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Cellular Aging, Taurine, Nutrition, Senescence, Longevity, Mitochondria, Metabolism | Vijay Yadav

Updated: Aug 9

Full auto-generated transcript below. Beware of typos & mistranslations!

Vijay Yadav 5:31

So my name is Vijay Yadav. I'm an assistant professor of genetics and development at Columbia University. My lab investigates how different changes that happen with age contribute to the aging process, and to identify novel interventions to treat or diseases of aging. And the overall goal of my lab is to increase healthy lifespan in humans.

Nick Jikomes 5:59

And, you know, it seems like a basic question, but what is aging? Exactly? Is it? Is it just sort of a generic term that refers to the general tendency of things to sort of break in our bodies over time? Or is aging Is it is it more of like a regulated process, that's, that's sort of more definable.

Vijay Yadav 6:23

So, in my opinion, is that aging is a process which is to an extent regulatable, but at the same time, it is a process that is eventually going to happen. The goal here is how we can delay this process, and how we can make sure that we are having a least amount of disease phase at the end of our life. So, all of us are going to have diseases at the end of the life, but the goal here is to minimize that period, which is a disease state. So, you can imagine aging as a process, which is equivalent to a house when you build a new house is like an adult human being, but with the age of the house, you start getting small damages, your pipe leaks, your roof is leaking, you have a problem in the house, the paint is starting to veer off and this is equivalent to what is happening with aging, there are cells in our body that repair these damages, there are organs that are able to replenish these damages much easily compared to other organs. But overall, there are organs which are more susceptible. To give you an example, for example, liver, if you remove part of the liver, liver has the ability to regenerate itself to re invent itself literally to be able to perform the function again, but if you remove part of the brain, it will not be able to do so. So, therefore, the aging is is a constellation of changes happening in our bodies that ensure that we have the not only a way to regulate some of these events, but at the present time in my personal opinion, we do not have a defined way to reverse these processes.

Nick Jikomes 8:37

And how how is aging different from development? How should we think about differentiating those two processes?

Vijay Yadav 8:46

So, development is a good question. Well, one can view development of processes as a way to look at aging. For example, during development, there are massive amount of proliferation going on organs are being shaped into the final shape of the organ, the way heart is going to look like when it is going to be an adult heart for example, or liver and then these cells are accumulating. So, in there is a concept in the aging field which is a developmental origin of aging, which says that during development, we have a defined set of processes that are happening, which can be looked into or which can be tapped into by manipulating those processes. When you are old human being you may have the ability to read care kept some of the devious changes that have happened in our bodies.

Nick Jikomes 9:57

I see and you know There's a lot of obvious external markers of aging that everyone sees, and everyone is familiar with. But when we start to think about physiology and stuff going on in the inside different molecules whose levels go up or go down different, you know, sort of metabolic pathways that start to go awry, what are some of the major hallmarks of aging, in terms of our internal biology.

Vijay Yadav 10:25

So at the end of the day, everything boils down to cells. So, if you look at different organs, they are composed of different cellular cellular properties. They have, for example, primarily, liver is composed of hepatocytes, a cell that has the ability to perform particular functions, so detoxification for example, therefore, at the end is the cellular functions which are present in a an organ. And with age, we have a variety of changes happening in these cells, it limits their ability to function, not only it limits their ability to function, it limits their ability to send signal to other organs. So, cells are not working in isolation. So you have cell intrinsic events that are happening, which is happening within the cells. And then you have cell extrinsic events, which is regulated by the environment or the hormonal milieu that is present in which the cells are present. And in the cells, you have variety of changes happening with age, such as increased accumulation of DNA damage, because cells are not able to repair these processes very well, you have mitochondrial dysfunction, you also have loss of telomeres that open up the end of the DNA and make it more prone to damages. And you also have ability of the cells, which is changing as far as the nutrients are concerned, their nutrient sensing ability change. So these processes together, are classified roughly as nine hallmarks of aging, some years ago, and these processes are looked into when it comes to cell intrinsic events that are happening within the cells. But at the same time, you have gene, which is in the physiological milieu, or the circulating molecules, which cells are exposed to. And this is how organs communicate with each other. It is an integrative physiology, our organs are not functioning in isolation, they are talking with each other through sending signals to them receiving feedback, hey, I'm doing well. You need to, you need to regulate me, or I'm doing bad helped me. So these are the integrative the concept of integrative physiology, which is how organs communicate with each other. And how this communication deteriorates with age also contributes profoundly to the process of aging.

Nick Jikomes 12:56

I see. So there are cell intrinsic and cell extrinsic, extrinsic factors here, there's stuff sort of inside individual cells inherent to those cells that can start to break down things like the telomeres, which sort of regulate how exposed the DNA is the mechanisms responsible for repairing things like DNA damage, or responding to something like oxidative stress, you know, different pathways in the cell. And I would imagine those types of things are basically, they're shared by all cells, whether it's a brain cell or a liver cell, even though different organs and tissues might age at different rates, or something like the liver might be able to regenerate itself, whereas other organs can't do this. Those are problems that that all cells face. And those are things that start to break down over time, no matter what the cell is. And then there's the cell extrinsic things going on. And so you mentioned that there's, there's, you know, a lot of communication happening between cells between tissues and organ systems. So cells can release hormones, or nutrients can circulate throughout the blood. And all of that stuff is a factor here, too. And so, you know, up until your recent research, what are some of the major extrinsic factors, things circulating in the blood that people had been thinking about and looking at when they were thinking about aging.

