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Professor Venki Ramakrishnan, a Nobel laureate for his work on unraveling the structure of function of the ribosome, has written a new book WHY WE DIE which is outstanding. Among many posts and recognitions for his extraordinary work in molecular biology, Venki has been President of the Royal Society, knighted in 2012, and was made a Member of the Order of Merit in 2022. He is a group leader at the MRC Laboratory of Molecular Biology research institute in Cambridge, UK.A brief video snippet of our conversation below. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are available on Apple and Spotify.Transcript with links to audio and external linksEric Topol (00:06):Hello, this is Eric Topol with Ground Truths, and I have a really special guest today, Professor Venki Ramakrishnan from Cambridge who heads up the MRC Laboratory of Molecular Biology, and I think as you know a Nobel laureate for his seminal work on ribosomes. So thank you, welcome.Venki Ramakrishnan (00:29):Thank you. I just want to say that I'm not the head of the lab. I'm simply a staff member here.Eric Topol (00:38):Right. No, I don't want to give you more authority than you have, so that was certainly not implied. But today we're here to talk about this amazing book, Why We Die, which is a very provocative title and it mainly gets into the biology of aging, which Venki is especially well suited to be giving us a guided tour and his interpretations and views. And I read this book with fascination, Venki. I have three pages of typed notes from your book.The Compression of MorbidityEric Topol (01:13):And we could talk obviously for hours, but this is fascinating delving into this hot area, as you know, very hot area of aging. So I thought I'd start off more towards the end of the book where you kind of get philosophical into the ethics. And there this famous concept by James Fries of compression of morbidity that's been circulating for well over two decades. That's really the big question about all this aging effort. So maybe you could give us, do you think there is evidence for compression of morbidity so that you can just extend healthy aging and then you just fall off the cliff?Venki Ramakrishnan (02:00):I think that's the goal of most of the sort of what I call the saner end of the aging research community is to improve our health span. That is the number of years we have healthy lives, not so much to extend lifespan, which is how long we live. And the idea is that you take those years that we now spend in poor health or decrepitude and compress them down to just very short time, so you're healthy almost your entire life, and then suddenly go into a rapid decline and die. Now Fries who actually coined that term compression or morbidity compares this to the One-Hoss Shay after poem by Oliver Wendell Holmes from the 19th century, which is about this horse carriage that was designed so perfectly that all its parts wore out equally. And so, a farmer was riding along in this carriage one minute, and the next minute he found himself on the ground surrounded by a heap of dust, which was the entire carriage that had disintegrated.Venki Ramakrishnan (03:09):So the question I would ask is, if you are healthy and everything about you is healthy, why would you suddenly go into decline? And it's a fair question. And every advance we've made that has kept us healthier in one respect or another. For example, tackling diabetes or tackling heart disease has also extended our lifespan. So people are not living a bigger fraction of their lives healthily now, even though we're living longer. So the result is we're spending the same or even more number of years with one or more health problems in our old age. And you can see that in the explosion of nursing homes and care homes in almost all western countries. And as you know, they were big factors in Covid deaths. So I'm not sure it can be accomplished. I think that if we push forward with health, we're also going to extend our lifespan.Venki Ramakrishnan (04:17):Now the argument against that comes from studies of these, so-called super centenarians and semi super centenarians. These are people who live to be over 105 or 110. And Tom Perls who runs the New England study of centenarians has published findings which show that these supercentenarians live extraordinarily healthy lives for most of their life and undergo rapid decline and then die. So that's almost exactly what we would want. So they have somehow accomplished compression of morbidity. Now, I would say there are two problems with that. One is, I don't know about the data sample size. The number of people who live over 110 is very, very small. The other is they may be benefiting from their own unique genetics. So they may have a particular combination of genetics against a broad genetic background that's unique to each person. So I'm not sure it's a generally translatable thing, and it also may have to do with their particular life history and lifestyle. So I don't know how much of what we learned from these centenarians is going to be applicable to the population as a whole. And otherwise, I don't even know how this would be accomplished. Although some people feel there's a natural limit to our biology, which restricts our lifespan to about 115 or 120 years. Nobody has lived more than 122. And so, as we improve our health, we may come up against that natural limit. And so, you might get a compression of morbidity. I'm skeptical. I think it's an unsolved problem.Eric Topol (06:14):I think I'm with you about this, but there's a lot of conflation of the two concepts. One is to suppress age related diseases, and the other is to actually somehow modulate control the biologic aging process. And we lump it all together as you're getting at, which is one of the things I loved about your book is you really give a balanced view. You present the contrarians and the different perspectives, the perspective about people having age limits potentially much greater than 120, even though as you say, we haven't seen anyone live past 122 since 1997, so it's quite a long time. So this, I think, conflation of what we do today as far as things that will reduce heart disease or diabetes, that's age related diseases, that's very different than controlling the biologic aging process. Now getting into that, one of the things that's particularly alluring right now, my friend here in San Diego, Juan Carlos Belmonte, who went over from Salk, which surprised me to the Altos Labs, as you pointed on in the book.Venki Ramakrishnan (07:38):I'm not surprised. I mean, you have a huge salary and all the resources you want to carry out the same kind of research. I wouldn't blame any of these guys.Rejuvenating Animals With Yamanaka FactorsEric Topol (07:50):No, I understand. I understand. It's kind of like the LIV Golf tournament versus the PGA. It's pretty wild. At any rate, he's a good friend of mine, and I visited with him recently, and as you mentioned, he has over a hundred people working on this partial epigenetic reprogramming. And just so reviewing this for the uninitiated is giving the four Yamanaka transcription factors here to the whole animal or the mouse and rejuvenating old mice, essentially at least those with progeria. And then others have, as you point out in the book, done this with just old mice. So one of the things that strikes me about this, and in talking with him recently is it's going to be pretty hard to give these Yamanaka factors to a person, an intravenous infusion. So what are your thoughts about this rejuvenation of a whole person? What do you think?Venki Ramakrishnan (08:52):If I hadn't seen some of these papers would've been even more skeptical. But the data from, well, Belmonte's work was done initially on progeria mice. These are mice that age prematurely. And then people thought, well, they may not represent natural aging, and what you're doing is simply helping with some abnormal form of aging. But he and other groups have now done it with normal mice and observed similar effects. Now, I would say reprogramming is one way. It's a very exciting and powerful way to almost try to reverse aging because you're trying to take cells back developmentally. You're taking possibly fully differentiated cells back to stem cells and then helping regenerate tissue, which one of the problems as we age is we start losing stem cells. So we have stem cell depletion, so we can no longer replace our tissues as we do when we're younger. And I think anyone who knows who's had a scrape or been hurt in a fall or something knows this because if I fall and scrape my elbow and get a big bruise and my grandson falls, we repair our tissues at very, very different rates. It takes me days or weeks to recover, and my grandson's fine in two or three days. You can hardly see he had a scrape at all. So I think that's the thing that these guys want to do.Venki Ramakrishnan (10:48):And the problem is Yamanaka factors are cancer. Two of them are oncogenic factors, right? If you give Yamanaka factors to cells, you can take them all the way back to what are called pluripotent cells, which are the cells that are capable of forming any tissue in the body. So for example, a fertilized egg or an early embryo cells from the early embryo are pluripotent. They could form anything in the body. Now, if you do that to cells with Yamanaka factors, they often form teratomas, which are these unusual forms of cancer tumors. And so, I think there's a real risk. And so, what these guys say is, well, we'll give these factors transiently, so we'll only take the cells back a little ways and not all the way back to pluripotency. And that way if you start with skin cells, you'll get the progenitor stem cells for skin cells. And the problem with that is when you do it with a population, you're getting a distribution. Some of them will go back just a little, some of them may go back much more. And I don't know how to control all this. So I think it's very exciting research. And of course, if I were one of these guys, I would certainly want to