Ron Rosedale – Insulin, Leptin and the Control of Aging

Ron Rosedale says to keep your cells sensitive to leptin, insulin and other hormones for better health.

He gave this talk at the American Society of Bariatric Physicians (ASBP) meeting Oct 31, 2006.  They’re medical experts who work to reduce obesity.  As part of the 2006 presentations, the ASBP included a special segment that featured low-carb diets, researchers and scientists who are connected to the  Nutrition and Metabolism Society.  Special thanks to Instatapes for recording this presentation.

Listen to or download Ron Rosedale speech (60 minutes)

View PDF of keynote presentation that includes citations.

SPEAKER’S INTRODUCTION:  Dr. Ronald Rosedale is an internationally renowned expert on the biology of aging. He was at the International Conference on Aging Medicine at Rio de Janiero, and the first European Conference on Longevity Medicine and many more. He is the author of The Rosedale Diet: Insulin and its metabolic effects. He will be speaking to us this morning on the detrimental effects of too much protein. Please welcome Dr. Ronald Rosedale.

We might give a different view on protein intake and nutrition and actually health in general. First, you hear a lot about paleolithic nutrition, the idea being that ancient man can tell us how to be healthy. That we need to go back to our ancient roots and eat like they did, and then we’ll be healthy. But you have to go back even further and understand what Nature is after. And there are two prime prerogatives of all life, since the beginning of life. And they both involve making more life.

How do you make more life? Reproduce. What do you do to reproduce? You have to eat. You have to eat and reproduce. It’s all life does, and we evolved with those dictums.

We can’t use Paleolithic Man. We evolved with a diet to not allow a man to live a long healthy life.

Nature does not care about us living a long healthy life, or any life, for that matter.  Nature wants “Life” to live.

It’s like, you don’t care if there’s a little cell on your hand that dies, as long as the whole remains. Nature doesn’t care if you or I dies, or if all mankind dies. Nature wants life to live. The diet that ancient man grew up with was to maximize reproductive sense. Not necessarily the life of each individual.

We do know, there is a powerful connection between energy stores, reproduction and longevity. Certainly, we know that it takes a lot of energy to make babies. And if there was not a lot of energy around, Nature would put off reproduction, and it is that trick that we want to use. It puts off reproduction by allowing the organism to live longer. It appears that all organisms have genetic mechanisms to delay aging, to delay dying so that the organism can reproduce at a future more opportune time. And generally this is genetically controlled, and it’s controlled by the availability of nutrients, whether it’s good to reproduce now or put off reproduction into the future.

Because of this, we know now that there are nutrient sensors that tell the body and tell the genetics how much nutrition is available right now, and it is a liaison between nutrient stores and genetic expression that determines whether the body will move toward reproduction or maintenance and repair. This is on an organism level and on a cellular level. On a cellular level, increasing reproduction might not be such a good thing because when you push growth and reproduction too far, you stimulate cancer.

We’ll talk a little about diabetes because it’s the quintessential disease of nutrient stores. Ask anyone what is diabetes, and they’ll say it’s a disease of blood sugar. Diabetes is not a disease of blood sugar. If you get nothing else out of this talk today, realize that diabetes is not a disease of blood sugar. It is a disease of insulin signaling. What we have hear is a failure to communicate. Insulin tells the body a very vital message. Not how much sugar to have. The real purpose of insulin has to do with being a switch, a nutrient sensor, that is one of the pathways that will dictate whether a cell reproduces or whether it lives.

Caloric restriction, metabolism, IGF and insulin are integrated into this longevity pathway, and this pathway appears to be conserved through all of evolution.

It’s found in yeast and flies and worms. Everything down to yeast. Not bacteria. Bacteria has a different definition of life. In fact, it never dies. It just keeps reproducing. So you can’t throw bacteria in there. But yeast, flies, worms, rodents, primates, and certainly humans, it appears. Since the discovery of insulin, most studies have focused on the role of insulin in the metabolism of glucose, however a failure of insulin signaling is certainly associated with a shorter lifespan. What we’re seeing over the last decade is a central role of insulin signaling in lifespan. The discoveries indicate that aging is a programmed and well controlled process regulated by the same pathways that affect growth, metabolism and lifespan. It is an evolutionarily conserved process, so you can extrapolate, it appears, to humans, since it appears ubiquitous.

