Mark Mattson - Optimization of Cognitive Performance

thanks for the introduction and like to thank Ken for the invitation I met Canada meeting and Wyoming Jackson Hole aimed at trying to come up with new ideas to improve cognitive performance in particularly the military and people who have to keep focused on a task for extended time periods and one of the approaches that might help as I'm going to talk about today is intermittent fasting or reducing energy intake or eliminating energy intake for extended time periods and I'm going to talk about this from an evolutionary perspective that is to say why it is that it makes sense from an evolutionary perspective and what the data are that your brain should be working well when you're hungry and haven't been able to obtain food for a long period of time if your brain isn't working well you're not going to be able to compete with your competitors to obtain the food and I'm going to talk mostly about work we've done in animals where we can tightly control their food intake their eating pattern their level of exercise and we can directly look at their brain look at individual nerve cells in their brains put electrodes in those nerve cells study communication between the nerve cells take out the brain tissue measure levels of various neural chemicals to try to understand why it might be that fasting and exercise are good for the brain and then I'm going to talk a little bit about some of the translational work we've done asking a couple simple questions in human subjects can human subjects maintain intermittent fasting diets long term and if so does it improve their health and then hopefully if I don't forget about it at the end I'm going to mention a study a study we have ongoing where we're focusing on the brain okay there we go okay evolutionary perspective you don't see many fad predator or prey in the wild okay and so if you're a hungry Bobcat and you haven't been able to catch a rabbit in a long time you better figure out how to track down the rabbit and catch it and moreover you better be physically fit and be able to catch it on the other hand if you're the prey likewise you better figure out how to avoid the predator so the it just makes sense intuitively that the brain has to be functioning well and you have to be physically fit for maximum performance to survive at least in the case of animals in the wild and probably in the case of our human ancestors before the Agricultural Revolution okay here's another example we have an eagle swooping down to get a fish and so in addition to have being able to recognize visually and detect the the prey they have to have a good idea where to look and and what kind of patterns of rippling in the water represents a fish versus some some other disturbance in the water then also it's important social interactions are very important in survival among many species you know we see some wolves here surrounding a buffalo so they had to found that they work together they could kill an animal that an individual wouldn't be able to kill by itself you know so this is a example of the evolutionary basis of social interactions but again all revolving around figuring out how to obtain food this is a major force for evolution of the brain many organisms including humans okay our our boreal non-human primate ancestors so before we came the we became bipedal that our ancestors lived in the canopy and they had to learn where sources of the food are and I'm going to come back to this point in the end because it's kind of interesting from an evolutionary perspective so these primates had to know where tree fruit trees were they also had to know at what times of the year different trees the fruits were ripened and there's even evidence that this ability a good ability to know when and where to find these sources of food was a driving force for evolution of what's called the prefrontal cortex which is an area of the brain that has expanded most in our primate ancestors and in humans and it's a brain region and evolved in what's called executive function and decision-making which humans do really well in fact there's there's whole books written on on the evidence supporting this notion that our non-human primate ancestors the reason their prefrontal cortex started to develop was these it's being able to make decisions on how to obtain food and with limited resources so then we can go even to how am I going to spend much time on this slide but you know I could even make the case that development of tools was primarily early on devoted to making tools that enabled us to get food and compete to get food bow-and-arrow you know a complex weapon for hunting now we have guns and we we use guns not only to obtain food but unfortunately for more nefarious purposes a mass collection of food right mass production of food which is good and bad it's good and it makes it easy to get a lot of food nobody starves bad and because you have the big Agri and refining making corn syrup and people have constant access to high energy high energy density food they don't have to work for their food they don't have to challenge themselves to get food either physically or mentally and we think this is not good for the brain in the long run it's better to to challenge yourself physically and and maybe by fasting which will activate mechanisms in the brain that I talk they'll talk about now which seem to be good for learning and memory and and we think may reduce the risk for developing age-related neural degenerative disorders such as Alzheimer's and Parkinson's diseases okay you know processed foods okay so this is this quick summary this you know the point here being that in the past animals and our non-human primate ancestors and even hunter-gatherers humans had to work for their food and had to go extended time periods without food based on the seasons and other aspects of drought you know weather and so on and as you know the major killers in humans a hundred years ago were infectious diseases actually injuries and cardiovascular disease and diabetes were very rare back then and now with the processed food industries and our and technological