How does the food you eat contribute to your health? Do supplements help prevent disease? For the past 25 years, the Linus Pauling Institute has served as a world-renowned research center at Oregon State University. Our mission is to promote optimal health through cutting-edge nutrition research and trusted public outreach. We use a synergistic strategy, connecting several scientific fields to bring a better understanding to dietary components and the role that they play in obtaining optimal health. We provide that information to the world, allowing people everywhere to live longer, better lives. Welcome to the Linus Pauling Institute's webinar series. But hello and welcome to the Linus Pauling Institute webinar series. This is our next webinar in our 21st anniversary series. And this is keeping life in your years, dietary factors affecting health span and longevity with our own Dr. Tori Hagen. Before I get into details of the talk, there's a little brief introduction, but my name is Emily, Emily Ho, and I'm the director of the Linus Pauling Institute. The Institute is a research center at Oregon State University in Corvallis. And our mission is to promote optimal health through our cutting-edge research and trusted outreach programs. The large part of the work that we do is looking at the foods that you eat, the supplements that you take and help determine how they can help you live longer and better lives. For anyone who's new to us, the presentation today will give you an excellent overview of our research, especially our research in healthy aging that have long been a cornerstone of our research programs. As I mentioned earlier, 2021 marks 25 years of the Linus Pauling Institute coming to Oregon State University. This is our fourth webinar in our special 25th anniversary series. If you've missed any of the first three, they are all on YouTube and we'll provide links at a later time on this page so you can view them. Some of the other webinar topics included vitamin C in health, vitamin D in immune function, and the basics of brain aging. Today's webinar expands on the topic of healthy aging. We'll have an introduction to the concept of health span and what the science tells us about the path towards aging. As all of us are heading down those paths, this presentation is really important information for everyone. And many of you agree there are over a thousand people registered for today's presentation. So that's enough for me. I'll now hand off the reins to Dr. Alexander Michaels who will be our moderator for today's event. Thanks, Emily. As Emily said, my name is Alexander Michaels. For those who don't know me, I am a researcher and communications officer and for the Linus Pauling Institute. As with the other installments of this webinar series, I will serve as the moderator for today's event. As part of those duties, I wanna run down how this webinar is gonna work for everybody today. We're gonna keep this webinar to about an hour. We're gonna try to finish around noon Pacific time. And then we'll start with the presentation from Dr. Hagen as I'll get to shortly. And then as Emily mentioned, this presentation is gonna outline the basics of health span and aging. When the presentation ends, the remaining time that we have will be dedicated to a Q&A session. So speaking of that Q&A, if you look below me, there's a Q&A button. I'm kind of pointing to it on my screen. If at any point you have a question for the speaker, go ahead and pop it into that Q&A button down below. Now, I'll tell you, we have a little ground rules for the Q&A session. We're going to do our best to get to every question, but we know we won't be able to get to every single one of them. We've had some questions submitted during registration and I'm sure you guys will have some questions during the talk. We're going to be focusing on questions relevant to today's talk, so healthy aging and some of the topics that Tori, what we're speaking about. But I also should caution that the last point is who's not a medical institution. So we can't give medical advice. So if you have questions on a specific medical condition that you have or specific say supplements for a specific disease, we can't really comment on that. We give very generic, general information on supplements and specific, what the science says about these interactions. So as long as everyone's okay with that, we'll go ahead and get started. So it's my pleasure today to introduce Dr. Hagen. Dr. Hagen, would you mind turning on your camera? Welcome. Hello, everyone. Dr. Hagen is a principal investigator in Alliance Pauling Institute and he's a professor of biochemistry and biophysics to the biochemistry and biophysics department at Oregon State University. Before coming to OSU, Dr. Hagen completed his PhD in biochemistry at the University of Emory. Afterwards, he became a postdoctoral research fellow at the University of California, Berkeley, where he worked for Dr. Bruce Aims. And if you don't know who Dr. Bruce Aims is, you're missing out, really, because he's a leading researcher and a really amazing guy to talk to, very animated guy. And he was the first awardee of the Alliance Pauling Institute prize for health research. And besides Tori, Dr. Aims has trained several or a couple of the investigators of the Institute, including our current director, Dr. Emily Ho, and our former director, Dr. Baltz Frey. Now, getting back to Tori, Tori's been the lead researcher in the Institute's Healthy Aging Program since their inception here at the Institute. And he was one of the first principle investigators to the Alliance Pauling Institute after it made its move to Oregon.  As you will hear about just a minute, Tori's research program focuses on the understanding of the impact of mitochondria in the aging process, but his interest and knowledge on the topic of healthy aging are far reaching, making him an excellent speaker for today's talk. I've known Tori for my entire career at Alliance Pauling Institute because I mean, it was only about a year and a half after he came to Oregon State University that I came as a graduate student and came knocking on his door in 1999, asking to become a graduate student. And shortly afterwards, Tori became my PhD mentor and the rest is a topic for another webinar. So, leaving it with that, I'm gonna let Tori take it away. It could fill volumes, Alex, as to what I could actually tell the audience about you. No, it was a great pleasure of being a mentor to Alex. And so because we have very limited time, let me get my slides up and let's get going here, okay? So, first of all, thank you very kindly for that introduction, as well as this opportunity to come together today and talk to you all about an issue in an area that's near and dear to my research heart and that is factors affecting health span and longevity and perhaps how diet can strongly influence our overall health even into advanced age. As an outline for today's talk, I think what we should start with is some definitions of what biological aging is and then introduce a concept of what health span is and give definitions of that. And then move toward factors that affect healthy aging, which we can modify. And one of the biggest modifiers that I know of is how diet can play a positive role in our overall health, especially in older adults. We're gonna look at possibly effects of food quantity versus food quality, and then if time permits will touch on newer bioactive compounds that are being researched that may be able to improve and maintain health insurance for as long as possible in our lives. So to begin, we're interested in my laboratory under the underlying mechanisms of advanced aging, how younger adults are basically turned over time and at a rate of time dependent on the species into an older animal, in this case, an older human. We want to understand those underlying biological factors that influence this overall process. Now, our work on the biological aspects of aging is kind of separate from other fields of research such as psychosocial work on aging, which have very different kinds of definitions and outcomes than we have. To distinguish biological aging, our field tends to call it senescence. And the definition of senescence is illustrated on the screen right here. It is a natural process of our metabolism, which obviously is comprised of information directed from genes. So it's a normal part of our biology. Aging is a progressive and irreversible process. It starts early on in adult life and progresses from there. And unfortunately, there is no going back in biological senescence. So there's a rate of aging dependent on the species and that rate of aging is considered to be a senescence rate of aging because senescence in its very endpoint is a rather deleterious process. No one single aspect is deleterious, but an aggregate it is. And ultimately, aging increases the risk of pathologies, morbidities, and a failure to thrive, ultimately leading to the death of the individual and obviously at a rate of aging, the death of a cohort of a species which sets the longevity or the lifespan of a species. How important is biological senescence in our overall rate or trajectory of long life? It is really impressively important, especially after adulthood. If we took a magic wand and magically stopped senescence where mortality could only be from pressures of survival from outside our body, such as disease or accidents or temperature extremes or famine and the like, and we looked at a cohort of individuals over time, we would see a survival curve akin to what I'm showing you here on this slide where you would start out at a certain level, practically everyone surviving immediately, but then there would be a rate of loss of life of that cohort or that group of individuals being examined all the way until the end where there is no one left in that cohort. If we looked at that