Calorie restriction also appears to ubiquitously extend lifespan in laboratory animals, and so far, it appears to extend lifespan in humans, too. It extends lifespan in yeast, flies, fish, worms, mice, rats, monkeys, and perhaps humans. Some common, consistent effects of caloric restriction include lower fat mass, particularly visceral fat–remember that–lower circulating insulin and IGF concentrations, increased insulin sensitivity, lower body temperature. Flowers live longer if you keep them cooler. It appears to be a universal truth. Lower fat free mass. Lower sedentary energy expenditure. Decreased levels of thyroid hormone and decreased oxidative stress. Reduced metabolism and therefore free radical production is another possible explanation. And there Other effects such as lower body temperature, decreased insulin, decreased IGF, decreased sympathetic nervous system activity, altered gene expression have all been suggested as mechanisms that explain the extended lifespan associated with calorie restriction.

There’s also a connection between calorie restriction and chromatin structure. Genes are wrapped around chromatin, and their expression is often dictated by how well they’re wrapped. Basically, you uncover the genes to read them. Genetic expression is really the importance of genetics. It’s not the genes you have. Every cell in your body other than your sperm and eggs have the same genes. What makes a heart cell a heart cell and a kidney cell a kidney cell depends on which genes are read. That depends on chromatin structure and other molecular mechanisms such as methylation and acetylation and things like that.

This is talking about an important part of genetic expression dictated by a gene called SIR-2 which in the humans, the homologue is SIRT-1, and research at MIT and Harvard has looked and determined this pathway is NAD and NAHD dependent, meaning energy stores, and when SIRT-1 in humans and SIRT 2 in so called lower forms of animals goes up, animals tend to live longer, and it appears it does this by turning off detrimental pathways that can accelerate aging and turns on maintenance and repair pathways that extend lifespan, and at least partially, you can up-regulate SIRT expression and therefore, by suggestion, lifespan, by amino acid restriction.

Interestingly also, SIRT-1 protein binds to and represses genes controlled by the fat regulator PPR. Where have you heard that before? That’s Avandia, Actos. The first one was Rezulun but they had to take it off the market because it killed too many people. They still kept the other drugs on the market. These are supposedly insulin sensitizers. They are NOT insulin sensitizers. That’s just marketing hype. These PPR agonist drugs such as Actos and Avandia actually work by increasing fat mass. They multiply fat cells. They give you a bigger dumping ground to put sugar. So yes, it lowers blood sugar. Only because you turn it into fat. But is that a healthy thing to do?

Okay? You have to ask the right questions.

Is reducing kidney disease a healthy thing to do?

If I could snap my fingers and create a pill that cuts heart disease in half. Is that a healthy thing to do? Well not necessarily if it increases cancer. You have to look at mortality rate. What is the end result?

If you dig deeper into the answers, you always end up face to face with the biology of aging. Because it will give you the answers. If you slow the again process, and that doesn’t mean getting older, longer. that means staying younger longer, it’s probably a good thing to do, and then you’re going to repress the symptoms of aging. You’re going to repress diabetes and obesity and osteoporosis and cancer and arthritis. The diseases and symptoms we associated with aging. The only way we can really make a dent in that is to treat the underlying disease. And that is aging and that is a disease. In laboratory animals we can manipulate the process of aging to step back in time to a time when it no longer had diabetes. So it isn’t just to prevent disease. You treat disease this way.

Insulin/IGF represents a family of growth factors that regulate metabolism, growth, cell differentiation and survival. It links insulin action to the map-kinase pathway of cell division. Here’s a very important gene, one of the first genes that was discovered that can extend lifespan is DAF-2 discovered by Cynthia Kenyon at University of California in San Francisco that amazed everyone. They didn’t know at the time what it did, but they did know that DAF-2 mutants can live four times longer. They found a moderate decrease in insulin IGF-1 signaling has been shown to extend lifespan in mice. It’s associated with lower levels of insulin, and it’s similar to the improved insulin sensitivity that you see in caloric restriction.

