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太多蛋白質對長壽、老化與癌症的影響 |
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Dr. Ron Rosedale的演講
【內容】 Since I have a half an hour to discuss nutrition, cancer and aging, I will not waste time. And in fact I'll have to even do more. It's said that the only real way to learn it's first to unlearn things that you think you know. And that always seems to entail confusion. So I will not consider my job a success tonight, this afternoon, unless I have confused you. So remember that at the end. Here's the answer. It's really all you have to know. This is what I've said for many years, actually several decades. And if I'd have to summarize everything in one sentence it's this... That your health and lifespan will most be determined by the proportion of fat versus sugar you burn over a lifetime. You can gauge anything you hear about nutrition with that statement. If it helps you burn fat, it's probably good. If it doesn't, it's probably not. And that will be determined by the communication of hormones. And those hormones will be determined by what you eat. It's not the simple "calories in, calories out". You eat to affect the hormones that will affect whether you burn sugar or whether you burn fat. In other words every meal you eat, it's probably the most important effector of hormones that you will be exposed to that day. And that hour and a minute. Now 25 years ago there were a handful or less of people who were recommending low carbohydrate. And the impetus for that really was to lose weight. And it was found that a low carbohydrate diet was very good for weight loss. The other handful of people, other than myself, were, as I say, looking to lose weight, or looking to affect weight loss and a high-¬protein diet worked very well, plus fat was really vilified at that time and it's still vilified. But if you can imagine a quarter of a century ago, fat was the Darth Vader of health. And so nobody would even attempt to think of eating a high-fat diet. Except me. Because I was not dealing with weight loss, I didn't really care at all about weight loss. I wanted to treat diabetics and heart disease patients. And I knew that protein was very good at turning into sugar and the diabetics' one of the major problems was gluconeogenesis, where they turned protein into sugar, so I could not see the point of feeding a diabetic a lot of protein and certainly I didn't see the point of feeding a diabetic sugar and then giving them medications to get rid of that sugar. That made no sense whatsoever. Which is still being done. So what's left? I mean there's not a whole lot of choices here. Right? So I went into a high-fat diet. And worked very well for diabetes, cardiovascular disease... And diabetes in my studies, and my background was the biology of aging, was really a model for accelerating aging. So I knew I was onto something. And the only thing that I think I've changed over the years has been just how important it is to restrict protein. In the book that I put out maybe a decade ago, a little over, the only nutrient I had people count was protein. So I knew it was important, but I would have to say that today I would say it perhaps is more important to restrict protein than it is to restrict carbohydrates. And I know that's a new statement. But I told you I wanted to confuse you a little bit. And I will hopefully be able to give a few reasons why in the next 20 minutes or so. But to do so we have to go back pre-Paleo. And Paleo was at maybe half a billion years of something... When did Paleo start? Not even then, right? Few hundred million... Well, life started about 4 billion years ago. And that's really when the rules of eating began. Actually before that, but we won't go there. So let's quickly take an overview of life. We started out as single cell organisms floating around the oceans. Lots of them. Unicellular organisms whose requisite to stay alive was to divide. Divide as fast as you can and beat your neighbors to the punch. What does that sound like today? Cancer - okay, that's the history of cancer. It's our bacterial heritage. Unicellular organisms were dividing and that went on by the way for a billion and a half, maybe two billion years... Half of our entire lifetime. The history of life was single cell organisms flourishing in the oceans. Until one of them developed photosynthesis and started putting out oxygen into the atmosphere. Well, that killed about everything. There were no defenses, we talk about oxidation. That was the major pollution crisis for life. It's estimated that at least 90% of all life was wiped out. Until one smart bacteria figured out a way to use that oxygen... ...and burn organic material food with it. Which did wonderful things because it saved the organisms from being oxidized and generated tons of energy. And then another unicellular bacterial entity, organism, ate that proto-mitochondria, that we call mitochondria now and they became friends. Were