(gentle music) - Okay well thank you very
much for the invitation. And I know that you've all
been going through a lot, as have all of us in getting
ourselves to this point. And hopefully we can spend an enjoyable period of time together, delving a little bit
more 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 conceptualize
nutrition as it affects us, our health and our predisposition
for diseases chronically as we age. And so, as a leader I just
wanna make the point that, in particular, with respect
to 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 behavioral
recommendations for exercise, and healthy living, have traditionally been a one
size 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 more
precise recommendations, both in terms of diet, as well as in terms of a whole host of other potential interventions
we might be able to make, on our behalf to improve our
cardio metabolic health risk. And I just wanna sort
of highlight graphically and in terms of an example, how clear cut this idea
that 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 times
environment interaction. And there's no better example, to make the case that
cardiometabolic 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 on
the Mexican side of the border. And in Mexico, people with Pima genotypes tend to be lean, oftentimes, traditionally existing
in a subsistence manner, doing small farm work and have very low rates of diseases that we normally associate
with 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 the
American side of the border, Pima have a very different
socioeconomic status, very different result in
lifestyle factors including most notably diet and
quite sedentary lifestyles, because of the lack of
educational attainment, language barriers, and a whole host of other social determinants of health. Individuals who are Pima engage in work that tends to be promoting
of being quite sedentary. And all of those things conspired with a particular genotype
lean Pima in the United States to be relatively obese. In fact, in some segments of
the 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 their
genetically relatively identical family members, in many
cases on the Mexican side of the border. And so the only difference
that Pima experience, that leads to this incredible
increase in diabetes rates is just environmental. And so the genotype can
in 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 to
do with one's environment. And today, we're really gonna
be talking about those aspects of the environment that
dovetail with obesity, and we're gonna be focusing most notably on the diet in that regard. But just to note that even
if we look more broadly, the impact of obesity which
many of you may realize, is a well known risk factor for diabetes actually confers risk in a
quite heterogeneous manner. What I mean by that is, that even though people with obesity, generally speaking have
increased risk for diabetes, that risk isn't borne out
equally 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 for
and 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 metabolically
healthy forms of obesity, and because obesity itself
is becoming so common in the population, we actually see this diversity
and this heterogeneity in the obese phenotype play out. So some individuals are
highly cardiovascularly fit, they have no markers of
disease risk in terms of lipid profiles, inflammatory markers, or imaging related markers looking at their coronary
arteries, for example. Whereas other individuals who are obese even much less so, have all of these proximal
indicators of disease risk, and one of the really
key 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 having
mutations 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 a
gene 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 mutation
in a gene in the brain, that governs the brakes on appetite, and the trigger that initiates hunger. And so the two colored lines
represent growth curves, for those two kids born
with 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 population
of 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 they
reached 18 and beyond, they were far above
anybody else of their age in terms of their level of obesity. However, neither of these
two individuals had diabetes, not only that, but their
hemoglobin Aic exam, as you can see in the
table next to the graph actually reveals that
their glucose control is quite normal, in fact even healthy. If you just looked at
the lipid parameters, and the hemoglobin A1c data for these individuals without
knowing that they were obese, you would think that they were cardio metabolically quite
healthy maybe even athletic. And so you can see that from these data, it's clear that obesity by itself is not a direct link
to developing diseases that we normally associate
with 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 minimize
the number of individuals, who do not respond to
the efforts that we make on their behalf to improve their health. And on the entirely other
end of the spectrum, Asian individuals, both South Asian, as well as several East Asian subgroups, and also, certain individuals
in Middle Eastern countries tend to develop type two
diabetes at a much lower BMI, than the worldwide average and certainly the average
in the United States. And the number of individuals in those genetic subgroups, and ethnic segments of the
population in the United States has risen rapidly enough, that in many states, we've adopted something
called Screen at 23, where at least in the
public health setting, we can now get diabetes screening, without copay on behalf of the patient. For individuals who have
a BMI of 23 or above, which in the general population isn't even categorized as
overweight much less obese. On the other hand, for
Caucasian 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 example
of precision medicine. We're making different cut
offs, thresholds and guidelines, for screening and potential intervention for one subgroup differently than we are for another subgroup. Because we understand a little
bit about distinct aspects of risk from one group to another. Here, it's relatively
crude because we're making the distinction based
specifically only on ethnicity, without a deeper understanding
of 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 get
even more refined indicators of risk that might be manifest
at the individual level, as opposed to the level across an entire ethnic group, for example. And when you think about