In mouse models, decreased food intake can extend lifespan, and there’s a special role for insulin signaling in fat in the longevity process. Reduced fat tends to lower insulin and protects you from diabetes. They found, by testing various tissues that if you just reduce fat levels, and you enhance insulin sensitivity while reducing fat levels in fat tissue, you extend lifespan. So it doesn’t have to be all over. Fat tissue is a particularly important part of this process. Just a moderate decrease in insulin and IGF signaling has been shown to extend lifespan in mice. This was done by a friend of mine, Andre Bartke and he’s done a lot of studies in mice and shows that if you down regulate insulin and IGF signaling, and you increase insulin sensitivity, you can increase lifespan in mice. A couple of years ago he won the Methusula award. It’s given to the researcher who can extend the life of a mouse the longest. I think he’s extended lifespan about six years now in mice. The normal lifespan is two years. What they’re doing in these laboratories is amazing. They’re tripling lifespan. They’re doing it by the same pathways of genetics that we have in humans. They’re going into the genetics of it, which we can’t quite do in humans yet. The genetics are altered by nutritional stores and nutrient sensors. We do have a way to dig into these genes. Maybe not with pliers yet, but by what we put in our mouths.

Centenarians, people who live to be 100 or older, have lower insulin and IGF levels. One of the nice ways to study aging in humans is on centenarians. Centenarians, they’ve been showing now for quite a few years that there are differences among centenarians. They eat different diets, they smoke and have different personalities. There are not a lot of similarities between centenarians. But they universally have lower IGF, lower insulin, lower temperature and lower thyroid levels. Those go together.

Conclusions: Strong similarities exist between insulin and IGF systems. Maybe linked to oxidative stress, lifespan. It suggests that the Insulin-IGF system arose early in evolution and it is an essential component of anti-aging systems which is conserved from yeast to humans.

Now let’s look at a slightly different view on how insulin works. The typical thinking is that the most important organs that will determine whether a person will become diabetic is how insulin sensitive the muscles, fat and liver are. But that doesn’t seem to be the case. In mice, they turned on and off genes of insulin receptors in different tissues of the body. They determined that the two organs most important by far in determining whether an organism will be diabetic or not are whether it has insulin sensitivity in the brain and liver. Two big keys in determining health and diabetes. These researchers say that we’ve overestimated how important insulin is in muscle and fat and underestimated its importance in other tissues.

This is where we get to leptin.

How many people have heard of leptin? Unfortunately there hasn’t been as much publicity on leptin as there probably should because there aren’t yet any drugs to control it. But leptin is very critical to your health. We’re going to spend time talking about it and its connection to the diseases of aging and actually aging itself. It has a key role in regulating glucose. We get to the brain-liver circuit, which regulates glucose. Brain will tell the liver how much sugar to make. About half the sugar you have floating around in your body on a day to day period depends on how much your liver manufactures. The other half is how much sugar you put in your mouth. I agree with Mike and Mary Dan Eades and many other people about the importance of not putting a bunch of sugar in your mouth. If you want to keep your insulin and sugar low, it doesn’t take an Einstein to figure out, just don’t eat it. You want to keep low the amount of sugar you put in your mouth. That means all the foods that turn into sugar, even rice, potatoes, cereal, pasta, bread. Those are just other names for sugar. Bread is just a slice of sugar, potatoes are just a lump of sugar. Within minutes after swallowing it you just digest these foods into sugar. Fastest way to up-regulate IGF and insulin and sugar and accelerate aging and all the diseases associated with aging is by eating sugar. We’re not going to go there. The mountains of evidence that show that a high carbohydrate diet is bad could fill this room. We’re going to assume we’re on common ground, that eating sugar is bad for you. One of the reasons is because of the up-regulation of insulin and IGF which accelerates aging. One of the ways you up-regulate sugar is that your brain takes signals and tells your liver to manufacture a bunch of sugar. That’s why diabetics can wake up and find their sugars are higher than when they went to bed. They haven’t eaten for twelve hours and their sugars are high, sometimes higher than when they went to bed. It’s because the liver is pumping out glucose. The major control of the liver is the brain. What controls the brain? The hypothalamus. There is cross talk between the brain and liver that couples central nutrient sensing to peripheral nutrient production, ie, glucose. Disruption may lead to hyperglycemia, and that crosstalk between the brain and liver, and the central nutrient pathway involves leptin, your fat. Leptin modulates the meal regulated food intake. It leads to Increased vagal outflow to the liver which produces more sugar. Your fat speaks to the brain via leptin, and is supposed to tell it how much sugar to produce.