Vijay Yadav 14:16

So, there have been a lot of advances, growth factors, for example, the a lot of studies that have been done to look at protein molecules that circulate in our blood and that may impact the aging process. For example, vascular endothelial growth factor VGF. People have looked into the IGF one as a hormone that can affect the aging process, growth hormone axis. So these are the factors that have been looked into in the past to in order to look at the communication between the organ systems, and these different molecules are secreted by specific organs predominantly, for example, growth hormone acts through the liver to produce IGF one which is circulating in the body. Principally, it does not mean other organs don't produce IGF one, it only means that the major contributor to the IGF one circulating IGF one is labeled. And, and these have been looked at interventions to in order to alleviate various processes that happen with age. And this is what one needs to investigate how organs are communicating with each other, because humans are multicellular species much more complex than a unicellular, eukaryotic or East for example, because we have much more dependency on other organs, we have developed circulatory system, we have developed nervous system, we have developed neuromuscular systems, we have developed a skeletal system. So bones, for example, and these are organs allow our bodies to perform different functions, and they need to be regulated properly, in order for us to maintain a healthy body.

Nick Jikomes 16:17

Yeah, and, you know, there's when we think about these circulating factors that cells can sense and that are involved in cell to cell or organ to organ system communication. You know, there's a couple of different things that come to mind. For me, there. On the one hand, there are things like hormones, which are produced by our own cells, certain cells produce these, they secrete these, they coordinate different, you know, physiological changes throughout different systems in the body. Of course, you can add exogenous hormones, and people are doing that, you know, people are taking testosterone or growth hormone therapies now, but under natural conditions, so those are things that are produced and secreted within the body. But then there are also things like nutrients which come from the external world. And you know, there's obviously many different nutrients. And you know, at a very coarse grained level, we all understand that certain things are basically good for you, and certain things are bad for you, depending on the molecule and the concentration. What have we known up until recently about, you know, certain nutrients that might play an outsized role in the aging process, either promoting more rapid aging or having anti aging effects? Are there nutrients that clearly have one or the other?

Vijay Yadav 17:31

Yes, indeed, there are. So if one looks at the historical perspective and biology, one gets a glimpse of the importance of nutrients. For example, I'll give you an example of a disease here, which was very prevalent up until the 1920s. It is it was known as Pernicious anemia. So Pernicious anemia was a disease where patients were anemic and they were bedridden, they were not able to move very well. And they died. That is why it was turn pernicious. And so up until 1920s, there was no cure for this disease. And then, many investigators started investigating how Pernicious anemia is, is developing in these patients. And what they discovered initial experiments were done in animals, in fact, dogs, so one of the investigators, he bled dogs to make them anemic, a blurred dogs profoundly. And now the blood dogs will anemic and then He fed them different diets. What he discovered when he fed dogs animal based diet, in particular liver, raw liver, the anemia was reversed.

Nick Jikomes 18:54

So he gave us raw liver, it reversed the anemia. And for those who don't know, anemia, is that just mean that the blood is not delivering oxygen?

Vijay Yadav 19:02

Yeah, red blood cells are depleted and these anemic patients. And then based on this foundation is an annual experiment to clinicians, one in Canada and one in the USA, decided to feed humans with Pernicious anemia or Oliver. And this led to a very controversial at that point, a experiment in humans where they were feeding Oliver. The surprising part was anemia was reversed in humans as well. And these three individuals got Nobel Prize in 1934. To feed humans are audible and that was Whipple minnow and Murphy. So that to cure to find a cure for Pernicious anemia. We did not know what liver had till that point. And that is why it was very challenging. I would say that even for the Nobel Prize Committee, it would have been challenging the season.

Nick Jikomes 20:11

So just before you go on with this piece, so you said they started doing experiments in dogs, they discovered that feeding them raw liver cured this form of anemia, what other diets and they try,

Vijay Yadav 20:24

they tried different diets, for example, vegan based diets and other diets, but we are looking at a specific disease here Pernicious anemia. So we did not know till 1934 What liver contained which reverse the anemia. And then, people started purifying what was present in liver that was securing anemia. And it was discovered in 20 years later, that the molecule present in the liver was vitamin B 12. That humans cannot synthesize it. And we absolutely need it in our diets. Therefore, in today's world, for example, nutritionist supplement Bidwell for people who are on a pure vegetarian diets. So it tells you an example here that liver are there is a nutritional component of our health, it's which and in the absence of these nutrients, we have dramatic diseases which were incurable, just 120 years ago, because we didn't know about them. One can talk about vitamin C, here, we can talk about many other nutrients which are coming from the animal based on plant based diets. And what it is tell you, these evidences tell you is that the way human society has evolved, our nutritional preferences have evolved. And we have developed these nutritional preferences based on our needs, because some human societies or some groups migrated to colder climates, and they were probably having more animal based diets, some migrated to more tropical climate, and they developed more grain based diets and then had to supplement milk and eggs and things like that to have a more complete diet, in my view. And this also tells you that nutrition is very important for the health of our human being.

