 So thank you all for being here, and I'm going to say that I really started getting more interested in this as I got older, and you know, next month is another birthday, and so this is one of these things that I kind of like, is there something that I can do about this? And that's really the question. And as a kidney doctor, one of the, you know, there's not very much you can do about advanced kidney disease. So we're always looking for modifiable factors, and so that, and before, you know, it's only been in the last decade or two that we've begun to actually say, you know, there are actually some specific systems that are associated with aging. So one is telomeres, which are these DNA tandem repeats at the end of the DNA molecules, and the longer they are and the more the activity of the enzyme that puts them on the chromosomes, the better off you are. And another one is something called Clotho, which is associated with phosphate metabolism, but also they found that in animals where you overexpress Clotho, those animals live longer. And so these are two systems that are associated with aging, and the question is, is there something that we can do that could modify how they work? And since I'm a kidney doctor, one of the interesting things about advancing kidney disease is that a lot of the physiologic effects and the cellular systems, you see the same thing as kidney disease advances as you do with aging. And that includes things like increased TGF beta, which produces scarring, more cell breakdown and cell death, which is apoptosis. The telomeres get shorter both in aging and kidney failure. You get lower levels of Clotho. You get more toxic end products like AGEs and the mitochondria. The energy systems don't work so well. And then the other thing that I've been interested in for so long is that as your kidney disease progresses, your ability to get rid of the acids in your body goes down and down. And that is the same thing that you see in aging. And we know that there are some very specific systems that are affected in uremia, which appear to be related to the amount of acid in the system. And so if you're saying, well, the amount of acid in the system goes up as I get older, and it goes up as kidney function declines, which also declines as you get older, how about some of the things that we see with aging? Could this at all be related to how much acid is in the system? And some of the things include things like your bone mass starts to deteriorate actually once you're about 30 or older. Your muscle mass starts to go down. And in general, and this is on average for all the population studies that we've looked at, kidney function declines every year. And so by the time you're 60, your kidney function has gone from about 140, and these numbers are in milliliters per minute, to about 80. So you've lost a great deal of kidney function just because now you're 60 years old. And so these are the things I'm going to talk about today, how acids accumulate with renal failure. We'll talk about clotho, we'll talk about telomeres, and then finally we'll talk about specific anti-acid therapy, which is alkali. And so really the question here is, can I show, and let me just step back. I'm going to talk about what I can prove, and then I'm going to tell you about what I believe is possible to do more research on. So this is the stuff that we know. We know that when you're younger and your kidneys work better, you tend to keep your acid levels at the high end of normal, which is over here. And very slowly as the decades go by, your ability to get rid of all those acids goes down and down, so that when you're about 80. So six decades later. Instead of keeping your blood pH around 7, 4, 2, 7, 4, 3 with your blood bicarbonate levels 26, 27, you're running a blood pH of 7, 3, 7, 7, 7, 3, 8, and your blood bicarbonate levels are 20, 3, 24. And the question is, over a really long period of time, does that make a difference? Are there pathophysiologic consequences to having decades of more acid in your system? And let's just talk a little bit about diet acids, because I think there's, it's not really clear to everybody what I'm talking about here. So acids come from what you eat and from metabolic processes inside the body. And the body really cares about maintaining these acid levels where it wants it to be as high as possible, or excuse me, the acid levels as balanced as possible. So there's a lot of systems inside the body that help get rid of the acids that are floating around. And so you can put them into cells like red cells, or you can put them into muscle, which makes the muscle tissue breaks down, or you can neutralize them with bone. Bone is a lot of essentially alkali. And so there's a chemical reaction where you can dissolve the bone in order to get, to help release the products that neutralize the acid. And the acid also activates the bone cells that eat the bone up so that you release more bone mineral to neutralize the acid. And then a lot of the acid in our body is turned into carbon dioxide and it's excreted in the lungs. And then all the rest of the other acid compounds are excreted by the kidney. And all these other acid compounds come from the diet. So sulfates from cysteine and methionine, lactic acid from glucose, acetoacetic acid from triglyceride