that proto-mitochondria got nice room and board in exchange for lots of energy. So then you had eukaryotes. And you had the ability then to fuel multicellular organisms. Multicellular organisms have a lot more genes. Not necessarily you need an individual cell, but you have a lot of cells with a lot of genes. And they have to multiply - it took a lot of energy. That couldn't have occurred until you had that nice symbiotic relationship between one bacteria and a proto-bacteria and a lot of energy informed and protection from oxidizing. So it was a great little symbiosis, probably the greatest event in the evolution of life. Because that allowed for everything else, culminating maybe, if you want to call us a combination... us. So is allowed multi-cellularity and a division of labor. The greatest division of labor came between the genome, our genes, the information of life and the other cells around it. The other cells around it, called the soma - its purpose is to protect that genome and pass it along. That's the purpose of the division of labor between the genome and soma. Huge distinction and a huge event in the history of life. Why? Because that is why we die. There was no death until then. And the purpose of that soma is to protect that genome, pass it along and then nature doesn't care. Which is why we die. Nature doesn't care we're going to die. It takes a lot of effort to stay alive. Now that tells us something that a lot of people don't realize. And this isn't going to be a very popular thing to say here. However it tells us that we can study Paleo all we want. And we can argue and debate what Paleo-¬man ate. I will tell you they won't tell us much. If we finally figure it out, all it would tell you is what diet did we evolve with that might have maximized our reproductive success. Not what will give us a long post reproductive lifespan that nature doesn't care about, nor is there a way, even if there was, something like a longevity gene, it would be no way to pass it along. Since the power of selection wins quite rapidly, post reproductively. So we can use nature in general to tell us how to live a long, happy, healthy life. Because nature doesn't care. We are probably the only species certainly on earth that's ever even thought about it. Nature's purpose is to get those genes passed along. But that also created a problem with the allocation of energy. As the multicellular organisms flourished in the ocean, there was competition and an arms race, especially for food. It wasn't so plentiful anymore, they had to compete. But that also meant you had to use it wisely and you had to decide, "Do we have enough food to replicate, to reproduce? Or do we direct our resources to staying alive?" That's what nature cares about. Nature will keep us alive long enough, such as we have a sufficient opportunity to pass our genome along. Nature has a lot of tricks to do that. It will up regulate DNA repair, heat shock proteins, intercellular antioxidants... All sorts of cool stuff that nature has that will keep us alive so that we can pass our genetic information to the next generation. All we want to do is to apply that science post reproductively. In other words what does nature do that allows us to be healthy such that we can take care of our genome and pass it along, so that we can use that knowledge and continue using it post reproductively. Has nothing to do with Paleo. So that's the why we age. Mostly because nature doesn't care that we do. The how we age is a little bit of a different story. You can consider aging to be a competition between damage and repair of damage. If we could repair damage as fast as it occurred, we would live forever. However, our repair mechanisms become damaged too overtime. And that's why we don't. And we can't stop that damage. Now there are different reasons why we can stop that damage. One being we can't stop breathing. And so you hear about antioxidants... Well, your best antioxidant would be to not breathe. But wouldn't get you very far. And we glycate. Glucose combines with proteins and DNA and gums up the works... You know, the food industry is called caramelization. Oxidation is called rancidity. So we turn rancid and we caramelize with age. That's "the how". But because we had to allocate energy towards either repairing damage and repairing damage is really where it's at... We're not going to stop damage. We're much better off at up regulating repair of damage. We know that we can do that. We can do that because all life apparently has mechanisms to allow our cells or single cells to outlast a nutrient deprivation - A famine. So some organisms will go into a deep freeze, some will desiccate and then come back to life at a future more opportunity nutritionally advantageous time. Because of this competition for food, the choice between whether we should allocate our resources towards maintenance and repair, i.e. living longer, or investing those resources into replication or