and actually looked at the longevity of this group, we would find that greater than 95% of us would reach 100 years of age and 50% of us or the mean or average lifespan, would be around 1,200 years of age. So I don't think that any of us in our own lives have actually been around someone that old and that does tell you then that the pressures from within our own biological makeup really are the means by which drives overall longevity, especially in advanced cultures or the developed world. What we actually see in terms of survival curves here, let's say in the developed world is something more like this, where again, young adults, there are very limited number of loss of life in young adulthood, again from pressures normally from outside the body, where 12 to 15 year olds in this country have won in 2,000 chance of dying at any given time. But after about what we're considering middle age around the mid 30s, you start seeing more and more loss of life and that is at a consistent rate, all the way down until there's an asymptote and finally the end of life of a given group. This is sets our mean lifespan or average lifespan, which is what we normally talk about in everyday circumstances. And in America, that is right now at about 79 years of age on 2021 estimates. This also sets the maximum lifespan of a species. Basically it's the time when the last member of a group survives and our maximum lifespan right now is 122 years and five months, which was set by a lovely lady named Jean Calment, who died in the 1990s at this very, very advanced age. So this is what we normally see and you can see then as we go further that what is happening here is this rate of aging where then at the end of life, let's say 100 years of age, you have a one in two chance of dying. The pressures of survival, especially after middle age are becoming more and more related to your biological or senescence aspects of metabolism versus those pressures from without, which are kind of set more earlier in life at a rate of mortality. So what happens then is that the physiological function correlates with that rate of senescence. On this graphic I'm showing you are changes in various physiological aspects of life. And as you can see here, there are two things to take away from this slide. It one is that your physiology just doesn't deteriorate at one moment or on a given set of anatomical and physiological functions, they don't deteriorate at a given rate either but rather different rates depending on what you're talking about in terms of your physiology. Mostly though, you don't see changes in physiological function until around middle age. That's the other aspect to take away from this. And then you see a progressive decline in overall physiological function in regardless of what your type of physiology you're talking about. For instance, cardiac reserve declines right about middle age and at a rate thereafter. So does lung capacity. That's why you don't normally see elite athletes after let's say middle age at the top of their game anyway because of the changes in the physiological pressures that are occurring because of senescence. But you see other aspects of your physiology kind of declining relatively early such as eyesight accommodation can occur even in your 20s or before and as well as kidney function and blood flow there can start at a small change as even early in life. And so aging and senescence is not a one size fits all. You don't wake up one moment and are old. It is a progressive change and it's a change in aggregate that ultimately leads to a failure to thrive. Now, none of these changes that I'm showing you here on this graph actually do lead to those pressures of survival. But we're looking at here in the normal physiology of a given species is a change or a decrement that sets up risks for disease. And that's really what is driving the loss of life and the loss of health into advanced age. And that is seen more on this slide right here where this is a kind of look at the prevalence of many chronic diseases, chronic diseases of aging with broken down into age groups. And as you can see on the early part of this graph near the origin, there is not a lot of chronic diseases in prevalence. You know, you can see some but not very much. But really again, right when those physiological deterioration starts becoming an aggregate, you start seeing a rise in the incidence of chronic disease is almost across the board such as that cancers, which is this green line, increase with the fourth power of age. Heart disease and arthritis, which is kind of a disuse syndrome for pain also increases rather dramatically right around your thirties and all like that. So this tells you something. All of this says that age itself is the leading risk factor for many of the prevalent chronic diseases that have flipped our society today. Only asthma does not have an aging component. And so in other words, the physiological changes brought about by the senescence process is also the driver of diseases that occur in advanced middle age and later on in life, which ultimately leads to a failure to thrive. This also tells you something else. If you take those two figures in aggregate, it says that our lifespan, which we showed was about 79 years of age, is not keeping pace with health or our health span. Health span is defined as the time of one's life spent free from disease and disuse. And what we mean by disuse is syndromes of pain like I showed you about arthritis or mobility issues, frailty and the like. So health span is not the same as lifespan. And what we're seeing here in the United States is actually been codified by the World Health Organization in their Healthy Average Life Expectancy Scale, where again, our lifespan on average is around 79 years of age, but our health span in America is clocked in only at 64 years of age, which means this is when we are starting to see diseases and maybe multiple diseases prevalent in a person. So if we take these two numbers together, we basically are showing that 20% of our lives are lived with some form of disease or inability to carry out daily activities of living that we would normally do in a younger lifetime. This is telling us a big, big thing. This tells us that health span and lifespan don't meet up and that we are, our last years of life are not necessarily healthy years where we can really do what we want. So at the Lions Pauling Institute, we're asking a question. Is there a way to bridge the gap between lifespan and health span? In fact, this is what drives many of the researchers here in this institute and what we can do about this big gap. Can we actually compress morbidities where then health and life more or less match up and a long period of life too? So what we have identified though, there are five factors that really strongly influence health span in America today. And fortunately, and we're gonna look at this later, these are modifiable factors as opposed to other senescence factors that we may not be able to modify as much. These five factors I list right here, one is a sedentary lifestyle which leads to enhanced frailty and disuse syndromes. It can also perhaps drive other of these risk factors like obesity and diabetes. Hypertension is another one. Hypertension is known as a silent killer. It's a real risk factor for stroke but also is known to increase the chances for kidney failure as well as other cardiovascular diseases. We talked about obesity already in terms of sedentary lifestyle but a gain of weight or a weight above a body mass index of 25 leads to increased risk for the so-called metabolic syndromes of insulin resistance, changes in inflammation and chronic inflammation which also leads to cardiovascular diseases.  So obesity is a really driver of those chronic age related diseases that we talked about earlier. Diabetes is another one we all know about that. It's a real risk factor for cardiovascular diseases, for neurocognitive dysfunction as well as polyneuropathies and pain. And finally, smoking is a huge factor, major risk factor for the loss of health, especially later in life. And we're certainly advocating no smoking if you can possibly avoid it. Don't start and definitely stop if you are smoking because smoking is a huge risk factor for cancers, cardiovascular diseases and the like.  How important are these risk factors? Well, I think it is very well illustrated in this slide right here. This was a research done by Yates et al. And they were asking a question of those folks, let's say 70 year old men, which is near the mean lifespan of the United States population. What is the probability of those 70 year olds to survive well into advanced old age with any one or more of these risk factors? In other words, do you have the probability to live an additional 20 years if you had any of these risk factors that we went over? Well, they looked at epidemiological evidence and longitudinal data and showed that if you had none of those risk factors at the age of 70, you had a remarkably good chance for living 20 additional years and living well, to be very honest with you. However, if you had any one of those risk factors, your probability of living another 20 years was virtually cut in half. And if you had more than one, as it's shown down here on this scale, portion of this scale, you had an increasingly less likelihood of surviving an additional 20 years. That really tells you that those risk factors that we just went over are extraordinarily powerful about limiting health and frankly then, limiting life because of them. The good news is that all of those factors at least are modifiable. They can be modified in what we're calling also the three legged stool of longevity and health. And that is one around your own personal genetic makeup, an epigenetic makeup, where again, folks that are from long-lived families tend to have a 15 to 25% longevity