advances that allow us to to go our whole life earn a living without expending any energy you go to your car drive to work take the elevator sit down all day come back and and with ready access to food but now the you know major killers are cardiovascular disease cancers diabetes much of this driven by the couch potato lifestyle what I would also point out here that and I guess I didn't put this slide in with advances in research in the areas of cancer cardiovascular disease and diabetes so for example early detection of some cancers colon cancer is a good example and where you can detect it early get rid of it before it kills you and and treatments for cancers and then cardiovascular disease people who would have died in their 50s 80 years ago and now getting bypass surgery living another 20-30 years same with diabetes there's some effective treatments although none of them are as effective as exercise and reducing energy intake so many people who would have died when they're in their 50s and 60s are now living into their 70s and 80s which is the danger zone for Alzheimer's and Parkinson's disease in terms of age and unfortunately there are none zero treatments that are effective for Alzheimer's in slowing the progression Parkinson's there are symptomatic treatments early on in the disease but invariably the the patients will have progressive degeneration and die so this is a huge problem not only from the demographics of the baby boomers reaching the danger zone for these brain disorders of aging but also from the fact that advances in and allowing people who would previously have died at earlier ages to live to these ages ok this is a schematic diagram showing the nerve cell circuitry of a brain region called the hippocampus it's a brain region critical for learning and memory and the reason is because it receives inputs from our different sensory inputs vision hearing touch all of the sensory information funnels in to the hippocampus and so that since that's where these inputs converge that's where the pairing of a of an image and a sound for example are paired temporally so when you look at my slide and you listen to my voice then that visual and auditory information is converging and what happens here in the hippocampus is critical for the at least the short-term memory of that so that you know 10 sec 20 seconds from now I can ask I can change the slide and I can ask you verbally what was on my previous slide and you can give me a visual description of what was on the slide and that's because of this important brain region the hippocampus this is a brain region where nerve cells become dysfunctional and degenerate in Alzheimer's disease now it's been shown by other labs in our lab that vigorous physical exercise like running for example and dietary energy restriction and also intellectual challenges in doing what we're doing now increase excitability of these nerve cells in the hippocampus and what happens is there's a neurotransmitter represented by the red dots here I guess called glutamate its amino and amino acid but it's also the major excitatory neurotransmitter in the brain so it's released from an axon terminal it is synapse and it activates receptors on the subsequent cell in the circuit and you get flow of information and also with activity in these nerve cell circuits this electrochemical activity that stimulates production of a protein called BDNF brain-derived neurotrophic factor this neurotrophins levels increase in response to exercise intermittent fasting and and intellectual challenges and it's been shown in animal studies and also there's some evidence I'll briefly show you one slide from human studies that BDNF plays very important role in learning and memory so if you block BDNF production or it's action that will impair cognitive performance in animals and there's also correlations between enough levels and cognitive performance in humans another interesting aspect of this hippocampus is that there are stem cells dividing cells that can replicate and then when they get the right signal such as exercise or fasting these cells stop dividing and they form new nerve cells which are then integrated into the nerve cell circuits and one of the investigators in my group Henriette von Prague has shown that the production of these new nerve cells in response to exercise enhances a form of learning and memory called spatial pattern separation and I'll show you one or two slides on some of those data and this becomes very important in thinking about how exercise might benefit human cognition even higher cognitive functions such as imagination and creativity in humans and I should also point out you know this intellectual enrichment this can be you know thinking about complex problems such as we're thinking about now are can be music learning and playing music recalling and and maybe improvising in music so that's another type of environmental input that seems to activate these pathways that enhance synaptic plasticity and promote the production and integration of new nerve cells ok I'm going to briefly talk about exercise before I had talked about intermittent fasting I'm dr. Bob Prague Prague showed that if she puts running wheels in the cages of mice and then MIT and then identifies the number of stem cells in the hippocampus each black dot here is a stem cell I don't need to go into the technical details of how we label these stem cells she finds that running increases the number of stem cells and then when she follows over time what happens to these stem cells she finds that many of these stem cells form new nerve cells so this is an individual nerve cell with a cell body here the dendrites here these receive information coming into the hippocampus and so yeah and so this is this is my son here Elliot this is my daughter M is the coach high school cross country I quit doing that a number of years ago actually after Emma graduated and but I would tell the kids on the team that you know this is really good for your brain and we all the parents you know so we'd have pasta parties the day before the the meet and it's kind of the carbo-loading type thinking I'm not sure