carry on doing that research. But I don't think it's anywhere near ready for primetime in terms of giving it to human beings as a sort of anti-aging therapeutic.Aging and Cancer Shared HallmarksEric Topol (12:31):Yeah. Well, I couldn't agree more on that because this is a company that's raised billions of dollars to go into clinical trials. And the question that comes up here, which is a theme in the book and a theme with the aging process to try to artificially, if you will affect it, is this risk of cancer. And as we know, the hallmarks of aging overlap considerably with the hallmarks of cancer. And this is just one example, as you mentioned, where these transcription factors could result in generating cancer. But as you also point out in the book at many places, methylation changes, DNA, repair, and telomeres.Venki Ramakrishnan (13:21):And telomeres.Venki Ramakrishnan (13:24):All of those are related to cancer as well. And this was first pointed out to me by Titia de Lange, who's a world expert on telomeres at Rockefeller, and she was pointing out to me the intimate connection between cancer and aging and many mechanisms that have evolved to prevent cancer early in life tend to cause aging later in life, including a lot of DNA damage response, which sends cells into senescence and therefore causes aging. Buildup of senescence cells is a problem later in life with aging, but it has a role which is to prevent cancer early in life. And so, I think it's going to be the same problem with stem cell therapy. I think very targeted stem cell therapy, which is involved in replacing certain tissues, the kind of regenerative medicine that stem cells have been trying to address for a very long time, and only now we're beginning to see some of the successes of that. So it's been very slow, even when the goal and target is very specific and well-defined, and there you are using that stem cell to treat a pretty bad disease or some really serious problem. I think with aging, the idea that somebody might take this so they can live an extra 10 years, it's a much higher bar in terms of safety and long-term safety and efficacy. So I don't think that this is going to happen anytime soon, but it's not to say it'll never happen. There is some serious biology underlying it.Eric Topol (15:13):Right. Well, you just touched on this, but of course the other, there's several big areas that are being explored, and one of them is trying to deal with these senescent cells and trying to get rid of them from the body because they can secrete evil humors, if you will. And the problem with that, it seems that these senescent cells are sort of protective. They stop dividing, they're not going to become cancerous, although perhaps they could contribute to that in some way. So like you say, with telomeres and so many things that are trying to be manipulated here, there's this downside risk and it seems like this is what we're going to have to confront this. We have seen Venki with the CAR-T, the T-cell engineering, there's this small risk of engendering cancer while you're trying to deal with the immune system.SenolyticsVenki Ramakrishnan (16:07):Yeah, I think with senescent cells, the early in life senescent cells have an important role in biology. They're essentially signaling to the immune system that there's a site that's subject to viral infection or wounds or things like that. So it's a signal to send other kinds of cells there to come and repair the damage. Now, of course, that evolved to help us early in life. And also many senescent cells were a response to DNA damage. And that's again, a way for the body that if your DNA is damaged, you don't want that cell to be able to divide indefinitely because it could become cancerous. And so, you send it into senescence and get it out of harm's way. So early life, we were able to get rid of these senescent cells, we were able to come to the site and then clean up the damage and eventually destroy the senescent cells themselves.Venki Ramakrishnan (17:08):But as we get older, the response mechanisms also deteriorate with age. Our immune system deteriorates with age, all the natural signaling mechanisms deteriorate with age. And so, we get this buildup of senescent cells. And there people have asked, well, these senescent cells don't just sit there, they secrete inflammatory compounds, which originally was a feature, not a bug, but then it becomes a problem later in life. And so, people have found that if you target senescent cells in older animals, those animals improve their symptoms of aging improved dramatically or significantly anyway. And so, this has led to this whole field called senolytics, which is being able to specifically target senescent cells. Now there the problem is how would you design compounds that are highly specific for senescent cells and don't damage your other cells and don't have other long-term side effects? So again, I think it's a promising area, but a lot of work needs to be done to establish long-term safety and efficacy.Eric Topol (18:23):Right. No, in fact, just today in Nature, there's a feature on killing the zombie cells, and it discusses just what you're pointing out, which is it's not so easy to tag these specifically and target them, even though as you know, there's some early trials and things like diabetic macular edema. And we'll see how that plays out. Now, one of the things that comes up is the young blood story. So in the young blood, whether it's this parabiosis or however you want to get at it, and I guess it even applies to the young microbiome of a gut, but there's this consistent report that there's something special going on there. And of course the reciprocal relationship of giving the old blood to the young mice, whatever, but no one can find the factor, whether it's platelet factor 4, GDF11, or what are your thoughts about this young blood story?Venki Ramakrishnan (19:25):I think there's no question that the experiments work because they were reproduced and they were reproduced over quite a long period, and which is that when you connect an old mouse or rat with a young equivalent, then the old mouse or old rat benefits from the young blood from the younger animal. And conversely, the younger animal suffers from the blood from the older animal. And then people were wondering whether this is simply that the young animal has better detoxification and things like that, or whether it's actually the blood. And they gave it just as transfusion without connecting the animals and showed that it really was the blood. And so, this of course then leads to the question, well, what is it about young blood that's beneficial and what is it about old blood that is bad? But the problem is blood has hundreds of factors. And so, they have to look at which factors are significantly different, and they might be in such small quantities that you might not be able to detect those differences very easily.Venki Ramakrishnan (20:40):And then once you've detected differences, then you have to establish their mechanism of action. And first of all, you have to establish that the factor really is beneficial. Then you have to figure out how it works and what its potential side effects could be. And so again, this is a promising area where there's a lot of research, but it has not prevented people from jumping the gun. So in the United States, and I should say a lot of them in your state, California somehow seems to attract all these immortality types. Well, anyway, a lot of companies set up to take blood from young donors, extract the plasma and then give it to rich old recipients for a fee for a healthy fee. And I think the FDA actually shut down one of them on the grounds that they were not following approved procedure. And then they tried to start up under a different name. And then eventually, I don't know what happened, but at one point the CEO said something I thought was very amusing. He said, well, the problem with clinical trials is that they take too long. I'm afraid that's characteristic of some portion of this sort of anti-aging therapeutics community. There's a very mainstream rigorous side to it, but there's also at the other end of the spectrum, kind of the wild west where people just sell whatever they can. And I think this exploits people's fear of getting old and being disabled or things like that and then dying. And I think the fear seems to be stronger in California where people like their lives and don't want to age.Eric Topol (22:49):You may be right about that. I like your term in the book immortality merchants, and of course we'll get into a bit, I hope the chapter on the crackpots and prophets that you called it was great. But that quote, by the way, which was precious from, I think it was Ambrosia, the name of the company and the CEO, but there's another quote in the book I want to ask you about. Most scientists working on aging agree that dietary restriction can extend both healthy life and overall life in mice and also lead to reductions in cancer, diabetes, and overall mortality in humans. Is that true? Most scientists think that you can really change these age-related diseases.Caloric Restriction and Related PathwaysVenki Ramakrishnan (23:38):I think if you had to pick one area in which there's broad agreement, it is caloric restriction. But I wouldn't say the consensus is complete. And the reason I say that is that most of the comparisons are between animals that can eat as much as they want, called ad libitum diet and mice that are calorically restricted or same with other animals even yeast. You either compared with an extremely rich medium or in a calorically restricted medium. And this is not a great comparison. And people, there's one discrepancy, and that was in monkeys where an NIH study didn't find huge differences, whereas a Wisconsin study found rather dramatic differences between the control group and the calorically restricted group. And so, what was the difference? Well, the difference was that the NIH study, the controlled group didn't have a calorically restricted diet, but still had a pretty reasonable diet.Venki