Eating Precisely: Merging Nutrition with Individualized Factors to Optimize Metabolic Health

Eating Precisely: Merging Nutrition with Individualized Factors to Optimize Metabolic Health

(gentle music) – Okay well thank you verymuch for the invitation.

And I know that you've allbeen going through a lot, as have all of us in gettingourselves to this point.

And hopefully we can spend an enjoyable period of time together, delving a little bitmore deeply into an area that I think is fascinating.

And that I think is rapidly becoming part of the norm with which we think about and conceptualizenutrition as it affects us, our health and our predispositionfor diseases chronically as we age.

And so, as a leader I justwanna make the point that, in particular, with respectto cardio metabolic health, which is my area of expertise and the area in which we think really most deeply about nutrition.

That human beings are both genetically and functionally quite heterogeneous.

And so dietary strategies, medical strategies for disease management, and even behavioralrecommendations for exercise, and healthy living, have traditionally been a onesize fits all type of approach with respect to recommendations.

But I think we are really realizing now that we're entering an era where data, and the types of depths to which those data allow us to go in terms of understanding ourselves, will allow us to make moreprecise recommendations, both in terms of diet, as well as in terms of a whole host of other potential interventionswe might be able to make, on our behalf to improve ourcardio metabolic health risk.

And I just wanna sortof highlight graphically and in terms of an example, how clear cut this ideathat cardiometabolic risk really has an always been, an interaction between our genotype and the biological characteristics that go along with our genome, and the lifestyles that we live.

So the classic gene timesenvironment interaction.

And there's no better example, to make the case thatcardiometabolic disease risk works this way, than the example of Pima Indians.

And so, Pima are native peoples who live in the interior portion of California, the very Southern Tier of Arizona as well as an enriched population in the southern aspect of New Mexico.

But notably, there are also Pima who live in the adjacent areas, to all those three states onthe Mexican side of the border.

And in Mexico, people with Pima genotypes tend to be lean, oftentimes, traditionally existingin a subsistence manner, doing small farm work and have very low rates of diseases that we normally associatewith obesity for example, diabetes rates among Pima living in Mexico is on the order of about 5%, in most studies.

On the other hand, on theAmerican side of the border, Pima have a very differentsocioeconomic status, very different result inlifestyle factors including most notably diet andquite sedentary lifestyles, because of the lack ofeducational attainment, language barriers, and a whole host of other social determinants of health.

Individuals who are Pima engage in work that tends to be promotingof being quite sedentary.

And all of those things conspired with a particular genotypelean Pima in the United States to be relatively obese.

In fact, in some segments ofthe population quite obese, and in the context of that obesity, US Pima people have upwards of 50% rates of type two diabetes, far greater than theirgenetically relatively identical family members, in manycases on the Mexican side of the border.

And so the only differencethat Pima experience, that leads to this incredibleincrease in diabetes rates is just environmental.

And so the genotype canin isolation be viewed as neither protective nor risk inducing, the ability of one's genotype to confer or protect against disease risk really has everything todo with one's environment.

And today, we're really gonnabe talking about those aspects of the environment thatdovetail with obesity, and we're gonna be focusing most notably on the diet in that regard.

But just to note that evenif we look more broadly, the impact of obesity whichmany of you may realize, is a well known risk factor for diabetes actually confers risk in aquite heterogeneous manner.

What I mean by that is, that even though people with obesity, generally speaking haveincreased risk for diabetes, that risk isn't borne outequally in all segments of the population.

Indeed, there are up to 15% of individuals who are not characterized as obese, will be at high risk forand go on to get diabetes.

Where 70% of people who are obese will never go on to get diabetes.

And so we've understood that there are metabolically unhealthy, as well as metabolicallyhealthy forms of obesity, and because obesity itselfis becoming so common in the population, we actually see this diversityand this heterogeneity in the obese phenotype play out.

So some individuals arehighly cardiovascularly fit, they have no markers ofdisease risk in terms of lipid profiles, inflammatory markers, or imaging related markers looking at their coronaryarteries, for example.

Whereas other individuals who are obese even much less so, have all of these proximalindicators of disease risk, and one of the reallykey cutting edge areas is to determine exactly what it is, that creates protective factors in the context of obesity for some people, but disease promoting risk in the context of obesity for others.

And I'll give the example another way.

There are individuals who develop obesity, by virtue of havingmutations in a single gene.

We call this so called monogenic obesity, and thankfully it contributes to a very, very small percentage of overall obesity.

And so these very rare cases in which a person inherits agene defect in only one gene, that leads them to develop obesity rapidly and progressively over their lifetime, are known and we have a lot of information about these rare individuals.

And so what I'm showing here is an example of two individuals that have a mutationin a gene in the brain, that governs the brakes on appetite, and the trigger that initiates hunger.

And so the two colored linesrepresent growth curves, for those two kids bornwith the same mutation in that gene in the brain called POMC.

And you can see those curves ascending at a far greater rate, than the general populationof age match kids.

And many of you who have been parents may have seen your kids growth curves, and you can see that these two kids went above the 90th percentile, than the 95th percentile, than the 99th percentile, very, very early in life and by the time theyreached 18 and beyond, they were far aboveanybody else of their age in terms of their level of obesity.

However, neither of thesetwo individuals had diabetes, not only that, but theirhemoglobin Aic exam, as you can see in thetable next to the graph actually reveals thattheir glucose control is quite normal, in fact even healthy.

If you just looked atthe lipid parameters, and the hemoglobin A1c data for these individuals withoutknowing that they were obese, you would think that they were cardio metabolically quitehealthy maybe even athletic.

And so you can see that from these data, it's clear that obesity by itself is not a direct linkto developing diseases that we normally associatewith obesity when we think of the entire population.

And so I make this point just to say that there's a lot of heterogeneity, and because of that heterogeneity we need more precise approaches, to identify individuals at risk, and precise approaches to intervene so that we can minimizethe number of individuals, who do not respond tothe efforts that we make on their behalf to improve their health.

And on the entirely otherend of the spectrum, Asian individuals, both South Asian, as well as several East Asian subgroups, and also, certain individualsin Middle Eastern countries tend to develop type twodiabetes at a much lower BMI, than the worldwide average and certainly the averagein the United States.

And the number of individuals in those genetic subgroups, and ethnic segments of thepopulation in the United States has risen rapidly enough, that in many states, we've adopted somethingcalled Screen at 23, where at least in thepublic health setting, we can now get diabetes screening, without copay on behalf of the patient.

For individuals who havea BMI of 23 or above, which in the general population isn't even categorized asoverweight much less obese.

On the other hand, forCaucasian individuals, the public health system in many states will not cover that kind of screening, on the basis of weight alone, until somebody ascends to a BMI above 30.

And so here's an exampleof precision medicine.

We're making different cutoffs, thresholds and guidelines, for screening and potential intervention for one subgroup differently than we are for another subgroup.

Because we understand a littlebit about distinct aspects of risk from one group to another.

Here, it's relativelycrude because we're making the distinction basedspecifically only on ethnicity, without a deeper understandingof genotype specific factors that may fuel that risk.

But in the near future and certainly over the next 10 to 20 years that will change, and we'll be able to geteven more refined indicators of risk that might be manifestat the individual level, as opposed to the level across an entire ethnic group, for example.