the risk for diabetes in the context of obesity, another thing that we see is that people develop something
called insulin resistance before they go on to
develop type two diabetes. And again, we think of
obesity as a spring factor that triggers the development
of insulin resistance as an antecedent to type two diabetes. And in this graph, I'm showing you the relationship between an index of insulin
resistance 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 indicator
of excess body weight, with higher numbers indicative of a greater degree of obesity. And in general, the fit of that curve with
all the dots that you see representing individuals,
shows an inverse relationship such that the individuals
with the highest BMI have the greatest amount
of insulin resistance, the y-axis is an index
of insulin sensitivity. So the higher the number,
the more insulin sensitive, the lower the number, the
more insulin resistant and you can see that, the people with the lowest
numbers are the most obese. But the rectangle that I've placed in the middle of that point, is reflective of what
we might normally call a lean individual, somebody with a BMI below 25. And you can see in that
vertically oriented rectangle, that there's a number of
individuals 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 obesity
on any given individual can be exceptionally variable. And we have actually created at UCSF a cohort of individuals
to study this very thing, to get a better idea
about precision medicine related factors at play
in 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've
enrolled in the IDEO cohort, is to use dual energy x-ray
absorptiometry or DXA, which many of you may be familiar with, because we also use that
to check bone density in people when we're
concerned about osteoporosis. Well, we can also use
DXA to get an analysis of lean mass and fat mass, and use computer-driven
algorithms to understand where in the body certain
parts of their total fat is located, inside the
belly around the organs, which we call visceral
adiposity 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 are
individuals 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 a
much larger percentage of her fat located in the
visceral adipose tissue or VAT compartment as a
function of her total body fat. And that increased visceral fat content, the fat inside the belly around the organs that creates what we
oftentimes in popular parlance, called an apple shape is conferring a far
greater risk for diabetes for that Chinese woman, than the total body fat is conferring for the competitor, Caucasian
woman, 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 indication
of precise body shape related characteristics
that confer diabetes risk. And we can connect those
imaging related parameters to a whole host of
blood 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 for
diabetes or heart disease, that they may be able to
actually track the rise and the fall of these biomarkers, because we can validate
them versus other parameters like in this case, DXA based imaging. So in trying to get a even
better 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 many
GWAS 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 is
a graphical representation of the types of genes that
come 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 talking
anymore about people who have a single gene defect, But we're talking about
large 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 individuals
versus lean individuals. And that the meta-analyses that have been done to date show clearly, that the genes that are
associated with obesity, and code for proteins
that 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 altered
normal functionality in the brain, due to a number of different gene defects, each of which produces a
very small effect size, but when added up together, produce a large effect on hunger, satiety, our desire to comfort eat, and a whole number of
other factors that relate to our desire to eat more
versus less food per day, over a long period of time. And so that big peak of
dense vertical lines, shows how clearly the genes
that are associated with obesity are concordant with brain function versus function of a number
of other competitor tissues in the body. Now, if we compare that to that big tower of vertical lines, about two thirds of the way
towards 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 drivers
of 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 large
populations 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 proximately
associated with that risk, are genes that target the
function 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 related
to our vulnerability to developing insulin resistance
in the context of obesity, should we develop obesity. And that we think is
an indication as to why some people who develop obesity don't have any metabolic
complications associated with it, whereas other people who do, have all of the metabolic
complications associated with it. Okay, so now that we have a
little bit of an understanding about the fact that there
are indeed genetic drivers that we can assess population wide, that exerts small, incremental
increases or decreases in our overall risk for disease, we can look at diet as
an 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's
just quite instructive with respect to how society
and human biology intersect. And this is the example of Wonder Bread. So bread until the 1920s
was minimally processed. We did not have fine milling
of grains in our society, and so a lot of bread was baked at home. A lot of bread was
purchased at local markets and not mass produced. And the reason why Wonder
Bread came to get its name and what the purpose of the science that went into developing Wonder Bread, was that we needed or
felt we have the need to insert more nutrients into bread than normally came in bread. Bread was traditionally viewed
as being a pretty bland food with minimal nutritional value. And we felt like during
the 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 worked
on 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 and
minerals into the bread, and therefore "enrich it." It also allows you to put more
preservatives into the bread and give it the greater shelf life, that we now know a lot of
mass produced processed grains, cereals and breads have. And so once we went ahead and did this, and reformulated the entire
milling infrastructure in the United States to create