Ramakrishnan (24:50):It wasn't given a unhealthy rich diet of all you can eat. And then they tried to somehow reconcile their findings in a later study. But it leads to the question of whether what you can conclude is that a rich all you can eat diet, in other words, gorging on an all you can eat buffet is definitely bad for you. So that's why you could draw that conclusion rather than saying it's actually the caloric restriction. So I think people need to do a little more careful study. There was also a study on mice which took different strains of mice and showed that in some strains, caloric restriction actually shortened lifespan didn't increase lifespan. Now, much of the aging community says, ah, that's just one study. But nobody's actually shown whether there was anything wrong with that study or even tried to reproduce it. So I think that study still stands.Venki Ramakrishnan (25:51):So I think it's not completely clear, but the fact is that there's some calorie dependence that's widely been observed across species. So between the control group and the experimental group, whatever you may, however, you may define it as there's been some effective calories intake. And the other interesting thing is that one of the pathways affected by caloric restriction is the so-called TOR pathway and one of the inhibitors of the TOR pathways is rapamycin. And rapamycin in studies has also shown some of these beneficial effects against the symptoms of aging and in lifespan. Although rapamycin has the same issue as with many other remedies, it's an immunosuppressive drug and that means it makes you more prone to infection and wound healing and many other things. I believe one of them was there's a question of whether it affects your libido, but nevertheless, that has not prevented rapamycin clinics from opening up, did I say in California? So I do think that there's often serious science, which leads to sort of promising avenues. But then there are of course people who jump the gun and want to go ahead anyway because they figure by the time trials are done, they'll be dead and they'd rather try act now.Eric Topol (27:36):Right. And you make a good, I mean the rapamycin and mTOR pathway, you really developed that quite a bit in the book. It's really quite complex. I mean, this is a pleotropic intervention, whether it's a rapalogs or rapamycin, it's just not so simple at all.Venki Ramakrishnan (27:53):Right. It's not at all simple because the TOR pathway has so many consequences. It affects so many different processes in the cell from including my own field of protein synthesis. It's one of the things it does is shut down global protein synthesis, and that's one of the effects of inhibiting TOR. So, and it turns up autophagy, which is this recycling of defective proteins and entirely defective entire organelles. So I think the TOR pathway is like a hub in a very large network. And so, when you start playing with that, you're going to have multiple consequences.Eric Topol (28:37):Yeah, no. And another thing that you develop so well is about this garbage disposal waste disposal system, which is remarkably elaborate in the cell, whether it's the proteasome for the proteins and the autophagosome for the autophagy with the lysosomes and the mitochondria mitophagy. Do you want to comment about that? Because this is something I think a lot of people don't appreciate, that waste management in the cell is just, it's a big deal.Venki Ramakrishnan (29:10):So we always think of producing things in the cell as being important, making proteins and so on. But the fact is destroying proteins is equally important because sometimes you need proteins for a short time, then they've done their job and you need to get rid of them, or proteins become dysfunctional, they stop working, or even worse, they start clumping together and causing diseases for example you could think of Alzheimer's as a disease, which involves protein tangles. Of course, the relationship between the tangles and the disease is still being worked out, but it's a characteristic of Alzheimer's that you have these protein tangles and the cell has evolved very elaborate mechanisms to constantly turn over defective proteins. Well, for example, it senses when proteins are unfolded and essentially the chain has unraveled and is now sticking to all sorts of things and causing problems. So I think in all of these cases, the cells evolved very elaborate mechanisms to recycle defective products, to have proper turnover of proteins. And in fact, recycling of entire organelles like mitochondria, when they become defective, the whole mitochondria can be recycled. So these systems also break down with aging. And so, as we age, we have more of a tendency to accumulate unfolded proteins or to accumulate defective mitochondria. And it's one of the more serious problems with aging.Eric Topol (30:59):Yeah, there's quite a few of them. Unfortunately, quite a few problems. Each of them are being addressed. So there's many different shots on goal here. And as you also aptly point out, they're interconnected. So many of these things are not just standalone strategies. I do want to get your sense about another popular thing, especially here out in California, are the clocks, epigenetic clocks in particular. And these people are paying a few hundred dollars and getting their biologic age, which what is that? And they're also thinking that I can change my future by getting clocks. Some of these companies offer every few months to get a new clock. This is actually remarkable, and I wonder what your thoughts are about it.Venki Ramakrishnan (31:48):Well, again, this is an example of some serious biology and then people jumping the gun to use it. So the serious biology comes from the fact that we age at different rates individuals. So anyone who's been to a high school reunion knows this. You'll have classmates who are unrecognizable because they've aged so much and others who've hardly changed since you knew them in high school. So of course at my age, that's getting rarer and rarer. But anyway, but you know what I mean. So the thing is that, is there a way that we can ask on an individual level how much has that individual aged? And there are markers that people have identified, some of them are markers on our DNA, which you mentioned in California. Horvath is a very famous scientist who has a clock named after him actually, which has to do with methylation of our DNA and the patterns of methylation affect the pattern of gene expression.Venki Ramakrishnan (33:01):And that pattern changes as we age. And they've shown that those patterns are a better predictor of many of the factors of aging. For example, mortality or symptoms of aging. They're a better predictor of that than chronological age. And then of course there are blood markers, for example, levels of various blood enzymes or blood factors, and there are dozens of these factors. So there are many different tests of many different kinds of markers which look at aging. Now the problem is these all work on a population level and they also work on an individual level for time comparison. That is to say, if you want to ask is some intervention working? You could ask, how fast are these markers changing in this person without the intervention and how fast are they changing with the intervention? So for these kind of carefully controlled experiments, they work, but another case is, for example, glycosylation of proteins, especially proteins of your immune system.Venki Ramakrishnan (34:15):It turns out that adding sugar groups to your immune system changes with age and causes an immune system to misfire. And that's a symptom of aging. It's called inflammaging. So people have used different markers. Now the problem is these markers are not always consistent with each other because you may be perfectly fine in many respects, but by some particular marker you may be considered old just because they're comparing you to a population average. But how would you say one person said, look, we all lose height as we age, but that doesn't mean if you take a short person, you can consider them old. So it's a difference between an individual versus a population, and it's a difference between what happens to an individual by following that individual over time versus just taking an individual and comparing it to some population average. So that's one problem.Organ ClocksVenki Ramakrishnan (35:28):The other problem is that our aging is not homogeneous. So there's a recent paper from I believe Tony Wyss-Coray group, which talks about the age of different organs in the same person. And it turns out that our organs, and this is not just one paper, there are other papers as well. Our organs don't necessarily age at the same rate. So giving a single person, giving a person a single number saying, this is your biological age, it's not clear what that means. And I would say, alright, even if you do it, what are you going to do about it? What can you do about it knowing your biological, the so-called number of a biological age. So I'm not a big fan. I'm a big fan of using these markers as a tool in research to understand what interventions work because otherwise it would take too long. You'd have to wait 20 years to see some large scale symptoms. And certainly, if you want to look at mortality, you'd have to wait possibly even longer. But if you were to be able to follow track these interventions and see that these markers slowed down with intervention, then you could say, well, your interventions having an effect on something related to aging. So I would say these are very useful research tools, but they're not meant to be used at $500 a pop in your age.Venki Ramakrishnan (37:02):But of course that hasn't stopped lots of companies from doing it.Eric Topol (37:07):No, it's just amazing actually. And by the way, we interviewed Tony Wyss-Coray about the organ clock, the paper. I thought it really was quite a great contribution, again, on a research level.Venki Ramakrishnan (37:19):He's a very serious scientist. He actually spoke here at the LMB as well. He gave