Nick Jikomes 22:38

Yeah, and so like, we don't have the ability to synthesize vitamin B 12. Now, I don't know if this is your area, but is that like an example where we never had that ability? Or did we lose that ability and other animals have that ability and perhaps we lost it because it was so plentiful in our diet ancestrally

Vijay Yadav 22:55

no animal can no no animal eukaryotic cell cans in the size v 12. vitriol. The only species on the planet that can synthesize B 12 are some bacterial species. And some ruminants, for example, cows and other ruminants have this bacteria, which are synthesizing betrayal in the part of the stomach before the toll is absorbed. And they are able to host these bacteria able to absorb these becoming beetles synthesized by bacteria into their bloodstream, then they store in their liver and muscle. And that is why liver which is a principal storage organ, beside muscle in the animals, when they eat animal based products, it was curing Pernicious anemia because labor stored betrayal and recycled it. And that tells you that some things we cannot just synthesize just evolutionarily, we have not evolved synthesize those molecules, but they are essential. In the absence of dung beetle. We have anemia. And it is very prevalent in aged population, the Cubans you have the majority aging, we have the reduced ability to absorb bitumen from our diet. And therefore we develop anemia and other diseases consequences of that.

Nick Jikomes 24:24

I see. So because something like B 12 is stored in certain animal tissues, like the liver, or the muscle, is that why that's why those organs have such high concentrations of nutrients like this. And that's why you have to supplement if you're not eating a diet that that doesn't enable you to consume those animal organs. Yeah, and the amount of it Yeah, you're right. Interesting. So you know, obviously if you're deficient in something, you can supplement with it. You can just, you know, consume it one way or another and that can reverse the deficiency Um, what? So you did some work recently where you were looking at, you know, things that can be found in the diet, and things that circulate throughout the body. And the relationship between these things and aging and whether or not you know, there's, there's always this question of, you know, if you look at animals across their age, things change, obviously. So, you know, different nutrients or different molecules or different kinds might, you know, decrease or increase as an organism ages, then there's always this question of, it's as a consequence of aging, or can these things actually actively regulate the aging process? So you've looked at something recently called taurine? And I'm hoping you can talk to us about that. And if you just want to start out by describing, you know, how did you narrow in on this molecule, and and sort of get started on this project?

Vijay Yadav 25:50

Sure. So almost 12 years ago, when I was in Cambridge, in England, actually, we were doing a metabolomic screen in humans in the blood. And the goal there was to identify what is changing with age. And this experiment, that we did identify that many molecules were changing with age. And among these screen, the molecules that were changing dramatically with age, we found that one molecule in particular was going down with age. And this molecule was touring. So up until that point, I didn't know much about touring. So in 2011 12, I didn't know much about touring. In fact, when my senior investigator came and told me, do you know what touring is? My first response to her was? I don't know much about it. I have heard about it. But I don't know. What does it do? Let us find out. So, at that point, we started investigating, okay, what is touring? And what is it doing the body? Well, Torah is not a new molecule that was identified in 1827 in ox bile by to German scientist. And almost 440 years, nothing much was known about Tallinn. Because biochemistry, molecular biology, and all these areas of science were evolving at that point. In 1950s, people became rich. And there was introduction of pet foods in the society. So because people were having nine to five jobs, they needed some kind of a pelleted diet to be given to their pets when they went to office. And this introduction of pet foods in the society by pet food industry, led to precipitation of many diseases in pets. Cardiovascular abnormalities, growth defects. One of the most striking aspect of this entire episode of introduction of pet foods in the society was many cats started going blind. Now you can imagine the rich household having a cat that is not growing very well and there's going blind is hitting walls. It is dropping VAs at your home. And it's very distressful sight for any pet owner. So, well, society came together to because there was so prevalent, they came together, they said, Okay, let us find some scientists and try let them figure it out what is going wrong with my cat and why this blind? So this took around 2025 years for scientists to figure it out. Why cats were going blind on a pet food. In 1975, there was a seminal paper published in Science that showed blindness or retinal degeneration in cats is caused by deficiency of a single molecule in their diets. And that molecule was taurine. Also, that cat food was supplemented with touring and blindness went away overall. Oh, wow.

Nick Jikomes 29:15

So so that one molecule was responsible for all of all of those particular health problems in cats, and I guess the whole, the whole idea here is up until people had cats in the house as a common thing. pet cats were sort of just domesticated feral cats that still went outside and ate birds and ate mice and you know, all of the normal foods a wild cat would basically eat. So then we start domesticating cats further, they're spending time indoors, we need to come up with pet food, if our cats aren't going outside and feeding themselves, and just due to our ignorance, I guess not knowing all of the things that the cat needs in its diet from a nutrition standpoint, we just made What we thought they needed and it was deficient and things like taurine and other nutrients?

Vijay Yadav 30:04

Yeah, maybe we don't. And it's true for human beings as well. Because we don't know what the ideal nutrient composition that we need for a specific body needs. We are evolving, we are trying to understand this requirement as best as we can. Almost 100 to 100 years ago, we didn't know we didn't do it well. We didn't know that we needed a specific components coming from the vegetarian diets, for example. So these, these nutritional composition is also dependent on the specific ethnicities, the specific dietary styles, a specific location or the environment we live in as a human being. And I think it's still we are not 100% finite, or we don't have the complete understanding of what this nutritional requirement is, because our genetics also has been shaped up. And now with the movement of populations across the world, it is the movement, we are moving around. And we are living in environments we never lived in. For example, a person who is coming from a tropical climate, he synthesizes enough vitamin D, for example. And then if he moves to a colder climate where there's less sunlight, suddenly he is deficient. So now, the changes in these nutritional composition of the diet is becoming much more important than it was, let's say 4050 years ago when the movement was limited. And these these things need to be given careful consideration when we are looking at a perfect nutrition to have a healthy body.