that's necessarily right but anyway and but you know all the parents including us we notice during the cross-country season the kids their mood is better exercise has an antidepressant effect it improves mood and we think that actually occurs through increasing BDNF levels there's good evidence for that in fact the most commonly prescribed antidepressants Prozac Paxil etc increased BDNF levels in the brain and at least in animal models if you if you block BDNF then these antidepressants don't work but also their grades are better in the during the cross-country season okay so now I'm going to go back to the study in mice so one one way we can test cognitive function in mice is using touch screens so this is actually very new only in the last five years or so this started to become widely used so first you can teach a mouse that if it touches its nose to a touchscreen it will get a food reward so these are small boxes with a touchscreen and then this like half a foot away from the touchscreen a food reward bin and this is all computerized then what we do is we put one lid I con on the screen and over a period of a couple weeks the mouse will learn if it touches this icon with its knows it gets a food reward and then we put two icons on the screen we teach it train it to touch this one for a food reward if it touches this one it doesn't get a food reward then we decrease the distance between the lid icons and as we decrease the distance going from big to small icons the mice make more errors you know they have more trouble distinguishing which one they should touch because they're closer together so we call that spatial pattern separation ability and however if we put running wheels in the cages of the animals here they make fewer errors significantly fewer errors as we decrease the distance between these icons so running improves the ability of the mice to distinguish between these icons when they're close distance and we found a correlation with production of new neurons that is fewer errors more new neurons ok I'm a trail runner and from from an evolutionary perspective a human evolution trail running is the quintessential human experience it's what our ancestors did a lot of but walking or running on trails and it become became very beneficial for an and you know that the data suggests that we lived in small groups tribes hunter-gatherer tribe scenarios and so is a big advantage for us when we're running you know going some distance say 20 miles away from from the where the tribe lived to be able to remember what we encountered we when we went on that trail run or walk so that when and and I think this was actually a driving force for development of language or at least one driving force because it's obviously a value to transmit the information on what you saw and encountered to your tribe mates so that then you know they can go out and you can tell them to you go on the blue trail you go on let's see where do we go so our running group we have a running group Saturday mornings we go trail running so for example we'll say ok we're going to take the yellow trail to the blue trail and then we're going to come back or we're going to go this route or the other and after a few runs on the trail not only do you remember that general route you remember details of where individual rocks rocks and roots are and what's coming up you know there's a big hill coming up so maybe I should back off now because I don't want to be dead at the end of that but from the standpoint of cognitive function if you're if you have to be focusing on what you're doing while you're exercising I think that promotes optimal brain function in the long run no pun intended ok so let's go back to animal studies diabetes is a big problem now and no pun intended again but you know being overweight is a big risk factor for diabetes so we have animal models of diabetes one model is leptin receptor mutant mice leptin is a hormone when you eat a meal its released from fat cells and and into your blood and it travels to your brain and it tells you to stop eating you're getting full so people obese people often have what's called leptin resistance and actually have high levels of leptin so they produce the leptin but the leptin is not effective in telling the brain to stop eating so they continue to have the perception that they're hungry even though they're clearly not in danger of starving but they you know so this is a and there's also another problem with diabetes which is well understood it's called insulin resistance so individuals with type 2 diabetes often have elevated insulin levels and the reason is because for example the muscle and liver cells that normally respond to insulin by taking up glucose from the blood and moving it into the muscle or storing it in the liver those cells don't respond to insulin properly and so your pancreas starts putting out more insulin to try to get the glucose out of the blood okay so anyway we have mice that can't respond to leptin and so they have constant hunger essentially and they overeat they become obese and diabetic and so what we did is we looked at these neurons in the hippocampus and we looked at individual dendrites these regions that receive information coming into the hippocampus and so this is one dendrite here and along this dendrite you'll see these perpendicular projections in each of these perpendicular projections which are called spines represent one synapse and then we simply count the numbers of these synapses and we quantify this and so in this experiment what we had is four groups of diabetic mice and four groups of normal mice we call them wild-type mice one condition was the normal laboratory housing conditions ad libitum fed they can eat whenever they want eat as much as they want and sedentary know these small cages no running wheel then we had a group they were fed ad libitum but had running wheels in the cages we had another group we reduced their cow daily calorie intake by about 30% but they were sedentary and then finally we had a group that was calorie stricted and they had running wheels in their cages and if we look at the normal mice here you see