a very nice talk here.Is Aging A Disease?Eric Topol (37:26):He's the real deal. And I think that's going to help us to have that organ specific type of tracking is another edge here to understand the effects. Well, before we wrap up, I want to ask you a question that you asked in the book. Is aging a disease?Venki Ramakrishnan (37:49):That's again, a controversial subject. So the WHO, and I believe the FDA decided that aging was not a disease on the grounds that it's inevitable and ubiquitous. It happens to everybody and it's inevitable. So how could something that happens to everybody and inevitable be considered a disease? A disease is an abnormal situation. This is a normal situation, but the anti-aging researchers and especially the anti-aging therapeutics people don't like that because if it's not a disease, how can they run a clinical trial? So they want aging to be considered a disease. And their argument is that if you look at almost every condition of old age, every disease of old age like cancer, diabetes, heart disease, dementia, the biggest risk factor in all of these diseases is age. That's the strongest risk factor. And so, they say, well, actually, you could think of these diseases as secondary diseases, the primary disease being age, and then that results in these other diseases.Venki Ramakrishnan (39:07):I am a little skeptical of that idea. I tend to agree with the WHO and the FDA, but I can see both sides of the argument. And as you know, I've laid them both out. My view is that it should be possible to do trials that help with aging regardless of whether you consider aging a disease or not. But that will require the community to agree on what set of markers to use to characterize success. And that's people, for example, Tony Wyss-Coray has his proteome, blood proteome markers, Horvath has his DNA methylation clock. There are a whole bunch of these. And then there are people with glycation or glycosylation of various proteins as markers. These people need to all come together. Maybe we need to organize a nice conference for them in some place like Southern California or Hawaii or somewhere, put them together in a locked room for a week so that they can thrash out a common set of markers and at least agree on what experiments they need to do to even come to that agreement and then use that to evaluate anti-aging therapies. I think that would be a way forward.Eric Topol (40:35):Yeah, I think you're bringing up a really valuable point because at the moment, they're kind of competing with one another, whether it's the glycosylated proteins or the transcriptomics or the epigenetics. And we don't know whether these are additive or what they're really measuring.Venki Ramakrishnan (40:53):Some of them may be highly correlated, and that's okay, but I think they need to know that. And they also need to come up with some criteria of how do we define age in an individual. It's not one number, just like we have many things that characterize our health. Cholesterol is one, blood pressures another, various other lipids. They're all blood enzymes, liver enzymes. All these things are factors in defining our so-called biological health. So I don't think there's some single number that's going to say this is your age. Just like there isn't one single thing that says you're healthy, you're not healthy.DNA RepairEric Topol (41:38):Right, that's well put. Last topic on aging is on about DNA repair, which is an area that you know very well. And one of the quotes in your book, I think is important for people to take in. “Nevertheless, they will make an error once every million or so letters in a genome with a few billion letters. That means several thousand mistakes occur each time a cell divides. So the DNA repair enzyme, as you point out the sentinels of our genome, the better we repair, the better we age.” Can we fix the DNA repair problem?Venki Ramakrishnan (42:20):I think maybe, again, I'm not sure what the consequences would be and how much it would take. There's one curious fact, and that is that there was a paradox called Peto's paradox after the scientist who discovered it, which is why don't big animals get cancer much more frequently than say a mouse? In fact, a mouse gets cancer far more readily than an elephant does, and in reality, the elephant should actually get cancer more because it has many orders of magnitude more cells, and all it takes is for one cell to become cancerous for the animal to get cancer and die. So the chances that one cell would become cancer would be larger if there are many, many more cells. And it turns out that elephants have many copies of DNA repair proteins or DNA damage response proteins, not so much DNA repair, but the response to DNA damage and in particular, a protein called p53. And so, this leads to the question that if you had very good DNA repair or very good DNA damage response, would you then live longer or solve this problem? I'm not entirely sure because it may have other consequences because for example, you don't want to send cells into senescence too easily. So I think these things are all carefully balanced, evolutionarily, depending on what's optimized to optimize fitness for each species.Venki Ramakrishnan (44:13):For a mouse, the equation's different than for a large animal because a mouse can get eaten by predators and so on. So there, it doesn't pay for evolution to spend too much select for too much spending of resources in maintenance and repair, for larger animals the equation is different. So I just don't know enough about what the consequences would be.Eric Topol (44:40):No, it's really interesting to speculate because as you point out in the book, the elephant has 20 copies of p53, and we have two as humans. And the question is that protection from cancer is very intriguing, especially with the concerns that we've been talking about.Venki Ramakrishnan (44:57):And it was also true, I believe they did some analysis of genomics of these whales that live very long, and they found sorts of genes that are probably involved in DNA repair or DNA damage response.Eric Topol (45:14):Well, this is a masterful book. Congratulations, Venki. I thoroughly enjoyed it. It's very stimulating. I know a lot of the people that will listen or read the transcript will be grabbed by it.Crackpots and ProphetsVenki Ramakrishnan (45:28):I think what I've tried to do is give the general reader a real understanding of the biology of aging so that even a complete non-scientist can get an understanding of the processes, which in turn empowers them to take action to do the sort of things that will actually really help. And also it'll guard them against excessive hype, of which there's a lot in this business. And so, I think that was the goal, and to try and present a balanced view of the field. I'm merely trying to be a realist. I'm not being a pessimist about it, but I also think this excessively optimistic hype is actually bad for the field and bad for science and bad for the public as well.Eric Topol (46:16):Well, and you actually were very kind in the chapter you have on crackpots and prophets. You could have been even tougher on some of these guys. You were very relatively diplomatic and gentle, I thought, I don't know if you were holding back.Venki Ramakrishnan (46:28):I had two lawyers looked at it, so.Eric Topol (46:33):I believe it. And now one thing, apart from what we've been talking about because of your extraordinary contribution on the structural delineation of the ribosome back in the early 2000s and 2009 Nobel Prize. Now, the world of AI now with AlphaFold 3 and all these other large language models, would that have changed your efforts? Would that have accelerated things or is it not really?Venki Ramakrishnan (47:09):Well, it would've helped, but you would still need the experimental data to solve something like the ribosome, a large complex like the ribosome. And the other thing that would really change well has changed our world is the advent of cryo-electron microscopy of which Scripps is one of the leading places for it. And that has really changed it so that now nobody would bother to crystallize a ribosome and try to get an X-ray structure out of it. You would just throw it into an EM grid, collect your data and be off to the races. So new ribosome structures are being solved all the time at a fraction, a tiny fraction of the time it took to solve the first one.Eric Topol (48:02):Wow, that's fascinating. This has been a real joy for Venki to discuss your book and your work, and thanks so much for what you're doing to enlighten us and keep the balance. And it may not be as popular as the immortality merchants, but it's really important stuff.Venki Ramakrishnan (48:19):Yeah, no, I hope actually, I found that many of the public want to read about the biology of aging. They're curious. Humans have been curious ever since we knew about mortality, about why some species live so short lives and other species live such a long time and why we actually have to age and die. So there's natural curiosity and then it also empowers the public once they understand the basis of aging, to take action, to live healthy lives and do that. It's an empowering book rather than a recipe book.Venki Ramakrishnan (49:01):I think a lot of the public actually does appreciate that. And of course, scientists will like the sort of more balanced and tone.Eric Topol (49:13):Well, you do it so well. All throughout you have metaphors to help people really understand and the concepts, and I really applaud you for doing this. In fact, a couple of people who we both know, Max and John Brockman, apparently were influential for you to get to do it. So I think it's great that you took it on and all the power to you. So thank you, and I hope that we'll get a chance to visit further as we go forward.******************Headshot photo credits by Kate Joyce and Santa Fe InstituteThe Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff tor audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in.A Poll on Anti-Aging Get full access to Ground Truths at erictopol.substack.com/subscribe