And when you think aboutthe risk for diabetes in the context of obesity, another thing that we see is that people develop somethingcalled insulin resistance before they go on todevelop type two diabetes.

And again, we think ofobesity as a spring factor that triggers the developmentof insulin resistance as an antecedent to type two diabetes.

And in this graph, I'm showing you the relationship between an index of insulinresistance on the y-axis with higher numbers meaning, individuals are more insulin resistant, and therefore much are more at risk for developing diabetes imminently, and on the x-axis, BMI or again an indicatorof excess body weight, with higher numbers indicative of a greater degree of obesity.

And in general, the fit of that curve withall the dots that you see representing individuals, shows an inverse relationship such that the individualswith the highest BMI have the greatest amountof insulin resistance, the y-axis is an indexof insulin sensitivity.

So the higher the number, the more insulin sensitive, the lower the number, themore insulin resistant and you can see that, the people with the lowestnumbers are the most obese.

But the rectangle that I've placed in the middle of that point, is reflective of whatwe might normally call a lean individual, somebody with a BMI below 25.

And you can see in thatvertically oriented rectangle, that there's a number ofindividuals with varying degrees of insulin sensitivity versus resistance, all of whom have a relatively similar BMI.

So again, you can see that even at the level of tissue insulin resistance, the impact of obesityon any given individual can be exceptionally variable.

And we have actually created at UCSF a cohort of individualsto study this very thing, to get a better ideaabout precision medicine related factors at playin cardiometabolic health.

We call this a cohort IDEO, or inflammation, diabetes, ethnicity, and obesity.

And one of the things that we do for all the individuals we'veenrolled in the IDEO cohort, is to use dual energy x-rayabsorptiometry or DXA, which many of you may be familiar with, because we also use thatto check bone density in people when we'reconcerned about osteoporosis.

Well, we can also useDXA to get an analysis of lean mass and fat mass, and use computer-drivenalgorithms to understand where in the body certainparts of their total fat is located, inside thebelly around the organs, which we call visceraladiposity or visceral fat or in the extremities under the skin, buttocks, thighs, arms, et cetera, which we call subcutaneous fat.

And what I show here areindividuals of three ethnic groups, roughly similar by BMI, three women, roughly same age, roughly same BMI.

So if we only used body mass index as an indicator of diabetes risk, these three women would be viewed as having roughly the same diabetes risk.

However, using dexa.

We can see, for example, that compared to the Caucasian woman, the Chinese woman has amuch larger percentage of her fat located in thevisceral adipose tissue or VAT compartment as afunction of her total body fat.

And that increased visceral fat content, the fat inside the belly around the organs that creates what weoftentimes in popular parlance, called an apple shape is conferring a fargreater risk for diabetes for that Chinese woman, than the total body fat is conferring for the competitor, Caucasianwoman, even though by BMI, she's just as obese as or just as lean as the Chinese woman is.

And so we are able to now use imaging, to give a better indicationof precise body shape related characteristicsthat confer diabetes risk.

And we can connect thoseimaging related parameters to a whole host ofblood derived biomarkers to see if we can identify over time, very precise and very specific biomarkers that are not only able to predict risk, as well as these imaging studies, and certainly better than BMI, but that might also be dynamic.

So if someone does something to try to improve their risk fordiabetes or heart disease, that they may be able toactually track the rise and the fall of these biomarkers, because we can validatethem versus other parameters like in this case, DXA based imaging.

So in trying to get a evenbetter understanding of this, we are also able to show heterogeneity in terms of the genes themselves, that confer risk.

And the way we normally do this is, to look at something that we call a genome-wide association study or GWAS.

And there have been manyGWAS done to look at obesity, and the genes that predispose individuals for increased risk for obesity.

And those GWAS studies that have been done would indicate that, and all I'm showing here isa graphical representation of the types of genes thatcome out of these GWAS studies, when meta analyzed to look for genes that are most common associated with increased risk for obesity.

Now, we're not talkinganymore about people who have a single gene defect, But we're talking aboutlarge populations of people, where we don't know anything about what genes they may or may not have that are driving their obesity.

We just compare obese individualsversus lean individuals.

And that the meta-analyses that have been done to date show clearly, that the genes that areassociated with obesity, and code for proteinsthat work in the brain, and by that definition, obesity, at least the heritable component, the genetic component of obesity, writ large across the large population, is a function of alterednormal functionality in the brain, due to a number of different gene defects, each of which produces avery small effect size, but when added up together, produce a large effect on hunger, satiety, our desire to comfort eat, and a whole number ofother factors that relate to our desire to eat moreversus less food per day, over a long period of time.

And so that big peak ofdense vertical lines, shows how clearly the genesthat are associated with obesity are concordant with brain function versus function of a numberof other competitor tissues in the body.

Now, if we compare that to that big tower of vertical lines, about two thirds of the waytowards the right hand side of the set of lines that you see in this graph shows that, if you do the same kind of analysis looking for genetic driversof insulin resistance, we're not talking about diet, we're not talking about any single gene, we're not talking about rare patients, We're talking about largepopulations of people looking at insulin resistant people, at great imminent risk for diabetes versus people who are metabolically quite healthy by comparison.

You can see that the genes that are most proximatelyassociated with that risk, are genes that target thefunction of the fat tissue itself.

So where we store the fat in our bodies, and how we store the fat in our bodies, and how that fat functions, has a genetic component that drives it, and alterations in the genes that run the function of fat, are proximately relatedto our vulnerability to developing insulin resistancein the context of obesity, should we develop obesity.

And that we think isan indication as to why some people who develop obesity don't have any metaboliccomplications associated with it, whereas other people who do, have all of the metaboliccomplications associated with it.

Okay, so now that we have alittle bit of an understanding about the fact that thereare indeed genetic drivers that we can assess population wide, that exerts small, incrementalincreases or decreases in our overall risk for disease, we can look at diet asan overlay on top of that in order to get deeper understanding.

And so now just a little bit of history, I like to give this example because I think it'sjust quite instructive with respect to how societyand human biology intersect.

And this is the example of Wonder Bread.

So bread until the 1920swas minimally processed.

We did not have fine millingof grains in our society, and so a lot of bread was baked at home.

A lot of bread waspurchased at local markets and not mass produced.

And the reason why WonderBread came to get its name and what the purpose of the science that went into developing Wonder Bread, was that we needed orfelt we have the need to insert more nutrients into bread than normally came in bread.

Bread was traditionally viewedas being a pretty bland food with minimal nutritional value.

And we felt like duringthe run up to World War Two and during that time, that we need to have stronger kids because of worldwide pressures in the context of our views about the war.

And so scientists workedon ways in which we could integrate more minerals, vitamins and nutritional factors into foods like for example bread.

And the only way that you can do that is if you mill the flour excessively prior to making the bread with it, and that not only allows you to put in vitamins andminerals into the bread, and therefore “enrich it.

” It also allows you to put morepreservatives into the bread and give it the greater shelf life, that we now know a lot ofmass produced processed grains, cereals and breads have.

And so once we went ahead and did this, and reformulated the entiremilling infrastructure in the United States to createbig, factory-based mills to mass produce enrichedgrains for cereals and breads, we never went back.

And instead, what we didwas focus on the other, what we thought at the time was the large nutritionalcategory and that was fat.