We go back to the beginning.

What we have here is a failure to communicate. That’s how you get sick.

We’re ten trillion cells. They have to communicate with one a other. We think of ourselves as a single individual. Well, we’re not. We’re more like a beehive or an ant colony. There has to be constant and really harmonious signals hitting each and every cell, all the time, and when the communication goes awry, you get sick. That’s the difference between life and death. If I died right now, I’d have the same parts. But they wouldn’t be speaking to each other properly.

Leptin modulates glucose by acting as an insulin-sensitizing factor in most insulin-target tissues. Leptin can modulate, in an inhibitory manner, insulin sensitivity, Directly as an autocrine signal and indirectly through neuroendocrine pathways. These pathways may be relevant to conditions caused by hyperleptinemia, such as in aging. As we get older, and as indicated in accelerated aging, and in people who are older chronologically, they have higher levels of leptin, due to leptin resistance. Almost all fat people have high levels of leptin. Fat is associated with diseases of aging. Leptin is a pro-aging hormone. You want to keep it down. Not up.

Are people here familiar, cause I’m skipping over and assuming people are familiar with what leptin usually does.

Here’s a very brief review. Leptin was discovered about ten years ago. Produced by fat. It’s supposed to tell your hypothalamus how much fat you’ve got and whether to produce more fat. And whether you should keep eating to produce more fat or get rid of some excess. In our evolutionary history, it was good to store some fat. All of our ancestors encountered a famine. You needed to have a good energy source. Fat’s a good, efficient energy source, but it wasn’t good to be too fat, because if you were too fat, you were going to end up as a meal for another organism. Because if you are running from a lion in a group of people, which one is it going to catch? If you got too fat, the lion catches you, because you can’t run up a tree. And those genes would have been eliminated from the gene pool. Leptin tells the brain how much fat there is, and whether you should get more fat or you shouldn’t..

Which means, leptin controls whether or not you’re hungry.

It, leptin, knows people are only going to do what they feel like doing. The only way to get people to lose weight is, which means to lose fat, is to get people to not eat too much. That means they can’t be hungry. Trying to not eat in the face of hunger is an impoosibility, it’s bound to fail. That’s why you see this yo yo dieting. If you’re hungry, ultimately, you’re going to eat. It’s like holding onto a cliff. You look down two miles, and you know if you let go, you’re going to die. Gravity is unrelenting. So is hunger.

Therefore, there are signals to the brain that will tell you how hungry you are. These are the same things that will control, also fat storage. The same master signal that controls hunger also controls your ability to store and burn fat. It also controls how much sugar is available. It also controls through the nutrient sensing pathways, the rate of aging, and therefore the diseases associated with aging.

I can’t stress how important that is, because no drugs control it. You can control it by what you eat. Very important, because you dig right into the same genes that are regulating all these aging process in all these laboratory animals.