In one sentence...Aging is malleable and there is a particular, mysterious protein of interest that may enable new therapies for age-related diseases such as stroke, diabetes, and obesity.Young blood in old bodies has been demonstrated in several studies to counteract some age-correlated ailments. Mark Allen, a medical doctor by training and an entrepreneur in practice, co-founded Elevian to understand and commercialize therapies using a recombinant growth differentiation factor known as GDF11, a ‘magic' protein, as referenced by the New York Times. Dr. Allen describes how his team is developing new medicines targeting the aging process, rather than the prevailing approach of most pharmaceutical products that target individual diseases. Highlighting a surprising result, if humanity was able to eradicate cancer completely, the outcome would only increase the average human lifespan by an estimated two to three years, while doubling the incidence of age-related diseases such as Alzheimer's. With its scientific foundations beginning emerging from the Harvard Stem Cell Institute, the Elevian team is rigorously exploring GDF11 and its effective use while navigating commercialization challenges. Specifically, how can an age-related therapy be reimbursable when “age” is not yet officially a disease (based on medical billing code)? We discuss with Dr. Allen about Elevian's path ahead and the strategies at work.

Steve Perry discusses the latest GDF11 results

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.05.510925v1?rss=1 Authors: Bajikar, S. S., Anderson, A. G., Zhou, J., Durham, M. A., Trostle, A. J., Wan, Y.-W., Liu, Z., Zoghbi, H. Y. Abstract: Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, though identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we identified that MeCP2 finely regulates Growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and is inversely up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased longevity and survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Scientists are zeroing in on blood proteins as a tool that could regenerate aging organs. Journalist Eilene Zimmerman joins host Krys Boyd to discuss the protein known as GDF11, which has sometimes shown promise stimulating the growth of the brain and blood vessels. And we'll hear about Elevian, the company hoping to unlock its secrets. Her article published in The New York Times is called “Can a ‘Magic' Protein Slow the Aging Process?”

Dr. Mark Allen, Co-Founder and CEO, Elevian is looking to disrupt the longevity business by developing a recombinant GDF11 to treat and prevent multiple age-related diseases. The first application being investigated is for stroke recovery drawing on the discovery that GDF11 decreases with age and when replenished, returns the brain to a healthier pattern of vascularization. Not looking to extend just the life span, the goal is to target the aging process and extend the healthy lifespan. @ElevianInc #aging #StrokeRecovery #AgeRelatedDisease #GDF11 Elevian.com Download the transcript here.

Dr. Mark Allen, Co-Founder and CEO, Elevian is looking to disrupt the longevity business by developing a recombinant GDF11 to treat and prevent multiple age-related diseases. The first application being investigated is for stroke recovery drawing on the discovery that GDF11 decreases with age and when replenished, returns the brain to a healthier pattern of vascularization. Not looking to extend just the life span, the goal is to target the aging process and extend the healthy lifespan. @ElevianInc #aging #StrokeRecovery #AgeRelatedDisease #GDF11 Elevian.com Listen to the podcast here.

Dr. Mark Allen, MD, co-founder and CEO of Elevian, developer of therapies to treat age-related diseases like stroke and diabetes, discusses the drug candidate, recombinant growth differentiation factor 11 (rGDF11) with broad therapeutic benefits demonstrated in numerous animal studies. "Science" recognized GDF11 as a top scientific breakthrough calling it “the rejuvenation factor”. Dr. Mark Allen is the co-founder and chief executive officer at Elevian. Dr. Allen has a BS in Applied Physics from Columbia University and an MD from UCLA. During his medical training, he developed one of the first web-based clinical decision support systems to guide ER physicians to make the right patient care decisions. After clinical trials demonstrating significant improvements in healthcare quality and cost, Dr. Allen founded Corticon to bring this new technology to market. Under Dr. Allen’s leadership as CEO, Corticon became one of the leading commercial rules engine software products, powering automated decision-making in healthcare, insurance, banking, retail and manufacturing. When Corticon was acquired by Progress, Dr. Allen took roles as Chief Technologist and then General Manager. In early 2017, excited by the recent scientific progress in the longevity industry, Dr. Allen left Progress with a passion to extend healthy lifespan. He partnered with Elevian’s scientific co-founders at Harvard to develop their GDF11 technology into new drugs, recruiting and leading a team of leading scientists and drug development veterans.

In this week's episode, Ceren Ozek joins us to discuss how Growth Differentiation Factor 11, GDF11, affects the ageing process in the brain. As the brain ages, it's cognitive functions also decline, which can have huge effects on quality of life. Identified as a potential longevity factor found in the blood in 2014, GDF11 might have the potential to slow the ageing process in brain areas such as the hippocampus.This episode discusses the initial parabiosis experiments in young/old mice, the controversy surrounding GDF11's effects on skeletal muscle, the role that the vasculature plays in mediating the effects on the brain, and experimental designs.Ceren Ozek is a Postdoctoral Fellow in the Rubin lab, within Harvard’s Stem Cell and Regenerative Biology Department. Ceren completed her Ph.D. in Neuroscience at the University of Pennsylvania before coming to Harvard.

On this episode of Living Beyond 120™, Mark and Dr. Gladden discuss the therapeutic value of introducing younger blood into your system. There is some experimentation happening at places like the Young Blood Institute to explore the positive benefits that younger blood can provide for health and longevity. They consider the old medical procedure of bloodletting and why that could have been helpful. They also discuss the GDF11 protein, an endogenous signaling molecule involved in cell repair, and how this is being utilized in treatments. For more information, visit https://gdf11rejuvenation.com/. Finally, they discuss the immune system and whether or not to get a flu vaccine every year. They talk about what can help the immune system and what can possibly weaken in – including the impact of mindset. They discuss the concept of physiological congruency, in which your brain will perform in ways to match your mindset, disseminating the message throughout your body.