We thought we had achievedsomething healthy, in terms of enriching flour to make better breads and cereals, but we felt like the fat was the place where all of the adulthealth risks came from.

And that really cameto a head in the 1980s with our low-fat dieting, and the excessive focus onboth fat and cholesterol.

And so the change indietary recommendations initiated during the veryearly 80s and late 70s, had a great impact.

And you can see over time, the reduction in theconsumption of butter, the reduction in the consumption of lard, the reduction in theconsumption of margarine even that went along with, the focus on an increasingly low fat diet, and the increased consumptionby comparison of oils that are more polyunsaturatedand vegetable rich, and shortening for cooking that was based on vegetable fat as opposed to animal fat.

And so we thought that we weredoing something very healthy by making this massive shift in macronutrient consumption patterns.

But of course, however, what we learned in theperiod from the 1980s until even quite recently, that beyond dietary fat, smoking and sedentary lifestyle, there are a number ofother factors both genetic, which we have a much betterunderstanding of now, as well as dietary factors that really play into cardiovascular risk.

And this, I show inthe context of pictures of Jim Fixx, who many of you may remember as being both a running guruand a low fat diet aspirant who actually died of heartattack at a relatively young age, and had tremendous blockageof major coronary arteries in the context of his major heart attack, which he subsequently died from.

And so, it really brings to light the idea that a very simplisticviewpoint on nutrition, and a very simplisticviewpoint on the genes that contribute along with that nutrition, to cardiovascular andcardio metabolic risk actually has led to wildswings in health and disease.

And when we thought we were doing things to make people healthier, we were actually playing whack a mole and creating increasedhealth risks in other areas.

And so, in addition to, not identifying allrisk for heart disease, our dietary recommendations led to an increased consumption of carbohydrates.

So if you're not eating fat, you've got to eat somethingfor your calories, and the something that people tended to consume more of was carbohydrates.

Now, we thought at the time, that because the carbohydrateswere all enriched, and had increased vitaminsand minerals in them, that we probably weren'tdoing anything too harmful.

But what we didn't realize was, that in the context ofthe mass milling operation that we had created, we also created much more in the way of processed carbohydrates.

And those processed carbohydrates have a lot more sugar and fructose in particular add it to them, and in the context of all of that sugar and carbohydrate consumption, people began to gain weight and you can see weight gain go up across different age demographics, and in association withthe increased body weight since the 80s until now, there's been an associated increase in the rates of diabetes.

And paradoxically, eventhough we didn't know it in the 80s, we now fully realizedthat type two diabetes is actually one of the very biggest, if not the biggest risk factor for cardiovascular disease events, on par with smoking, for example and so people who havediabetes we now consider as having a cardiovasculardisease risk equivalent, as bad or perhaps even worsein some cases than smoking.

And the increased rates of diabetes are actually a functionof at least in part, dietary recommendations wemade over the prior decades in the context of tryingto be more healthy.

And here's a good exampleof what that looks like.

So these are branded as beinghealthy snacks, Snack Wells, and they are healthy specifically because they're low in fat, but of course, they're exceptionally high in refined sugar-added carbohydrates.

And this is I think, become a sort of aposter child for that era of misguided nutrition.

And so this is just to giveyou the orientation chemically as to what we're talking about when we think of fructose in particular, it's a disaccharide combinationof both glucose and sucrose.

And unlike glucose, which when we consume it, is assimilated through theintestine enters the bloodstream, and then can be utilized bycells throughout the body in conjunction with insulin, which we make to help process that sugar.

Sucrose and more importantly, fructose which is liberated from it, must be processed specificallythrough the liver first, and as I'll show you, that fact alone leadsto a lot of disease risk associated with excessfructose consumption.

And so here's just an exampleof what that looks like.

So when we eat glucose, and that little tube-shapedstructure in the center of the image is the intestine, the intestine absorbs the glucose and then it goes immediatelyinto the bloodstream, and it will go to the adipose tissue, the fat, the muscle, brain, as well as two organs like the liver.

Fructose on the other hand, when it's absorbed through the intestine it goes first to the liver, and one thing that it does through several transcriptional pathways, is to force the liver to make fat.

And so fructose leads tofat synthesis in the liver.

And excess chronic fructose consumption is well known now to produce fatty liver and the liver both gets fattier, and that fat increasesassociated with inflammation in the liver, and that inflammationdrives insulin resistance in the liver, and that leads the liverto put out glucose.

And that's one of the reasonswhy people's blood sugar tends to creep up over time, as they eat foods rich in fructose, namely, processed carbohydrates.

The other thing that the liver does to try to protect itself, is to kick out excess fat in the form of a particle called VLDL, which is enriched with fat, which then circulates into the body, deposits in the fat tissue, and makes people gain even more weight.

And so there's a viciouscycle that gets set up when people consume too much fructose.

And you can see that in theseglucose tolerance curves, that there's a specific impact of that on the pancreas.

And so these curves represent the response of an individual to consumption of glucose, in this case on the lefthand side for nine weeks, or a diet rich and fructose for nine weeks as a comparison.

And then what you do, is you give that individuala dose of glucose and look at the rise in insulin.

And what you can see, is the people who consume fructose for a long period of time in excess, have a much more severeHyperinsulinemic response when they eat anything, and so, that burden on thepancreas to kick out more insulin with every meal we consume, leads to a more rapid demiseof pancreatic function, and that is something thatthen clearly leads to diabetes.

And so the excess consumptionof fructose I think, really cannot be emphasized enough as a risk we've learned about for cardiometabolic decline in people.

And this is a journalcover from gastroenterology from colleagues here at UCSF, including Rob Lustig, KathyMulligan and Jean-Mark Schwartz, showing that if you take adolescence and you limit theirconsumption of fructose, specifically by deprivingthem of sugary beverages, and just fructose rich processed foods, you can see a reduction in liver fat even in the context of 10 days, of cessation of the fructose consumption.

And so the proximal relationshipbetween fructose intake, and liver fat is actually dynamic.

And so I just wanna put a positive spin on all of this as well to say that, if you improve your diet with respect to fructose consumption, you can see improvementsrelatively rapidly, even if you already have fatty liver and associated insulin resistance.

And even more recently, this article in diabetes cares from just a few weeks ago, even in the context of whole grains.

Okay, so many of you may know that we've now made apush towards promoting whole grain consumption, to minimize the amountof processed-refined simple carbohydrates that people consume.

But even in the context ofwhole grain consumption, consuming more finely milled whole grains produces a greater impact on blood sugar than consuming very minimallyprocessed whole grains.

And so in these two graphs, I'm just outlining theseindividuals in this study who were being compared, were eating whole grains thatwere nutritionally identical, the only difference wasthe extent of milling and the fineness of theflour that was created from that milling process.

And that's what the bottomrectangle highlights they just pass the flour through sieves, and you can see that the more milled flour pass through smaller sibs, and the minimally processed flour didn't.

And then these other two rectangles, show the statistically significant effect that that had on the bloodsugar rise with specific meals, both all meals combined, and more specifically bread breakfast, because after all, breakfast tends to traditionally be the meal where we usuallyconsume carbohydrates in terms of foods thatare enriched with flour, cereals and breads, for example.

And so the impact on bloodsugar we now understand is quite specific, and the wholeness of the grains can be modulated across a wide range, and that entire range ofmodification of the foods that we may be having an impact on are cardio metabolic health.