reproduction. There had to be nutrient sensors, there had to be something that says, "How much food is there available to do this?" And because this is so important there are lots of them. We've got insulin we know, IGF... And they are close cousins. In fact they are one and the same in the early organisms - worms. There's no such thing as a distinction between the two, they are just called IIF. Insulin IGF, one and the same. And that's one, leptin... You've got energy itself. The ADP to ATP ratio, NAD to NADH ratio, AMPK which is the enzyme involved in changing AMP to ATP. You have all these nutrient sensors, but to keep yourself from becoming schizophrenic, there had to be something that organizes all of these. And indeed there is. And it's called the mammalian target of rapamycin. Most people haven't heard of it. The most important pathway in your body. It will sense all the nutrient sensors and decide should this self replicate or should it stay alive and replicate at a future more opportune time. That's what we want. TOR, the target of rapamycin has been around since the beginning of animal life. It's found in bacteria, it way predates insulin... It started almost with life, because that was such a critical decision. Calorie restriction. We know that that's a mechanism that's been used since 1930 to extend lifespan. It slows aging, extends life. How? Well, a friend of mine actually received the first Methuselah prize, which is given to the aging researcher that is able to keep double a mouse's lifespan, from two to four years, by inhibiting IGF receptors. So if you inhibit the growth of a mouse, it lives longer. In other words, if you inhibit IGF, there is a dichotomy apparently between growth reproduction and longevity. That's what this slide shows. The role of insulin and IGF. Insulin and IGF represent a family of hormones, growth factors that regulate metabolism, growth, cell differentiation and survival of most tissues in mammals - that's us. Insulin and IGF initiate their action by highly homologous signaling systems. I left that in there because a lot of what we thought had to do with insulin signaling and extending lifespan wasn't really insulin, but IGF. They cross-¬react. High insulin is bad and I talked about this 20 years ago, about the detriments of insulin and health, and still believe it. But the reason high insulin is so bad is because it also stimulates IGF receptors. It's a growth hormone. You also then become insulin resistant, but that insulin resistance by the way is more of the metabolic aspects you become insulin resistant, but not the anabolic aspect. So the anabolic aspect of high insulin flourishes. Well, the insulin resistance cells are actually protected from the glycation. I talked this in there too, again in this article as a quote. "Some of the common and consistent effects of calorie restriction in rodents and nonhuman primates include lower fat mass, particularly visceral fat, "lower circulating insulin and IGF concentrations increase insulin sensitivity, "lower body temperature, lower fat-free mass, decreased levels of thyroid hormones and decrease oxidative stress." So when people see that their thyroid hormones are going down a little bit, when they follow a so--called ketogenic high-fat diet and they're worried about and you hear these blogs that say, "You've got thyroid disease." Not in the least - there's a very healthy way to live. You're running cooler, you're allocating more resources towards maintenance and repair and longevity. It's not thyroid disease and I know that, because your TSH does not go up, which is how you actually define hyperthyroidism in medicine. So don't believe all that stuff. "In conclusion, strong similarities exist between insulin IGF in yeast, worms, flies, mammals and humans." "... Suggest that insulin and IGF arose early in evolution "and is a central component of an anti-aging system, which is conserved from yeast to humans." In other words it's important. Does it apply to people? This is a family of people in Ecuador that has a very rare disorder known as Laron syndrome. They basically have exactly what the mice have. Mice that lived twice as long. They have an IGF receptive mutation, cancer and diabetes is unknown despite them being fat. Now they have a very hard life, they died a lot of alcoholism and accidents. But if one controls for those, they also live lots longer. So if you control for kind of non-age related diseases, they have a very long lifespan. "In yeast, worms and mice the restricting growth hormone "could make those creatures live longer. Guevara-Aguire-- if I'm pronouncing that correctly... He is the one who kind of discovered this Ecuadorian family. It's a rare syndrome caused by a gene mutation. Over the course of his years with the family members he noticed the people with Laron syndrome almost completely avoided cancer and diabetes. An observation that squared with the research of Longo and others who have done this in yeast