Radio Show electronic music , deep-house, club-house, funk-house, tech-house, prog-house and trance . One hour with the best electronic music this moment every week.

Radio Show electronic music , deep-house, club-house, funk-house, tech-house, prog-house and trance . One hour with the best electronic music this moment every week.

Radio Show electronic music , deep-house, club-house, funk-house, tech-house, prog-house and trance . One hour with the best electronic music this moment every week.

Radio Show electronic music , deep-house, club-house, funk-house, tech-house, prog-house and trance . One hour with the best electronic music this moment every week.

Radio Show electronic music , deep-house, club-house, funk-house, tech-house, prog-house and trance . One hour with the best electronic music this moment every week.

My life is a little bit...strange. As an immersive journalist, self-experimenter and self-professed “biohacker”, I do relatively unconventional things to upgrade my body and brain. For example, I have this blood glucose monitor installed in my arm. It monitors my blood sugar 24-7. I wear a cognition-enhancing laser light helmet at work during the day, and stand naked in front of a giant red light panel while I’m replying to emails. I give myself weekly IV’s full of a cocktail of special vitamins. I’ve also had the fat sucked from my back and the marrow from my bones to concentrate my own stem cells, and had surgery to have these cells placed into every joint of my body and mainlined into my bloodstream. I have tens of thousands of dollars of advanced medical technologies housed in my basement. You get the idea. I’m not normal. But as a man who spends much of my life immersed in the modern health and longevity movement, attending anti-aging conferences and researching all the newfangled things people are doing these days to upgrade their bodies, I often survey the landscape of fringe supplements, biohacks, and anti-aging technologies and wonder… ...would our ancestors laugh at us? When it comes to living a long and healthy life, would their ancestral wisdom beat our modern science, hands down? After all, despite our modern infatuation with longevity and optimized bodies and brains, we are not strikingly healthier or longer-living than previous generations. In today's podcast, adapted from my recent TedX Coeur D' Alene Talk, I'll tackle this topic in detail. You'll discover: -Why modern medicine, for all its marvels, may not be all it's cracked up to be...4:10 CDC reports life expectancy has dropped 3 consecutive years. It's a false assertion to assume we'll live significantly longer than previous generations "Life expectancy" is calculated by insurance, mutual fund companies as number of years after retirement, not after birth. We would be seeing many more 100+ year olds; not the case We have a better chance of surviving childhood (disease, etc.) but not necessarily living longer. Our ancestors didn't always live nasty, brutish, short lives -Popular current fads to extend human lifespan...7:43  Vampire therapy, parabiosis (young blood) Ancient Greeks considered to blood a magic elixir Pliny the Elder, Homer, wrote about the healing efficacy of others' blood GDF11, a primary anti-aging proteins activated by young blood transfusion, is increased by oxytocin Stem cells More accessible than in years past My "biological age" dropped from 37 to 20 after my first stem cell transfusion Dietary adjustments to increase/enhance stem cells Food compounds, superfoods: colostrum, aloe vera, etc. Cryopreservation Modern day mummification  Metformin slightly modified version of a compound that was discovered in the French lilac plant (goat's rue) Adverse side effects: Lactic acidosis Mitochondrial disruption Vitamin B12 deficiency Increase risk for Alzheimer's and Parkinson's Natural alternatives: Bitters, herbs, wild plants, bitter melon Rapamycin Inhibits excessive activation of immune cells via MTOR Upregulation of cellular cleanup mechanisms called autophagy Increases risk of infectious diseases and diabetes Natural alternatives: spermidine Intermittent fasting Nicotinamide adenine dinucleotide (NAD) Levels markedly decrease with age Natural alternatives: Raw honey Fermented foods Sauna sessions Pau d Arco tea  -Supplements and medicines used by our ancestors...19:25 -Natural ways to enhance our vision...22:45 Ancestors trained their vision; they didn't look at screens all day Plant compounds known to enhance vision: Zeaxanthin Carotenoids (kale, spinach, bell peppers) Innate ability to "see" in the absence of light or even sight -Natural hearing enhancement...24:45 Hunter gatherers were better equipped, physically, with their ears; perhaps because of time spent outdoors attuned to the frequencies of nature Turnip greens, collard greens, parsley, mustard greens, broccoli, etc. shown to decrease risk of hearing loss Adjusting your diet would be far cheaper and less convenient than what some self-experimenting types are doing (ear implants) -The natural "sixth sense" within us to navigate to True North...26:42 We possess a tiny amount of magnetite in our ethmoid bone (located between the eyes in the nasal cavity) Researchers suggest this built-in compass made hunting, migration, etc. possible We have perhaps lost this ancestral skill with the advent of road maps, GPS navigation -Natural ways to enhance our brains...27:30 Walnuts are rich in omega fatty acids, melatonin Lion's mane mushroom Bacopa flower (memory) Green tea (cognition) Psilocybin All of the above have been used for centuries, if not millennia -Natural alternatives to things like photobiomodulation, light therapy, PEMF, etc...29:15 Greeks engaged in "heliotherapy"; sunbathing akin to what we know as photobiomodulation St. John's Wort, chamomile, etc. can be used to ward off seasonal affective disorder -And Much More! Episode Sponsors: - is your ultimate source for everything you need to achieve peak performance, look amazing, defy aging and live an adventurous, fulfilling, joyful and limitless life. - Sleep Better, Live Better With A Relaxing Cup Of Golden Tea. Use discount code "greenfield" at checkout and save 20% off your entire purchase! Got a question for me? Just leave a comment below, and I'll get back to you!  