Okay, so now we'llswitch gears a little bit and talk about calories and dieting.

And again, there's heterogeneityand room for precision in this arena.

So just to let you know, that many studies havebeen done on the topic, and this is one of themost sort of fundamental ones that people quote, all diets allow one to lose weight.

So I can get someone to lose weight, if I'm managing their weight loss by following any of anumber of weight loss diets.

And so here you're comparing the zone, which is focusing on carbohydrates and glycemic index of foods.

Learn, which is a low fat focus diet, Ornish, which is againfocusing on lowering fat to the extent possible, and replacing that withvegetables and fruits, for the most part, but really focusing again on the fat in favor of more healthy proteinand fruits and vegetables.

And then finally, the Atkins diet, which is really focusingon minimizing carbohydrates to the greatest extent possible, and has really no limitation on fat consumption by comparison.

And yet, you can see that all of the diets produce weight loss.

One of the things aboutdietary weight loss though, and I wouldn't again take a read much into the relative difference withrespect to the Atkins diet, on this plot, because none of the diets produced all that much weight loss, and you're only talking about a couple of pounds of difference.

But the take home for diets is, that all diets work, all diets plateau at a certain point.

So you can see all these curves stop producing any additional weight loss, even though the peoplewere still on the diet.

And that's because the bodyhas a lot of mechanisms that fight back againstfurther weight loss, when we continue to depriveour bodies of calories.

And so no diet will produceweight loss all the way until your target weight necessarily, it all depends on your body's physiology.

And then finally, when the people went off the diets, they all gained the weightback within six weeks.

And so these are thefundamental Hallmark features of diet-induced weight loss.

On the other hand, if you think about calorie restriction, not just for weight, but for lifespan and moreimportantly healthspan i.


the number of yearswe live in our lives, before we have the first manifestation of life shortening chronic disease, calorie restriction hasconsistently been shown to increase lifespan.

And so you can see heredepending on the degree of calorie restriction, on the left hand side, we're showing data fromcalorie restricted mice.

And on the right hand side, the graphic has switched that to say, well what would that be ifan individual were to undergo that degree of chroniccalorie restriction, as a person, and you can see that, you're talking even with 25% reduction in calories per day, chronically.

And major change in the50th percentile of mortality for people in terms oftheir overall lifespan.

And so people who might live to be 79 in this graphical extrapolation, are living to nearly 100 because they're reducing 25% of calories from that that's necessaryto keep weight neutrality under normal conditions.

And so the impact of calorierestriction really is profound.

And we see it from fruit flies, and roundworms all the way to people.

And it's not just lifespan, but it's also healthspan.

And we can talk aboutthis maybe in the question and answer afterward.

But here's an example of two monkeys that are siblings raisedin separate cohorts, one that is eating an ad lib diet, able to have as much food as it wants without having to haveany restrictions placed, and the sibling with a 25%calorie restriction in place, and you can see clearly thatone of these rhesus macaques is looking much younger, morevibrant, alert, skin tone, everything, looks likean animal much younger than stated age.

Whereas the sibling who doesn't have that dietary restrictionprotocol in place, ages in a manner that'smuch more commensurate with the chronological age.

And so, this is a reallyintriguing area of biology.

And we're doing a lot to try to understand the chemical mediators that are involved, in regulating the switchesthat either protect or hasten metabolic aging and healthspan, in the context of how muchfood we eat in our lives.

People have taken thisidea of calorie restriction one step further, and have thought aboutfasting as a potential way to recapture some of the benefits of calorie restriction overall, without reducing the overallconsumption of calories.

And so there are a couple ofdifferent ways to do this.

In fact, there are many youcan reduce periods of time when you eat by doingvarious fasting protocols, you can also restrict the amount of time in every day that you'reallowing yourself to eat.

So the periods of timebetween meals and snacks is extended from what we might think of as normally grazing style, ad lib, kind of access to and consumption of food.

And this images is meant to show that in many ways, our bodies work on a setof biological clocks.

And those biological clocksare entrained by both light and they're also trained by our behaviors, including when and how much we eat.

And these clocks are alsoevolutionarily conserved, because mammals and theirpredecessors have evolved on earth with a 24 hour light dark cycle in place, for long enough thatwe've been able to adapt to that very fundamentalaspect of life on earth.

And so we have a centralclock located in the brain that governs a lot ofour diurnal activities, hormonal functions, sleep wake, as well as other physiological parameters.

And then we have clocks inall peripheral organs as well, that in train not onlyto that central clock, but also to our nutritional intake, as well as many other behavioral factors.

And so, in light of thiscoincident integration of our nutritional habits and our clocks, people have tried torestrict our time when we eat to better match our own biological clocks, preferred and treatment cycle.

And when we do that, we see that there are alot of health benefits that people can get in thiscartoon just illustrates, a number of those across many parameters.

And it would take too much time to go into all of the individual ones.

But the effects are quite pervasive and this is a growing area of research, that many people are getting into.

And one of the thingsthat people have done to even take this idea of time restricted feedingand fasting one step further, is to look at one of the mostHallmark metabolic shifts that takes place when we fast.

And that is the production ofsomething called ketone bodies by the liver as a sourceof fuel for the brain.

So when individuals forexample, run marathons, and the reason that theyload up with carbohydrates is so that they can goas long as possible, by allowing the liver to generate glucose from the glycogen that it deposits, as a function of all thatcarbohydrate consumption the day before.

And the intent is to haveglucose be produced by the liver, for long enough to allow forthe fat tissue in our bodies to mobilize fat and sendthat fat to the liver, for the live to then turnthat fat into glucose.

And so you have a continuoussupply of glucose, and the liver also makessomething called ketone bodies from that fat that go tothe brain specifically and allow us to remain alert, aware, and on top of things, even though we haven't eatensince the night before, and we're in the middleof running a marathon.

But if people don't manage the carbohydrate consumption correctly, and if they're devoid ofsufficient glycogen to bridge until the fat reserves fromthe fat go to the liver, and the liver can makeketone bodies with them, you will have a fuel gap.

And if you are unableto make ketone bodies for your brain before theglucose supply runs out, then you hit the wall, and I think you many ofyou may have seen images of people who do thataround mile 20 or 21.

And that shows how vulnerablewe are in the brain to the need for a constant supply of fuel.

And ketone body production by the liver is that evolutionarilyconserved source of fuel, that keeps us alert and aware when it's been a longtime since our last meal.

So what we've learnedis that carbohydrates, and their consumption is what shuts off the generation of ketone bodies, because it's associated withthe production of insulin, it means that we've now eaten a meal, and all of our physiologygoes to the Fed state again, it resets like a typewriterback to the beginning.

And so, by learning this, we've been able to harness specific diets, which we now call ketogenic diets, by limiting the amountof carbohydrates in favor of protein and fat, allow us to enter a state of mild ketosis, even though we're not fastingspecifically to do so.

And what we found is thatif we can limit the ketosis and keep it in a very mild state, there are a lot of health benefits that come from that as well, because we are evolutionarily very, very conserved to rely on ketones, because it is ourhormonally driven indicator of a prolonged fast, and we can mimic that by putting ourselves on a specific diet Asian.

All right, so this isjust a quick overview of the ketogenic diet.