quotient, which seems to be a means by which you can resist the development of those chronic diseases and may even have some resistance even if you are involved with those risk factors that we had. But that is a very small, small dividend. So your genetics are not your destiny. In fact, the bigger effects that you can modify those risk factors come from lifestyle choices. So our friends in the cycle social fields of aging tell us that if we have a good social network as we get older or a belief system, we tend to live longer and healthier. We also know more on a physiological basis. Again, if you're a couch potato, that's not a good thing. That's one of those risk factors. So that means if you were to be exercising and active, that would be very helpful, and that's a lifestyle choice. Dr. Magnuson went over in her seminar a few weeks ago that if you exercise your brain by keeping fit and changing up your overall kind of processes and learning, you will do better as you get older and that will improve your health. The thing that I want to dwell on today though is that diet is a major means of modifying those big five risk factors and a major means of improving both health span and possibly even lifespan. That's something that is still being looked at here. So healthy eating matters and it is by far the biggest means by which we can modify risk for health, especially in old age. How important is diet in terms of healthy aging? Well, I think it can be well illustrated by talking just briefly about a paradigm of diet called dietary restriction. Dietary restriction is a means by which you basically restrict the amount of caloric intake while still maintaining all of the vitamins, minerals and micronutrients that are necessary for normal metabolism. This has been done since the 1930s on experimental animal models of aging, such as yeast, drosophila, mice, and now even primates where if you restrict the amount of calories, you actually change the survival curves of a given group of those species. So if we're looking at let's say mice here on this curve, the survival curve, this is the ad libitum curve. These mice could eat anything they wanted and on average this red dashed line tells you that they lived about 30 months of age and their maximum lifespan was about three years. This is what we know and we can have in mice in a vivarium in an institute like the Linus Pauling Institute that is very pristinely maintained. So what happens though if we restrict the calories in mouse cohorts? Well, we find that with a 25% dietary restriction, look at this, these mice on average live longer and if we restrict even further, like the 55% or 65%, you get a huge dividend in the average lifespan. You've almost doubled it all the way at the 50 months of age and look at this, with any type of dietary restriction, you've also changed the maximum lifespan of those groups. That tells us that you have actually modified the rate of aging. This is the only known paradigm and so diet can modify the rate of aging in this type of experimental plan. Does that mean that these mice are living longer but not well? Well, I think a picture is worth a thousand words. Here is a dietary restricted old mouse on the left-hand side. Here is an ad libitum fed old mouse, meaning that they're the same age. One is just dietary restricted versus the other. You can actually see a huge difference, can't you? The one that was fed whatever the animal wanted, he is really moribund, doesn't move around a lot, very likely has cancer and the like, probably has learning and memory impairments and various factors of aging. Whereas the dietary restricted mouse has a very youthful appearance, is very active and very limited levels of chronic diseases. So health span is directly modified too to the positive, meaning that caloric restriction improves health and it improves lifespan. So that is the power, that's the gold standard power of diet in terms of longevity and healthy aging. Now, can we do this type of paradigm? It would be very, very difficult for humans to restrict their calories to the extent that we can do this in an experimental conditions like here at the LPI. However, we can kind of take this as an issue and use this to say what can we do in our own lives to maybe get some of the good as we're seeing here in this experimental feeding paradigm. And the easiest one and the one that I'd like to leave with as a first kind of means by which our recommendations are coming from our group is that avoid overeating. You may not be able to live that spartan existence of cutting down your calories to the extent that we can in a vivarium to a living cohort but you can't avoid overeating and you can't avoid overeating, which is again hard to do, but you can really work on that. So avoid energy dense foods or highly processed foods and foods with refined sugars and all because overeating is a major risk factor for obesity, which also leads to diabetes and hypertension and actually may even contribute to the sedentary lifestyle. We've talked about this already to some degree. I'll just mention again, obesity because of overeating can catalyze a number of health associated problems that we're working on here at the Linus Pauling Institute, I'll tell you, but just to kind of name a few again, cognitive decline, fatty liver disease with Dr. Jump is working on this, brittle bones, especially for osteoporosis and chronic inflammation too. So overeating leads to a lot of problems in other words and we can't avoid that. What about other aspects of it? Here is one that you may not have thought about but it is really, really important. As you get older, you tend to dehydrate. Young adults are comprised about 75% of water whereas older adults are only about 50% of composed of water. So we tend to dehydrate with age, which can lead to dizziness, falls, hip fractures and the like, it's associated with cardiovascular events and even loss of cognitive function. So the lack of water is kind of a real risk factor that most people don't really think about but really can matter in terms of your overall health. We're advocating drink plenty of water. You can also eat, again, non-processed foods which has a higher water content as well as fruit juices if you don't like plain water or coffee and tea. But please don't drink sugar added drinks or sports drinks especially in older adults because they don't add very much food value and they really, really don't possibly even help you in terms of hydration that much. What we're recommending is exactly what the National Institutes on Aging recommends and that is for women over 50 years of age, drink about three quarts of water a day which equates to about nine cups of water and the rest from food. Whereas men need a little bit more water so we're advocating four quarts of water a day which equates to about 13 cups of water versus the rest from food. And I think that you'll see an improvement in your overall life just by doing that if you're one of the many that just don't get enough water in their diet already. So don't overeat and maybe replace some of those dense calories from processed foods with more liquid nourishment. The other thing is, is watch out for food quality. The food quality really matters. The USDA has actually created a so-called healthy eating index where they are advocating that we get a variety of very colorful foods that are non-processed and we agree with this. So some of these foods include fruits, vegetables, beans, polyunsaturated from nuts as well as protein but the protein not from dense meats that have a high amount of saturated fats but rather from seafood and plants and also dairy. So it's not the quantity of food, it's the types of food and the quality and so we're advocating a rich variety of foods in your diet and that would be a quality diet. We're also advocating not taking in so much saturated fats, refined sugars or salts in the life. The USDA has created an actual index as I mentioned that kind of equates the types of food you're getting and they've created a score. So an adequacy score is if you get a variety of foods and a moderation score if you limit these foods, the processed foods that we talked about. You can go to the USDA website and look at how they create this score but just because of timing I'll just give you kind of like an overview of it. A healthy eating index score of greater than 80 is considered very good diet, very good quality diet. A 50 to 79 score is considered with some deficiencies. Americans are right now on average are about 60 so we definitely have some deficiencies as well as a poor quality diet has let a score of less than 50. Does this matter? I think it does because if you look at large longitudinal surveys where people are followed over time over years and looking at overall health and diet assessments, this is like the National Health and Nutrition Examination Surveys, those with a high healthy eating index meaning a high quality, high variety of those foods we talked about had fewer cardiovascular events, cancers and diabetes than those with a very poor healthy eating index. Unfortunately that's only about 17% of the total of the people in these large, large surveys. Not very good but it also tells us that we definitely have room for improvement and we can improve things. What happens if we parse out from these surveys just for older adults meaning at least 65 years of age and if you follow their overall health and diet over let's say a 13 year period or more and quantify the disease risk and mortality what would a healthy or a high healthy eating index versus a poor index afford you? Well it's listed down here. The benefits of a high quality diet causes you to have a 37% decrease in overall mortality incidents after the age of 65 so that's quite good and that mortality, lower mortality correlates again with lower incidences of those chronic diseases that we talked