big, factory-based mills to mass produce enriched
grains for cereals and breads, we never went back. And instead, what we did
was focus on the other, what we thought at the time was the large nutritional
category and that was fat. We thought we had achieved
something 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 adult
health risks came from. And that really came
to a head in the 1980s with our low-fat dieting, and the excessive focus on
both fat and cholesterol. And so the change in
dietary recommendations initiated during the very
early 80s and late 70s, had a great impact. And you can see over time, the reduction in the
consumption of butter, the reduction in the consumption of lard, the reduction in the
consumption of margarine even that went along with, the focus on an increasingly low fat diet, and the increased consumption
by comparison of oils that are more polyunsaturated
and vegetable rich, and shortening for cooking that was based on vegetable fat as opposed to animal fat. And so we thought that we were
doing something very healthy by making this massive shift in macronutrient consumption patterns. But of course, however, what we learned in the
period from the 1980s until even quite recently, that beyond dietary fat,
smoking and sedentary lifestyle, there are a number of
other factors both genetic, which we have a much better
understanding of now, as well as dietary factors that really play into cardiovascular risk. And this, I show in
the context of pictures of Jim Fixx, who many of you may remember as being both a running guru
and a low fat diet aspirant who actually died of heart
attack at a relatively young age, and had tremendous blockage
of 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 simplistic
viewpoint on nutrition, and a very simplistic
viewpoint on the genes that contribute along with that nutrition, to cardiovascular and
cardio metabolic risk actually has led to wild
swings 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 increased
health risks in other areas. And so, in addition to, not identifying all
risk 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 something
for your calories, and the something that people tended to consume more of was carbohydrates. Now, we thought at the time, that because the carbohydrates
were all enriched, and had increased vitamins
and minerals in them, that we probably weren't
doing anything too harmful. But what we didn't realize was, that in the context of
the 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 with
the increased body weight since the 80s until now, there's been an associated increase in the rates of diabetes. And paradoxically, even
though we didn't know it in the 80s, we now fully realized
that 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 have
diabetes we now consider as having a cardiovascular
disease risk equivalent, as bad or perhaps even worse
in some cases than smoking. And the increased rates of diabetes are actually a function
of at least in part, dietary recommendations we
made over the prior decades in the context of trying
to be more healthy. And here's a good example
of what that looks like. So these are branded as being
healthy 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 a
poster child for that era of misguided nutrition. And so this is just to give
you the orientation chemically as to what we're talking about when we think of fructose in particular, it's a disaccharide combination
of both glucose and sucrose. And unlike glucose, which when we consume it, is assimilated through the
intestine enters the bloodstream, and then can be utilized by
cells 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 specifically
through the liver first, and as I'll show you, that fact alone leads
to a lot of disease risk associated with excess
fructose consumption. And so here's just an example
of what that looks like. So when we eat glucose, and that little tube-shaped
structure in the center of the image is the intestine, the intestine absorbs the glucose and then it goes immediately
into 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 to
fat 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 increases
associated with inflammation in the liver, and that inflammation
drives insulin resistance in the liver, and that leads the liver
to put out glucose. And that's one of the reasons
why 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 vicious
cycle that gets set up when people consume too much fructose. And you can see that in these
glucose 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 left
hand 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 individual
a 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 severe
Hyperinsulinemic response when they eat anything, and so, that burden on the
pancreas to kick out more insulin with every meal we consume, leads to a more rapid demise
of pancreatic function, and that is something that
then clearly leads to diabetes. And so the excess consumption
of fructose I think, really cannot be emphasized enough as a risk we've learned about for cardiometabolic decline in people. And this is a journal
cover from gastroenterology from colleagues here at UCSF, including Rob Lustig, Kathy
Mulligan and Jean-Mark Schwartz, showing that if you take adolescence and you limit their
consumption of fructose, specifically by depriving
them 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 relationship
between 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 improvements
relatively 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 a
push towards promoting whole grain consumption, to minimize the amount
of processed-refined simple carbohydrates that people consume. But even in the context of
whole grain consumption, consuming more finely milled whole grains produces a greater impact on blood sugar than consuming very minimally
processed whole grains. And so in these two graphs, I'm just outlining these
individuals in this study who were being compared, were eating whole grains that
were nutritionally identical, the only difference was
the extent of milling and the fineness of the
flour that was created from that milling process. And that's what the bottom
rectangle 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 blood
sugar 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 usually
consume carbohydrates in terms of foods that
are enriched with flour, cereals and breads, for example. And so the impact on blood