I think I already went over this.

But normally, when wefast fats are liberated from our fat tissue.

That's one of the reasons why we have fat is to actually provide a fuelsource when we're fasting.

Those fats go to the liver, the liver turns the fat intoa number of different things, including glucose for itself, fat to send to the heartand other muscles for fuel, and ketone bodies whichprimarily as I said, go to the brain.

We can recapitulatethat by just eliminating or lowering the amount of carbohydrates that we consume sufficiently, to reduce insulin levels.

And by doing that, fool the body into thinking we're fasting in a manner of speaking, and liberate this ketogeniccycle purposefully.

And we can also, by the way, engage in the same kind ofthing by consuming ketones.

And that's another areaof precision medicine and nutrition that you are gonna see coming out over the next few years.

And that is supplemental nutraceuticals that are designed to provide ketones, so that we can get thatincreased ketogenic bump without having to substantiallyalter our diets at all.

Now, the science inthat area is really new, but that's one directionwhere many researchers are trying to take it.

And so the ketogenic diet is again, like time restricted feedingassociated with a number of different health benefits, and the ones that are shown in dark are the ones that have a lot of evidence to back them up both in animalmodels as well as in people.

And the other areas that are more gray are a little bit less well recognized as being bona fide benefitsof the ketogenic diet, but are emerging areas thatwe think are also relevant to what you might be able to expect in response to this diet.

And we're trying to findout mechanistically, how all of these health benefits work, and that's a very vibrantarea of research right now in nutritional physiology.

Okay, so even more recently, this again is just a couple of weeks old and this is from another colleagueof ours who we work with, named Peter Turnbow.

And his lab has done a study showing that, not only does ketogenic dietproduce physiological effects that have contributionsto metabolic health, but they also produce immunologic effects.

And immunological aging isanother aspect of healthspan that we would like to intervene in.

And so they looked atpeople on a ketogenic diet and what they found was, that the levels in the gutlining, as well as in the blood of a cell type a T celltype called Th17 cell, which is elevated in individualswith cardiometabolic risk and in comparisons of people with diabetes versus no diabetes, goes down in responseto consumption of a diet that is ketogenic in nature.

And in their study they showed that, one of the mediators of that relationship between ketogenic diet andimmunological improvement, was a change in thenature of the microbiome.

And so this is anotherarea I think, now, really, the frontier area of precision nutrition, that is really coming to the fore, and that is the microbiome.

And so, I think, all of you have probablyheard one way or another about probiotics, themicrobiome, meta genomics and its impact on cardio metabolic health.

And we're gonna spend just afew minutes talking about this.

Okay, so, just briefly, the microbiome representsall of the bacteria that live in and on our bodies, and in particular, the gut microbiota represents the bacterial species that colonize our intestinal tracts, and there's upper gastrointestinal, and lower gastrointestinal microbiota.

And the intestinal microbiota, has now over the lasttwo decades been shown, to have a tremendous impact on our metabolic health and healthspan.

Two things that are fundamentalfor you to know happen in the context of aging, and metabolic disease versus health to the microbiome.

One is that the microbiomeand its composition changes from birth until adulthood, and then in the later phases of life in the last quarter ofour lives again, changes.

And the second thing is that, in response to advancing age, and accelerated inresponse to for example, changes in diet and inthe context of obesity, is a shift not only in thecomposition of the microbiome, but it's a narrowing of thediversity of the microbiome or the richness of thenumber of different species, that are normally presentin one's microbiome.

And so it's this lack ofdiversity or narrowing, to fewer enriched speciesthat comprise one's microbiome that we think is associatedwith individual vulnerabilities to disease risk.

And this is just anothergraphical representation of this, looking at the levelof individual species.

And you can see that before adulthood, in response to what wouldbe called a healthy diet, in response to a high caloriediet or diet induced obesity, and then in late life, there are profound changes in the composition.

And here we're onlylooking at four or five of the constituent speciesthat make up our microbiomes, in response to these dietary changes, as well as differentphases of our lifespan.

And we're now veryfocused on understanding not only these individual species, but their interactions with one another, and their impacts on our host physiology in determining how the microbiome impacts health and disease risk, and how we might adequatelyintervene to control the shape and structure of themicrobiome for health benefit.

And again, this is probably something that you may be somewhat aware of, but there's this term called dysbiosis, which says that there's been an alteration either because of longterm antibiotic use, adherence to a poor processdiets, sedentary lifestyle, toxic or other unhealthyenvironmental exposures, that shifts the balance of the microbiome.

And that shifted balance, that alteration in microbial composition in our guts, places us at risk for a number of diseases across a wide spectrum.

Another factor that I think is really coming to the fore with respect to microbiome research is, that globalization isimpacting our microbiota.

And so you can see that individuals living in Asian countries have onaverage richer microbiota than people living inthe United States do.

And if you track immigrationof people from Asian countries, just as an example, to the United States andthen look over generations, and with time present in this country, over one's lifespan, the microbiota drops inassociation with the exposure to the United States environment.

And so traditionally, that would have been thought to have been an increased reliance on processed foods in the United States versus, less so in Asia.

But in the last 10, 15 years, even Asia has had a huge proliferation of processed food consumption, and microbiome diversityin Asian individuals even living in Asia, has dropped over time as well.

So now we're starting to see this lack of diversity in the microbiome, affecting people worldwide.

And I think the coolestthing that gives us hope, that intervening in the microbiome, could be sufficient to impacthealth and disease risk comes from the fecal transplant studies that individuals like Dr Turnbull's lab, and now we're doing these hereat UCSF as well have shown.

So in the graphs thatI'm showing you here, these are transplants donefrom two monozygotic twins.

Okay, one twin that was obese, and the other twin whichwas relatively lean.

And that can happen for many reasons.

Twins that are separated after birth, raised in different households, different environments, different habits, different dietary patterns over their lifespans, one may develop obesity the other not.

And there were enough donors that this study group got in contact with, that they could get microbiomes from those people through stool samples, and then they could Just themicrobes themselves purified, put them into the gutsthrough the stomach's of mice.

And they could show that, these previously germ free mice were rendered with microbiomes, that mirrored those of thedonors they got the bugs from.

And then, if you track those animals, you could see that theygained increased weight if they got a microbiomefrom a human being with increased weight, and they gained increased body fat mass, if they got microbiomes from people with increased body weight.

And in this case, we know that the donors own genetics had nothing to do with why that was so, because the donors were twins, and they were genetically identical.

The only things that weredifferent about them we presume, were in the microbiomesthemselves, the bugs, and so these specific species of microbes that these mice got, was sufficient to changethat mouse's physiology.

That's very profound.

And I think we've spentthe last decade plus now, trying to build on those findingsin terms of interventions that are applicable to humans.

And this brings us to, I think, the mostapplication oriented place that we are right now in this arena, and that is to use multiplestreams of data acquisition.

So this is the classic study from the group at the Weitzman Institute, that was published in cellwhere they took individuals, large number of individuals, they asked them to consumedifferent types of foods, okay.

And what they found was, for example, that whereas most people, if they consumed a slice of white bread would have a rise in theirblood sugar that was more so than if they consumedthe same amount of food, but in the context of, for example, whole grain oatmeal.

Some people didn't haveany rise in blood sugar when they consumed white bread, and some people had amassive spike of blood sugar when they consume the oatmeal.

