those. It is this based on,
which is this, is anecdotal evidence. Is this research-based evidence? How do we know these things about these different
peptides? Yeah, most of these come from Mouse studies and then there are anecdotal from from studies that that clinicians are currently doing. But yeah, again, I want to stress that most of these things that we're saying our anecdotal and not yet scientifically
validated. These are some people's experiences. And and this is all one of the reasons why there is a pretty
Never got movement right now. This sort of like, save peptides movement of people who are contacting the FDA and saying, please make these things more available to
us again. Well, yeah, there's one in particular thymosin alpha 1, which has been known since the 1970s to be beneficial. It seems to be great particularly for helping against while fighting bacteria and viral infections, but it was also listed on the banned substances in 2020, and there's a movement to bring it back because with covid-19. It's thought that it could help talking about other ones that
Some of these work with fat loss. Apparently, we've got to some oral and CJC 1295 is taken with one called April moral. And there's a OD 9604, and the bpc 157. Again can be good for weight loss. Apparently, one of the other ones I mentioned human and is, again, one of those mitochondrial derive peptides like motsi and in mice, at least has been shown to help against type 2 diabetes, high blood sugar, cardiovascular disease. And even help with neurodegenerative diseases like Alzheimer's but in humans, it's not clear if that's true.
Peniel on is a really interesting one. It's actually an active peptide, complex and has been thought to treat memory attention, deficits brain, injury stroke, chronic fatigue, Etc. But again, early days, we don't know for sure if this is actually true in humans. And then finally, we should just mention. There are others that are being used to combat fatigue and also boost the immune system. They go by names. Like dioxide cerebral Eisen semak's selling or even be PC.
57 is used with some accents, our beliefs, and together, again. These are all pretty much experimental. They've been shown to be effective in mice. But still, we have a long way to go before we know if they're truly effective in humans and their we always need placebo-controlled. Double-blind, clinical studies,
which are underway and there's lots and lots of clinical studies going on. It's just not moving as fast as I think. A lot of people would really like it to move, but that's that's the reality of the space that we're in right
now. Well it is and often it is frustrating.
I can speak from personal experience, how long it takes to make a drug can be extremely slow and we're all getting older. We're not getting. In the case of most of us. We're not getting any younger, and there is a desire to rush into things, but I think we need to exercise some caution here because you can have these negative side effects. Particularly in the case of peptides and immune reaction. They could be deleterious in the long run.
And in that long run though. You see these as a very promising Avenue for a lot of therapies that are going to help a lot of people including not,
Just with individual conditions, but you think with
aging oh for sure, not all of these of course, but those that mimic adversity, matze is a good example of one that I think has the right signature. I think they have a lot of
Promise because there is an explosion of research going on, sort of at the same time with peptides and this other thing that we're about to talk about exes. Ohms. I think these happened in the same breath. A lot of times people, talk about peptides and exosomes both of these or cellular signalers, but exosomes work. Well, they are different and they
work a little
All differently. Well, very different. These are packages of information. They contain well, they're membrane-bound. So their little vesicles about the size of a virus. So they travel between cells and in to Salisbury easily and inside it's not just one message. There's multiple messages. There's peptides inside. There's DNA. There's RNA even what are called micro rnas, which are similar to peptides very small pieces. In this case of nucleic acid material that can go from the brain to other tissues from tissues, back up to the brain. And this is essentially
Way the body can coordinate. So if there's an injury on your hand, your brain will know. Or if your brain gets injured, the rest of your body knows you need to have these Messengers to coordinate the system in the same way. You could imagine that the u.s. Post and so these are little mail deliveries or Cargoes that we can both intercept and read. Perhaps in. We can use these to diagnose diseases, including cancer. But also we can make more of them and Infuse them into people to give a false alarm. Perhaps even to simulate this ad.
Varsity and make us live
longer. And before we get to those therapeutic process has one of the really fast. Moving avenues for using X's. Ohms, is basically collecting them from the blood counting them up and being able to diagnose different injuries. And even like you can pull from people's blood these X's, ohms and then you can say like, oh they have an injury here. They have a disease there,
right? Yeah. That there are companies now that there's one.
Olds are Therapeutics are others that you can read the cargo and you can say, okay that comes from the pancreas. That is the signature signature of a stage three pancreatic cancer. So we may be able to use these to diagnose cancer years in advance
without biopsying,
right? Just a blood test or even a finger prick at home, send it off and diagnose cancer.