that the black bars calorie restricted group had increased number of synapses the animals with running wheels in their cages had increased number of synapses compared to the couch potato mice and then the combination of calorie restriction and running had the maximal effect in increasing in the number of synapses and in fact these animals do the best in learning and memory tasks then we look at the diabetic mice here you see overall they have much lower number of synapses than to the normal mice however nevertheless both calorie restriction and running increased approximately doubled the number of synapses and this isn't immediately this occurred over three to four month time period and then finally in this lower panel we see a nice correlation between synapses and BDNF levels so calorie striction and running increased BDNF levels the combination you get a further boost in BDNF levels and we think BDNF is playing a role in the improved learning and memory what about humans well it turns out there are certain families that have reduced levels of BDNF levels because they have a mutation that they in hitting the gene encoding BDNF that they inherited from one of their parents so these are B D and F heterozygous humans and then if you compare and in this study was done in young adults so high school kids either kids normal kids or kids with reduced BDNF levels and this is testing their cognitive functioning so there's a statistically significant were poor performance of the kids with reduced BDNF levels compared to the normal kids and then this study was done recently published in 2013 autism is a very big issue and problem now so they also tested these kids for behaviors that are characteristic of autism and the kids with reduced BDNF levels had significantly higher score on these autism like behaviors compared to kids with normal BDNF levels so these data we're obtaining in mice isn't not just relevant to my sweet ink it's very relevant to humans okay I mentioned in humans that we have a big prefrontal cortex also to our other regions of the brain that have expanded in humans are those that are related to language evil either indirectly or more directly so visual cortex and associated regions so language is central essentially processing of visual and auditory information and correlating them you know you read something and it's all recognizing patterns the letters and their sequences and patterns language audit you know speech is also the same thing of case sequences of sounds okay so I wrote this kind of a provocative article if any of you are interested you can access it easily on the internet it's called superior pattern processing is the essence of the evolved human brain so I showed that exercise and also intermittent fasting can improve cognitive function and spatial pattern separation and I think even things like creation creativity imagination being able to foresee events that might scenarios that might happen in the future in decision-making all revolve around processing visual and auditory patterns okay now that we're going to talk about fasting and so I gave a TED talk on this so if you're interested you can find this on the internet easily but from a historical perspective there's many cases where you can find famous people who claim that they did their best thinking and work when they were fasting so Plato for example he found that he did his best thinking in writing when he was fasting so he subjected himself to sort of intermittent fasting type scenarios Gandhi and also you know many religions fasting is commonly practiced and because it clears the mind we think that's actually true and from an evolutionary perspective a non religionist non-religious true to evidence perspective fasting should be good for the brain from the standpoint of being able to compete to obtain food and resources and now compete your competitors and but also a lot of interesting quotes for example Mark Twain little starvation can really do more for the average sick man than the best medicines and best doctors and so on also very interesting Upton Sinclair who wrote the book the jungle that exposed problems in the meatpacking industry around turn-of-the-century 1900 he also wrote a book called the fasting here and published it in 1911 very interesting they interviewed 200 and some people who had some ailment they went on some fasting diet of various types and and almost uniformly found benefits for their health you can find the full text of that on the internet - okay in the 1990s we we were working on trying to understand what's going wrong in the brain in Alzheimer's disease Parkinson's disease mainly in animal models and we either used models that are based on putting a mutated human gene that causes Alzheimer's disease for example mutation in the amyloid precursor protein gene a mutated gene that causes inherited Parkinson's disease for example mutation in a gene encoding the protein alpha-synuclein we put those genes into the genome of mice and those mice the Alzheimer's model they'll get accumulation of amyloid in their brains as they get older and they'll have cognitive dysfunction the Parkinson's model the mice will develop accumulation of this alpha synuclein protein in their dopaminergic neurons and other neurons and they'll develop motor dysfunction and actually die and then we also had neuro toxin based models where we administer a toxin to the animals that selectively damages nerve cells in the brain regions in which the nerve cells degenerate in the human disease so for example in this one of the first papers we published on intermittent fasting we use toxin based models of severe epileptic seizures and and kind of an acute amnesia and and then a model of Huntington's disease it's based on using a toxin that impairs the mitochondrial function in nerve cells so what we do in these experiments is very simple in design we have two groups of rats or mice one group there they eat every day as much as they want the other group we have them fast every other day so one day we go in we remove the food from the cage the next day we go in at the same time we put food back next day remove it next