breakdown, uric acids, phosphates, okay, phosphates are in everything we eat because it's an intracellular anion and chlorides. Not a lot of chloride in raw food, chloride mostly comes from table salt. So first part of my talk, I want to say that I think that aging and kidney failure have many of the same physiologic effects and that with increasing age and kidney dysfunction, the steady-state acid levels, and this is tissue acid levels, not even so much blood acid levels, but tissue acid levels rise. And that the diets are the source of a lot of the acids that we get. And so now let's talk a little bit about clotho. So from a kidney point of view, clotho is important to try to keep your phosphate levels normal. And we know that if you're eating a diet that's high in acid, so high in methionine, which is a sulfuric amino acid, if you restrict sulfur in these mice and rats, they live longer. And in cats, if you put the cats on a phosphate-restricted diet, then the phosphate levels, blood phosphate levels are lower and their parathyroid hormones levels are longer, and the rats are the cats that are on a phosphate-restricted diet live longer. So what does clotho do in humans? So if you have normal kidney function and you eat a high phosphate diet, so a high acid diet, in order to get rid of the phosphate, phosphate is regulated by something called FGF23, which comes from bone. And the FGF23 goes to the kidney cells where membrane clotho is a cofactor. And this helps split off part of the clotho molecule, which then goes to a different part of the kidney, where it gets rid of the transporter that reabsorbs phosphate, and it allows more phosphate to go out in the urine, so you ate a lot of phosphate, you now pee out a lot more phosphate, and you go back into phosphate balance. And as you get older, and assuming you continue to eat a high acid diet, which is a diet without a lot of fruits and vegetables in it, then as your kidney function declines, it's going to be harder and harder to get rid of the phosphate, requiring more and more FGF23. And FGF23 decreases the activity of active vitamin D, so 125 vitamin D. It does this by decreasing the enzyme that makes 125 and by increasing the activity of the enzyme that breaks it down. And active vitamin D is a cofactor for the production of clotho. So you continue to eat a high phosphate diet as you get older and older, and when I talk about what this is called Stage II kidney disease, this is when you're about maybe 50 or something years old. So you keep eating a high phosphate diet, FGF23 goes up and up, vitamin D and clotho go down and down. And then as kidney failure progresses, finally you can't keep the phosphate under control. And by the time your kidney function is down at around 25%, you're really not making any more active vitamin D at all. And so what happens when you knock out the clotho gene in mice? So when you have, this is a normal mouse, and here's a clotho deficient mouse over here. So this mouse is unable to get rid of the extra phosphate that it's eating, and it forms calcium phosphate precipitates in the kidney and essentially damages the kidney. This is the level of how much creatinine is increasing in the body. So you can see that in this mouse over here, kidney function has decreased by more than half. So if you now, in the clotho deficient mouse, also knock out the phosphate transporters, so now it can't reabsorb the phosphate anymore, and you put those mice on a low phosphate diet, then actually you can protect the kidneys. But if you feed them a high phosphate diet, then even though you've knocked out this one transporter, this is the clotho selective transporter, you start to put more phosphate into the kidney. This is what you see in advancing kidney disease, is that you see these calcium phosphate salts precipitating in the soft tissues, damaging the blood vessels, damaging the kidneys. It's one of the reasons why people with kidney disease die of diseases related to the blood vessels, like the heart and the brain. On the other hand, if you restrict the amount of phosphate in the diet in either wild type mice or mice that have CKD, you can increase the amount of clotho. So phosphate restriction increases the amount of clotho in these mice, even as they get older. And if you take a clotho knock out mouse over here, this very small animal over here, and then you give it bicarbonate, that mouse lives longer compared to the clotho deficient mouse that was just fed a regular mouse diet. Now just to give you an idea, a real mouse, a wild type mouse, would live about twice as long. But even so, these mice treated with alkali therapy, presumably to get rid of the acid, lived longer. And so what we see is that low acid diets, especially low sulfate and low phosphate diets, are associated with longer life spans in these small animals. And that high phosphate diets are associated with worsening kidney function and lower clotho levels. And if you're clotho deficient, phosphate restriction and bicarbonate therapy lets these animals live longer, possibly because you're improving their kidney function. Kidney failure is really bad for you. And if I think clotho deficient, I could maybe put in here older animals who are relatively have lower clotho levels. And now let's talk about telomeres. So