If you inject leptin into the brain, right into the hypothalamus, you increase glucose uptake. All those people who are hyper-leptinemic, they have high levels of leptin because their brains can’t listen to leptin. If your hypothalamus can’t hear the leptin signal. If you’re a fat slob, and the fat signal’s trying to yell, quit eating, and the brain can’t hear the signal, it’s getting a whisper, and it’s not hearing the signal to stop being hungry. It’s hearing that you’re too skinny and there’s a famine and you need to eat more fat, and so that’s what you’ll do. There’s a disconnect. A failure to communicate. So you make more fat, you make more leptin, until finally the volume goes high enough that your hypothalamus can hear it, but in the meantime, you’ve increased your set point for how much leptin it takes, and how much fat you have,df before your hypothalamus can hear the signal. You’ve got much more fat than you should have had, if your thalamus had better hearing. You have to restore that hearing.

It appears that with insulin resistance, that’s because your cells can’t listen to insulin, so your pancreas produces more insulin so your pancreas can yell at your cells. Because speaking normally wasn’t getting the message through, so your pancreas has to yell. That’s not a good thing because you raise insulin and accelerate aging.

Same thing appears to happen with leptin. Hypothalamus can’t listen to leptin. You have to yell at it. Well, Increasing leptin so it can be heard has detrimental effects. One of the things is increased glucose.

Leptin prevents triglyceride accumulation, provided it can be heard. Well, fat regulates insulin sensitivity. Leptin also regulates glucose homeostasis independent of energy balance. Leptin has a direct effect in promoting glycemic control. It acts directly on insulin production by the pancreatic beta cells, apparently through signals sent through the vagus nerve. Leptin goes up, you make more sugar.

Just remember, your fat apparently is in charge of your brain.

We kind of thing of the brain as being in control. Fat influences your brain. It’s not just an ugly energy storage tissue you’ve got to get rid of. With the discovery about ten years ago that fat is an endocrine organ that produces hormones that regulate lots of important processes in the body, we now know that your brain listens to fat. When I say we’re ten trillion cells that need to listen to communication signals, it’s kind of like the military. You’ve got generals and colonels and lieutenants and captains. It appears from what we know thus far, that leptin is a four-star general. I put insulin as a three star general. Reproductive hormones and insulin listen to leptin. Thyroid listens to leptin. And ovarian hormones. They listen to instructions from above. Leptin appears to integrate everything, including aging. Your lifespan will be determined by the communication of hormones, primarily insulin and leptin.

Hypothalamic arcuate nucleus . . . Leptin signaling in the arcuate nucleus is an affect on glucose. The restoration of leptin signaling remarkably improves the homeostasis of the mouse. Eight weeks after treatment blood glucose levels fell.

Deficits of leptin activity in certain regions of the central nervous system might underlie type 2 diabetes. We think of diabetes being a disease of blood sugar. No. Insulin signaling? That’s what I thought. Now, It appears that leptin might actually supercede insulin in causing or treating diabetes.

Here’s a study that raised eyebrows. After you’re born, everybody thought your brain had fixed neuron connections and they showed that leptin actually changes nerve endings in the brain to do its bidding. If it wants to make you hungry, it doesn’t just do it by neurotransmitters. The “fat brain” actually changes the anatomy of the brain, and leptin is a crucial regulator, including synaptic plasticity and axon guidance within the hypothalamus. Links between nutrition and adipocyte driven instructions from leptin . . . leptin makes you hungry, it actually changes the anatomy of the brain. It’s talking about the fat brain accesses a new dimension in the journal science. Axon guidance within the hypothalamus.

Very important clinical implications. Leptin controls not only how fat your are, but where you’re fat. For a long time we’ve heard about the apple shape versus the pear shape. The apple shape is associated with much more detrimental physiological processes. The pear shape might look ugly, but it’s not particularly unhealthy. It’s visceral fat versus subcutaneous fat. Visceral fat is a totally different organ than subcutaneous fat. It produces different hormones. Visceral fat is really bad for you. If you’ve got visceral fat, it’s because of leptin resistance.