sugar we now understand is quite specific, and the wholeness of the grains can be modulated across a wide range, and that entire range of
modification of the foods that we may be having an impact on are cardio metabolic health. Okay, so now we'll
switch gears a little bit and talk about calories and dieting. And again, there's heterogeneity
and room for precision in this arena. So just to let you know, that many studies have
been done on the topic, and this is one of the
most 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 a
number 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 again
focusing on lowering fat to the extent possible, and replacing that with
vegetables and fruits, for the most part, but really focusing again on the fat in favor of more healthy protein
and fruits and vegetables. And then finally, the Atkins diet, which is really focusing
on 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 about
dietary weight loss though, and I wouldn't again take a read much into the relative difference with
respect 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 people
were still on the diet. And that's because the body
has a lot of mechanisms that fight back against
further weight loss, when we continue to deprive
our bodies of calories. And so no diet will produce
weight 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 weight
back within six weeks. And so these are the
fundamental 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 more
importantly healthspan i.e. the number of years
we live in our lives, before we have the first manifestation of life shortening chronic disease, calorie restriction has
consistently been shown to increase lifespan. And so you can see here
depending on the degree of calorie restriction, on the left hand side, we're showing data from
calorie restricted mice. And on the right hand side, the graphic has switched that to say, well what would that be if
an individual were to undergo that degree of chronic
calorie 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 the
50th percentile of mortality for people in terms of
their 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 necessary
to keep weight neutrality under normal conditions. And so the impact of calorie
restriction 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 about
this maybe in the question and answer afterward. But here's an example of two monkeys that are siblings raised
in separate cohorts, one that is eating an ad lib diet, able to have as much food as it wants without having to have
any restrictions placed, and the sibling with a 25%
calorie restriction in place, and you can see clearly that
one of these rhesus macaques is looking much younger, more
vibrant, alert, skin tone, everything, looks like
an animal much younger than stated age. Whereas the sibling who doesn't have that dietary restriction
protocol in place, ages in a manner that's
much more commensurate with the chronological age. And so, this is a really
intriguing area of biology. And we're doing a lot to try to understand the chemical mediators that are involved, in regulating the switches
that either protect or hasten metabolic aging and healthspan, in the context of how much
food we eat in our lives. People have taken this
idea of calorie restriction one step further, and have thought about
fasting as a potential way to recapture some of the benefits of calorie restriction overall, without reducing the overall
consumption of calories. And so there are a couple of
different ways to do this. In fact, there are many you
can reduce periods of time when you eat by doing
various fasting protocols, you can also restrict the amount of time in every day that you're
allowing yourself to eat. So the periods of time
between 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 set
of biological clocks. And those biological clocks
are entrained by both light and they're also trained by our behaviors, including when and how much we eat. And these clocks are also
evolutionarily conserved, because mammals and their
predecessors have evolved on earth with a 24 hour light dark cycle in place, for long enough that
we've been able to adapt to that very fundamental
aspect of life on earth. And so we have a central
clock located in the brain that governs a lot of
our diurnal activities, hormonal functions, sleep wake, as well as other physiological parameters. And then we have clocks in
all peripheral organs as well, that in train not only
to that central clock, but also to our nutritional intake, as well as many other behavioral factors. And so, in light of this
coincident integration of our nutritional habits and our clocks, people have tried to
restrict 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 a
lot of health benefits that people can get in this
cartoon 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 things
that people have done to even take this idea of time restricted feeding
and fasting one step further, is to look at one of the most
Hallmark metabolic shifts that takes place when we fast. And that is the production of
something called ketone bodies by the liver as a source
of fuel for the brain. So when individuals for
example, run marathons, and the reason that they
load up with carbohydrates is so that they can go
as long as possible, by allowing the liver to generate glucose from the glycogen that it deposits, as a function of all that
carbohydrate consumption the day before. And the intent is to have
glucose be produced by the liver, for long enough to allow for
the fat tissue in our bodies to mobilize fat and send
that fat to the liver, for the live to then turn
that fat into glucose. And so you have a continuous
supply of glucose, and the liver also makes
something called ketone bodies from that fat that go to
the brain specifically and allow us to remain alert, aware, and on top of things, even though we haven't eaten
since the night before, and we're in the middle
of running a marathon. But if people don't manage the carbohydrate consumption correctly, and if they're devoid of
sufficient glycogen to bridge until the fat reserves from
the fat go to the liver, and the liver can make
ketone bodies with them, you will have a fuel gap. And if you are unable
to make ketone bodies for your brain before the
glucose supply runs out, then you hit the wall, and I think you many of
you may have seen images of people who do that
around mile 20 or 21. And that shows how vulnerable
we are in the brain to the need for a constant supply of fuel. And ketone body production by the liver is that evolutionarily