telomeres are these tandem repeats at the end of the chromosomes. And when your cells are young and when you are young, you have really long telomeres at the end. And as the cells get older, the telomeres get shorter and shorter, and then finally the cells die. And there's an enzyme called telomerase which puts the telomeres back onto the cells. And as you get older, telomerase activity decreases. And one of my friends at UCSF, Alyssa Apple, has done a lot of studies on stress and telomeres. So we know that stress is bad for you. And this is one of the ways why stress actually can shorten your life. So she looked at caregivers who were taking care of chronically ill people. And what she looked at was how much telomerase did they have and what lengths were their telomeres. And what she showed is that the more that the caregivers had less telomerase activity, even when they did stressful things that like giving talks in front of people. Their telomerase just didn't act like normal people and it was much lower. And the longer they had been to caregivers, so presumably the more stress they were under, the lower their telomere length were. Excuse me, the shorter their telomere length were. And so she wanted to know, like how does that happen? Like what is psychological stress doing? And she said, well, maybe it's increasing cortisol levels, maybe it's increasing insulin levels, maybe it's increasing oxidative stress. And what she was able to show is that if you looked at telomerase, the people that had the lowest level of the telomerase were the ones that had the highest level of cortisol, the highest level of epinephrine, and the highest level of norepinephrine. And these are stress hormones. And in addition, the ones that had the shortest telomeres were the ones that had the highest levels of cortisol, epinephrine, and norepinephrine. So what we're really looking at here is a potential physiologic mechanism for why all this stress is actually making you not live as long. And she was able to show that it had effects on some of the cardiovascular risk factors that we look at, such as your heart rate variability goes down. We think it's better for your heart rates to be able to go very fast and very slow. And if you decrease that variability, that's bad for you. They had higher resting heart rates. They had higher levels of various types of bad cholesterol and lower levels of good cholesterol and higher levels of fasting glucose. So all these things that are cardiovascular risk factors. And the reason that I'm talking about stress and cortisol and cardiovascular risk factors is, of course, one because you die of cardiovascular disease and kidney disease. And specifically with glucocorticoids, a friend of mine in Germany, who's been studying this for many years, has shown that the higher the glucocorticoid levels in your body, the higher the amount of acid in your system. And he looked mainly at children trying to decide if eating a high acid load was bad for the kids. But what he showed was that, in fact, it was the high glucocorticoid levels were bad for the kids. And if you look at diet, then you can show that if you're eating a Western diet, so red meat and saturated fats and a lot of junk food, the more of that you eat, the shorter your telomeres are. And if you're eating a healthy diet with lots of fruits and vegetables and mono-unsaturated fats, then, in fact, the more of those you eat, the longer your telomeres are. So there does appear to be a relationship with these specific kinds of diets and telomere length. And if you say to yourself, so what's in these really healthy diets? Well, a lot of them contain a lot of fruits and vegetables. And in general, fruits and vegetables are low acid foods. And they're low acid foods, not because they don't contain acid compounds, they do. But they also contain compounds that are metabolizable to bicarbonate, so that in balance, fruits and vegetables on balance are low acid foods. So this would be a low acid diet. And there's been one study that's looked at dietary phosphate and telomeres. And not too surprisingly, the more dietary phosphate you ate, the lower your kidney function was, the lower your vitamin D was, the shorter your telomeres were, and the higher the inflammatory markers were. So there is a little bit of data specifically suggesting that phosphate and acid may actually affect telomeres. And so just to summarize what I just told you, telomere length and telomerase activity increase with deak with increasing stress. This is related to elevated levels of cortisol and adrenocorticoactivity, which potentially is actually by itself increasing the acid load in the body. The acidotic stress may contribute to telomere loss in aging, and we know that calorie restriction has been associated with longer life in animals. So then the question is really do low acid or low phosphate diets, is that possible too? So if this is so, then one potential way of looking at this would be, how can I neutralize the acid in the system? And so we know that if you eat a high fruits and vegetable diet, the acid load in the system is lower. And this is from one of our studies where we took all the calories from dairy products and junk food and grains, and we turned them into calories from fruits and vegetables. And so a relatively