You've no doubt heard of it by now... In an attempt to live longer, some anti-aging enthusiasts are getting themselves injected with the blood of young humans, via a process deemed: plasmaphoresis. This podcast is about several age reversal therapies. It's also about biohacking Alzheimers. It's about all these therapies (senolytics, exosomes, gdf-11, etc) that scientists have been talking about for age reversal. The podcast is about biological aging clocks and biomarkers to measure them. You'll learn about ways that you can biohack Alzheimer's disease, how to measure your biological age, how to reverse aging, what the biggest obstacle to age reversal is, how to get more involved in the anti-aging community and more. About the Guests Mark Urdahl, is a technology entrepreneur from the Silicon Valley.  He has numerous patents and has worked in big data.  He began his career at IBM's medical instruments subsidiary that pioneered plasmaphoresis.  Mark founded  to advance new uses for well established therapeutic plasma exchange therapies which have recently evidenced a previously undocumented potential to rejuvenate the body's own stem cells, restore aging immune systems, and prevent the onset of many age-related disease condition, so that we might live healthy as we age and ultimately live longer lives.     Tom Ingloglia first appeared on this podcast in the episode ""  As you learn in that episode, Tom is a private investor with a master’s degree in finance. In the midst of trading, investing in technology and developing real estate in Costa Rica, Tom became very sick. He was initially prescribed antibiotics, suffered from an adverse reaction and was told that he’d have stomach problems for the rest of his life. In the years that followed, Tom also developed severe food allergies. His symptoms worsened, and he next began dealing with insomnia, anxiety, muscle pain, tendinopathies, joint pain, chronic fatigue syndrome, altered and clouded cognition and headaches. He finally had a mental breakdown in 2008. After a prolonged period of taking antibiotics, Tom began experiencing tendonitis throughout his fingers, hands, wrists and ankles and feet, so he started taking pain medications to relieve this pain. He had to give up his career in trading because his sole focus for the next eight years would be on finding a cure to his growing symptoms. His life consisted of working with physical therapists, going to the gym, going to new doctors, and trying new foods to see if it would help. Throughout Tom’s eight-year battle, he was prescribed consistently and persistently more medication. For six years, he was taking excessive amounts of Hydrocodone and Tramadol every day. Tom became obsessed with researching symptoms and treatments, and learned about the NAD+ treatment. He visited a clinic, and on Day 7 of his treatment, “It hit me. I started feeling better. I felt amazing. There was a calm that came over me. I felt safe. I just had no cravings for drugs or pain meds. There was no need for them. I just didn’t have the excruciating pain that I had before. I felt eight years of pain melting away.” Tom has nearly fully recovered, using related treatments to NAD+, and has engaged two cofounders to assist him in building out a facility to help bring this treatment to others in similar situations. In my conversation with Mark and Tom, you'll discover: -The history of and how "heterochronic plasma exchange" works...16:00 Heterochronic plasma means simply removing old plasma and replacing it with "young" plasma. Others are experimenting with this concept. What Mark does is different from a plasma "infusion." Plasma is approximately half of our blood volume.  Mark began with IBM Biomedical Systems, who had invented what we now call the "blood cell processor." -The intricate means of testing used on mice...22:15 Basically creating "siamese twins" with mice by stitching them together. Similar procedures have been conducted on humans for over 50 years. Mark wanted to recruit the best medical professionals to the Young Blood Institute. Many of them have been doing it for 30-40 years. -What, if any, are the risks of these plasma exchanges...29:10 Roughly a 4% risk of a transfusion reaction, which is akin to what you might experience donating blood. One of the safer procedures in the medical field today. You go through 6 exchanges as part of a protocol. -The network of doctors that Mark and Tom have built to do a plasma exchange...32:42 There are medical professionals all over the U.S. that can do the procedure. Submit an inquiry on the website to find a doctor that is near you. -What anti-aging biomarkers Mark is tracking at the Young Blood Institute...34:51 They have more technology testing capability than Stanford, Johns Hopkins and Harvard combined. Key technology: time of flight mass cytometry. Single cell proteionomics. They are trying to develop early detection biomarkers that enables them to prevent the onset of diseases before they become significant. -The lowest hanging fruit for people to track...46:15 The YBI's concern is the function of the body, rather than the age. Your cells are not aware of your "age". -What a biological aging clock is...50:20 Zymo is a lab that has worked with Steven Horvath.  Looked at DNA, and seen a pattern from methyl groups attached to certain parts of the genome. -How can we track biological aging, or slow down our biological aging clock?...52:30 Inflammatory markers, heart age, brain age, lung age, skin elasticity. -The anti-aging booth that Mark and Tom will be operating at a conference called RAAD Fest...54:45 Want to have a contest where people calculate their age, and track their progress. Mark and Tom have one of the largest booths at the conference. -Whether NAD actually gets absorbed into a cell via injections or IV...1:00:30 How does Ben feel with an injection? Answer: Incredible. Tom doesn't recommend the injection due to the level of discomfort. -Why compounded formulas such as glutathione and Vitamin B could be taken off the market soon...1:07:30 There's a review similar to a court hearing, where people argue for and against glutathione. Taken off the market for compounding pharmacies. Tom "has his own reasons" for why this could be deemed unsafe. Core problem: the vitamins don't have any intellectual property. Could affect the costs of healthcare. -How to use technologies such as Vielight and exosomes to address Alzheimer's...1:14:30 Alzheimers is a $500 billion industry; the 6th leading cause of death. A Vielight is basically a laser light for your nose and head; photobiomodulation on your skull. -What GDF11 mRNA is and how it works to improve hearing, smell and sight...1:25:30 GDF11 is a DNA repair molecule; makes stem cells active again. Patients see improvements in sex drive, vision, smell, hearing, etc. Legal hurdles to being able to administer it. "Unofficial" results are very positive. -How senolytics works as a therapy for aging and Alzheimer's, and the importance of quercetin and tocotrienols...1:33:45 Describes small molecules that lead to the death of "zombie" cells that don't help the rest of your body.  "Natural Compounds that Remove Aging Cells" -And much more... Resources from this episode:  - - - - - - Use discount code "BenlovesNAD" at check out - - - - - - - - - - - -Book:  by Dr. Dale Bredesen - -Exosomes Podcast:  - - - - - - and  - 500-800mg Quercetin and 150mg tocotrienols per day for 3 months - Episode Sponsors: - Whether you’re looking to stimulate faster muscle growth, recover more rapidly from exercise, become more resistant to fatigue during a grueling workout, or just benefit from additional amino acids in their most absorbable form to support aging or a vegan, vegetarian, or ketosis diet, Kion Aminos essential amino acids has you covered. - "How to eat gluten and get away with it..." Get 10% off the already discounted price when you use my link! - Makes healthy living easy and affordable at 25-50% off traditional retail prices. Use my link and get an additional $60 off your order. - The revolutionary bedroom biohack for guys who want optimal sexual performance. Do you have questions, thoughts or feedback for Tom, Mark or me? Leave your comments below and one of us will reply!  

Peptides are a grouping of 50 or fewer amino acids (more than 50 is a protein). Peptides are natural substances, though those covered in the show are variations on the naturally occurring versions. They can be beneficial in many ways, often amplifying the body’s ability to heal itself. They discuss the history of the use of peptides in a medical environment, as well as the future of peptides becoming available commercially in the U.S., with over 7,000 in clinical development currently. Cancer research is one of the leading development areas for peptides (ALRN-6924 is one of the prominent ones studied). Antimicrobial research is also being done to potentially create new antibiotics. There are different methods of delivering peptides to the body. They are not very bioavailable orally and are prone to hydrolysis, so injection is the best for the majority of peptides. They explore some of the benefits of peptides over traditional medications, such as allergic reaction is limited with peptides, and neither the kidneys nor liver have to process them like traditional medications require. They also consider the potential side effects of using peptides. They warn against purchasing peptides from online companies, as many of them are produced overseas in bulk without any regulation, often not containing what they claim. The only safe way to get access to peptides is through a reputable doctor who practices integrative medicine, with access to compounding pharmacies like Tailor Made Compounding. Some of the peptides covered on the show: Human growth hormone (HGH) secretagogues like Ipamorelin, CJC-1295, Sermorelin and Tesamorelin encourage the pituitary gland to increase HGH production. They also explain the significant risks of using human growth hormone therapy directly. GLP-1 and Semaglutide could be used for diabetes treatment. Melanotan 2 stimulates melanocytes to produce melanin, causing a tanned appearance of the skin. Epitalon resets the HPA (hypothalamic-pituitary-adrenal) axis, with a number of potential positive effects on disease states, possibly helping to lengthen or preserve the length of telomeres, increases melatonin for better sleep and more.  BPC-157 is orally bioavailable, unlike most peptides, with a variety of reported benefits. This includes helping with neural inflammation, muscle improvement, improved immunity, improved collagen synthesis, increased bone density and accelerated recovery/healing. It is most often used clinically to treat gut and bowel issues and tendon and ligament repair. Thymosin beta-4 is beneficial for soft tissue injury by increasing blood flow to the area, encouraging healing. Thymosin alpha 1 is FDA approved (commercially available as ZADAXIN™ for treatment of viral hepatitis), encouraging increased immune response to some cancers, Lyme disease and sexually transmitted diseases. PT-141 has a benefit for treating some erectile dysfunction and female sexual dysfunction. Follistatin (actually a protein, not a peptide) has the potential to inhibit myostatin, which prevents muscle breakdown. Cerebrolysin is a combination of peptides with potential useful for brain repair in neurodegenerative conditions such as Alzheimer’s, Parkinson’s and strokes. Selank and Semax are Russian peptides that are nasally bioavailable that have been reported to help with anxiety. MIF-1, ACTH, Dihexa have limited research but have been considered to help with depression, bipolar disorder and PTSD. IGF1 has nerve regenerative capabilities. GDF11 may be beneficial in tissue repair, so useful in anti-aging, but with potential health drawbacks. About the guest: Ryan Smith attended Transylvania University and double majored in Philosophy and Biochemistry. In that time, he had multiple research internships at the University of Kentucky and University of Pennsylvania, studying large scale protein synthesis and physical chemistry. After graduation, he attended medical school at the University of Kentucky for 2 years.   After finishing all the educational curriculum and passing USMLE Step 1, he decided to leave and help open up a pharmacy in the United States that focuses on peptide synthesis and formulations for pharmaceutical preparations. Since that time, Tailor Made Compoundinghas become licensed in over 45 states and territories, including Dubai, and has become the leader in the compounding of peptides and proteins for pharmaceutical use.  Follow Tailor Made Compounding on Facebook @TailorMadeCompounding  and Twitter @TMCompounding.  