Nick Jikomes 32:02

So, you know, by through this study of pet food and what was going on with cats domesticated cats, they discovered taurine, obviously, it had a profound impact on the cats. I mean, if it was, you know, having that big of an effect. You know, it's amazing that a single nutrient just supplemented can have, you know, that big of an effect. What exactly is taurine? What type of molecule is it? And what do we know today about it's just very basic physiological functions.

Vijay Yadav 32:33

So, Tallinn is is very small molecule is an amino acid. And it is a typical amino acid because it has its own amino acid have two groups, an h2 group and a carboxyl group that allowed them to form peptide bonds and to be incorporated into proteins. But taurine is a typical, it lacks this carboxyl group, it has a cell phone will group. Therefore, to the most part, it remains as a free circulating molecule within the cell. And taurine is can be synthesized in our bodies by labor to an extent and some other organs. And we are also dependent on its consumption in the diet. So, for example, when a child is born, it is deficient in the ability to produce for him and is dependent on it. And therefore an almost a few decades ago baby formula was supplemented with touring. And then as we grow for the me start developing some capacity to synthesize touring. But in two give you a glimpse of it, we do not know the dietary versus the endogenous synthesis component responsible for the promoting healthy life because during the development or during gestation when the baby is in uterus, it has five to 10 fold higher concentration of taurine in there in its body. As soon as it is born, it is out of the mother's womb. Now mother is not able to supply the taurine the the levels fall down and it is dependent on exogenous supplementation in the baby formula for example for human and then during it it starts developing some capacity, then it goes down further as it ages. As humans age, it could be different ability to have a differential nutrient absorption and as well as different ability to produce darling endogenously.

Nick Jikomes 34:54

So So taurine is an amino acid, but it's an atypical amino acid Acid, it's not like a lot of the other major amino acids that maybe people have heard about. So when we talk about amino acids, right, there's, for those that don't know, there's essential and non essential amino acids, sometimes our bodies can produce them. So we don't need to get them in the diet, even though we don't strictly need to get them to the diet, but we often still do need to consume them. But then there's, there's other ones that we can't produce at all. And then we need to get through the diet. And then my understanding is, you know, there's, there's, there's some wiggle room there, some of them are semi essential, and we can produce them to some extent, but not maybe as much as we need. So we still need to get it in the diet. And it sounds like so taurine is one that some of our cells can produce to some extent, but we get a lot of it exogenous ly from consuming it. And it's also different from other amino acids in that it's, I think you've said, it's typically not incorporated into proteins as a component like a building block of the proteins, but it acts as as it just floats around through the bloodstream as its own molecule, and it does various other things,

Vijay Yadav 36:02

and do things plenty of things. In fact, on it is taurine is classified as essential and during development is essential, it is promoting the growth of the body organs. And it is very much important to during the early growth period post naturally. And then you have a phase when it starts regulating different processes. And it has been known since the those studies in animals and cats and dogs, which showed that taurine was important for growth. Touring was important for IE problems, which they were precipitating because of pet diets, cardiovascular problems, cardiac failures. And these are studies in started, I think, a profound interest in the society and in scientists in general to find out what taurine is, and what does it do. So these studies made people interested. And since these discoveries in up to 1990 people have been interested in taurine. They have shown that it regulates muscle function, it regulates brain functions, it regulates obesity, it regulates pancreas functions and so on and so forth. But what was not known till when we started investigating is whether Tallinn affects the process of aging. And that is where we started investigating because taurine levels were down in the old animals compared to very young animals, we started asking question is the levels that are going down? Are they a driver of aging, or they're just a passenger of aging, which are just going along for a ride? There's a collateral damage happening with the aging process. And that question that you asked in the beginning is the causal event. And that is the exactly the question we started investigating almost more than a decade ago. By looking at old animals, then we supplemented them with taurine. Once daily after optimizing the dose and frequency of administration for life. And these mines that were supplemented once daily Bitcoin for life from Middle Ages, when touring abundance was low, live longer. On average, females lived around 12% longer and means that only 10% longer.

Nick Jikomes 38:38

So 10 Plus is reliving 10% longer. So that was a human being assuming that you got a comparable effect. You know, you're talking about about a decade of time

Vijay Yadav 38:48

almost a decade. Yes. It took 20 years of life you can add on to that. Yeah.

Nick Jikomes 38:52

So you said so in mice and other animals taurine levels go down with aging, and you started supplementing mice in middle age.

Vijay Yadav 39:02

Yeah, absolutely equivalent to 4550 year old human

Nick Jikomes 39:05

and are the mice just like eating the taurine is it part of their diet, how do you give it to them?

Vijay Yadav 39:10

So, that is that is where the nutrition comes in picture. So, mouse diet lack story. So therefore, we looked at first we looked at and in our pilot studies giving taurine in their food. That means the continuous continuously mice is eating and is able to consume taurine. And at the same time he did once daily oral administration of taurine. What we found out this initial pilot study is once we gave animal once daily taurine. These animals were much more healthier compared to when the provided there At Tallinn in their food, because Tallinn was not elevated enough, in my view in the blood, to be able to impart the health benefits as robustly as when it did when it was given once daily like once a pin once they've been. So that is where we gave once a day administration oral administration of talking to the mice.

Nick Jikomes 40:27

And when you say oral does, that still means that they're swallowing it, and it's going through their digestive system?

Vijay Yadav 40:32

Yeah, it is going through the digestive system in mouth how you do it, because well, you cannot give a pill to mouse and is going to swallow. So there is a procedure known as a gouge, which is given where you administer in a solution, the molecule that you want to administer. And that way animal does not consume the entire dose of the molecule.