low acid diet. And then there have been studies, for example, this study in older men and women where they gave them potassium citrate and showed that after two years, their bone mineral density had improved. And this is something you would expect, because they're not breaking their bones down to get the base to neutralize the acid because we're giving them base, so they don't need to break their bones down, so their bones should be better. Also shows improvement in nitrogen balance, and this is in people with kidney failure. And most important as a kidney doctor, even in people, so this is a GFR of 85, which is approximately what your GFR would be if you're 55 years old. And if you give these people bicarbonate, and this is baking soda, after a couple of years you can show that your kidney function doesn't decrease as quickly. So this is something that might be potentially useful, not just to people with advanced kidney disease, but actually anybody who's getting older. It's that you may slow the progression of your kidney failure, declining kidney function. And why do I think this is important? Because, while I said earlier that on average when you look at population studies, kidney function declines with age. In this study, the Baltimore Longitudinal Study on Aging, where they followed men for a couple of decades and looked at kidney function over time, there was this group over here whose kidney function did not decrease over the 20 years or so that they followed these people. And the people who did this study didn't know why. They tried looking to see whether they had underlying high blood pressure, or kidney disease, or some other factor, and they couldn't figure out what it was. Just that these people had their kidney function maintained normal over two decades. So we looked at it in a study that we had done with post-menopausal women who were like in their 60s and 70s. And we also saw the same kind of curve. And this group over here, where we had been giving these women sodium bicarbonate, these people over here were the ones who had the least amount of bicarbonate therapy, were also the ones who had the most decline in kidney function. So this group over here, over three years of time, maintained their kidney function. And the question is, is this related to, you know, the fact that they were eating a lower acid diet, or getting bicarbonate therapy, or both? And then finally, in this study by Dean Arnish, so, you know, the Dean Arnish lifestyle is you eat a low-fat diet, and you get a lot of exercise, and you do stress reduction, and he talks about like getting more love and social support. And so these men had prostate cancer, and for three months they did this Arnish treatment. And what he showed is that after three months, okay, the majority of the men had improved telomerase activity, just by doing these couple of different things. So suggesting that there are in fact ways where we can modify the amount of acid in the system, potentially how much telomerase activity works, potentially over the longer run, you know, how our telomeres, how long our telomeres are, potentially how much cloth though we have in the system. And so now what we've been trying to do is trying to figure out how do we study this? Because the gold standard for studies is, you know, you have two groups, and you randomize them to different treatments, and then you follow them. But we're talking about little effects that occur over decades, in fact occur over your lifetime. And so really what my group has been looking at now is like, who exactly do we study this in, and how can we try to either prove or disprove some of what I've been talking about here. And so with that, I will leave you. I'm trying to show you that aging is multifactorial, and that some of these factors may be modifiable. I'm going to suggest that a high acid, and specifically a high phosphate diet, makes specifically lower survival by worsening kidney function and decreasing clotho levels. You know, we've been telling people for a long time that stress is bad for you, and I think that we should be able to link increased stress to higher acid diets and decreased telomere length and telomeres activity. And I suggest that these factors all work together, okay, that in fact, as you get older and as your kidney function declines, if you continue to eat a high acid diet, the high acid diet is going to damage the kidneys, and then your kidneys can't get rid of the acid as easily, and so the acid levels build up, and that then worsens the kidney function. And that all of this may be, if some of the physiologic factors associated with declining kidney function are the same as with aging, you know, can in fact we modify how we age by changing how much acid we eat in our diet and modifying our blood acid levels. And so perhaps either low acid diets or alkali therapy may help you live longer. And just some pictures of San Francisco in August, so anyway, thank you. Thank you. Great, I've got two questions for you. You mentioned a high phosphate diet. Is the phosphate content of meats a lot higher than it is for beans and grains? I mean, is it something, is that a big difference? So the answer to that one is no. As a matter of fact, beans are extremely high in phosphate. So if you want to eat a low phosphate diet, you