Furthermore, they lookedat other kinds of foods that are not normally associatedwith a rise in blood sugar, in large population basedstudies, for example, tomato, and they found that somepeople had massive rise in blood sugar whenever they ate a tomato.

And the reason that they knew that, is because they had a monitor continuously tracking their blood glucose.

And so now with external devices that we can integrate withour nutritional habits, we may be able to geta lot more information about changes in temperature, changes in glucose, sodium, blood pressure, weight, than we ever would havebeen able to get before, and we can integrate those streams of data with our nutrition andalso with our microbiomes.

They were able to do this very thing, and they were able to, from this approach, find microbiome signatures that could predictpeople's glycemic response, to individual foods.

And that really representswhere we wanna be.

Because if we can find out at a given individuals predilection, via their microbiomes, and then develop bloodbased biomarker strategies that connect to thecomposition of that microbiome, and then give instructive advice as to how that personcould alter their diet, take a specific probiotic, or another intervention, that could reconstruct theshape of their microbiomes to better align with a morehealthful response to food, we would really have something.

And this is the present butmore so really the future, of where we wanna gowith precision nutrition.

And so finally, nowcircling all the way back to the beginning of the talk, and Wonder Bread and the low fat diet.

We have really made a lot of advancements, because now we can talkabout a more nuanced, more precise view of dietary fats than we had in the 80s by a large margin.

And so if you look at the American HeartAssociation own materials, they show you a really nicedescription of good fats.

And so we can talk aboutomega three fatty acids, we can talk about gettingthose omega threes from different kinds of sources, whether they're fish related omega threes, or whether they're omega threes that we get fromvegetable related sources.

We can talk about nuts, and legumes, and other sources offat that are much better than traditional vegetable related oils.

And then of course, wecould talk about olive oils, and mono unsaturated fats, versus saturated fatsand polyunsaturated fats, and dissect the specifichealth and disease related parameters, thatthese individual lipid species in our diets can modulate.

And then we can use that information to develop interventions and so next.

So this study is from last year in the New England Journal of Medicine, and it shows that nutritioncan be drugged, it's druggable.

A nutraceutical can be developedthat can actually limit one's risk of developing heart disease.

So this is a drug which now is available as a branded product called Vascepa, which is icosapent ethyl, which is also known as EPA one of the nutritionalomega three fatty acids that's found in deep sea fish, also present in maternal milk.

That when turned into a pill, purified and given to peopleat a specific dose over time, had a tremendous impact on people who had previously high levelsof blood fat, triglycerides, and excess cardiovascular risk.

It could serve to mitigatefuture events, cardiac events, in those people, simplyby taking what's otherwise a component of a healthy dietin isolation as a supplement.

And if you go further, you can see that anothermanifestation of this very thing is the Mediterranean diet.

So the Mediterranean diethas sort of just flipped, the enrichment of variouselements of the diet to favor monounsaturatedfats in the form of nuts, and legumes, as well as wholegrain related carbohydrates, but also an overt reliance on olive oil, which is rich in oleic acid, which is a mono unsaturated fatty acid, very much associated withcardiometabolic health and anti inflammatory properties, even in animal models.

And so again, for the last slide, you can see how you can turn this into a bonafide randomized control trial.

And so this is the PREDIMED study, and this is a primary prevention study.

So these are people who've never had a coronary artery disease event, or equivalent event, and they're looking at acomposite of cardiometabolic risk for these individuals via event rates.

And in the top line, you can see the rate ofthese events over time five years in the studyfor the control group, who had no dietary intervention.

And you can see that people who had a greater reliance on nuts and legumes, in the context of a Mediterranean diet had a much lower event rate for these same cardiometabolic acute events.

And that could be mimicked, by taking the diet that people are on and adding a specific amountof extra virgin olive oil to the diet per day.

And so again, it's harnessing nutritional information to create a nutraceutical intervention, that can limit someone's likelihood of having a coronary event.

Now, again, there's caveats here because this study wasdone on a large population.

And as you remember fromthe beginning of the talk, there's a lot of heterogeneityin the human population.

So it's quite possible thatthere are hyper responders and relative non responders, and we haven't doneenough research to know how to distinguish thosefolks from one another.

But the idea here is, that with increased relianceon genetic information, multiple streams of datathat can be obtained from biomarker based assessments, transcriptomic analysis of individual cells, forexample from people's blood, as well as wearable devices, will be able to get thekind of precise information that we can link to interventions, to ultimately find out exactly what any of us should be eating, with the intention ofstaving off specific diseases that we might be at highgenetic predisposition for, to the greatest degree possible.

And that's really the goal.

And if we do that, then we'll be able to createthe proper healthspan increase that we want, with a minimalnumber of non responders who don't seem to derive benefit from whatever we're trying to do for them.

So with that, I'll stop.

Thank you, and I think UCSFreally is one of the few places in the country, if not the world that has the breadth of talent to really explore in allof these different areas.

And I tried to sprinklethroughout the talk, multiple studies that really centrally involve UCSF researchers, showing you that we'reactually really deeply engaged in this kind of work, not just trying to harnessit to show patients, but actually doing the basic science, that underlies it as well.

So thank you very much, and I'm happy to take anyquestions if there's time.

– Thank you so much Dr.

Koliwad, that was fantastic.

And I know I'm almost positivethey got everybody thinking.

Because this is like something, it's so tangible, it's our diet, it's what we do every dayor throughout the day.

So some great questions, which I will try and convey to you.

So, tiny spiritose says the POMC mutation that causes the severe obesitythe single gene mutation.

Can you do CRISPR andreplace that appetite? Great, great question.

– That is an amazinglyinsightful question, amazingly insightful.

And I will tell you, that it's so insightfulthat scientists have tried to do that exact same intervention and we haven't done itin human beings yet, and the main ethical reasonswhy we wouldn't move to that necessarily yet.

Although, the most ethicalCRISPR based intervention we can come up with wouldbe to reverse a disease that's otherwise completely untreatable.

But there's another single gene defect in the same pathway as PAMC, in fact, is a receptorthat listens to the neurons that express PAMC, and that receptor is calledthe melanocortin 4 receptor, or MC-4, and it's the MC4 receptor MC4R, that when mutated causesa very similar picture as what I showed for PAMC.

And two investigators from UCSF in fact, Christian Vaisse lab, working with two other labsactually at Mission Bay.

Did use CRISPR to correctthe haploinsufficiency, meaning one of the illegals, giving it back again and getting the mouse in this case, to reexpress MC4R andthat CRISPR based strategy was sufficient to completely ameliorate, the obesity phenotype, which otherwise was transmitted from generation to generationin this inbred mouse colony, and they completely curedit for that individual mouse and also for the progenythat came from that mouse in perpetuity after that.

So, the answer to your question is yes, CRISPR is precisely the type of strategy that might be able to fixthat kind of monogenic form of obesity in an individual.

– Wow, awesome.

Tanya also asks, polycystic ovary syndrome.

So if those patients are obese, they typically start metformin before trying to induce ovulation.

What if your normal weight with PCOS and ovulation do you start metformin? Similarly, or do you skip that? Very interesting interest– – That's a great question.

So the question has to dowith the role of metformin, and the contributing factors to an ambulatory cycles in PCOS.