about earlier. So the quality of diet as well as perhaps maybe limiting the overall calories in the diet are a prescription for really moving the needle in terms of health span more toward matching up with lifespan. Another thing about quality foods is that they supply all the vitamins and minerals and the micronutrients that you may need and these are very important as you know for general metabolism cause a lot of the B vitamins are involved in energy metabolism. They provide antioxidants like vitamin E as well as blood clotting like vitamin K and immune response such as vitamin D. But unfortunately we're simply not in this country getting an adequate amount of vitamins and minerals in our diet even with those that are eating a relatively good diet. And that's shown over here again by the NHANES survey where you see this is the percent of the population not meeting the estimated average requirement for these vitamins and minerals. And if you see here, there are huge swaths of our society, our population that are not getting many of the vitamins and many of the minerals that you actually require for proper metabolism. We don't even know how this is working for older adults. It's not really that well defined yet. In fact, we are looking at the Linus Pauling Institute right now, we're doing clinical trials to see whether older adults need more vitamins than their diet just to meet the normal that they need for the dietary intakes. There's just really not that much studies been done on older adults. And so hopefully we can report that back to you in the near future. But right now, what this tells you is, is that if you're not getting an adequate quality diet, you may want to supplement your diet with a vitamin and mineral tablet. It would be kind of like an insurance policy. Again, we're not advocating getting all of your vitamins and minerals from a pill. We'd rather have you be eating a very rich quality food but if you feel like you're not having an adequate diet or for whatever reason it's just not going to happen, just create an insurance policy by taking a vitamin supplement. I think you'll be happy that you did. So in this respect, let's pause and have kind of like a interim summary here. We're advocating to take control of your health by healthy eating. The easiest way to phrase this is keep it fresh by mixing up the foods. Eat a variety of fruits and vegetables, meats, beans, dairies, grains and the like. Drink plenty of fluids. That's again, going to be very helpful as you go forward in life. Don't overeat and then again, make sure you are daily intake of key vitamins and minerals are age appropriate. Hopefully from your diet but if not from a vitamin supplement. So in the remaining few minutes that I have with you, I'd like to touch on the next generation of let's say bioactive compounds that we are looking at not only at this institute but across the field of aging research that may come into play to augment a normal macro diet that we've been talking about. And these would be supplements or compounds that could be affecting health and life if you're giving them in an adequate high amount. In fact, we're calling them gerosuetical compounds to improve health span and right now, there are about 2000 of these compounds under study throughout the research world. I kind of lump them together that affect various aspects of longevity assurance system in biochemistry. There are natural compounds but given at very high level. So they're taken out of let's say a normal food stuff and then provided let's say as a supplement or almost as a pharmaceutical compound but they're usually from natural foods. So these would be things like resveratrol which is again found in red wine which are involved in stress response and perhaps DNA repair. Vicetin and quercetin are polyphenols from grapes and apples that are limit cell senescence that it looks like in the laboratory. They may be also be functioning in terms of improved immune response as does green tea and the like. There are other categories of these gerosueticals. They may be chemicals that may have become limiting in the cell as you get older maybe because they're no longer synthesized in the cell to the extent that is needed. This is something that I'm looking at in my laboratory and we're using compounds like lipoic acid which is involved in biological energy transduction as well as stress response. Carnitine which is a means by which you convert fatty acids into useful energy. Anacetylcysteine which again improves the resistance to cells senescence as does nicotinamide riboside which is again really important it seems like that declines with age. Just to move on, there are pharmaceuticals that are now becoming repurposed. They were used for other reasons and have been approved for other reasons such as rapamycin as an antifungus agent is now looked at as maybe perhaps longevity assurance compound as is metformin which is now used for type two diabetics but it is now being looked at as an anti-aging and I hate to use that term. I use it very loosely but as a means of lowering risk factors for health. Let's put it that way.  There is yet another area of research called next-gen pharmaceuticals that will target drugs to a specific organelle within the cell or a specific cell type in the body to effectuate its function in a very positive way. And I'd like to leave you with this because this is some work that is being undertaken by me and my colleagues here at the Linus Pauling Institute. We are looking at mitochondrial dysfunction with age. Mitochondria is one of the major nexies of aging we think in the cell. It's the Achilles heel of the cell for many ways mainly because it's known as the cell's power plant. It's providing energy for cellular function and we certainly know that mitochondrial decay as we call it affects the cell in many way in the body such as not only bioenergetic decline but redox active stresses, inflam aging as we're calling it or inflammation, cell senescence and even stem cell decline. We have created a compound again with my colleagues Dr. Beckman and Dr. Magnuson. We have taken a compound that is natural in the body, glutathione, which declines precipitously with age and we have modified that compound with another portion of this molecule which targets glutathione, this very, very strong detoxicant, to the site where its decline is most prominent, meaning the mitochondria. And we are looking at whether this will improve resistance to certain diseases of aging. For this, we're using a mouse system called the 5XFAD mice which in all intents and purposes creates a conditions in these poor mice similar to Alzheimer's disease in humans in that the mouse brain develops plaques, synaptic degeneration and even dementia. And we're seeing whether this compound that we're calling mito G can help improve resistance to dementias. I'll show you very quickly what we're seeing here. So this is an electron micrograph of a mouse brain where these little lozenges here and with the M are mitochondria. These SVs are synaptic vesicles just to orient you that we're looking at the nerves in the mouse brain and in an area called the hippocampus which is the memory center of the brain. So the mitochondria look very normal, very small, discreet, dense little organelles that are churning out energy for brain function in a normal mouse. However, in a 5XFAD mouse at the same age, look at the mitochondria here. They're swollen, they're distended and enlarged, they're broken here, they're certainly not functioning the way they should be. And that leads again to a loss of neuronal function, definitely. However, mito G treatment completely reverses this change where the mitochondria are normal and we're now following this to see whether or not this actually wards off the dementias syndrome later in these mice lives. So we're very, very high on these prospects and this should give you an example of the next generation of compounds that researchers are now starting to field and try to use in order to stave off health related issues and perhaps improve longevity as well. So I'll leave you with in this last interim report that geropharmaceuticals are coming into play. They're rapidly advancing through animal studies and into clinical work. And the targets for these geropharmaceuticals are the cells power plant, the mitochondrial work as well as work on certain genes and effects on epigenetic and immune function. So stay tuned, we're working as fast as possible on this next generation of compounds and it's sort of very, very exciting work for us all in this field. But it looks like my time is up with you. I want to have some time where we can ask and have questions answered as well. And so I'd like to now thank you for your time and again, your support of both my research as well as the Linus Pauling Institute as a whole. Okay, well, thanks Tori for that presentation. That was great. Every time I hear you talk, I learn something new. I really liked the part about hydration and that actually stimulated a lot of questions. And as a clinical research coordinator for the Linus Pauling Institute, I definitely know that hydration can be an issue, especially when we're trying to get blood. And older folks, actually after giving that talk, I need some hydration myself. Got some while you were talking. But it really is a kind of a unrecognized factor that really could change your health trajectory. So I'm pretty high on that myself. And that's a very simple thing to do. Yeah, yeah, absolutely. So I know you gave mostly, it was a broad overview of everything and you don't really get to go into too much detail. So I'm gonna try.  