and animals. It could be, because cells must invest energy in either trying to grow and reproduce or in protection. I.e. maintenance repair, what I've been saying. It's a huge decision and we want to swing it towards maintenance repair. When we talk about cellular replication, we want to curtail that for the most part. Right? Because then you curtail cancer. In nature dwarf models live longer. Ponies live longer than horses, small dogs live longer than large dogs. It's a very fascinating field, a fascinating field in aging. Un-growth hormone increases longevity. It's a drug that counters growth hormone and it inhibited several human cancers, including prostate, brain, breast and lung cancers. Long-term effects of calorie or protein restriction on serum IGF and IGF binding protein. Our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans. And suggest that reducing protein intake may become an important component of an anti-cancer and anti-aging dietary intervention. There is a huge difference between a low carbohydrate high-¬protein diet and a low carbohydrate high-fat diet. Namely one is healthy and one isn't. And so early on when the few people 20 or 25 years ago who were advocating low-carb-- That was a kind of a revelation, it was good enough, but the distinction wasn't made between high-¬protein or high-fat particularly. And virtually everyone else went to high-protein, because fat was so vilified. And that really set it back, because there were a lot of problems with high-protein. And it worked certainly for weight loss. And so, the advantageous publicity was more for weight loss, not as much for disease and diabetes. And certainly not for cancer. But you didn't find that out for years. But now we know. An anti-Atkins low-protein diet extends lifespan in flies.
Now Atkins, bless his soul, at least got low carbohydrate known... His deal was just low carbohydrate and pretty much anything else went and since nobody wanted to eat fat back then, they all gravitated to high-protein, that was the problem. It appears that high-protein accelerates aging, reducing protein extends life. Why? We talked about insulin and IGF and all these different things that can extend life and affect health and longevity and they all intersect at the mammalian target of rapamycin. Rapamycin is an antifungal agent. It was discovered in the eastern island of Rapa, so they called it rapamycin. And they found it, well, inhibits cancer. So it's an immunosuppressant. And it's used to this day as an immunosuppressant for organ transplantations, especially kidney transplantations. So people take rapamycin which inhibits mTOR. They found that those kidney transplantation patients who were taking rapamycin ended up having a far lower incidence of cancer. Lo and behold. Even though it inhibited immunity. In other words it was something else there that was really working wonders as far as cancer. Okay, so this is what you will be quizzed on.
Now, the amino acids affect TOR directly. No middleman. Doesn't have to affect hormones, it doesn't have to raise insulin or IGF. It just goes right to mTOR, does not pass go. You've got insulin and IGF, so you've got growth factors. See that at the very top? All the growth factors up regulate TOR. You've got glucose - again, directly it will affect increase insulin but all by itself it increases TOR. Here is TOR, it's actually in two complexes - TORC1, TORC2. They do slightly different things. It's complicated. But it's been so important that it's been almost unchanged since bacteria. That's how ancient this is and that's how important it is. And it is what regulates growth or not. And when you keep it down, you up regulate maintenance and repair, that translates to longevity. That's what we want, we want to keep it down. But we know that it began with bacteria, ancient life and it senses nutrient availability, what are those nutrients that it evolved with... Glucose and amino acids. Those where the components and fuel necessary to replicate life. You keep those down and you keep all these other things down that otherwise would increase mTOR and prevent this up regulation of the genetic expression of maintenance and repair. It's really quite elegant. We know that TOR is also largely responsible for something called autophagy. Autophagy is really important - it gets rid of the crap. So if you have malfunctioning proteins in your cells, you want to get rid of them before you can make new ones. Just like we purposely try and break down our bones so that we can rebuild our bones. You have to get rid of the bad proteins to replace them with good proteins. You do that with autophagy. Part of that is also mitophagy to get rid of bad mitochondria, so you can replace it with good mitochondria. That's largely controlled by mTOR. "mTOR from growth signal integration to cancer, diabetes and aging "and all eukaryotes - that's us-- the target of rapamycin "signaling pathway couples energy and nutrient abundance "to the