And now that would be reason enough to be excited. I think about the potential for exosomes to tell us what's going on in our bodies. But what else were learning right now about exosomes, is that if
We supplement these into the bodies of mice. Like, by injecting them into their back into their bloodstreams. It can help with injury.
Yeah. I mean, there's a really well-known paper now from August 2017, by my good colleague down at Albert, Einstein College of medicine medicine, dongsheng, Chi and his expertise is looking how the hypothalamus the little organ at the base of the brain communicates to the rest of the body. And he's found that inflammation in and damage to that part of the body, affects the rest of the animal including aging. And in this case.
Found interestingly that neuronal stem cells. These progenitors in the hypothalamus. They secrete exosomes that tell the body to hunker down and survive, and the mouse can actually live longer if you isolate these X's, ohms and give it to the mouse. They also did the opposite. They deleted these special cells that make the X's, ohms and the mice got diseases of aging and lived shorter. What why is it happening? Well, we don't know in most cases. There's so many things within the exposome. So we it's very hard to figure out which of those particular cargos is
Possible for the biological effect, but ultimately, if we can figure that out, we could make exosomes with just that particular component and that could be a drug in the future.
There was another fairly recent paper on exosomes 2019 paper from some Chinese researchers that used exosome replacement to address ulcer healing and what they concluded was that the exosomes are actually rejuvenating senescent cells.
Really fascinating here.
Well, that we so senescent cells. If you missed the previous episode ourselves that as they get old and they have X differentiation. They lose their ability to read this, their DNA correctly. They become senescent. They stop dividing, they sit there and they start secreting. Inflammatory molecules can even cause cancer to develop.
We try to delete these cells. We know that in a mouse and probably, in a human, if you get rid of these inflammatory senescent cells, it's good for health. But here, we are saying, what the researchers are saying, is that, these X's arms, the particular type of exercise can reverse an Essence that's unheard of. If that turns out to be true. That would be quite a remarkable thing. Meaning one day. We don't have to kill off these cells which in the brain. You wouldn't want to do that necessarily. We could actually rejuvenate them and get them to grow again
healthily right now, the way we understand,
To do that, is through the yamanaka factors, but this would be another Avenue toward that. Same goal of taking X, differentiated cells and sending them back into a differentiated
State. Well, it yamanaka Factor Rejuvenation of senescence cells is preliminary. This is some of the work we're doing in my lab and it's not even clear if the yamanaka factors a potent enough to reverse senescence, but this finding that you referred to is the first instance of that that might be
possible. All of this.
This is why there's a lot of excitement around this, this particular potential therapy. But again, just like peptides. This is sort of the Wild West right now, but people are already taking exosomes and and having them shot into their
bodies. They can be delivered by Ivy or intramuscularly. But again, we don't know what the long-term benefits or side effects are. So we have to be careful. It's still available in some parts of the US, but we don't know
if this is not one of those.
And you have to go to Costa Rica for at least as of right now. The FDA hasn't cracked down. They haven't said this is a step too
far. That's right. But while exosomes on completely banned the United States, you can bet that the FDA is looking at this for potential safety concerns. And we'll see how things go over the next few years.
That's not the same thing as saying like go do it now.
No, no, that's not what we're here for. We want to educate and look at what might be available down the line once things are proven to be safe and
effective. And this is another one of those things, like, like,
Peptides you're feeling positive that there is going to be actual clinical research that will show us, the actual benefits of these. We don't have to make super, super guesses. We can actually see in the research, how exosomes are going to be beneficial and then start to implement them into our longevity regimes in a responsible
way. That's right. And just to be clear exosomes are highly validated scientific Pursuit and there are
Companies, pharmaceutical companies, building, giant factories for billions of dollars to make exosomes to treat diseases. The question is do they work for long-term Health and Longevity and how safe they are to be used over decades that we don't know yet.
Okay, let's move then into an area of research that is even further. Along still. We're learning more about every single day, but also has potential anti-aging implications stem.