day put it back so they go 24 hours no food 24 hours food that's the way they go for months and months and then we expose them to a toxin or are we we follow the outcome as the disease develops in the genetic models we test their learning in memory we test their motor function and so on and so for example in this study we found that this intermittent fasting alternate day fasting is neuroprotective and improves functional outcome in mouths of severe epileptic seizures and Huntington's disease this is a different model of Huntington's disease where we have mice that express the mutated human Huntington's gene this is a model of Alzheimer's disease here that we developed about 13 years ago these mice develop amyloid accumulation and cognitive dysfunction interestingly we found that the intermittent fasting prevented the cognitive impairment as these animals get a lot older but it didn't prevent the accumulation of the amyloid so somehow and and we think we know in part how the intermittent fasting is protect being the neurons against the amyloid and that's very interesting because it turns out that there are many humans who they live into their 80s 90s even a hundred their sharpest attack but then when you look at the brains at autopsy they're loaded with amyloid so somehow those individuals resist the their nerve cells are resistant to the adverse effects of the amyloid whereas in other individuals the nerve cells are not resistant and and we think in the case of exercise and fasting we have some insight into why and I'm going to show you in the next slides some of that and we also found for example if we animals that have been maintained on intermittent fasting diet they have a better outcome following experimental stroke there's less brain damage when when we block off the blood supply fewer neurons died in the territory supplied by that mainly by that blood vessel and they have improved functional outcome okay so what what might be the mechanisms whereby fasting is good for the brain well we know one major thing that happens from the standpoint of energy metabolism is that if you eat three meals a day plus snacks every time you eat the energy goes in your liver it's stored in the form of glycogen and that's always tapped into first the glycogen is metabolized and released the glucose is released into the blood so if you eat three meals a day plus the snacks you never deplete the glycogen stores in your liver however if you go for example say 16 hours without eating certainly by 24 you've completely depleted the glycogen stores in your liver then what happens is fats are mobilized so fatty acids are released from your fat cells they go into the liver and they're metabolized to what are called ketone bodies such as beta hydroxy butyrate and acetoacetate and and so then and and you can you know we all know this you can survive for weeks and many people a month not eating anything as long as you have water available and don't become dehydrated and the reason is that you're running if you will on ketones okay and it turns out ketones are an energy source for neurons similar to glucose in that both glucose and ketones can be converted in the nerve cells to ATP adenosine triphosphate and and ATP is what the molecular energy substrate is that allows our muscle cells or brain cells to work okay ketones are good for brain cells not only because they're an energy source but we think they actually have signaling functions they have it's a signal that's coming from the blood to the brain that's alerting you and in the case of our animal studies the animals to the fact that there's this shift in energy metabolism which is an indicator that you better start finding a new food source because eventually you're going to run out of fat stores too and then you're in big trouble and we find it in fact that ketones increase BDNF production in in the brain and we think that that's a ketones are one peripheral signal that alerts the brain that had better start working well okay so we did all these studies and animals and then I was through correspondence communicated with a number of MDS who work with mostly with overweight subjects for example Jim Johnson works with asthma patients so we did a study with him where we took small study twelve asthma patients they're overweight we put them on a diet where every other day they only 500 calories which is a kind of a very severe change these are overweight subjects who are normally eating three meals every day and they're taking in too much energy but ten of the twelve subjects were able to go two months on that diet they lost weight as you can imagine they their asthma symptoms improve their airway resistance improved Jim Jonsin sent us blood within about two weeks and and and then particularly by a month markers of oxidative stress and inflammation in their blood were way down and stayed down through two months and so Jim wrote a book called the alternate day diet based on that and published it I just let let these people publish the books because two reasons they did a good job another reason I'm working for you you pay my salary I can't make any profit on publishing a book I'm a US government employee and then we did a study in collaboration with dr. Michele Harvey at the University of Manchester in England who works with women at risk for breast cancer because of their family history and and they're also most of them are overweight and so in that study there was about a hundred women we divided them into two diet groups one group they reduced their daily calorie intake by 25% the other group we had them two days a week and in this study was two consecutive days although we don't think they necessarily have to be consecutive but on those two days they ate only 500 calories that's now called the 5:2 diet or the the fast diet and so what we found in and they stayed on these diets for six months and we had good compliance week not only were they losing weights but we measured leptin levels we measured ketone levels and we took we took blood on the days they're supposed to be doing only 500 calories the other days so we we can tell from a scientific standpoint where