execution of cell growth and division, "owing to the ability of TOR protein kinase "to simultaneously sense energy, nutrients and stress, "and in metazoans - meaning animals - growth factors. "In the past few years a significant advance in our understanding "of the regulation and functions of mTOR "has revealed the crucial involvement of this signaling pathway in the onset and progression of diabetes, cancer and ageing." And I might also add obesity. When we say growth factor, when mTOR is up regulated, it makes you fat also. That's kind of a newer association between mTOR and health. Amino acids mediate the mTOR/raptor signaling through activation of phosphatidylinositol. "We found that a major pathway by which amino acids control mTOR signaling is distinct from that of insulin." And there have been experiments recently to determine what are the most powerful signals that stimulate mTOR and without question the most powerful signals that stimulate mTOR are the amino acids. In fact there's nothing else you can do that if you eat excess protein and the cells were exposed to excess immuno acids, you can be good about everything else - you could keep glucose down and insulin down and IGF down, and mTOR would be still elevated. That's how important restricting protein is and that's why I say now, even though I knew 20-25 years zero that restricting protein was important, now I would say it's even more important than restricting carbohydrates. And here we have it. "The ratio of macronutrients, not caloric intake, dictates cardio metabolic health, aging and longevity in ad libitum-fed mice" "Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake." "The results suggest that longevity can be extended in animals "that feed whenever they want to by manipulating the ratio of macronutrients to inhibit the mTOR activation." Now it didn't test it against a high-fat diet. This was strictly testing carbohydrate versus protein. And they found that if they increased the carbohydrates, which then satiated the animal enough that they wouldn't eat extra protein, they lived longer. In other words protein restriction was more important than carbohydrate restriction. There is a drug Novartis Afinitor. It helps women with advanced breast cancer live longer. The protein targets mTOR and cancer cells, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism. Resistance to hormonal therapy in breast cancer has been associated with over activation of the mTOR pathway. And I might add now that almost all cancers up regulate mTOR. So we don't want to do that. How do you not do it? Restrict protein. The best drug to reduce mTOR signaling, to slow aging and the chronic diseases associated with it is present. You don't need Afinitor. Reduce your protein intake! It doesn't mean that I want you to eat carbohydrates. No, no, no. What's left? Fat. You want to eat a high-fat diet. These are really compelling reasons for that. Now I told you I wanted to leave you a little bit confused. So far I have just giving you answers. I can't just give you answers. First we'll talk about what's high. I used to say about a gram, protein per kilogram of lean body mass. In other words estimate what your mass is without any fat and as a fudge factor, you could have up to a gram of protein per kilo of lean mass per day. And diabetics I would give 0.75. What I would say now is that everybody should have 0.75 and you can even go lower. Your body would conserve that protein. You will lower mTOR, you will increase maintenance and repair. And you will be healthier. Now here is where you'll get confused. Ketone body utilization drives tumor growth and metastasis. There have been finding and this actually I think went around the Paleo community. And everybody were scratching their heads and coming up with really unfortunately rather bogus excuses. I think that Eric Westman had the best comment on it when he said, "Cancer is complicated." Yes it is. But there actually is an answer to this. And again it's not going to ingratiate too many people... But it's not ketogenesys really that we are after. It's fat burning. They're not the same - it's a high-fat diet. It's not the same. You can have a ketogenic diet by eating high-protein. It isn't the ketones necessarily that give you the benefit. It's the fact that you are burning fat. The ketones are a byproduct so you have to specify if you're going to say a ketogenic diet it's a high-fat ketogenic diet. And it's really the burning of the high-fat that's of benefit, the burning of the fatty acids. As a result you will get ketones that your brain needs. They do good things too and they signal, but you don't want to be after 4+ ketones in the blood. That's not what you're striving for. That's not why it's a good diet. So a ketogenic diet is a good diet, but not because it's ketogenic. It's because it's an indication that you are burning fat. And I'm going to just to take questions.
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