have to stay away from dairy, and this is just standard kidney patient advice. You have to stay away from dairy products, legumes, chocolate, nuts, and some specific vegetables. But all foods contain phosphate, because phosphate is an intracellular ion. The other question is, if I want to look at my labs, either for phosphate levels or cloth though, I don't know if you can even get that measured. What could you look at as even an indicator of whether your phosphate is under control or not? No, you can't. What you need to look at is FGF23, and we hope, when I say we, I mean kidney doctors in general are hoping that they turn FGF23 into a test that we can order clinically, because that is the next thing for us to be able to look at to decide exactly how well somebody's keeping their phosphate under control. That's actually the more important level, because your phosphate levels are going to be in the normal range until you have advanced kidney failure. Thanks. Cool. Thank you for your talk. You touched on this, I would assume if we're doing like a nutrition analysis, looking at a prowl score would be useful. And then the follow-up question is, is there a range or a number you would kind of want to see people at for that? So the answer to that one is, yeah, sort of useful in the very gross sense that really positive is bad, really negative is good. But could I say, well, anything below 20 is what you want? I have literally no idea about that. But more or less, okay, if your prowl scores are approximately zero or negative, typically your acid levels or your acid excretion is going to be pretty low, pretty close to zero. Cool. Thank you. So I have just a couple of questions on this. When patients show up with kidney stones, is that indicative in older age? Is that indicative of phosphate imbalances and issues with the colo? Sorry. Okay. So kidney failure in western countries is generally due to high blood pressure, diabetes, obesity, and cardiovascular disease. That's three out of four people with advanced kidney failure have that. All the other kidney diseases combined are like 25%. If you talk about just kidney function declining with age, we believe that that's related to vascular disease. But all of these things, high blood pressure, diabetes, obesity, and presumably high acid levels are all of these things are contributing to progression of kidney disease. It's not just one factor. And what we try to do in kidney disease, we're already trying to control the blood pressure, control the diabetes, control the obesity. We're looking for other things that we can try to treat. I mean, we have so little we can do. But are oxalic acid stone formation also kind of indicative of some sort of a misbalance in the whole... No, that's probably an actual kidney tubular cell problem or some other reason why you're not handling oxalate very well. And then the last question was, is there any work on ketogenic or low carbohydrate paleo diets in how this affects what you've been talking about in terms of the acid? Only in the sense that ketogenic diets can be keto acid diets, and so they're acid diets. Yes. Thank you for your excellent research. The question I had was, you talked about nuts, beans, and legumes as being high in phosphate, which leads to more acid, which is not a good longer term according to some of the research data you've seen. Now, how does that correlate with the studies of some of the blue zones where they're routinely eating nuts, legumes, and beans a lot and they're living over 100 years easily? How does the data match up? What is your perspective on that? Right. So when I talk about low phosphate diets, we routinely talk about, when we talk about people with low kidney function, we're talking about the bottom 25%, where the blood phosphate levels are high, where we know that if they eat these foods, they go up really high and we have to limit the quantities that they eat. So I'm not sure that you can say the same thing about what happens to people, the kind of people I take care of, let's say at the VA I work at, who smoke, who drink, who have high blood pressure, who have diabetes, and who eat a terrible diet, compared to people who eat, who don't smoke, don't drink, follow a healthy diet, exercise a lot, and live to be a lot longer. So I think that's such a complicated mix. I'm not sure you can even compare the two. But if we're just talking about lowering the phosphate in the diet, I'm just telling you what has a lot of phosphate in it. Thank you. I'm curious about vitamin K2 and how a deficiency in that would affect heart disease and kidney disease, and if supplementing with K2 will help in preventing heart disease or the deposits of calcium for kidney stones as well. So vitamin K is mostly, most of the time when we're talking about this, we're talking about people who have blood clotting disorders, at least with kidney failure. I'm talking about K2, not K1. So we generally have to supplement with both, because we put everybody on such a low, like we limit what they eat, so we generally have to do supplementation, and we supplement both. So we're talking about coagulation problems, so something totally different. I mean, that's a specific kind of cardiovascular problem. Thank you. Okay, thank you all. Don't have applause for Dr. Lino-Fresetto.