conserved source of fuel, that keeps us alert and aware when it's been a long
time since our last meal. So what we've learned
is that carbohydrates, and their consumption is what shuts off the generation of ketone bodies, because it's associated with
the production of insulin, it means that we've now eaten a meal, and all of our physiology
goes to the Fed state again, it resets like a typewriter
back 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 amount
of carbohydrates in favor of protein and fat, allow us to enter a state of mild ketosis, even though we're not fasting
specifically to do so. And what we found is that
if 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 our
hormonally driven indicator of a prolonged fast, and we can mimic that by putting ourselves on a specific diet Asian. All right, so this is
just a quick overview of the ketogenic diet. I think I already went over this. But normally, when we
fast fats are liberated from our fat tissue. That's one of the reasons why we have fat is to actually provide a fuel
source when we're fasting. Those fats go to the liver, the liver turns the fat into
a number of different things, including glucose for itself, fat to send to the heart
and other muscles for fuel, and ketone bodies which
primarily as I said, go to the brain. We can recapitulate
that 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 ketogenic
cycle purposefully. And we can also, by the way, engage in the same kind of
thing by consuming ketones. And that's another area
of 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 that
increased ketogenic bump without having to substantially
alter our diets at all. Now, the science in
that area is really new, but that's one direction
where many researchers are trying to take it. And so the ketogenic diet is again, like time restricted feeding
associated 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 animal
models as well as in people. And the other areas that are more gray are a little bit less well recognized as being bona fide benefits
of the ketogenic diet, but are emerging areas that
we think are also relevant to what you might be able to expect in response to this diet. And we're trying to find
out mechanistically, how all of these health benefits work, and that's a very vibrant
area 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 colleague
of ours who we work with, named Peter Turnbow. And his lab has done a study showing that, not only does ketogenic diet
produce physiological effects that have contributions
to metabolic health, but they also produce immunologic effects. And immunological aging is
another aspect of healthspan that we would like to intervene in. And so they looked at
people on a ketogenic diet and what they found was, that the levels in the gut
lining, as well as in the blood of a cell type a T cell
type called Th17 cell, which is elevated in individuals
with cardiometabolic risk and in comparisons of people with diabetes versus no diabetes, goes down in response
to 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 and
immunological improvement, was a change in the
nature of the microbiome. And so this is another
area 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 probably
heard one way or another about probiotics, the
microbiome, meta genomics and its impact on cardio metabolic health. And we're gonna spend just a
few minutes talking about this. Okay, so, just briefly, the microbiome represents
all 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 last
two decades been shown, to have a tremendous impact on our metabolic health and healthspan. Two things that are fundamental
for you to know happen in the context of aging, and metabolic disease versus health to the microbiome. One is that the microbiome
and its composition changes from birth until adulthood, and then in the later phases of life in the last quarter of
our lives again, changes. And the second thing is that, in response to advancing age, and accelerated in
response to for example, changes in diet and in
the context of obesity, is a shift not only in the
composition of the microbiome, but it's a narrowing of the
diversity of the microbiome or the richness of the
number of different species, that are normally present
in one's microbiome. And so it's this lack of
diversity or narrowing, to fewer enriched species
that comprise one's microbiome that we think is associated
with individual vulnerabilities to disease risk. And this is just another
graphical representation of this, looking at the level
of individual species. And you can see that before adulthood, in response to what would
be called a healthy diet, in response to a high calorie
diet or diet induced obesity, and then in late life, there are profound changes in the composition. And here we're only
looking at four or five of the constituent species
that make up our microbiomes, in response to these dietary changes, as well as different
phases of our lifespan. And we're now very
focused 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 adequately
intervene to control the shape and structure of the
microbiome 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 long
term antibiotic use, adherence to a poor process
diets, sedentary lifestyle, toxic or other unhealthy
environmental 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 is
impacting our microbiota. And so you can see that individuals living in Asian countries have on
average richer microbiota than people living in
the United States do. And if you track immigration
of people from Asian countries, just as an example, to the United States and
then look over generations, and with time present in this country, over one's lifespan, the microbiota drops in
association 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 diversity
in 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 coolest
thing that gives us hope, that intervening in the microbiome, could be sufficient to impact
health and disease risk comes from the fecal transplant studies that individuals like Dr Turnbull's lab, and now we're doing these here
at UCSF as well have shown. So in the graphs that
I'm showing you here, these are transplants done
from two monozygotic twins. Okay, one twin that was obese, and the other twin which
was 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 the
microbes themselves purified, put them into the guts
through the stomach's of mice. And they could show that, these previously germ free mice were rendered with microbiomes, that mirrored those of the