Islets within the pancreas can get fat. We think of ourselves as a single individual. We have to think that we’re 10 trillion cells, and cells can get too fat. Just as getting fat is not good for us, being fat is not good for cells. Beta cells in the pancreas can get fat, and when they do, they can’t produce insulin properly. That’s another way that leptin controls glucose and determines whether you’re a diabetic or not. Whether the cells are getting fat or not is being proposed to be caused by leptin. We propose the signal is leptin and its function is to create for adipocytes a monopoly on fat storage, to maintain a constancy of intracellular triglycerides and adipocytes. So when things are working properly, you store fat in fat cells. When the signals or getting messed up, you start storing fat in other places,and it’s when you start storing fats in other places you get really unhealthy.

Bears get really fat prior to hibernating. But bears don’t get heart disease, because their fat is stored almost all in subcutaneous fat, not in visceral tissues. So being fat doesn’t make you sick. Being fat in the viscera makes you sick. Being fat in places other than the subcutaneous tissue makes you sick. And that’s determined by leptin.

The other tissue that’s very importantly regulated by leptin is the liver, via the vagal nerve from the hypothalamus, but it also determines how fat the liver is, and a few studies here talk about non-alcoholic fatty liver disease. Fatty liver is grossly under-diagnosed. It affects at least two thirds of obese people, perhaps more, and also some people who are not obese. It almost totally parallels the incidence of the so-called metabolic syndrome, and many people believe that metabolic syndrome is actually caused by fatty liver. Which is determined by leptin.

Fatty liver disease is strongly associated with diabetes. High cholesterol. Hypertension. The process starts when there’s so much dietary fat in the blood it can no longer be stored in normal places such as fat cells.

Leptin treatment decreased visceral fat specifically, supporting the role of leptin in determining fat distribution. That’s a very important role of leptin. Determining not only whether you’re fat, but where you’re fat. Perhaps more important.

We’re talking about cardiovascular disease now. There’s a link between insulin action and cardiovascular disease. And Insulin resistance in the development of diabetes can be reduced by preventing the age-dependant accumulation of visceral fat.

When you do liposuction, it doesn’t really help health by taking out subcutaneous fat. It didn’t really help diabetics. But if they took out the omentum in mice, they could totally reverse diabetes in mice. So they’re starting to do this in humans, at Vanderbilt. Leptin activity increases aromatase activity, in visceral fat (not subcutaneous), which converts testosterone and estrogen, which is why you see all these overweight men with breasts. That’s because of an increase in aromatase, and that’s not good because it’s also a powerful increaser of cancer, particularly prostate cancer.

Leptin is linked to autoimmune diseases.

Some of this has to do with how it promotes hypoandrogenicity. Leptin is also a powerful pro-inflammatory agent. You’ve heard of the link between chronic inflammation and cardiovascular disease. Leptin is itself an inflammatory cytokine. But it also dictates the production of interleukins and TNF alfa, Which are pro-inflammatory agents linked to heart disease and diabetes.

Leptin is a novel independent risk factor for coronary heart disease. Leptin enhances the calcification of vascular cells. This was new to people. Leptin also helps control osteoporosis. It helps control where you put calcium. We think of osteoporosis, and women are being given the dictum to take a bunch of calcium. As if osteroporosis is caused by a lack of calcium. That is ridiculous. That’s like saying, I’m going to put a bunch of bricks on an empty lot, and stand back and watch a house be built. I could take a cup calcium carbonate or coral calcium, any type of calcium you want, and dissolve it in a bucket of your blood and stand back and watch for the better part of eternity and I would never see a bone form. And you won’t see a bone form. It won’t happen. You have to have the right signals to make bone. And there’s a powerful correlation between ostereoporosis and calcium buildup and plaque in arteries. You’ve got the calcium but you’re putting it in the wrong place. Just as you can end up with fat in the wrong place, with calcium, whether it’s put in the right place or the wrong place, lot of it is apparantly controlled by leptin. Leptin kind of dictates where you put calcium.

How can one hormone make a difference in all these different things? It has to do with leptin’s ability to control the rate of aging. Aging, or the lack of it, is determined by proper communication. When that communication goes awry, all kinds of things go wrong.

They have shown leptin inhibits bone formation.