Nick Jikomes 40:57

So So you give taurine to middle aged mice once per day, and they can live something like eight to 12% longer, you start giving them in middle age, because that's, that's probably when taurine starts dropping off or when it gets particularly low. That's a pretty major effect. You know, one question people might have is, did the mice live longer? Or, and or did they feel better or look better? Did we it's sort of increased the end of their life when they were old? Or did they actually have an increase in their so called healthspan the amount of healthy, functional life that they actually had?

Vijay Yadav 41:39

Absolutely, there's a very important criteria for any anti aging intervention. So not only we want to live longer, we want to live healthier, or reduce the period of the disease period that we face at the end of our lives. And that is what indeed we did next. We now supplemented mice, middle aged mice with all humans daily for one year, and then measured a variety of organ system functions, either in life or terminal. And what these studies showed is that no matter which organ function we looked at, in our studies, we looked at bone density, it was improved neuromuscular function was improved. They had less anxiety, they had a better memory, better glucose tolerance, better insulin tolerance, better gi transit, and their immune system was functioning closer to the younger immune system. So these studies told us not only taurine was in making animals live longer, it was making animals live healthier lives.

Nick Jikomes 42:47

Interesting. So basically, anything that you looked at whether it was brain function, you know, how well their their mouse brains were working, and how well they could remember whether it was bone density and muscular skeletal function, whether it was just general metabolic health, and how they're processing energy and stuff, whether it was immune function, basically, everything that you looked at, it sounds like you looked at a whole bunch of things. Everything looked better. The older mice looked like younger mice in terms of their physiology, when they were supplemented with taurine.

Vijay Yadav 43:19

Yes, you're right. You're right. And not only so the mouse is just one model organism. We use it as a model for interventions. We then investigated, okay, is this effect that you see in mice is it also observed in other species? When we looked at once, another model organism C. elegans, which is the invertebrate model organism, used in aging research, and what we found is that worms that was supplemented with taurine, they live longer as well. At a higher doses, they lived somewhere between 10 to 23% longer compared to ones that were not given falling. To these two species, we saw a robust effect on lifespan and health of these different organs. Then, the major question at that point was, how about humans? So we went to as close to humans as possible. We did a monkey intervention study, where we supplemented monkeys once daily with taurine, and then looked at their organ functions six months later. So monkeys that were supplemented with taurine, they had reduced adiposity they had more bone density, better liver function, they had a better glucose or glycemic index. Also, their immune system was functioning better and in the blood, they had a less oxidative damage markers. So in these three species one can say is that okay, taurine increases Is healthspan and lifespan in mice and once and healthy spend in monkeys, because in monkeys, we only investigated healthspan.

Nick Jikomes 45:08

Just because they live longer, and you didn't probably didn't have time, up to 30 years they live. So So you see this in multiple species, you see it in rodents, this effect where you get an increase in lifespan, and healthspan in rodents, you saw that in an invertebrate species, that's a very evolutionary distant relative. You also saw the increase in healthspan in monkeys, another mammal obviously closer to humans. I mean, this would imply I would think that you know, taurine is just tapping into very basic biology that's evolutionary conserved to a large degree between all of these different species. And that would imply that there's a high likelihood that you might see similar effects and human beings. So what do we know about Torian? And humans? Do the taurine levels go down in a similar fashion as humans aged like they do in other animals? And do we know whether taurine supplementation works in humans? Are people doing those trials? Or do we think it's plausible?

Vijay Yadav 46:04

So we did some studies ourselves, and I'll tell you more about what data exists in literature. So people have noted that all in abundance goes down in some tissues in humans. For example, in brain it goes down in skin, it goes down the content of taurine. In plasma, people have shown that it goes down. And in our studies, we noted that taurine levels were going down with age as well, in particular, compared to the younger humans. So what this told us, okay, taurine levels, which are down in bold people may contribute to different age diseases. And we investigated this process, we had access to longitudinal health data for Around 12,000 people. And this study also had measured taurine levels and taurine metabolite levels. So we perform the association clinical risk factor and Tallinn and its metabolite Association. And this association analysis showed that humans that had low taurine levels had more obesity, they had more type two diabetes, they had more hypertension. They had more BMI. They also had their glycemic index was poor. And they had a variety of other health condition. In other words, taurine, low taurine levels in humans is also associated with variety of diseases in a large cohort of people. And this also raises the question, What about a healthy state of a human being? So what happens to taurine and just metabolites in a healthy state? So the reason at that point, the exercise a very healthy state of human being. So let us put a bunch of people on a bicycle and exhaustion run, and then measure their taurine levels and metabolite levels before exercise and at the end of the exercise. So when we measured taurine and metabolite levels, taurine levels and its metabolite levels went up in after exercise went up in sedentary individuals, which don't exercise normally. It went up in bodybuilders. It went up in marathon runners, and it went up in sprinters.

Nick Jikomes 48:40

It goes up in response to a behavior like exercise. Does that mean it's stimulating endogenous taurine synthesis? We don't

Vijay Yadav 48:47

know. That is the question that we don't know. Is it endogenous synthesis that is going up? Or is it the release from organs that are storing in goes up?

Nick Jikomes 48:59

I see. So it could be that it's a storage of exogenous taurine that we've gotten from the diet or something and it just gets released? Yeah, I see. So where do we get exogenous taurine? Naturally from certain foods?