Yells. Let's start with a little primer. Stem cells are stem cells are cells. That
can divide asymmetrically to produce cells that go on to make tissues. So for skin, you need stem cells to make all the skin that goes over your lifetime and they retain youth so that they can keep dividing over and over. And they don't become any particular certain cell type
overtime. And stem cells can become more stem cells or they can become any kind of
cell and there's a few different types, right? The two main classes are
Potent which can make a few different types of tissues. These are cells that you typically get from an embryo or can go all the way back to age 0 and what are called pluripotent stem cells which can make any type of cell and any type of
tissue you can think of this sort of like, as one of those trees, right? Like, like you have the pluripotent cell that can do anything and then after a while a little further down in the development, you have the multipotent cells which are still able to transition into
several different kinds of cells, but not all of the different kinds of cells.
Exactly. And so if you want to build a mini human brain or rebuild a kidney out of a skin cell, you have to wind the clock all the way back to zero start again, and that's called inducing, a pluripotent stem cell
State, and that goes back to what we were talking about earlier, the yamanaka factors. This is one of the ways that we've identified that we can turn a stem cell or any kind of cell from being a stem cell back into a state of
pluripotency yet. Let's just talk about shit.
Yamanaka. Because it's really quite an amazing story. So yamanaka in Japan in the early. Well, 2010's was in his lab was figuring out. What trying to figure out, how do you take an adult cell from an animal or human and make it pluripotent? Because if you could do that, imagine you could build any tissue you wanted and he was trying lots of different Gene combinations and hit upon five genes that when put together worked to take. So I could take your skin cell. Now, using yamanaka is jeans or yamanaka factors and make it plural, potent, stem cell line and
You, I could even turn you, by the way into a sperm and an egg in Clone you, but I won't do that. So yamanaka found the following jeans. So klf4 socks to see Mick and Lynn 28. We use three of them particularly in my lab. We'll talk about that later. Oh, S and K for short, but this was a major breakthrough because finally, you could take anybody's skin cell, which you could easily get from the cheek or biopsy grow that in a dish, look, a reprogram them, which takes about a week, once you put these genes in, and when they grow up into what we call,
Honey, which is an assemblage of about 100 cells. You pick those in a could grow, basically anything you want from Matt or plant
cells. Well, and I've seen this in your lab where you've taken cells from a mouse, you've induced them into state of pluripotency. And then you have trained them for lack of a better word to grow into brain cells. And now you have the little, these little clusters of brain cells that look like little brains.
Well, you've done that for myself.
Yes, and we've done that, for human way of many human brains and we take these from old individuals. I'll normal individuals and also patients that have susceptibility to Alzheimer's disease. And again, we I think I want to talk about this later but we have the ability in my life to drive aging forwards in those what are called cerebral organoids and even in reverse and that's what's important really for being able to study the human brain without having having to touch patients and you can go a lot quicker that
way before we
Sort of go down that rabbit hole. Can I take us back just a couple of steps to how this actually happens. Like how do you take these factors and put them into a
cell? It's actually really easy. Any high school student could do it. There are a number of ways, the old ways of doing it are you can pause electricity through the cells in the dish and they take up DNA that encodes these yamanaka jeans. You can put them in what are called liposomes or
Liposomes, which are fat membrane-bound, little balls, but the way we do it in the lab, which is the most efficient, is we use viruses, domesticated viruses, that are typically used in patients for gene therapy. We use them in the lab. They called, adeno-associated virus, has or aavs, we packaged inside those the yamanaka genes and just throw them into the dish and they infect, all the cells in the dish. And now, those cells are transgenic. They carry these genes and we can turn those genes on and off at will using drugs and see what
happens.
And the implication here is that we can take these these now, pluripotent cells and then we can use them to treat areas of the body where the cells just aren't acting the way that they're supposed to act anymore. But there's still a problem with pluripotent cells, right? Or sorry, induced pluripotent cells right now and that is cancer.
If you take the age of a cell back to zero and allow it to just grow and put it if you put it into a mouse and probably a human.
You'll get cancer teratomas, bitch'll, particularly pernicious, type of cancer, which can be, you know, hairy ball of mass m times with teeth in it. You don't want that. So you have to be very careful. Not to put these pluripotent stem cells back into the body and just let them grow,
which is why right now most himself therapies aren't using induced pluripotent stem cells. They're using harvested stem cells and we can get those from a variety of
places. Right? Mainly what we're using, what?