I just wanted to make sure the audience knew that. I know many people want to have specifics, but for a talk like this, a general talk like this, I wanted to stay more related to the human condition and more related to the broader and larger pictures of healthy aging and what we know. We can get into specific supplements and the like, but it becomes a little bit nebulous because I'll be very honest with you, despite the large amount of literature out there, meaning webinars and the like, there's not a lot of vetting in terms of long-term effects of many of these compounds, nor do we really know the concentrations, the optimal concentrations, especially for the human condition. In other words, we don't know how things translate from the laboratory more on a short-term basis or an animal that doesn't live that long to the human condition. But with that being said, I do know that that's a very interesting and a very important topic that people wanna know about. Yep, yep. Yeah, so I'm gonna kinda preface some of my questions that I'm gonna ask you with. Unfortunately, I can't ask all of the very specific questions about amounts and types of supplements that you'd recommend because the recommendations, we just don't make these kind of recommendations. So we have some recommendations for older adults and I think we'll have the link available, but these contain a lot of options, not necessarily specific amounts. And as Dr. Hagen just said, the research isn't there on what's the right amount to take on some of these supplements. So anyway, so I guess we'll just get right into it. I think the first one I was gonna ask you, we actually got a lot of questions. Oh, well actually, before I start, we got a lot of questions about vitamin C, brain aging, a couple on vitamin D. I think for those, I'm going to refer the audience to the webinars that we did have earlier. There's a specific one on vitamin C, on vitamin D, and on brain health, which Dr. Magnuson talked about. So specifically, I think go to those webinars first because you'll get a lot of your questions answered. I agree and I kind of avoid it in my short time with you all because I knew that many of that had been covered on those very important vitamins as well as brain aging research that Dr. Magnuson talked about. But I'm a fan of vitamin C and vitamin D, that's all I'm gonna say. And Tori, I'd love to have you back for another webinar where we can talk about more of these specifics because I think you stimulated a lot of questions about just specific areas of research, in particular the FAD mouse, just alone stimulated a few questions. And that's a really hard one to describe in a short period of time. So- We're in the cap here, yeah. Yeah, yeah, so just bear with us. I'm sorry, this is a broad overview for everyone, but we're gonna try to get to a few questions and then we'll hopefully bring Tori back for another talk later on about something very specific. We did get quite a few questions about telomeres. And I know you didn't really talk about it in your talk. So if you wanted to touch on telomeres a little bit and tell people what telomeres are and why they're important to aging, to begin with. Telomeres are the ends of chromosomes that it's almost been described as kind of like a biological clock because once the cell divides, telomeres tend to shorten over time. And once it reaches a certain length, you get instability in the chromosome, which basically tells, let's say, that stem cell and all to shut off. So it has been described as an aspect of aging and it certainly is. So telomere function is very important. It's very important though. It's very controversial in some aspects. You may not get that from, let's say from the web, the worldwide web, but it's controversial only in that certain cells seem to be more affected by telomere loss versus other cells. And in fact, some cells of your body, even in humans, actually increase with time. So it's very cell-specific and I didn't touch on that because of that kind of lack of generality, but it is a considered aspect of aging and we're very cognizant about that, yeah. Okay, I have to ask one of these questions just because this is near to my previous research and the research we've done together. Alpha lipoic acid, what would you like to say about alpha lipoic acid in the recent research? Is there much we can say that's new on the anti-aging side of things or I know we've done a recent study on weight loss. So it's kind of... So lipoic acid is, again, you're right. It's near and dear to my heart. I've worked on it for a long time. Again, I was trying not to make this talk very centered only on my research, but more broad. But lipoic acid is one of those, shall we say, I call it a hormatic agent and that is a real area of research and senescence that is being looked at in general. Meaning that a small amount of a compound causes a mild stress to the body but then induces an endogenous response that is beneficial. And lipoic acid, I think it's very safe because I can say all the way from animal and cell work all the way up to humans, lipoic acid seems to be safe but it also seems to be triggering a positive response in the body in terms of a stress response. And so what I'm seeing here is that lipoic acid seems to reverse some of the age-related changes and I use the word reverse kind of loosely. It seems to rejuvenate cells in terms of ability to withstand stresses, certain stresses. And the newest work on lipoic acid is it seems to modify not only polyneuropathies of diabetes which the FDA is now looking at even in this country for using lipoic acid as a medicine. It is a prescribed medicine for polyneuropathy in Europe already but now the FDA is looking at it here in the United States. But it is now also being examined how it seems to modulate pain. So it is a broad-based compound like many compounds that may say to the cell this is a mild stress in the beginning but it triggers a positive response. And so that's part of the categories that I think are being looked at as some of these gerusutical compounds that we just talked about that can be very beneficial. In other words, antioxidants are not that well now received in terms of rejuvenating the body or maintaining the health of the body. Only in that it looks like one outside maybe just a few like vitamin C which is a very powerful antioxidant but they don't literally build up enough to really do anything in the older body or they're thrown out very rapidly. So these compounds like lipoic acid don't stay around long but triggering the endogenous cellular response seems to have a longer lasting effect. We have a question in the chat actually or in the Q and A session about NRF2. So I know that's one of the longer or the wave that lipoic acid can stimulate is an NRF2 response. So NRF2 is a transcription factor so it's regulating a cadre of genes. In this case, it's the cadre of genes related to stress resistance as well as a concept that's very important in aging it's called proteostasis. So it maintains the protein quality in the cell the enzymes and the like in a functional state and a non-aggregated state which is happening especially in certain diseases like Alzheimer's disease and the like. So NRF2, if you can trigger NRF2 for instance you seem to be able to improve that ability to respond and resist other stresses. And perhaps, and this is at least in the laboratory perhaps lower the risk for overt disease. Now, okay, I'm gonna switch topics a little bit because we're gonna try to get to as many as we can but you mentioned kind of even though you can try to eat healthy and I use that word kind of loosely we may not meet our micronutrient needs. And so one question that we did get and is why not if you eat the healthiest foods you can why wouldn't you be able to meet those needs? Well, that's an excellent question and what we're coming to is learning about what is the required intake for allowing let's say a vitamin to act as a vitamin? A vital compound necessary for its role and function in metabolism. But we're also defining like maybe you heard with vitamin D that there are additional roles that many of these vitamins, micronutrients and minerals play that are also very important for optimal health. Again, vitamin D may also be involved in immune function if you heard Dr. Gombartz talking the like. Outside of its role in calcium metabolism and all which is vital. So first of all, we don't necessarily know the actual optimal intake. What striking is, is that slide I showed you that despite that knowledge we're not even getting the required amounts. And it says then that our diets in the Western world even if you're eating a high quality food you may just barely meet it or maybe not meet it based on overall dietary intake overall quality. And it's kind of frightening to me that people that are really doing as good a job as they know how to do of eating a high quality diet are not necessarily meeting that required or certainly the optimum doses for these compounds. We certainly don't know what is an optimum dose. Most of the work done on vitamins and micronutrients in general are following the standard pharmaceutical line between 18 and 48. That is the age group that people are mostly looked at. We don't know whether there are even changes that need to happen in an older person. Let's say above 50 looks like it does especially for compounds like vitamin B12 because of the changes in your pH environment of your GI tract that are not allowing absorption. We don't know whether there is more of a need for certain vitamins and micronutrients because of the changes in metabolism that are occurring with age. And quite frankly, we're trying to address some of this. So we know about vitamins. We've known about vitamins since the 1930s and the like or many of them but we don't have a lot of research related to the right amount at the right time of life. And this is a major push by the Linus Pauling Institute to rectify this real gap in knowledge. We're actually doing clinical work on it right now. Alex, you're the research coordinator on this and we wanna know for instance what