Vijay Yadav 49:13

Yeah. So taurine is naturally present present in animal based diets, such as shellfish are very abundant in taurine. It is like a it's less in my view, one milligram per gram. So even if you eat 500 grams of shellfish, you're going to have 500 milligrams of taurine. And so animal based diets are rich in taurine. In particular shellfish, as I said, and we can get by eating those animal based diets we can get taurine. It is also present in milk and other products from animal based products. So we can get from animal based diets, yeah,

Nick Jikomes 50:01

so it's primarily found in animal based foods, protein rich animal protein rich foods that makes sense to amino acid. It's intuitive, at least, if it's if it's present in those foods that are part of human diets. What Why does it go down when we age?

Vijay Yadav 50:18

So that is the question that we need to investigate. Because it is, for example, it could be that the absorption of taurine is compromised as we age from the gut. As well as the production of taurine from the loo or primarily or other organs is goes down with age. Or it could be that there is the resistance of the action of taurine. In the cells,

Nick Jikomes 50:45

sort of like insulin resistance, we still have insulin in our bodies, but we are cell started responding to insulin.

Vijay Yadav 50:51

So these three events, we have noted that these are compromised. But we do not know how these processes are being shaped in humans, because taurine is a molecule that has diverse physiology across the spectrum.

Nick Jikomes 51:10

But I guess your your work in animals, because you were able to supplement rodents and other creatures and see the effects that you saw. This would suggest that at least in those species, it's not taurine resistance, because otherwise that that wouldn't work so well. So based on the animal research you've done, are you guys or anyone else doing clinical trials in humans are trying to figure out if this works in humans? Or would you expect it to work given what you've seen and what you know so far?

Vijay Yadav 51:39

So there have been few clinical trials looking at taurine. People have looked at for example, obesity. So people have looked at diabetes, people have looked at anxiety. People have looked at liver function. So people have done Discrete trials. And in all those trials, taurine had a positive effect. And there was no side effect or no red flags have been noted with for taurine. In these trials people have used somewhere from one gram to six gram of protein

Nick Jikomes 52:22

per day, per day. Yeah. And that's just giving like a pill.

Vijay Yadav 52:27

Yeah, yeah. So people have done some clinical trials. But as far as the aging is concerned, there is no comprehensive investigation looking at taurine as a an anti aging intervention, looking at various endpoints looking at health of various organs. So we have been putting together for last couple of years now, a team of international investigators to perform a multinational clinical trial. Because we do not know at the present time how taurine metabolism is changing in different ethnicities, for example, right? We do not know because the our metabolism is different depending on the ethnicity, as I alluded to in the beginning, that depending on our dietary lifestyle changes, depending on the environment we live in, our metabolism has shaped up a metabolism of a person who is living in colder climate is going to be different than somebody who's living in tropical climate. And our genetic makeup has changed over 1000s of years to accommodate those changes,

Nick Jikomes 53:35

as if that makes sense. Like as people just move to different parts of the world. You can imagine like the Inuit probably have adaptations to a high fat and very animal rich diet.

Vijay Yadav 53:46

Absolutely. And that is where we are at the present time, we are putting together this multinational trial looking in multiple ethnicities, looking in various populations, to look at how during intervention is going to improve the health of human beings. And that is coming up and hopefully we will be able to find and of resources and funding. There are a lot of interest already. We have clinical and basic science partners in Germany, in Singapore, in a couple of countries in Asia, the US we are developing such a team and we have a good interest at the present time. So right now we are developing the study. We have kind of a study protocol. We are we are bringing together different expertise, statistical expertise, clinical expertise, basic science expertise, to look at the endpoints. And hopefully we will be will be able to start the clinical trial that such a large vast clinical trial by the end of this year or somewhere in Lipitor next year.

Nick Jikomes 55:03

But it sounds like so so they've done clinical trials already for specific things. So the effect of Torian on liver function on glucose metabolism and things like that. You said that in all those studies so far, they've seen positive results in humans. And it sounds like everything that they've seen so far in humans is consistent with what you've seen in rodents and other species more or less.

Vijay Yadav 55:23

Yes, I think that is absolutely right. And that is where we need to now put together this set of endpoints to look at more closely how we are going to investigate that. This entire slew of things. There are already clinical trials, that is the good news. No red flags have been raised upon taurine supplementation. To give you an example, for example, when they looked at type two diabetes, they gave one gram taurine three times a daily for eight weeks. When we looked at obesity, they looked at three gram capsules for per day for eight weeks. When they look at the postmenopausal woman, they looked at 1.5 gram daily taurine for 16 weeks. In liver disease, they look at two grand touring per day in congestive heart failure. People have done doses, six gram per four weeks, three gram, four weeks, 1.5 grams, and things like that. So they're these doses are why am I illustrating these doses? The doses that we have used in animal studies is the will end to three gram per day, or six gram per day.

Nick Jikomes 56:44

I see. So use three, the human equivalent of three and six grams per day in your animal study, so So if you were to give people the same dose and do the same things that you guys did an animal it would be three or six grams a day. And in all of the clinical studies that have been done already in humans, they're using, you know, one to six grams per day, it sounds like, yeah,

Vijay Yadav 57:03

and also, according to European Food Safety Authority, up to six grams per day it or in in humans is under the safe limit

Nick Jikomes 57:12

mercy. So it's bioavailable enough to have an effect. There doesn't appear to be any negative side effects at these doses in humans. With all this in mind, like do you? I mean, do you supplement your diet with taurine?