Scientists and doctors are using a water called autologous stem cells. So but cells that you take out of your body from various parts of the body, typically fat cells on your back or your hips and then purifying them out, freezing them down and or putting them back into the body in different places or into the bloodstream,
so we can just suck stem cells, out of fat out of adipose tissue. A lot of people don't think like, well, why would we even go through the process of trying to induce pluripotency if we could just take stem cells out of fat, but one of the things that I
I think needs to be said and you've done some research on this is that stem cells age? Also,
they do they undergo epigenetic changes that make them less able to regenerate new tissues. And that's also true. You see that with gray hair and and hair loss. That's the loss of the stem cells in the hair. Follicle. One other thing that would just happen recently, as it was discovered that you don't just have stem cells getting old, they keep can even be kicked out of What's called the niche where they where they belong there. Like to reside and that's true for the hairstyle. It was
Fascinating video that I threw up on Twitter and the stem cell you could see. They captured it under microscope. You got kicked out and it suffice to say, well what is really going on? Is that these stem cells need to be slow down in their aging process, or even replaced. And we're only just learning how to do that.
The other thing that we can do is capture them at a much younger State. That's where cord blood comes in.
Right? And you can even do that for adults. The idea is that if you capture these cells when they
Are very young or if you're in your twenties and thirties, you can Bank them, put them in the freezer for later. Use either to replace the blood if you have leukemia or even using new technologies to modify them and grow new tissues, perhaps even replacing old blood when we get very old. And a lot of people are doing this
now. It's becoming more and more common for people to say. Hey, look, I want to preserve my child's ability to use those stem cells later on, even if we're not
Actually sure how they're going to be used. And so they're banking them. Your kids are in their teens and early adult years, but if you could go back in time, would you do
this? Yeah, we didn't do that because at the time it wasn't clear if they would be useful. But now it's very clear that there are uses for them. Especially if they get Childhood Cancer. And so I would do that if I was a new parent, I would aim to bank those. How about
you? Yeah, I mean, so as you know, I haven't followed you down every longevity rabbit hole that you've gone down and the other people have
Gone down. But this is definitely 100% something that if my child had been born today. I would absolutely do. I would be banking. There are Core Blood. Yeah, if I did want to do that now though, how would I go about? How would I go about doing
that? Well, there are companies you can contact and often the hospital and the doctors you work with know how to do this. But you need to get ready. You at least need a few days off in a week to get ready for this because you need to spin them down and put them in a freezer. But when you, when you have a placenta, there are particular Parts, the placenta you can take the
Blood are you can take a thing called Wharton's jelly, which is this gelatinous substance made of hyaluronic acid where there's particular concentration of stem cells. You can also isolate.
We can also isolate stem cells from adults. Again. These are stem cells that have, you know, gone down their trajectory from pluripotency often to multi potency. And so they're not, you know, they're more aged. But the earlier we do this the better, right?
Yeah. These stem cells in adults, don't just age and become dysfunctional.
They can out-compete each other. They can grow faster. If you have mutations in genes, like tet1 tattooed EMTs, they grow faster, and can actually out-compete the rest of the immune system. If you look at hundred year olds often, they only have 1 or 2, instead of thousands of types of immune cells, which is a real problem if they get pneumonia, it's often why these elderly people don't survive in infection. So, what you might want to do is to bank these hscs hematopoietic stem cells, when you're younger. So you can replace your immune system as you get
older.
However, we obtained the stem cells, researchers at using them for all kinds of diseases. They're being used to regenerate and repair diseased and damaged tissues in people with spinal cord injuries, type 1, diabetes, Parkinson's disease, ALS Alzheimer's, heart disease, stroke Burns, cancer arthritis. And the reason why I'm saying like making this big list is because now thanks to what I mean, like really you've done this to me.
Time, I hear a big list of diseases, and One Singular thing, that can address all of those diseases. I don't think of those diseases separately anymore. I think of aging and there's a lot of implications here for the potential to use stem cells, perhaps to treat aging, and a lot of people like these other things, we're talking about are really excited about this potential Avenue for, for
anti-aging. Well, they do have a lot of potential. First of all, we can make new organs using these induced pluripotent stem cells are
By PCS, and even these autologous stem cells. We're talking about that. You can pull out from children. And from adults. They can be used to replace stem cells, that get old but there's a real fundamental drawback to using stem cells to live longer and that is that they often don't find their Niche, their resting place. Even if you inject them into the, I often they don't find their their home. And in fact, one of the problems was, when researchers did this to patients in Florida, there were three people became blind when it wasn't done correctly, so,
That coincided with an FDA order that said, hey, everybody slow it down. Be careful.