they're following the diet both energy restriction groups lost weight but the women on the 5:2 diet lost more belly fat and they had greater improvement in insulin sensitivity and very likely the reason is because on those two days they're burning fat whereas the women who are eating three meals and just reducing by 25% calories each meal every time they eat they replenish the glycogen stores and they never shift to burning fat so that led to this to the BBC doing a documentary on this and this michael mosley the producer for the BBC he wrote this fast diet book and there's been some copycat books and and michele harvey wrote a book and then the other diet that's become popularized as what's called time restricted feeding so instead of you know focusing on maybe two days a week cut way back or eat no food and but maintain hydration another approach is every day limit the time period you eat to say eight hours six or eight hours it turns out most americans actually they put something caloric in their mouth when they get up and then they'll eat several meals and then they'll eat the snack in the evening so the only time they're not putting something caloric in their mouth and therefore not replenishing their glycogen stores and their liver is when they're sleeping so the idea with this time restricted feeding or 8 hour diet is you limit your time window that you consume food dude say eight hours or so I personally kind of limit to about six hours then I actually exercise after having not eaten for 16 or 18 hours I had to eat lunch today but anyway I didn't eat breakfast I ate a modest lunch can will attest to that not many calories and oh I'm feeling faint No now but I'm you know so you can run on ketones for quite a while okay but this is a different the point here is that from the standpoint of challenging yourself by oh energetically from from a you know short term fasting approach there are a number of different ways that people might think about incorporating this type of approach into their lifestyle based on you know their work schedule and so on for me it's easy to to get up go right to the lab start working I drink a lot of tea with you know seems and and then I don't eat lunch then a workout mid-afternoon and I find I'm fine I don't get hungry that much once you get adapted to it and I don't have any post prandial sleepiness you know that you might get if you eat lunch particularly if you eat carbs for lunch I'm getting kind of long winded I don't know how much time I have left oh my gosh okay keto ketones may be good for your brain okay so here's kind of a idea now what we're finding and I'm not going to have time to show you any data but if we look at the nerve cells themselves what's happening in the nerve cells with exercise with energy restriction particularly fasting and I'm going to talk about this at the end hormetic phytochemicals we think that mitochondria function better and actually we think there are more mitochondria in your nerve cells if you exercise regularly we find that that exercise in BDNF will increase a process called mitochondrial biogenesis it's the the growth in division of mitochondria so similar to what happens in your muscle cells when you exercise regularly you increase the number of mitochondria in your muscle cells that make sense then your muscle cells can they have more energy ATP we think that's happening in nerve cells with these types of bioenergetic channel is also very importantly we think that these are these challenges are stimulating a process called Auto Fei Jie Auto Fei Jie means self eating but essentially what happens is the cells enhance their ability to remove damaged molecules dysfunctional mitochondria so they're clearing out the garbage okay and then neural trophy cat factors increase we found that DNA repair ability increases and all together that we think that may counteract the accumulation of these proteins amyloid beta peptide tau and so on that accumulate in Alzheimer's and Parkinson's I'm going to skip all this essentially recently we showed through a number of approaches that that if we block the ability of nerve cells to increase the number of mitochondria that will block the ability of exercise in BDNF and and and we think fasting to increase the number of synapses so again we're looking at these synapses here and we find that if we block the ability of neurons to produce more mitochondria we block or decrease the number of synapses that's mainly what that is I'm going to skip this except to say that we discovered that there's a protein in mitochondria called sur 2 & 3 and exercise and BDNF will increase the production of this protein in the mitochondria and this protein cirthree makes the mitochondria more resistant to stress more resistant to oxidative stress that is free radicals more resistant to bioenergetic stress okay so in the last two minutes I want I wanted to get back to this because this is very interesting so I haven't mentioned a word yet a word that without a lot of interest in is called hormesis and the idea here is that and this is well-documented exposure of cells or organisms to a mild stress can enhance the ability of this the organism and the cells in that organism to more severe stress so the idea here is that low levels of stress are good high levels of stress can be bad that's even true with exercise you can overdo it in exercising you can overdo it in fasting you can starve to death that would be overdoing it there but there but there's a there's a big therapeutic window for fasting it's it's pretty hard to to overdo it there but from an evolutionary perspective we there's a lot of interest in what is it about fruits and vegetables it's good for health and and for many decades they convinced that dogma is that there are chemicals in the fruits and vegetables that scavenge and scavenge free radicals antioxidants so you go to the health food store the vitamin you'll see antioxidant antioxidant antioxidant that's encrypt the chemicals at least some of the chemicals that are in fruits and vegetables that are good for your health are good for your health from an evolutionary perspective because