So PCOS is a specific type offertility associated syndrome that is linked to two things.

One is hyper androgenism, excess amount of testosteroneand so called male hormones, in a female genetically.

And also an increasein insulin resistance.

And both of these factors play a role in the association between PCOS, and inappropriate orabsent menstrual cycles.

And so, women with PCOS traditionally take birth control pills totry to reestablish cycles.

They take sometimes adrug called spironolactone that blocks some ofthis androgenic effects, and promotes more estrogen like features and really helps reestablish cycles, and sometimes the birth control pill has a spironolactone like effectthat's specifically chosen.

And then finally they go on metformin.

So what does metformin do? Well, metformin I showedimagery of the liver, metformin, specifically reestablishes, the livers responsiveness to insulin, and so it limits the extent to which the liver kicks out glucose when it should not be doing so.

And metformin also has a number of other pleiotropic effects.

But we do think that individuals who are having featureshave the metabolic syndrome, altered blood, fat contentor triglyceride, obesity, slight hyperglycemia orelevated blood sugar, high blood pressure and afamily history of diabetes, their PCOC might be really benefited by putting them on metformin.

If an individual hasnone of those features, and only has the problemwith menstrual cycles, and maybe some acne to go along with it, they may not be as wellbenefited by metformin.

We oftentimes try metforminon those individuals anyways, but those individuals whomight not continue on metformin if I didn't see a beneficialeffect right away.

On the other hand, whether you're talking aboutan adolescent boy or girl, you might put somebodywith all the features of pre diabetes on metformin, because we know that it can do a lot to stave off the developmentof diabetes along with diet and exercise for both boys and girls.

And so in that context, metformin is quite useful.

And so I think your point is well taken.

We need to be a little bit more nuanced with respect to how wetreat diseases like PCOS.

I will say though, that PCOS is a unique condition, because unlike most men, women see doctors, right? Women see doctors when they're young, because of many reasons, they go to see doctorsfor sometimes dermatologic issues more frequently than boys do.

They go and see doctors forissues related to puberty and menstrual cycles andtheir development in ways that are probably morefrequent oftentimes, than boys do.

And they continue to seedoctors if for no other reason, than for pap smears and femalefertility related well visits and many men don't go and see a doctor until they have symptoms, relevant to a chronic adultdisease for the first time after their last physical forschool sports for example.

And PCOS is an indication, in many cases that somebodyis at increased risk for developing type two diabetes, and can lead a woman to get intervention that will not only help the periods, but also limit the likelihoodthat she gets diabetes sooner versus later.

Men oftentimes don't havethat kind of check in for another reason that getsthem to medical attention.

And so I think PCOS is avery important disease.

With that in mind as well.

– Oh, fascinating, fascinating, huh? So you're saying that guysshouldn't just ignore everything and should see the doctor occasionally? – I think that's probably a good idea.

I think that's probably a good idea.

Yes, exactly.

And we don't have enough reasons, that force us to go see doctors and maybe I wish we hada few more of those.

But in absence of that, I think yes, you're right weneed to take it upon ourselves.

– Great, great.

So the ketogenic diet.

What are the risks of that? So the effect on the kidneys, or other things that sortof may balance out benefits in liquid profiles, and inweight, and things like that.

Any insight? – Yeah, that's a great question too.

So I will note that most if not actually, almost all of the most revealing studies that show the cardio metabolicbenefits of ketogenic diet, have been done on obese individuals.

So when you put an obese individual, someone with a BMI above 30, and even though I said there'sall this heterogeneity, the studies haven't taken thatheterogeneity into account and we'll get to that in a second.

If you take people with BMI over 30 put them on a ketogenic diet, you tend to see profound weight loss with ketogenic diet.

In part because ketogenic dietdoesn't do some weight loss, but in part because most diets induce the greatest amount of weight loss in the people with the highest BMI.

So if you pre select people with high BMI to put on these diets in thecontext of these studies, you'll see a lot of weight loss.

And in the context of that weight loss, you see a lot of cardiometabolic benefits.

We're now working to try to make sure, that we're correct aboutascribing those benefits specifically to the ketosis, and not necessarily to theassociated weight loss per se.

And several studies have have done that.

But there are otherpeople now getting back to the heterogeneity, who have all of the riskfactors for diabetes and metabolic syndrome, but they are not necessarily obese.

South Asians, for example, other East Asian populations, Middle Easterners, Native Americans, several Hispanic subgroups, develop type two diabetes and cardiovascular disease at a lower BMI than the general population.

Putting individuals likethat on a ketogenic diet that's very strict, may cause a dangerousamount of weight loss, and given that some of these individuals may not be obese or anything close to it by classical definitionsin the first place, you may not wanna put them in such negative energy balance, given their weight going in.

So we don't know theimpact of ketogenic diet across diverse populations, in this kind of much more granular way and that's something thatI think a lot of people are now really focusing on, and wanting to get answers to.

So, the other thing youasked about was risks, and certainly, I thinkthere are a few risks.

If you overdo it andcreate substantial ketosis, you can actually alterphysiological function.

People who don't make insulin.

Those people who have theother type of diabetes that is less common than type two, called type one diabetes.

Those individuals, if theydon't take their insulin on a regular basis, will develop what we calldiabetic ketoacidosis.

And that's because theirketone body levels go up tremendously high, itaffects the blood pH, and actually alters physiologicalfunction more broadly, including their abilityto retain consciousness, and these people can go into coma if that condition lasts for too long.

And so in lean individuals, you certainly don't wannaoverdo the level of ketosis that you produce, because all of thesecomplications may be relevant to those individuals as well.

And then finally, you brought up theissue of kidney disease.

Certainly, going into steep ketosis for a long period of time, is a little bit harder on the kidneys than we would like it to be.

And I think hydration is very important for people who areattempting a ketogenic diet.

And check in with your physicianabout your kidney function, to make sure about the antecedent risks before you start it, especially given what yourage may be at the time is probably a very wise thing to do, and I would recommend it.

– Great that was from KateSimmons that question.

So Joanne Whitney asked us, what are the measurableendpoints of ketogenic diet and microbiome changein terms of diabetes? Does it decrease med use? Does it decrease insulin resistance? Like what are the actual measured impacts? – Yeah, so diet associatedchanges to the microbiome.

The way the studies have been done is kind of the reverse.

Which is to say, we give medications that weknow improve insulin resistance, or lower blood sugar in variety of ways and look at what thatdoes to the microbiome.

Or put people on diets that we think are cardio metabolically healthy.

And in association with the improvements in those cardio metabolic parameters, we look at what thatdietary intervention does to the microbiome.

In terms of flipping it inthe way you asked the question and say, well, when youhave an unhealthy diet, or you age in the context ofyour genetic risk factors, and you start developing pre diabetes and head towards diabetes, how do changes in themicrobiome facilitate that unhealthy change thatgoes on in the context of age? There are many studiesout there looking at that, and the jury is completely still out.

There is one set of studies that I think has beenwinning out thus far, though.

Maybe two ideas that are competing.

One is that, as the microbiome shifts becomes less diverse andcertain species start dominating in the overall composition.

Those species produce specific metabolites through the way thosebacterial species work on the foods that we eat.