You can get some stem cell therapies now, but the majority of them have been banned for now, but what is really a problem is that if you can't get them to the right place, they're not going to regenerate a rejuvenate the whole body. So what we're looking at now is how do you reduce innate, the existing stem cells and stop, then getting older or even reverse the aging of the stem cells in situ where they exist and we'll get to that. But this
Is the reprogramming technology that should work not just on normal cells, but even stem cells to make them young, truly young again
and there's been a lot of research showing that stem cells can have a therapeutic effect in like specific parts of the body. But when we talk about this like aging umbrella, in general, there was one study. Actually, two studies of phase. 1 Study to phase 2 study from researchers at the University of Miami in 2017, that gave stem cell therapy. Harvested stem cells from a younger.
Our donors gave them to older. Frail, patients and small scale, but it showed improvements in the distances that these people could walk it lowered. The levels of cytokines. It improved their mental state and they had a reported quality of life Improvement as
well. Yeah. I mean, that's a remarkable. Couple of studies if it can be reproduced. But for now, what most people are using the mesenchymal stem cells for is in,
Joints, when you wear out the joint, and there's not a lot of collagen injections of stem cells into those joints, seems to be, at least they're up, you take for a short amount of time, whether or not it's because the stem cells stay in there, or the secreting, exosomes, or other peptides. It's unclear.
So this is another area of research, then that again, probably people don't want to just walk into a clinic tomorrow and get a stem cell injection because like you said, the stem cells, might not even know where to go. But
In the future. This is likely to be part of people's common anti-aging
regimen. Well, I'm sure, I think the future looks like this that we can keep our bodies healthy by eating right doing physical exercise taking the right medicine, sesh supplements. And when that doesn't work and things fail, you can then rebuild the body replace cells put in your organs and that way, we'll live probably many decades longer than we can currently live. And then there's one
more thing that in the future. We may be able to
In this leads us to this thing that you're doing in your lab right now, if you had a, quite a few published studies on that are pretty darn exciting. Talk about cellular
reprogramming. Well, this is the big one. We've been working for many years on, slowing aging, but we've wondered. How do you get that to be reversed? Is there a reset switch in an old cell? And we think we found it. We're standing of course, on the shoulders of shinya yamanaka who showed
I'd you can reset the age of a cell back to zero but that of course causes cancer. And if you do that in a mouse, it will die within days. So that's not going to be a therapy anytime soon. I don't recommend it. But what a wonderful student. One Chang. Liu did a few years ago in my lab. Was he found a set of genes that are yamanaka factors that were able to reverse the age of cells and tissues in an animal and in human cells to a certain points. Going back about 80% over age, but not to 0. So that this was a new
Approach to reversing the age of the body without any negative side-effects. And
he did this by instead of using all five yamanaka factors. He used three of
them three and the the cmake which is the m. We definitely don't want that in there or Lynn 28. These are what are called oncogenic genes cancer-causing Gene. So we left those out and surprisingly those other 30s, MK4 short worked not just in cells in the dish, but even in the whole animal, we focused on the eye because we thought reversing blindness would be pretty cool.
Cool and could be a drug very quick drug to develop relative to the whole body. I'm and it worked one Chang. Send me a text of an of a picture of an eye where he also regenerated the optic nerve that was crushed. And then he went on to restore Vision in mice that were given glaucoma, which is pressure in the eye and even restore eye sight to Blind old
mice. Let's slow this down a little bit and take people through the process because we've gone from like, you know, yamanaka factors to restoring, eyesight and mice. Let's talk about first the condition.
That were trying to be fixed were damaged, optic, nerve cells and you used aavs these delivery. Viruses to send these three yamanaka factors into the cell. Once they were there, what started
happening? Well, to be clear. Our genome has the Anunnaki genes in it, but they're normally only turned on when we're a little embryos. So, we had to reintroduce, those three genes with a system where we can turn them on at will. And we using
An antibiotic to turn them on called doxycycline. We injected them with the virus into the eye. It's a it's a very simple procedure. In fact, a lot of patients that are blind. Get this treatment already with other drugs. So it doesn't hurt only takes 10 minutes. We put into the eye of the mouse, we damage the eye and ask could those reprogrammed eyes that we reprogram for a month? Could they regrow and the answer was?