Leptin controls osteoblastic activity in bones and vascular cells. High leptin inhibits bone formation via the hypothalmus. And the arterial wall may be an inportant target for leptin action. All the treatment for osteoporosis has to do with osteoclastic activity. Osteoclasts break down bone. They want to prevent the breakdown of bone. The drug treatments don’t make new bones.

But bone strength is determined by the protein content, not the calcium content of bone. It’s the flexibility of bone, which has nothing to do with bone density. It’s the protein content of bones. You want to have protein, you need protein, but you want it in the right places, and you want it in the right amount. High leptin levels are a potent inhibitor of bone formation.

Life is not in the parts. We’re all made of the same stuff. it’s what you, or more accurately, your hormones, do with the parts, that will will determine whether you’re healthy or not. That’s really the way to think.

By changing leptin sensitivity, the Hypothalamic set point can be reversed. In regards to leptin levels, there’s a Possible role of protein.

You know, leptin controls sweetness. I’m just recognizing that this is my next talk.

It doesn’t matter. The problem was, they’re both so linked. You got off easy. I really blast protein in the next one!

I just talked about leptin regulating inflammatory responses. So this is a talk about hormones and aging. The next talk is going to go into problems with proteins and aging. And we’ll go a bit deeply, through a pathway called the M-TOR pathway.

How many people have heard of M-TOR? A couple of people. Not too many. It’s extremely important. It’s another nutrient sensing pathway. You have insulin that senses sugar stores, and leptin that senses fat stores. M-TOR senses the amount of amino acids available and also regulates aging similar to insulin but using amino acids as the key to energy stores. The two major sources of nutrition that determine whether an organism will reproduce or live longer, you have to have fuel available and you have to have parts available. The fuel early on was glucose and not fat. These signals arose in evolution was very long ago. It’s a very ancient mechanism when there wasn’t oxygen in the atmosphere. Life had to flourish before there was oxygen in the atmosphere. Plants had to flourish before they put out oxygen, so these pathways arose with glucose as the fuel availability, and amino acids for the parts availability, and those are the two things you need to make more cells.

So the next talk, we’re going to talk about the MTOR pathway that dictates the amino acid availability and how it plays into the aging process.

Getting back to hormones — Reduced leptin concentrations lead to reduced temperature. You live longer. Temperature kills. You heat something up and it disrupts molecules. It denatures proteins. If you’re going to live longer, one of the ways is by toning down the temperature. In dietary restriction, there may be diverse mechanisms, often known as calorie restriction.

How many people have heard of caloric restriction as a way to enhance lifespan. The dictum has been that it’s strictly a reduction of calories. It doesn’t matter where they come from. As long as you restrict them, you’ll live longer. What they’re showing in more recent studies is that is not true. There are specific nutrients that you can restrict that mediate the effects of dietary restriction. In this particular study by Linda Partridge in London, who’s done a lot of work with aging, the reduction of either dietary yeast or sugar can reduce mortality and extend lifespan by an amount that’s unrelated to the calorie content of the food, with yeast having a much greater effect per calorie than sugar. Get that. Yeast having a much greater effect per calorie than does sugar. Yeast was the form of protein they were feeding these animals. So when you reduce protein, you live longer.

Here, they’re showing that a fall in leptin is one of things that mediates dietary restriction. If leptin doesn’t fall, you’re not going to live longer. In normal men, a fall in leptin in fasting may be both a necessary and sufficient physiological adaptation of these axes, which has to do with hypthalaumus, pituitary, gonads, IGF, thyroid. You have to drop leptin, or dietary restriction is not going to help.

Dietary restriction explained from an evolutionary viewpoint is an adaptive response by the neuroendocrine and metabolic response systems to maximize survival during times of food shortage. Adipose tissue is recognized as an endocrine organ, and leptin secreted by the adipocytes seems to be an especially important factor for the adaptive response to fasting and neuroendocrine response under caloric restriction.