could should be taken and how effective is it is even in a vitamin supplement for absorption. And this is again getting back to your original question about maybe why we're not meeting those needs. We don't even know about absorption characteristics of our own bodies after a certain age. So all these things go into a lack of knowledge but that lack of knowledge is really kind of detrimental for understanding this basic aspect of our health. Yeah. And I mean, as you and I both know but to reiterate for the audience it's not just absorption too. It's absorption, utilization, elimination and they all go into that balance that you're trying to get to. First and point is NAD. A lot of people are very interested on supplementing let's say with nicotinamide riboside and the like. Well, it is very clear that in animal models of aging and humans as well, as you age, NAD levels go way down. So it is a fact of aging across the board. We know that a supplement niacin is a B vitamin and we know that you can take precursors for NAD and you can reverse some of the levels or the changes that are occurring over time. So this is an active field. We know we can do this. Is this gonna help health span? The work on animal models are saying possibly yes. I always have a problem, oh, I'm off the screen. I always have a problem of saying that definitively for humans because of a concept in aging called antagonistic pleotropy. Meaning that simply because of a molecule goes down in our bodies. We can't necessarily say by supplementing it we have done a good job or we've done something great to improve our health. We may have, but there may be also a physiological reason why that compound is declining. And so therefore you may be actually antagonizing the benefit by rejuvenating it. This is a concept in aging. So in other words, you may not be doing as well without this metabolite, but you may be stating off an even worse problem with this. Again, a case in point would be growth hormone. People talk about that, but we're certainly not advocating supplementing yourself with growth hormone after a certain age. Yeah, so we definitely have comments on potassium being a major, shortfall nutrient, magnesium. And we don't know always if supplementation is the answer for everything or if it's dietary changes or it really gets hard to make recommendations on, especially for specific nutrients. Right, that's it. We can do things in a laboratory, but if you're talking about aging and you're talking about health span, we have to do longitudinal studies that for humans it takes decades. This is the real issue. And so I understand the impatience of people wanting to know. I wanna know myself, but it's very hard for us to make those longer recommendations. All I can say is, is I don't see downsize to things like a general vitamin and mineral supplement if you have worries that you're not getting an adequate amount in a healthy quality diet is what I'm getting at. No, I don't wanna call it just yet, but we'll just try to do some of these briefly because there's so many questions to get to. One more answers, yeah. Yeah, they're all good. One of them is intermittent fasting. People wanna know about intermittent fasting and so can you comment on that one? Intermittent fasting looks very, very interesting to me. It has some of those grand qualities of caloric restriction in a way that humans could do it. Short term, and this is the only thing we now know is short term meaning only a time when you're losing weight or something. It looks like there are true improvements in like insulin sensitivity, overall factors that I would say are tickling some of those same caloric restriction kind of aspects in terms of metabolism, which I find positive. What I don't know is again, a long term issues whether there are again antagonistic things toward those benefits. And I'll just throw this out for the audience very quickly. Caloric restriction itself looks very good in a pristine environment like a vivarium. We can get animals to live longer. If you do those kind of caloric restriction experiments that say in a free range population, that's when it gets a little iffy because you then start seeing more or increased opportunistic infections and the like. So in other words, the amount of caloric restriction has kind of set you on a very, very lean metabolic course which is improving things. But if you have other factors around here like again, what we're dealing with now with a pandemic and all, do you have enough energy to ward off some of these stresses? That's an open question. So I leave that with the audience. Intermittent fasting has really good intended consequences metabolically, but do we know all the possible down terms? That's the question and I cannot answer that. So again, switching topics again, but exercise is also another one. People want to know about types. What, I mean, obviously you're not gonna have any specific recommendations for exercise, but just general what type of exercise seems to be effective and there's also questions about sarcopenia. Exercise quickly is a true lifestyle benefit to you. We see true benefits in terms of average lifespan across the board, across the species. We do not see changes very much in the lower species in terms of extending lifespan like caloric restriction does in terms of maximal lifespan, but health span, it certainly does improve matters. Exercise, I would say small amounts of exercise actually seem to be the best benefit in terms of overall maintaining an exercise regimen and also improving your health. The Copenhagen study I refer to as a jogging study where again, it's only the amount of, they looked at exercise in terms of how much you did in terms of jogging from relatively limited almost walking, but to the point that you can still talk to a partner, but still have your heart rate up versus very much overall running. And it looks like those levels where you can still talk to somebody, but walk at a certain high pace had the best benefit over the long term. And that tells you then that you don't have to kill yourself in terms of getting good benefits from exercise. So I would say walking would be a very good one at a brisk pace, swimming is a very good exercise. That's what the National Institute on Aging would recommend. And again, just like in diet, mix it up. Getting back to sarcopenia and the quality of muscle, it looks like weight-bearing exercises really do matter there, but you don't have to be a weightlifter to get the benefits from that. Okay. So I think I'm gonna have to call it at this last question just because our time are already over. So can you measure biological aging? I mean, there's definitely been people who've talked about measuring biological aging. What are your comments on tests? There are now scales that's coming in to play some call it the Horvath scale and others that are combining underlying metrics of metabolism. Horvath is looking a lot at immune function and the like, where you can see kind of like a general guidepost of what is happening over time because we have enough data for that and what are the deteriorations from the norm. And so there are coming into play just like what you can now order like your genetic makeup, your background. There are scales coming in to look at your overall health. And in general, these are very interesting. They have not been kind of examined on a large epidemiological scale yet, but that's coming very rapidly. There's papers coming out all the time on that. And so we're moving on that one end toward that broader kind of metrics. But on the other hand, we're moving toward individualized medicine where you can start looking at your changes like what we just saw in mitochondrial function in terms of insulin resistance and the like. And you're gonna get your overall metric yourself and saying, well, you need this and you need this compound or you need to change this in your life. So both of those are coming in. This is a, I'm sorry to be kind of like more generalized, but they are advancing very rapidly. Burgeoning area. Yeah, epigenetics too. This is a big kind of scaling factor that we can look at now. And this is coming in where we can look at both ends of the spectrum on a population basis and on an individual basis. Okay, well, I'm sorry to everyone for not getting to their questions. There are so many. We could be here for hours. I hope to get them all addressed in some future addition. Maybe we'll bring Tori back for just specific small Q and As for some of these questions. But thank you again, Tori for talking today. It was a pleasure having you on. I'm gonna bring Emily back on so she can close this up. Again, sorry for going over time. Well, thank you everyone. I appreciate it. Yes, thank you everyone. Thank you, Alex. Big, big thank you to Dr. Hagen for his fascinating presentation. Thanks to all of you for coming. I hope you learned a little bit. Bottom line, there's still a lot more work to do, a lot more questions that are out there to really answer these tough questions about healthy aging. I also wanna send a thank you and mention to all our generous supporters. I know there's many of you in the audience today. The research presented here and all the resources that the Institute provides are funded by our donors and supporters. Without these contributions, we would not be able to do this great work and bring you programs like this. There's been many donors that specifically given to the Healthy Aging Research Program that goes support Dr. Hagen and a lot of the work that you talked about today and many, many others. If you're interested in this content or research, please consider donating to the Institute. Every small amount makes a huge difference. Check out our website for more information. So big thanks to you all. Thanks for taking the time to learn with us and we'll see you again soon. Take care.