donors they got the bugs from. And then, if you track those animals, you could see that they
gained increased weight if they got a microbiome
from 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 were
different about them we presume, were in the microbiomes
themselves, the bugs, and so these specific species of microbes that these mice got, was sufficient to change
that mouse's physiology. That's very profound. And I think we've spent
the last decade plus now, trying to build on those findings
in terms of interventions that are applicable to humans. And this brings us to, I think, the most
application oriented place that we are right now in this arena, and that is to use multiple
streams of data acquisition. So this is the classic study from the group at the Weitzman Institute, that was published in cell
where they took individuals, large number of individuals, they asked them to consume
different 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 their
blood sugar that was more so than if they consumed
the same amount of food, but in the context of, for example, whole grain oatmeal. Some people didn't have
any rise in blood sugar when they consumed white bread, and some people had a
massive spike of blood sugar when they consume the oatmeal. Furthermore, they looked
at other kinds of foods that are not normally associated
with a rise in blood sugar, in large population based
studies, for example, tomato, and they found that some
people 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 with
our nutritional habits, we may be able to get
a lot more information about changes in temperature, changes in glucose, sodium,
blood pressure, weight, than we ever would have
been able to get before, and we can integrate those streams of data with our nutrition and
also with our microbiomes. They were able to do this very thing, and they were able to, from this approach, find microbiome signatures that could predict
people's glycemic response, to individual foods. And that really represents
where we wanna be. Because if we can find out at a given individuals predilection, via their microbiomes, and then develop blood
based biomarker strategies that connect to the
composition of that microbiome, and then give instructive advice as to how that person
could alter their diet, take a specific probiotic,
or another intervention, that could reconstruct the
shape of their microbiomes to better align with a more
healthful response to food, we would really have something. And this is the present but
more so really the future, of where we wanna go
with precision nutrition. And so finally, now
circling 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 talk
about 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 Heart
Association own materials, they show you a really nice
description of good fats. And so we can talk about
omega three fatty acids, we can talk about getting
those omega threes from different kinds of sources, whether they're fish related omega threes, or whether they're omega threes that we get from
vegetable related sources. We can talk about nuts, and legumes, and other sources of
fat that are much better than traditional vegetable related oils. And then of course, we
could talk about olive oils, and mono unsaturated fats, versus saturated fats
and polyunsaturated fats, and dissect the specific
health and disease related parameters, that
these 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 nutrition
can be drugged, it's druggable. A nutraceutical can be developed
that 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 nutritional
omega 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 people
at a specific dose over time, had a tremendous impact on people who had previously high levels
of blood fat, triglycerides, and excess cardiovascular risk. It could serve to mitigate
future events, cardiac events, in those people, simply
by taking what's otherwise a component of a healthy diet
in isolation as a supplement. And if you go further, you can see that another
manifestation of this very thing is the Mediterranean diet. So the Mediterranean diet
has sort of just flipped, the enrichment of various
elements of the diet to favor monounsaturated
fats in the form of nuts, and legumes, as well as whole
grain 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 with
cardiometabolic 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 a
composite of cardiometabolic risk for these individuals via event rates. And in the top line, you can see the rate of
these events over time five years in the study
for 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 cardio
metabolic acute events. And that could be mimicked, by taking the diet that people are on and adding a specific amount
of 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 was
done on a large population. And as you remember from
the beginning of the talk, there's a lot of heterogeneity
in the human population. So it's quite possible that
there are hyper responders and relative non responders, and we haven't done
enough research to know how to distinguish those
folks from one another. But the idea here is, that with increased reliance
on genetic information, multiple streams of data
that can be obtained from biomarker based assessments,
transcriptomic analysis of individual cells, for
example from people's blood, as well as wearable devices, will be able to get the
kind of precise information that we can link to interventions, to ultimately find out exactly what any of us should be eating, with the intention of
staving off specific diseases that we might be at high
genetic predisposition for, to the greatest degree possible. And that's really the goal. And if we do that, then we'll be able to create
the proper healthspan increase that we want, with a minimal
number 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 UCSF
really is one of the few places in the country, if not the world that has the breadth of talent to really explore in all
of these different areas. And I tried to sprinkle
throughout the talk, multiple studies that really centrally involve UCSF researchers, showing you that we're
actually really deeply engaged in this kind of work, not just trying to harness
it 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 any
questions if there's time. - Thank you so much Dr. Koliwad, that was fantastic. And I know I'm almost positive
they got everybody thinking. Because this is like something, it's so tangible, it's our diet, it's what we do every day