Vijay Yadav 57:27

Well, that is the question that I have avoided to answer to the most part, because in my personal opinion, any answer I will give you is going to influence a lot of people. I tend to believe in the data and therefore I would wait for the clinical trials to be completed. Because if I tell you I supplement or in laudable say, Hey, this guy looked at 11 years of his life on taurine, he's supplementing, so I should do it. If I tell you I don't take some taurine. Hey, this guy worked on 11 years, he doesn't believe in himself. So I should not take it. So I don't want to be an influencer. Because these are anecdotal evidences, we need a randomized placebo controlled clinical trial looking at different ethnicities, larger populations, in order for us to come to conclusion. And next three to four years, I think we will accomplish these goals for the clinical trial. And four years later, they can go out to public and say hey, look, this is these are the effects that you see. And these are the conditions that you see that are benefited by training supplementation, you can go for it, or you cannot go for it. Under some concert circuit certain circumstances you cannot take taurine, for example, people with kidney disease, they cannot excrete taurine. So you one has to look at all these different parameters in order for us to provide a suggestion to the public at large.

Nick Jikomes 59:03

So going back to some of your rodent studies where you guys could dig into mechanisms and get into details a little bit more. You know, there's this concept in aging of cellular senescence. Can you explain for people what is senescence and what did you see in mice in response to taurine supplementation?

Vijay Yadav 59:23

So Samson cells are cells that accumulate with age. Normally, these are eight cells which undergo a variety of damaging processes in the cells, and they are cleared by our immune system. But with age, these cells accumulate in different organs causing dysfunction of those organs. And these cells are just one piece of puzzle in the aging process. They're not the only player in the aging process. They're one of them. Besides and since you have other processes all So that change with age. And we looked at these age of little changes in the cells to try to see what happens with the in taurine deficient animals. And what happens if you supplement aged animals with taurine. And we measured variety of different organs looked at these hallmarks of aging. As I said in the beginning, they were classified in nine halls. And in a transcriptomic study, what we noted is that citizens and other features of the aging were enriched in taurine deficient mice, which were having an induced or in deficiency. And when you supplement with taurine, these aging features were changing.

Nick Jikomes 1:00:47

I see so so when you guys make mice, taurine deficient, you see things like changes in gene expression, certain genes going up going down, that are associated with with aging and senescence and things and then when you supplement taurine deficient mice with external taurine, those markers go down.

Vijay Yadav 1:01:07

Yeah, those markers change in a positive direction does with some some markers. For example. Autophagy goes down with age, and if you supplement the taurine in organs that we looked into autophagy goes up. Samsung cell accumulation was reduced by taurine supplementation. We looked at mitochondrial dysfunction, which was in meetings, taurine, supplementation made mitochondrial health better. We looked at nutrient sensing, taurine made cells sense, nutrients better. We look at DNA damage, it doesn't surprise DNA damage consequences of DNA damage and reduce the inflammatory state the cells we're into.

Nick Jikomes 1:01:56

And when it comes to like mitochondrial health, no mitochondria are super important organelles for energy and metabolism generally, when you say that mitochondrial health was improved, what exactly does that mean?

Vijay Yadav 1:02:11

So just to give an idea, mitochondria are organelles in our cells that produce ATP. They're also classified as powerhouse of cells. So they produce lots of at the major production of ATP happens in mitochondria. And this ATP generation process leads to generation of reactive oxygen species. Because ATP is generated by oxidative phosphorylation system, there is electron transport chain in mitochondria, that produces ATP by generating the proton gradient. But during this process, some electrons leak and they then they create reactive oxygen is to see this, and they damage different cells, different parts of the cell. So in when the cells are younger, they're able to overcome this oxidative stress, they're able to produce enough antioxidants within the cells to douse this reactive oxygen species. But as we age, this accumulation of the reactive oxygen species increases, because cells are not able to handle it as well as they were when they were younger. And these D reactive oxygen species damage DNA damage, protein damage lipids, and that leads to this what is classified as mitochondrial dysfunction. ATP production is compromised, you have mitochondrial damage, and that compromises the ability of the cells to the the energy requirement of the cell is not met efficiently. And it is damaged and it dies, as a consequence it in mitochondrial dysfunction will lead to certain cells, for example, and that will kill the cell.

Nick Jikomes 1:04:02

So do you think, you know, there's been I've heard, you know, very prominent scientists in the aging field? In the recent past say that basically, they think we can completely stop and reverse aging, once we understand it enough, and that we might actually be relatively close to doing that. Do you think that's possible? Do you think it's you know, if if we just understand enough about the biology of aging, and you know, different lifestyle factors, different nutrition factors, do you think it's, it's possible in principle to completely stop or reverse aging or are we only going to be able to slow it down?

Vijay Yadav 1:04:44

My personal opinion would be that we do not understand the aging process biology of aging well enough at the present time to reverse this process. Because variety of changes are happening with your organs. specific sometimes. Therefore, we need to understand how these aging processes are accumulated in the cells. How are these aging hallmarks changing from one organ to the other. Because set of aging hallmarks, there is a different different level of different aging hallmarks contributing to leveraging versus brain aging versus muscle aging versus gut aging. Therefore, we need to understand our we are a multicellular species we are very complex, we need to understand these cellular phenotypes to be more precise manner. However, having said that anything is possible. We have evolved, we were living 40 years only a maximum life span 120 years ago. Now we are living 7080 years? Well, it is definitely possible that we will live 120 and 40 years and the 50 years down the line. The goal right now, I think the goal is to increase the health span in the foreseeable future. In my view, we can increase the health span or delay the process of aging so that we have less morbid period at the end of our lives. So we not only want to live longer, we want to live healthier and healthier span is the goal of any antiaging intervention.