they are toxins they are noxious the reason that they're produced by the plants is to prevent you from eating the plants and that is why the healthiest plants have them are the worst-tasting plants and why your kids don't want to eat the broccoli and the other bitter tasting chemicals and so I we I wrote an article for Scientific American that was published last year in the July issue and and so here's the points here I'll just read this quickly plants don't have the option of fleeing predators as a consequence they developed an elaborate set of chemical defenses to ward off insects and other creatures they want to make them into a meal these toxins that plants produce are consumed by us there's no question about that and the exposure of these chemicals caused the mild stress reaction and this is hence ability of ourselves to resist more stress so it was to our advantage to be able to eat a variety of fruits and vegetables that have a bit even those that have a bitter taste because they have nutrient value they have calories they have other nutrients and so we develop many defenses against these chemicals one is they are have come they have very bitter taste and indeed there are many plants that have toxins that can kill us even in low doses okay and we can overdose on some of the chemicals that probably everyone in this room commonly consume caffeine is a toxin you can kill yourself overdose with caffeine if you take pure caffeine and put it on your tongue you don't want to have any part of it you it's very bitter tasting okay the second defense after our tongue is vomiting okay the third defense which is very interesting is enzymes in the liver called cytochrome p450s that rapidly metabolize or degrade these noxious chemicals that are in the plants the fruits and vegetables so one pass through the liver most of these chemicals are removed from the body so they pass through our system once and and many of them get into the brain so our cells are exposed to them they induce a mild stress in ourselves and they're eliminated so it's a transient stress so we get this ideal of hormesis transgender row-level exposure to these toxins is good and high doses can kill us but we have many defenses that prevent that from happening so the final slide my talk so I talked about these challenges is what happens fast bioenergetic challenges intellectual challenges phytochemicals activate these pathways clear out the garbage increased neural trophic factors but recovery period is very important so after fasting eating is important because you have to get the nutrients in the cells and protein synthesis to allow growth of the cells building of muscles of your body builder you can build muscle with intermittent fasting but you've obviously got to eat but as long as you eat after fasting it's good in fact might even be better for bodybuilding that if you didn't do a short-term fast before you workout after exercising resting sleeping is very important for the brain and other particularly for the brain and we think what's happening during these recovery periods is that it's when protein synthesis goes up that's actually when the number of mitochondria is increase the the stimulation the pathways activated for the increase occurs with the challenge but it's then during the recovery period that you actually get the growth formation of new synapses and and then we think enhanced learning and memory so these cycles of a challenge to your system and then a recovery period challenge recovery and I'm talking about you know within the period of a day or over a period of a several days challenge recovery challenge recovery the best example of exercise which is very evident but we think it's also true with with with the food restriction and fasting and intellectual challenges right you sleep is very important for what we think consolidating what you've learned during your waking periods into long term memories so this is a my laboratory actually a couple years ago so these faces or many of the people who did a lot of the original research I talked about and this is since I quit coaching cross-country now I NIH has an annual relay race in Bethesda we're in Baltimore so we never entered this race until I quit coaching cross-country then I started coaching getting together teams at ni a and so this is one of the teams and we've actually there's typically ninety to a hundred teams in the race and each leg wears five runners in the race to have to be female each leg is a little over eight hundred meters and so we we what we finished first the first year we entered the last two years we've finished second point there is we we practice what we preach thank you very much that I'm okay thank you so much now we have time for some questions and answers any questions out there I will cut and wait for the microphone and I'm bringing it to you thank you so much for you talk have you looked into or are there other parts of the research that are looking at what the effect on mental illnesses would be that's an excellent question this hasn't been looked at much yet that's how you're talking about fasting it in particular yeah well there's good evidence that exercise is good for for many psychiatric disorders certainly for depression for anxiety disorders bipolar disorder is mechanistically there's quite a bit overlap with anxiety and depression as I mentioned exercise increases BDNF levels in the brain and that has an antidepressant effect intermittent fasting in animals from a neurochemical standpoint there's a lot of overlap of what's happening in the brain with intermittent fasting and exercise so there's some scientific rationale to suggest that it's worth pursuing controlled studies in human patient populations to my knowledge there have not been such studies done I think it's a very good question very important to do there's a question that comes up what about anorexia nervosa which is a psychic psychiatric disorder and it and so one question is well you know this particular particularly affects most heavily young girls and and women and so the answer is we don't know you know I think that would be a good study actually have some