And those metabolites thatthey produce, for example, certain short chain fatty acids, they can get across the intestinal barrier into our bloodstream, and they exert effects thatimpact inflammation in the body and Visa V inflammation, insulin resistance, putting a more greaterburden on the pancreas and ultimately leading to itsimpairment and then diabetes.

So the second area is that, some of the bacterial speciesproduce bacterial factors, toxins, for example, one calledlipopolysaccharide, or LPS.

That in the context of advancingage and unhealthy diet, can through what we arenow sort of loosely terming leaky gut, can get intothe circulation across the intestinal barrier.

And those toxins mediate achronic inflammatory state, and that inflammationfuels insulin resistance and then subsequent diabetes.

And so we're kind of trying to work on, what is the mediator molecule? That is the go betweenconnecting the changes we make in our diet, to the physiologicalalterations we see in ourselves, Visa V the microbiome.

And can we block those moleculesand arrest that process, even though the microbiomechanges its nature, its impact on ourphysiology could be halted if we knew how to do that.

– Great.

So actually, do you take probiotics? Should we all be taking them? – Good question.

I don't take probiotics, but I do try to really nowadays look, and we're doing this moreas a family, of course.

And there's lots of factorsassociated with trying to get your whole family to do something.

But we're trying to really focus on the minimally processed carbohydrates.

We're trying to focus onminimally unprocessed, completely unprocessed meats, limiting the consumption of red meat, and a greater reliance on raw nuts, and increased vegetables in the diet.

I think that those dietarychanges have been studied with respect to what theydo to your own microbiome, that it's almost, although it's one level removed, it's almost like a probiotic because you're making a shift that many studies havedefined at the species level, and you're doing thesame kind of intervention that should reliably producea similar shift in you, and that's on par with taking a probiotic.

The problem with probiotics is, that so for example, I showed you that microbiotatransplant into mouse.

So that mouse was raisedin a germ free environment for multiple generations, so that mouse was as a pup born without any intestinal microbiome.

And so when you put amicrobiome into it, it will take because there's nothing thatit has to compete against in order to establish firm footing in the intestinal mucosa for life.

Doing the same thing inhuman is much more difficult, because you'd have togive people antibiotics or something to cleanout their microbiome, that may have completelyunwanted side effects and other complicationsassociated with it.

Furthermore, you're almostnever able to really get rid of their microbiome anyways, because they're just so firmly entrenched from birth until the timeyou try the intervention that you can't.

And so when you do the microbiotatransplantation into people, which we do for certaininflammatory diseases now increasingly, we do in the context of certain bacterial nosocomial infections that we're trying to overcome.

You don't get a reallysolid and durable take, the original endogenous microbiome once again flourishes and outcompetes, the transplant in many individuals.

And same thing is truewith probiotics in that, we can't really guaranteehow that probiotic is shaping the microbiome of the persontaking it in everybody.

Because people are so heterogeneous, and their microbiomesignatures are so different from person to person at the outset.

And since we don't have an easy way to test one's microbial composition before they take the probiotic and after, we don't really have agood way to know that.

There are companies likeyou biome and others that are trying to get at this, but it's early days I think, in that area for very concrete guidance.

– So unfortunately, tosummarize healthy nutritional lifestyle Change is way moreimportant than a simple pill.

– At this point I thinkthat is absolutely correct.

And I think we're much closer to making more precise recommendations about how people mightconstruct the composition of their diets, then we are in developingpills that can bypass that.

And way further alongthan we are in deciding who those pills should be given to, to identify people whoare maximally responsive versus non responsive.

– Wow, great.

Let's see on the slideshowshowing where fat was stored in a white versus Hispanicversus Asian woman with similar BMI's.

Looked like the white woman was 37, and the other two were58 and 59 years old, which seems pretty different.

Could that have been thedifferentiating factor? Well, that was prettyinsightful to pick that up.

– Yeah, so that's a great point.

The images that I showed were selected because the BMI's were so similar just for pictorial clarity.

But in our overall cohort, we've matched on age.

So even though there arepeople who are younger, and people who are older, on average, all the individuals inthe studies that we do are matched for age.

So, in aggregate when wetake cohorts of people who are Hispanic, Caucasian, or Chinese, we guarantee that the ages are matched on because otherwise, you're right, you wouldn't be able tomake easy comparisons for the purpose of doing real scientific, comparative research.

– Sure, so that question was from Hannah, who also says that as anotherinsightful question that, the ketogenic diet andthe Mediterranean diet seem pretty different.

Is it likely that the peoplefor whom one is helpful wouldn't find the other helpful, or is there a group that, is responsive to one versus the other and it's worth trying both to see which is most helpful for you? – Yep.

So these are great questions.

And, we really don't know the answers, although there's every reason to suspect that such a thing could be true, that there are peoplewho are maximally suited for responsiveness tothe Mediterranean diet, and other people who aregonna respond very easily to even minimally ketogenic diet.

And perhaps, not the other.

I will say, though, that a couple of thingsare relatively common for humans overall.

One is that, all peopledo enter into ketosis.

If you fast for asubstantial amount of time, we all generate ketone bodies.

So that's a physiology that is present and essentially all of us, unless you have aspecific genetic mutation that prevents that fromhappening very aggressively, and that's very rare.

But most people will generate ketones and so you could play on thatmammalian physiology dietarily and get at least some benefitfor just about everybody.

The question is whether youcan get a lot of benefit, and it's clinicallyrelevant for that person.

The Mediterranean diet on the other hand, again, it plays on multiple factors, we don't really know what thespecific only major factor that determines the beneficialeffects of that diet, 'cause you're doing lots of things in the Mediterranean diet.

But if you just stick to the mono unsaturated fatconsumption Visa V olive oil, mono unsaturated fats exert some specific, healthy effects on cells.

And that's true whether you give it to, a worm, or a mouse, ora monkey, or a person.

So it's exceptionallybasic and fundamental in terms of its response.

And so, again, we don't know whethersomeone might be better off on a different diet yet.

Those kind of studies are being done now and they need to be done.

But I think that everyone canget some modicum of benefit from a Mediterranean diet.

I think the more fundamentalpoint I would make, though, is that, if you lookat that graph I showed from the paper in 2009, comparing multiple diets for weight loss.

One of the things about these diets, especially the ones with large followings, is that the acute phase, twoweeks, three weeks, four weeks, for example, where thediets are really different from one another.

If you take those acutephases and throw them out and just look at the maintenance, so called maintenance phase, a lot of these diets are quite similar once you reach the maintenance phase, and that has to do withpalatability over the long term, the ability to people stay on the diet and really take it to heart, versus what's actuallysustainable physiologically over the long haul.

Maybe you need to be in ketosis.

Steve ketosis for only acouple of weeks, and then, minimal amount of ketosis to maintain that is more than enough.

And so if you look at that, those factors and you say, well, wow, the zone diet, the Atkins diet, the South Beach diet, a lot of these diets, two months in look pretty similar.

I mean, there's no diet that'ssaying don't eat vegetables.

So, there's lots of similarities.

And I think, patientsand people in general should see past the acute phase.

That is what leads the bookto have the title it has, and look at the maintenance phase and ask how similar thesediets are to one another, and then maybe aspire tothose common principles.

'Cause those principles in books, oftentimes really mirror likeAmerican Diabetes Association, or American Heart Association recommendations relatively closely.

(gentle music).

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