or 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 obesity
the single gene mutation. Can you do CRISPR and
replace that appetite? Great, great question. - That is an amazingly
insightful question, amazingly insightful. And I will tell you, that it's so insightful
that scientists have tried to do that exact same intervention and we haven't done it
in human beings yet, and the main ethical reasons
why we wouldn't move to that necessarily yet. Although, the most ethical
CRISPR based intervention we can come up with would
be 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 receptor
that listens to the neurons that express PAMC, and that receptor is called
the melanocortin 4 receptor, or MC-4, and it's the MC4 receptor MC4R, that when mutated causes
a very similar picture as what I showed for PAMC. And two investigators from UCSF in fact, Christian Vaisse lab, working with two other labs
actually at Mission Bay. Did use CRISPR to correct
the haploinsufficiency, meaning one of the illegals, giving it back again and getting the mouse in this case, to reexpress MC4R and
that CRISPR based strategy was sufficient to completely ameliorate, the obesity phenotype, which otherwise was transmitted from generation to generation
in this inbred mouse colony, and they completely cured
it for that individual mouse and also for the progeny
that 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 fix
that 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 do
with the role of metformin, and the contributing factors to an ambulatory cycles in PCOS. So PCOS is a specific type of
fertility associated syndrome that is linked to two things. One is hyper androgenism, excess amount of testosterone
and so called male hormones, in a female genetically. And also an increase
in insulin resistance. And both of these factors play a role in the association between PCOS, and inappropriate or
absent menstrual cycles. And so, women with PCOS traditionally take birth control pills to
try to reestablish cycles. They take sometimes a
drug called spironolactone that blocks some of
this androgenic effects, and promotes more estrogen like features and really helps reestablish cycles, and sometimes the birth control pill has a spironolactone like effect
that's specifically chosen. And then finally they go on metformin. So what does metformin do? Well, metformin I showed
imagery 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 features
have the metabolic syndrome, altered blood, fat content
or triglyceride, obesity, slight hyperglycemia or
elevated blood sugar, high blood pressure and a
family history of diabetes, their PCOC might be really benefited by putting them on metformin. If an individual has
none of those features, and only has the problem
with menstrual cycles, and maybe some acne to go along with it, they may not be as well
benefited by metformin. We oftentimes try metformin
on those individuals anyways, but those individuals who
might not continue on metformin if I didn't see a beneficial
effect right away. On the other hand, whether you're talking about
an adolescent boy or girl, you might put somebody
with all the features of pre diabetes on metformin, because we know that it can do a lot to stave off the development
of 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 we
treat 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 doctors
for sometimes dermatologic issues more frequently than boys do. They go and see doctors for
issues related to puberty and menstrual cycles and
their development in ways that are probably more
frequent oftentimes, than boys do. And they continue to see
doctors if for no other reason, than for pap smears and female
fertility related well visits and many men don't go and see a doctor until they have symptoms, relevant to a chronic adult
disease for the first time after their last physical for
school sports for example. And PCOS is an indication, in many cases that somebody
is 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 likelihood
that she gets diabetes sooner versus later. Men oftentimes don't have
that kind of check in for another reason that gets
them to medical attention. And so I think PCOS is a
very important disease. With that in mind as well. - Oh, fascinating, fascinating, huh? So you're saying that guys
shouldn'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 had
a few more of those. But in absence of that, I think yes, you're right we
need 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 sort
of may balance out benefits in liquid profiles, and in
weight, 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 metabolic
benefits 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's
all this heterogeneity, the studies haven't taken that
heterogeneity 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 diet
doesn'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 the
context of these studies, you'll see a lot of weight loss. And in the context of that weight loss, you see a lot of cardio
metabolic benefits. We're now working to try to make sure, that we're correct about
ascribing those benefits specifically to the ketosis, and not necessarily to the
associated weight loss per se. And several studies have have done that. But there are other
people now getting back to the heterogeneity, who have all of the risk
factors 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 like
that on a ketogenic diet that's very strict, may cause a dangerous
amount of weight loss, and given that some of these individuals may not be obese or anything close to it by classical definitions
in the first place, you may not wanna put them in such negative energy balance, given their weight going in. So we don't know the
impact of ketogenic diet across diverse populations, in this kind of much more granular way and that's something that
I think a lot of people are now really focusing on, and wanting to get answers to. So, the other thing you
asked about was risks, and certainly, I think
there are a few risks. If you overdo it and
create substantial ketosis, you can actually alter
physiological function. People who don't make insulin. Those people who have the
other type of diabetes that is less common than type two, called type one diabetes. Those individuals, if they
don't take their insulin on a regular basis, will develop what we call
diabetic ketoacidosis. And that's because their
ketone body levels go up tremendously high, it
affects the blood pH, and actually alters physiological