Anatomy is very important. I always say the anatomy that you know from the microscope, from your brain surgery you're doing every day, it's not different from what we see with the endoscope, but the perspective is different. And you should learn the perspective through the endonasal transfenoidal route. You have to know the anatomy of the perinaseous sinuses, but of course you have to know the interdural structures, everything which is behind the skull base. We differentiate the endonasal transfenoidal route into three different compartments. The first is the nasal stage. And the nasal stage actually may be for the beginner the most difficult part of the surgery. Why is that? First of all, we are not familiar, usually as a neurosurgeon with the nasal stage. And the second is if you use an endoscope, you would see you have plenty of space once you're in this phenoid sinus because then you can work bimanually and binasally. But at the beginning, you have to bring in an endoscope and instruments through one nasal orifice. So it can be very narrow, especially in your population here, you have a lot of people with polyps, thickened mucosa, and it may be very cumbersome at the beginning to start with it. So just for the anatomy at the moment, I always insert the endoscope through one nostril, which I think is the larger nostril at the beginning. I always have a CT scan MRI before that. And then I study the perinaseous sinuses. Most of the patients have some septal deviation. And usually I start with the larger nasal cavity. And I always insert the endoscope at the floor of the nasal cavity in between the nasal septum and the inferior turbinate. Usually this gives you the most, you have the most space in between these two structures. And if you follow that route, you come down to what kind of anatomic structure? What will you see if you follow in between the septum and the inferior turbinate? What will you come to? To the corner. And these are anatomic structures that you cannot miss. And once you're at the corner, then you know where you are. And then you just follow midline in between the septum and the turbinates. And then you always are at the anterior wall of the sphenous sinus. So it's not that difficult. You can never miss. What you have to know is how to deal then with the mucosa, which I will show you with the next talk. And middle turbinate, for example, it's a midline approach. I insert the endoscope here and then go along this phenoethymide recess and follow it up to the superior turbinate. And meter to it, you find the ostium to this phenoid sinus. This is the koana with the eustachian tube and the nasal pharynx. And a very important structure is the superior apex of the koana. Because from here, you orientate further upward to the ostium to the sphenoid sinus. This is the ostium to the sphenoid sinus. This is medial to the superior turbinate. You have the inferior turbinate, the middle turbinate, the superior turbinate. And the ostium is medial to the superior turbinate. Here's the nasal septum. The anterior wall of the sphenoid sinus is about from here to there. That means that the natural ostium to the sphenoid sinus is in the upper third of the anterior wall of the sphenoid sinus. That means if you open the ostium here, you must be careful not to go too far superiorly.  You will come where? Where will you go to? You may enter the ethmoid. You may go wrong and enter the ethmoid and then maybe get confused and follow different routes and then you get a CSF leak at some point because you got wrong. So from here, I always go backward, open the anterior wall of the sphenoid sinus backwards, laterally to the origin of the superior turbinate. And then, of course, you have to go more medially. And for doing that, what will you have to do? You have to walk on the septum because there's this nasal septum.  Otherwise, you cannot enter this sphenoid sinus. And then you do the same story on the other side and then you combine the approach. I will show you how we have to do that. So the distance from the superior apex of the koana following the phenoethmoid recess, which is here, to the ostium is about 1 to 1.5 centimeter. The ostium of the sphenoid sinus is not always parent. It's not like here in this nice specimen. In most of the cases, you will still have some mucosa covering it. But if you look with the endoscope, you will see if you have the mucosa where there is bone behind it. It's a different color to where it is at the ostium where there is no bone behind it. It's more bluish. And always take a micro-sucker, palpate at the ostium side. And once I feel it's very thin plate or even nothing. I perforate. But there are patients where the ostium is completely blocked and you do not find any ostium. Never force with a sucker or whatever and perforate it with your hand. In these cases, I just push away the mucosa. And then I have to take a drill. And then I drill into the sphenoid sinus. Other people like the Italian group of capobianca, they are not going for the sphenoid ostium. They go directly midline. This is another possibility. That you orientate koana, ostium, then break the septum, do a posterior septostomy, and then go directly midline into the sphenoid sinus, which is OK. I personally like to go via the ostium. Because with the ostium, if it's parent, you can take kerosene, for example, and you are in the sphenoid sinus. And then you can orientate how thick, for example, is the vomer, the rostrum, and then you can take the drill. If you go midline, you always have to take the drill. Without a drill, you get lost. You cannot take it by punches or whatever. So the parasyptl approach that you may know from the microscopic area, if you take a speculum, do you know where you open the sphenoid sinus? What is your key structure? Your anatomic key structure is the keel of the vomer. Where is the vomer? Is the vomer here? Is the vomer here? Here. It's far more posterior. So that is where we go in microscopically. That is where we go in endoscopically, just by different anatomical structures you follow. But of course, you have to take off the vomer with an endoscopic approach as well. Why is that? Instruments, absolutely right. I will show you. The one truth is what you can see with an endoscope, but the other thing is how you can handle with the instruments. And these are two different things. So next, a very important vessel is the spheno-palatin artery. You know, with its branches, especially the posterior nasal artery for the septum and for the turbinates, you must know where they are. The spheno-palatin artery is behind the middle turbinate. Usually, you don't see the foramen. You just see the branches. This is not only important to know for your routine approach. It's especially important to know if you want, for example, to create a flap. I mean, this is now something very special, but you may know if you do extended skull-based surgery, duroplasty is a matter, a factor, a very important factor. Because if you go into duroly, you have to cover your defect. And one of the strategies that you have to use is creating vascularized flaps, pedicle flaps. And this is your vascularization for the main flap that you use, the nasal septal flap. So what you have to know is the vessels are in between the osteum of the sphenoid sinus and the superior apex of the koana. This is your pedicle. So if you want to keep it, then it is important if you do enter sphenodotomy just to push the mucosa with the vessels backward and then take off the bone right here so you can keep the vessels. So even in case if you want to do the flap later on, you can do it. But if you coagulate everything right here, you can do if you don't need a flap. I usually do it in pituitary adenomers. But then you must know that you have destroyed the vessels for a flap if you may use it. This is now just in a specimen. We use fresh frozen specimen in my department. We get it from the University of Mainz, transnasal approach. You see, first of all, starting in one nasal cavity. Bring it in the endoscope and the sucker. That is how you start. And just inspect first. As I said, identify the nasal septum. Identify the inferior turbinate, the middle turbinate. Going to between infraterbinate septum to the koana with the eustachian tube, the tubal elevation, the nasal pharynx, superior apex of the koana. Then turn the endoscope superiorly along the sphenoethmoid recess. Lateralize the middle turbinate. And then, as I said, 1 to 1.5 centimeter above that, just media to the superior turbinate is the ostium to the sphenoid sinus. Once you have identified this structure, you can bring in, for example, as I said, a charism. We call it the Elegant Charism, the one that we use, a very nice one. And then you widen the ostium of the sphenoid sinus. This was on the right nasal cavity. And now we are going into the left nasal cavity. There's some septal deviation, but not that much. You have to lateralize the turbinates, the inferior and the middle beforehand. We rarely take the middle turbinates for a pituitary adenoma, for example. Just to show you now, it's a midline approach. But if you go, you know how you can work on the middle turbinate, this is now, again, ostium on the other side, media to the superior turbinate. And just to show you, if you now move the turbinates to the midline, I think that's what we're doing now. Yes. Now we are in the middle miatus. And this structure here is, do you know what this is? This is the unsincerized process. And do you know what kind of sinus you will enter if you take? Maxillary sinus. That is where you go into the maxillary sinus. This is important if you do extended scale-based surgeon, if you work on the pterygoid. You have to take the unsincerized process. You have to open the maxillary sinus. Otherwise, you cannot go that far lateral as you need it. But for pituitary surgery, it's a midline approach. And mainly, in