Nick Jikomes 1:06:35

What else are you working on right now that we haven't talked about in terms of taurine? Or just other things that your lab is working on that maybe even have nothing to do with torium? What are some of the what are some of the areas of biology and the big questions that that you think you might have answers to coming up in the next couple of years.

Vijay Yadav 1:06:53

So we are creating at this present time is a investigation we are divulging into it. As I said, clinical trial is one of the things that we want to do accomplish in next few years. And that is a daunting task in itself. Then we are also looking at the basic biology of aging, how molecules are nutrients such as storing, my lab has also worked on vitamin B 12, in the past, how these nutrient molecules are shaping the function of cells, and how these nutritional requirements change with age by different cell types. So creating a kind of nutritional requirement landscape across human body, because different cells are having different requirements. And when we understand this requirement, we would be able to manipulate the aging process much better than when we don't have at the present time this information is in a very nascent stage is the very beginning of understanding the requirement of cells. So we need to understand what we require. Unless we know what we require, they cannot intervene. And that is what is the

Nick Jikomes 1:08:20

goal at the moment. You know what, um, so like, towards the beginning of the conversation you talked about, you had that really cool story of, of cats. And you know, as cats became more domesticated, we started engineering cat food, which meant we had to have some concept of what we thought cat food needed to have in it. But of course, we didn't know everything. And so there, there were deficiencies in their diet, when they weren't eating the natural whole foods they did in the wild, and they transition to these artificial foods. One of the most interesting things that I learned, you know, in the past year or so of my life is that, you know, when humans, you know, humans, essentially are a self domesticated species, we have domesticated ourselves analogous to the way that we've domesticated cats and dogs and other things. And so you know, when the agricultural revolution happened, and again, I didn't know this until recently from talking to other people on the podcast and reading about it. But basically, my understanding is very quickly when humans became sedentary, and they started sitting in one spot, and farming instead of being hunter gatherers. That had a lot of positive benefits that allowed us to build bigger societies and do things but it also had a lot of negative health benefits right away, people got shorter. They have certain nutrient deficiencies. And it sounds like there's an analogy there with the cat food story that, you know, we started making certain types of foods that were related to the types of grains and other things that we could farm. And we probably stopped eating a lot of other things that our hunter gatherer ancestors were eating, and therefore we became nutrient deficient in ways that we didn't understand. So with that in mind, you know, what are your thoughts in general as an aging scientist on, you know, just just diet and neutral And from from the standpoint of eating, you know, so called Whole or natural foods versus, you know, these days a lot of people take supplements they take, you know, drinks or other things that are supposed to have, quote unquote, all of the nutrition that you need. Is there any risk to focusing too much on supplementation? Given that there's so many question marks, that there's probably still a lot of things out there in our ancestral diet, that we don't even know that that we were getting?

Vijay Yadav 1:10:28

Yes, absolutely no idea. Absolutely right. In that context, we need to look at diet as a whole diet, in my view, because we don't know many things that are deficient in it, we need to supplement for example, many of the molecules which are which we know of which have been proven to go down and and are deficient in our diets, for example, vitamin B 12. And we need to understand these dietary lifestyle changes. And till the time we have a good intervention trial for these anti aging interventions or different dietary interventions, we would have to just have a healthy lifestyle and they will eat healthy and exercise. That is what one can do in the meantime. Right now there are many anti aging interventions are going on trial, such as rapamycin, Metformin, Thrall, and therefore, NAD analogs as the key to growth rate. And we want to put all in on that. So we just have to take this different anti aging interventions do the clinical trials robustly in a placebo controlled manner. Let all the horses run and see which horses perform better for particular function or all of them perform function, we have antiaging basket in front of us five years down the line, which clinicians can or nutritionist can choose from to supplementals to for a better health span. And that is what you need to do, we need to do the controlled clinical trials, and not supplement ourselves because our body needs are, as I said, in the beginning itself. Our dietary patterns, our genetic makeup has evolved together, depending on the environment we migrated to as a human society. We all came out of Africa a long, long time ago, but we changed our our genetics, our dietary patterns to accommodate different environmental needs. And we need to understand the body physiology in different ethnicities better before we know what is the ideal nutritional composition for particular ethnicities are, and that understanding we do not have, we cannot nobody can claim that understanding, because we don't have it. And we don't know how many molecules such as b 12 or taurine are changing with our nutrition. We don't know the entire answer to these questions, and we need to bail, do more research, I think in my view to find out what those things are missing.

Nick Jikomes 1:13:26

Well, BJ, I want to be respectful of your time and let you get back to the lab so you can figure this stuff out. Is there anything you want to reiterate for people or any final thoughts you want to leave people with about your work are about aging and nutrition in general?

Vijay Yadav 1:13:40

I will say that we are working aggressively on that aging field, we are coming up with the different anti aging interventions. And I think one should wait for the clinical trials to be accomplished, the full self supplementing themselves, because most of these molecules are present over the counter. And we need to have a better understanding in clinical trials before we do the supplementation. And there's a very bright future. We have a lot of molecules going on clinical trial end of this year or early next year. And within four or five years, we'll have a better understanding of the aging biology and these interventions. Till then eat healthy and do exercise.

Nick Jikomes 1:14:30

All right, Professor Vijay Yadav, thank you for your time.

Vijay Yadav 1:14:34

Thank you very much. It was a pleasure speaking with you.

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