subjects with anorexia nervosa and and and you divide them and try to change their eating pattern and and maybe maybe they would Mabel that actually maybe it's counterintuitive but maybe it actually actually increase their overall energy take during the week if they if they do some intermittent approach am but one interesting thing there that's that's very interesting we well from a new evolutionary perspective obviously anorexia nervosa is is not something that would be selected for in evolution okay and and I don't know if we go back you know historically and I guess there's no way we can know I don't know how you could possibly know did anorexia nervosa exist you know what when did when did it first appear because obviously it's going to be selected against and these women of course they stopped cycling you know so they're not going to reproduce we did a study and I don't want to I want to give more people chance for questions but we can since we're not having dinner tonight we can that we can we marching orders we can extend the question-and-answer period for an hour I don't think so I'm up for it I have to vote no on that but go ahead but uh as quickly as I can wait we did a study in rats we had male and female rats and we put them on either their normal diet you know ad libitum we had groups with 20% Daly reduction calorie 40% Daly reduction calorie alternate day fasting and we even had a McDonald's diet type diet and then we let them go for six months with the the severe calorie restriction 40 percent daily reduction in calories the the female mice aren't rats female rats became essentially emaciated I mean that they had zero observable body fat when we ended up killing them at six months the males and they also became much more physically active in their cage the males on the other hand they they maintained lean mass they even had some fat and they were they didn't have an increase in activity now from an evolutionary and the females quit cycling their estrus cycle completely stopped the males remain fertile so from an evolutionary perspective maybe that makes sense if if you're a female and there's not much food available you don't want to get pregnant because there's no energy for your offspring on the other hand if you're a male you want to remain fertile so you can pass your genes on before you starve to death yeah so okay then Thank You dr. Mattson for your research in your lecture here if I understood you correctly you were talking or you you feel that there's evidence to indicate that it is increased levels of ketones such as beta hydroxy butyrate and acity acetyl acetate that calls the increase of being the BDNF levels if if that is the case what are the implications for a ketogenic diet and/or exogenous ketones yeah that's a excellent question with and this is a question we're trying to address in a very clear-cut manner experimentally which it turns out not to be easy because I think I mentioned early on that nerve cell network activity in the brain is also increasing during exercise and with fasting in fact in the animals it's very obvious after they fasted the day you go in and they're like they're very active and you can tell they're hungry and searching for food and we know that activity in neural circuits increases BDNF production we also know however that hydroxybutyrate in even in cultured nerve cells we add hydroxy butyrate BDNF levels go up so we know that hydroxy butyrate can and we know it gets in the brain easy we know it can directly act on neurons so we don't know what the relative contributions are of the ketones versus the intrinsic changes going on in the brain now the way to experimentally address that which we're trying to do now is to selectively block the production of ketones in the liver by using a genetic tools to knock out the gene that's critical for conversion of the fatty acids to the ketones in the liver so then then we can fast animals or subject animals to exercise and not get the increase in ketones and then look at the brain and that you know that's the only way we can think of the way we can really critically address that but as far as not fast as far as eating three meals a day not exercising at but supplementing with ketones I think there will be some benefit but it won't be as great as exercise and fasting because exercise and fasting have much more complex integrated effects than any single molecule can have all right we have time for one last question I'm starving so we'll have two more questions because oh okay I have great conclusion Kai watch your brain function oh that's it see I'm looking out for your own interest okay okay excuse me is the production of BDNF and mitochondrial replication was there more in aerobic or anaerobic exercise or was there no difference yeah that's an excellent question we don't have a clear answer to that we know it beeped enough does increase with aerobic exercise and in animals it's hard to study the you know like weightlifting and my sir I read and and well the other aspect of that in humans was in animals we can take out the brain tissue and directly measure BDNF in humans we can measure BDNF in the cerebrospinal fluid and the blood but in the blood we're not sure where the BDNF is coming from because it's it's not produced just in the brain is produced other places and so in humans we we don't know yeah and and and and rodents we actually don't know either so we started a study now where we are we have subjects this is an exercise but we're doing intermittent fasting in individuals between the ages of 55 and 70 who are biess and have insulin resistance we're going to have them in two groups either intermittent fasting 5:2 diet or normal diet we're doing cognitive testing looking at functional Network activity by functional MRI and we're also taking cerebral spinal fluid at baseline and after two months on the diets and we can measure BDNF in the cerebrospinal fluid and that will give us an answer from the fasting standpoint great let's speak let's thank our speaker one more time

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Length: 63min 27sec (3807 seconds)

Published: Fri Feb 19 2016