The one known way to extend lifespan of every species studied since 1933 has been to reduce calories. Since that time, the emphasis has been to figure out why. Ten years ago, they discovered a gene that can control aging, Age-1 gene, discoered by Tom Johnson at the university of Colorado, and Cynthia Kenyon with DAF-2 expanded on this. These all link to nutrient sensors and it all links into a pathway that governs maintenance and repair or growth. They’re all linked to nutrient receptors, and it appears that in mammals, leptin plays a key role, and those animals that use fat as a prime energy store, leptin plays a key role in the aging process.

Prior to leptin, and it appears that they’re cousins, it was Insulin and IGF. Insulin and IGF in ancient organisms, insulin and Insulin like Growth factor were the same. Over time they evolved to have separate duties. Now insulin is more metabolic, and IGF is more anabolic.

Leptin has been proposed as a potential candidate for the adaptive response to Caloric restriction.

This was a longer talk than the other one.

So we’ll have to hurry.

A hypothesis for interpreting the extension of life from caloric restriction posits that normal food intake is geared toward optimizing the internal milieu for reproduction. That’s what Nature is after. Not after health. Nature doesn’t care whether you’re healthy or not. We have to use this trick, however. Nature wants us to live long if it thinks we can reproduce better in the future.

In our ancient life, that was dictated by fuel availability. We can use the science to regulate the nutrient sensing pathways to improve our lifespan and our health.

Here it’s showing that leptin is very much involved in reproduction.

Skinny women, women marathon runners stop ovulating. Inject them with leptin and they’ll start ovuating again. Reproduction and eating are the two main endeavors or all life, and they’re both controlled by leptin.

DAF-16, I don’t have the time. Here, it’s showing that Daf-16 is one of the genetic components that mediates caloric restriction. They’re finding that just activity in the intestines — In C-elegans, the intestines is where it stores fat. DAF-16 in fat, Determines lifespan in the worm.

Signals from fat regulate genetic expression.

Here again, talking about the importance of fat tissue in longevity. Leptin controls whether you’re satiated or not. It also has to do with life extension. With PPAR alpha. Not PPAR gamma. PPAR gamma is what people are taking drugs for. PPAR gamma accelerates life and reduces lifespon. PPR Alpha enhances lifespan. Exactly the opposite. Leptin modulates this through the PPR system because PPR gamma influences a lot of what happens in fat.

Failure of leptin suggests leptin plays a major role in dietary restriction. There’s a link between leptin concentration, with higher levels linked to telemere shortening, which is another theory for aging, that shorter telomeres reduces lifespan, and telomere shortening is controlled by leptin. Waist-to-hip ratio correlates with leptin levels. Centenarians have lower waist to hip ratio. Longer lifespan was predicted by lower levels of leptin. Here, they’re showing that a bunch of amino acids stimulated leptin production.

One of the ways that leptin is elevated that causes hyperleptinemia is caused by high levels of amino acids.

Whereas a high fat diet is associated with low leptin.

In membrane composition, insulin and leptin regulate the types of fat found in membranes.

Talking about IGF again and membranes, that omega three fatty acids improve leptin sensitivity.

This is a study that hasn’t been published yet, that is a collaboration between myself and Eric Westman and John Konhilas. What we’re showing is that a high fat, adequate protein, low carbohydrate diet with nutritional supplements in an outpatient setting, resulted correlates of aging. There were reductions in body weight, triglycerides, insulin, glucose, leptin, free T3 The same things you see with caloric restriction. But we were not restricting calories. The reduction in insulin and leptin levels was strongly correlated with reduction in weight, but the reduction in leptin levels was far greater than the initial weight loss. In other words, leptin is not dictated by how fat you are. It’s dictated by what you eat. Sugar increases leptin output, and amino acids increase leptin output.

You don’t have to have any sugar, but you have to have some protein. But you don’t want too much. Too much protein raises leptin and accelerates aging.

Your brain is a servant of your fat, your brain is what fat uses to do its bidding, and your fat’s bidding will determine your lifespan.

Special thanks to Greg and April at Instatapes for helping to track down the audio of this talk, and to Ron for permission to post the audio, transcript and PDF of the citations used in the talk.