most of the cases, lateralization of the inferior and middle turbinate is sufficient to work properly. So this is the widening of the ostium. Now we are in the sphenid sinus. In the sphenid sinus, there are often a couple of partitions. That's what Dr. Roy has shown to you. In some patients, you just have one intrasphenoid septum. In several patients, you have many. Interesting is, if you study it before on a thin-slice CT scan, you will realize that often one of the partitions run directly to the carotid canal, to the carotid, I'm sorry, to the bone, to the protuberance of the carotid artery. So if you study this, even if you don't have a neuro-navigation system that we routinely use in my department, even if you don't have this kind of device, you often can orientate just by analyzing the CT scan MRI beforehand. And once you're in the sphenid sinus, then you can follow these partitions and then you know where the carotid artery is and you just follow that. And now you see, once you have now take open the anterior wall of the sphenid sinus, then you have now to combine the approaches. And then you have to do a posterior septostomy. We usually break the septum 1 to 2 centimeter above its attachment at the sphenoid, taking the mucosa right there. And then with the mucosa, we usually take the cutting blakeslice, taking the mucosa, or you can use shaver systems. I'm much more in favor now to take shaver systems that the ENTs, some ENTs use. And once the mucosa has been taken off the bone, then you need drills. And a couple of different drill devices, whatever. I'm now using for this kind of thing a special drill with a continuous irrigation device that makes it much more easier, that you have irrigation all the time. And then you take off, as I said, the vomer and parts of the rostrum of the sphenoid. And this is important because otherwise you cannot bring in the instruments at the surgical site. Otherwise you always get stuck at the vomer. You have to absolutely flatten that, taking off the vomer so that you can go in parallel to the sphenoid sinus and then come to the cellar floor, which is not that easy here to detect. And this is another thing you should carefully, as I say, analyze the anatomy beforehand, especially in micro-adenomas. You sometimes have a very flat cellar floor. And even for an expert, you may miss the cellar floor in these cases. If you have navigations easy, otherwise it may be difficult. OK, and then you are in the sphenoid sinus. It's very important to create one single hole in the sphenoid sinus. Take off all the partitions. Go laterally to the border of the superior turbinate, both sides, open the lateral recess, and then have a wide opening. And before you start doing whatever you want to do, then at the skull base, you must be sure that you can bring in the instruments properly, and then you don't have any interference with your instruments. And there is the question on how much should the septum, the bony septum, been taken off? And always say, this depends on how you can bring in the instruments.  You can be sure that this is not sufficient. So then you have to take off more of the posterior septum until you can clearly bring in the instruments and do not interfere with the skull. So if it's too close, some people take then parts of the middle turbinate that you can do. The turbinates are pretty much important for moisterin, your nasal cavities. I'm no more in favor of just taking off the bula et moidalis. So what I'm doing is now then medialize the middle turbinate, take off the bula et moidalis, some posterior ethmoidectomy, and then usually you can move the middle turbinate very nicely. In extended skull-based surgery, if you have to go more laterally, then it is a must to take part of the middle turbinate. But for a routine transfenoidal, it's not necessary. This is the midline approach if you want to go transfenoidally to the cellar floor. That is sufficient. If you want to work in the cavernous sinus, you can visualize it by a pure transfenoidal route. But it's very difficult to bring in the instruments properly. Then we have to widen the approach more laterally. And that means that you have to combine the transfenoid with the transethmoid route. And if you want to work even to the middle cranial fossa, or let's say ganglion-gasary, these kinds of surgeries, you're going to have to go even more laterally. And then you have to combine the transfenoid with the transethmoid, as I said, the transterrigoid. And that means that you have to open the maxillary sinus as well. This is what I want to say, skull-based anatomy. Once you are at the skull base, you have to identify the bony structures. Cellar floor, tuberculum cellae, planems fenoidale. Then you see the bony protuberance of the optic nerve. You see the carotid artery. And you see the medial optical carotid recess and often much better the lateral optical carotid recess. You see the paraclival carotid right here. Paraclival or trigeminal segment, as you want to know it. And you see the clivus with the clival recess. This is something that you should see.  You know, this is the same specimen taken off the bone. You see the pituitary gland. You see the carotid artery. And you see how close the carotid, especially in elderly patients, come to the surface. That is interesting with the endoscope. You sometimes have patients where there's almost no bone or just a little thin plate covering the carotid at this upper vertical segment right here. And this is where you can easily do some harm to the carotid artery if you don't see the carotid artery. Carotid artery with a siphon here, the paraclival. The clivus, once you open the dory, you see the basilar artery right here. This is the chiasm here, the medial OCR, the lateral OCR. And this is still here, the arachnoid covering the rectus gyrus. This is more superiorly with the rectus gyrus here. And then you see the olfactory nerves on both sides as well. You see the ophthalmic artery. Ophthalmic artery coming from the carotid, pituitary gland, pituitary stalk. This is important. This is a very nice image that gives you a clue why, for example, for me, all the pathologies that are supercellularly going into the third ventricle or infracasmatic can nicely be approached anonasally because you come directly to these structures. And the big advantage, especially in the craniopharyngeumus, is you see the gland and you see the stalk. So the key structure of the stalk is directly on your view. And everything which is infracasmatically pushes up the chiasm so you are directly at the pathology and the nervous structures and vascular structures are pushed aside and you don't have to deal with them. Anatomy of the third ventricle, that you get an impression you can do with the endoscope the same approaches as you know it from your microsurgical route transcranially. You can open the laminar terminalis. You see it here above the chiasm. This is laminar terminalis approach with the endoscope. You see the ACOM, both A1, both A2 segments, inter hemispheric fissure. You can open the laminar terminalis. If you come from this route, you will see more to the posterior part of the third ventricle. And if you go prememulory what you can do and open the third ventricle as you do it with a ventricle ostomy, prememulory can do the same endoscopically then you can look up to the ferramen of Monroe. Paracellar area with a transphenoid, transethmoid approach, you should know that the pituitary gland has arachnoid fibers in between the carotid artery and the pituitary gland. You know the KnoS classification of the pituitary adenomas. So this is an area you maybe often have to deal with. And as pituitary adenomas are soft, you can often follow the tumors, especially once they are in the medial compartment of the cavernous sinus. If they are in the lateral compartment, that means in between the carotid artery and the superior orbital fissure, it becomes more difficult. If the tumor is soft, you can work in here. But for example, for a meningeomer, I never do that because you will do some harm to the nerves. As you know, this is the ocular motor nerve. This is the trochlea in between. This here is the abducent nerve and then there is the trigeminal coming more down. And you know that they are all attached to the lateral wall of the carotid sinus. So if you manipulate a lot there, patients will do some harm and the patient may have a ophthalmoplegia. Last is then clivalent anatomy. Clivus is very important. The nerve next to the midline is the abducent nerve. Must be very careful. If you open the clivus, always being in the midline and then carefully work laterally. But with the clivus, you have to know that there are a lot of connections from the basilar plexus to the sigmoid sinus and to the coronasinus. It can bleed a lot if you go through a normal clivus. Then there are different compartments of the clivus. If you work on the upper part of the clivus, you get a nice approach to the interpeduncal system. That's what I want to show you. These are mammillary bodies, basilar apex P1 segments, ocular motor nerve in between P1 and superior cerebellar artery. That is Pons and basilar artery. And that is where we do our ventriculostomy from the other side. Now endoscopically you can do it from this side as well. This is now the middle part of the clivus. If you open that, then you come to the pre-pontine cistern with the basilar artery. And then you can see the trigeminal nerve. You can see the bundle of the vestibular cork layer. You can see the pica down there, ferraman jugulari. And if you take the last part, then you can even go down to the ferraman of magnum and see even the rootlets of C1. This is all possible endoscopically, but then you have to go really drill everything down to the corona. Yes, I have to take the whole rostrum of the spinoid. So I think I stopped with the anatomy right now.