Yes, and not only did they regrow, but these mice that were effectively blind would the were blind.
You can do a little test and you can see that their eyes actually work, like young my size again.
Well, we put pressure in the eye to make glaucoma, which is a major cause of blindness in the world. Or we just let the, my sage out to one year of age and they were blind essentially, and we could tell that they were blind because we show them little images. That move lines actually that move from left to right and if a mouse can see that young mice will move their heads as called the opto motor. It's really,
you can see videos of this, is really cute. Like watching a tennis
match. Yeah, we do that, too. By the way, we also have
Of course, we measure the electrical activity of those nerves. We also measure the age of those nerve cells. We look at which genes are switched on, and off. And the conclusion was that the nerves went back in time, back to the reset full, reset to about 80% there, genes, the gene expression patterns as we call it, which is, which genes are on and off was reset to being young again, and the mice got their Vision back, as almost as good as they were when they were young.
So a lot of people hear this and say, man, this is really cool. You can reset blindness at a mouse or reset vision and a mouse.
Can we do this with other
cells? Yeah. Turns out that it's not just nerve cells that can be rejuvenated and sent back in time. We've done this for skin cells. We're doing it for muscle cells. We've done it for other parts of the eye. And in fact that the shape of the eye, in the structure of the eye. It doesn't just go back in time, but actually rebuilds itself like, it's young again. So we're super optimistic, that this may be a universal mechanism of age, resetting in the body that cannot just be applied to different Mouse tissues, but also in humans as well.
I'm in the process. Hopefully in a year year and a half of trying to restore Vision in human patients, that have lost their vision due to either glaucoma or genetic diseases.
So this is happening because it's accessing the backup copy, the original state of the genetic code that the cells are building themselves up by
well, the genetic code stays the same. The epigenetic code, which is the reader of the DNA which we talked about in episode one that gets reset. So the structure,
As of DNA folds that have gone to ride during aging, this x differentiation process where cells lose their identity. That gets reset back to youthfulness. But how that happens. How do you get a loop of DNA to go back? Go back into a bundle and a bundle to go back into a loop. We have no idea how that works. We know that there's a backup copy of not the genome but the epigenome, the structures that read the DNA similar to polishing the scratches on a CD with the analogy. We talked about in episode 1, but how does the cell?
That. How does it reestablish that original software and reinstall the software in the cell? We're only just trying to figure that out. Now eventually we will know how this works and maybe we'll even develop a pill instead of a gene therapy. That could reset the age, not just of the eye but the whole body and when that happens, Suddenly It's Gonna be very different world. But until then we'll work on vision and then we'll see where we go from there.
But suffice it to say there are several ways that we think that we can get the
Human body to do this to reset the epigenetic clock. We can do it through cellular reprogramming. It looks like it's possible to do through exosomes, and you just mentioned pills and it does appear that it's possible that this is what metformin is contributing to. And some of the other drugs and supplements that we talked about, in an earlier episode, but I mentioned metformin
There's a lot of people who are going to say. Okay, all of this stuff is great. You've told me a bunch of stuff that probably won't be accessible to me anytime soon. There is a treatment regimen that is being tested out right now that starts with metformin but a couple of other elements as well. Let's
talk about that. Yeah. This is my colleague, Greg Fahy. Dr. Greg Fahy and he's been working on anti-aging or longevity treatments for a while and he hit Upon a
Triple treatment he uses growth hormone, which is known to raise blood sugar levels. We talked about that as a downside, but then he realized if he could include DHEA or hormone that is depleted during aging as well as metformin. He could mitigate the negative effects of growth hormone. And he gave that for 12 months to 10 healthy men that were aged 51, to 65, and lo and behold. When he looked at the biological clock of those men. They went back two and a half years, which may not sound like a lot.
But as I thought about it, if you could truly reverse your age every year, by one year, that means you're not going to age. Or it something that confuses
me about this. Combinatory therapy regimen, that Fahey used in this small scale trial, is that it takes advantage of human growth hormone, which earlier in this episode. We said probably not a long-term anti-aging benefit. So what was the idea? Do you think?