Today we look at GDF11 and how it will potentially benefit your health in the future.  Enjoy the show.  www.mikedaciuk.com

GDF11 Rejuvenation Therapy

Sit back and listen to our podcast !!!!Will baby blood hit the anti-aging market? Is the young blood transfusion the new omega 3 / golgi berries for the prevention of cognitive decline? Stanford and Harvard scientists claim so. A new wave of interest was drawn from an old, yet neglected medieval medical technique, where two circulatory systems, one old and one young, were connected in order to refresh the old brain and facilitate its healing and rejuvenating mechanisms. The method, now fancily called heterochronic parabiosis, has recently been brought back to scientific focus for one simple reason: it looks like its working.source: http://tinyurl.com/qcr9bwyThe neurological decline and associated cognitive deterioration experienced during healthy ageing as well as neurodegeneration is one of the biggest mysteries in neuroscience. It seems like we cannot point out a single, culpable black sheep from the several factors that accounts for the progressive decline in the end of life. Rather, it is more likely that there is a cascade of "little things going wrong" that leads to the decline in overall performance. This is exactly why counteracting or slowing down this progress is not an easy task.  It is not surprising that a method offering an all-purpose "cure" against old age will rob the bank, especially if it can have headlines such as Vampire therapy of ageing, and put Fifty shades of grey ads in the corner.2014 was the year of young blood. I mean, apart from the season finale of True Blood, Katsimpardi and colleagues (2014) stitched an old and a young mouse together to connected their circulatory systems. This was not only beneficial for the vascularisation of the old brain compared to the young one but also upregulated the neurogenesis in one of the areas of the brain known for its role in the memory formation, the hippocampus. Pretty fascinating stuff, because it implies that we can now fight ageing in two ways: 1) better circulation in the brain (hence more food and oxygen to the neurons, and less probability of a stroke) and 2) more neurons in the area that is most likely to be the correlated with the contextual memory (decline). However, there is a rather big jump between the experimental evidence and literature review of possible candidate mechanisms to put behind all these effects. The authors finally pulled out the chocolate sprinkle (see the podcast) of growth factors called GDF11 to test on their parabionts. However, GDF11 is, according to my knowledge, too big a protein to cross the blood brain barrier (its concentration was not measured, it was only administered in the brain as a separate experiment). This does not mean that it cant account for a lot of circulatory beneficial effects, but I cant necessarily see the direct connection with the neurogenesis. The authors themselves highlight overall effects saying This suggests that neural stem cells exposed to young systemic factors increase their ability to proliferate and differentiate into neurons.(highlighting by me if you cant tell form the shade of purple immediately :P)Hhmmm...anyway... Are these newborn neurons functional parts of the network; can we correlate their operation with physiological and behavioural improvement? Stanford suggested that we can. This paper is an old-school, all rounder evaluation of the vampire approach, so much so that they are not even stitching the bellies together, just transfusing the serum of young mouse to older ones. Clever move, not just because it helps the PR part (stitching together old people with babies, not my dream advert for rejuvenation therapy), but it also makes the implementation easier. They also started by looking for the 'it' factor of rejuvenation by performing a genome-wide microarray analysis of the old and young hippocampi in the parabiont mice. They found a rather good chocolate sprinkle called Creb (cyclic AMP response element–binding protein), that is known for regulating game-changer proteins such as C-Fos (indirect correlate of neural activity), and to be essential for the sustenance of the good old LTP (see later). Now thats a start, but what else changed? If we compare levels of neuroscientific interest to a computer (dare I compare it to the brain itself), they found differences on all levels. If we take the hardware, they showed greater number of dendritic spines in the heterochronic parabionts in the dentate gyrus of the hippocampi, but not in another part (CA1). Sadly, the press was shouting Alzheimer, but in this neurodegenerative disorder, dentate gyrus stays intact for relatively long time.  Does not immediately shout Alzheimer to me. Difference of all levels (1. experimental groups, 2. anatomical remodelling: more spines (hardware), 3. change the physiological correlate of synaptic plasticity, more sustained LTP in the control group (software) )source: http://tinyurl.com/qxhdm35Anyway, the authors then addressed if there is anything upgraded in the software. They found that long term potentiation, the gold standard electrophysiological measure of long term memory function was maintained for the entire recording period in the old members of the old-young  pairs compared to the aged members of the old-old pairs (controls). We all know how slicework in neuroscience is the bread and butter of describing causality, but we know nothing about what happened in vivo from all this. Lastly, the IT wants to know what happens if we give a new task to this computer, so the behaviour of the heterochromic parabionts vs controls was tested in many, hippocampus-related contextual memory tasks. This tasks are basically the rodent version of the where did I park my car last night kind of lifehacks. Surprise, surprise, rejuvenated old fellow mice did better than re-not-juvenated peers. Now one last thought about this ... where is the evidence that it is a cure for Alzheimers??Taken together, what can modern neuroscience say about the fountain of youth compared to the good old times? Not more than that we can actually prove the effect of young blood. Converging evidence supports the method is somewhat, somehow working. Exactly how my grandma argues for superstition and folk wisdom. It is still a good guess, we might as well give it a go, even without knowing the chocolate sprinkle factor of it. Even if we have no idea how to implement a huge amount of young blood transfusions on a longer term. 

Francesco Loffredo, Brigham and Women's Hospital, Harvard Stem Cell Institute, Cambridge, MA, USA speaks on "GDF11: a novel regulator of cardiac aging and diastolic function?" This seminar has been recorded by ICGEB Trieste