Behind using
HGH y. XI H had been shown previously to reconstitute the thymus. This is a little organ gland that's here on your chest. That is important for the immune system is where your T cells. Your immune cells come from and growth, hormone can stimulate the Regeneration of this as it degrades over time. I'm age 50. I probably have a what's called a lot of thymic degeneration and involution. It's a Vestige of what it used to be and growth hormone. Can we can stimulate that but it comes with side effects, as we mentioned.
Not least of which is increase in insulin insensitivity or glucose intolerance. In other words, the cell doesn't take up the glucose from the body when you have a lot of growth hormone around. So he combined that with 2 diabetes therapies one. It is metformin, which everybody knows. And Greg also showed actually in an experiment that he did on himself. That DHEA, this hormone that some people take for longevity, can also control, blood glucose levels, so that combination of three gave the best effect, but I
So that measuring the clock in the blood doesn't mean the whole body is being rejuvenated. That's just one indicator. So, what I'd like to see Greg and his colleagues do is to measure aging of other tissues and measured using different clocks. Not just the Horvath or epigenetic
clock. We talked in an earlier episode about the proteomic clock.
There are a variety of clocks. There's glycan age which are sugars that are attached to proteins that change over time. And there's one called immuno age, you measure various changes in the immune system altogether. These can be used to get a better.
Picture of whether Greg's treatment is truly reversing aging or just some aspects of
it, but the really frustrating thing is even with these clocks right now. We don't know what we don't know, 5 years, 10 years, 20 years down the line. So it's a really good indicator. If we can get these clocks to reset. If we can get these clocks to lower like, like Greg did at least in the short term in the long term. Do we have to wait for
the long term? Well, it depends. I know that Greg's research is ongoing and it, I'm
I was with him a couple of months. You only told me that repeated treatments over more than a year actually reduce Age based on this blog clock even more. So and people are going back by a decade apparently, so it's super interesting time. I would say the jury's still out whether this is truly reversing aging or just some aspects of blood aging. But it's a very interesting time that we live in where people are ostensibly going back in
time. One of the commonalities I think in almost all of these things that we've talked
about.
Today, is
there these early indications, that something might have effects and people are jumping over one another, to get to them. And, you know, I mean, some people are going overseas. If they can't get it here. They're finding doctors willing to do this there, you know, Finding suppliers from wherever on the internet they can, and it's, and it's understandable, right? Because people are suddenly awakened to this idea that aging may not.
Something that we have to tolerate in the long-term, so they're eager. But there's still, there's still work. That needs to be done.
There is but what I think is really exciting. Is we wrote our book lifespan in 2018 19 and we envisaged a future where people could turn the clock back and be rejuvenated. It's only been a couple of years since then, and there's been huge, huge advance in the ability to reprogram the body to measure it. These tests are now available to the public to measure by.
Biological age from blood and and from spit, we're in an age where I would say it's hard even predict where we'll be in five specially in 10 years from now, but if you're
frustrated, if you're really overeager, there are things. I think this needs to be set. Like you could take steps right now. You don't have to necessarily be taking peptides and exosomes and you don't have to, you know, hunt down Greg and say, you know, like give me this this combinatory therapy.
Just slowing down the biological clock right now. Doing the things that we talked about in the first few episodes is going to buy you that time for these therapies to
To mature to the place, where we know that there's a, we know what they're going to
do, right? So stay young stay alive because the future looks bright. Just with the current pace of medicine and medical Technologies. If you live an extra year you get another three months of life. We could easily approach a time. Where every year you live, you get another year of life and that's when the world becomes super
interesting. What are we talking about? Next episode,
we are talking about aging on the outside. So we've talked a lot about how to keep your insides Young.
Next episode, we can talk about your skin, your hair, your nails, how to keep those looking good. And it's not just superficial. It's really important. It's actually been shown that if you look younger on the outside, you probably Young on the inside too. So stay tuned for that. If you're enjoying this podcast and would like to support us, please subscribe on YouTube. Apple podcasts and Spotify on Apple. You have the opportunity to leave us up to a five star review. Also, check out the sponsors that we mentioned at the start of the episode. That's probably the best way to support the show.
We also have a patreon account. That's patreon.com slash David Sinclair. There you can support the show at any level. You'd like. Thanks again for joining us on this episode of the lifespan podcast.