function more broadly, including their ability
to 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 wanna
overdo the level of ketosis that you produce, because all of these
complications may be relevant to those individuals as well. And then finally, you brought up the
issue 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 are
attempting a ketogenic diet. And check in with your physician
about your kidney function, to make sure about the antecedent risks before you start it, especially given what your
age may be at the time is probably a very wise thing to do, and I would recommend it. - Great that was from Kate
Simmons that question. So Joanne Whitney asked us, what are the measurable
endpoints of ketogenic diet and microbiome change
in terms of diabetes? Does it decrease med use? Does it decrease insulin resistance? Like what are the actual measured impacts? - Yeah, so diet associated
changes to the microbiome. The way the studies have been done is kind of the reverse. Which is to say, we give medications that we
know improve insulin resistance, or lower blood sugar in variety of ways and look at what that
does 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 that
dietary intervention does to the microbiome. In terms of flipping it in
the way you asked the question and say, well, when you
have an unhealthy diet, or you age in the context of
your genetic risk factors, and you start developing pre diabetes and head towards diabetes, how do changes in the
microbiome facilitate that unhealthy change that
goes on in the context of age? There are many studies
out there looking at that, and the jury is completely still out. There is one set of studies that I think has been
winning out thus far, though. Maybe two ideas that are competing. One is that, as the microbiome shifts becomes less diverse and
certain species start dominating in the overall composition. Those species produce specific metabolites through the way those
bacterial species work on the foods that we eat. And those metabolites that
they produce, for example, certain short chain fatty acids, they can get across the intestinal barrier into our bloodstream, and they exert effects that
impact inflammation in the body and Visa V inflammation,
insulin resistance, putting a more greater
burden on the pancreas and ultimately leading to its
impairment and then diabetes. So the second area is that, some of the bacterial species
produce bacterial factors, toxins, for example, one called
lipopolysaccharide, or LPS. That in the context of advancing
age and unhealthy diet, can through what we are
now sort of loosely terming leaky gut, can get into
the circulation across the intestinal barrier. And those toxins mediate a
chronic inflammatory state, and that inflammation
fuels 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 between
connecting the changes we make in our diet, to the physiological
alterations we see in ourselves, Visa V the microbiome. And can we block those molecules
and arrest that process, even though the microbiome
changes its nature, its impact on our
physiology 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 more
as a family, of course. And there's lots of factors
associated 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 on
minimally 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 dietary
changes have been studied with respect to what they
do 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 have
defined at the species level, and you're doing the
same kind of intervention that should reliably produce
a 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 microbiota
transplant into mouse. So that mouse was raised
in a germ free environment for multiple generations, so that mouse was as a pup born without any intestinal microbiome. And so when you put a
microbiome into it, it will take because there's nothing that
it has to compete against in order to establish firm footing in the intestinal mucosa for life. Doing the same thing in
human is much more difficult, because you'd have to
give people antibiotics or something to clean
out their microbiome, that may have completely
unwanted side effects and other complications
associated with it. Furthermore, you're almost
never able to really get rid of their microbiome anyways, because they're just so firmly entrenched from birth until the time
you try the intervention that you can't. And so when you do the microbiota
transplantation into people, which we do for certain
inflammatory diseases now increasingly, we do in the context of certain bacterial nosocomial infections that we're trying to overcome. You don't get a really
solid and durable take, the original endogenous microbiome once again flourishes and outcompetes, the transplant in many individuals. And same thing is true
with probiotics in that, we can't really guarantee
how that probiotic is shaping the microbiome of the person
taking it in everybody. Because people are so heterogeneous, and their microbiome
signatures 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 a
good way to know that. There are companies like
you 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, to
summarize healthy nutritional lifestyle Change is way more
important than a simple pill. - At this point I think
that is absolutely correct. And I think we're much closer to making more precise recommendations about how people might
construct the composition of their diets, then we are in developing
pills that can bypass that. And way further along
than we are in deciding who those pills should be given to, to identify people who
are maximally responsive versus non responsive. - Wow, great. Let's see on the slideshow
showing where fat was stored in a white versus Hispanic
versus Asian woman with similar BMI's. Looked like the white woman was 37, and the other two were
58 and 59 years old, which seems pretty different. Could that have been the
differentiating factor? Well, that was pretty
insightful 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 are
people who are younger, and people who are older, on average, all the individuals in
the studies that we do are matched for age. So, in aggregate when we
take 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 to
make easy comparisons for the purpose of doing real scientific, comparative research. - Sure, so that question was from Hannah, who also says that as another
insightful question that, the ketogenic diet and
the Mediterranean diet seem pretty different. Is it likely that the people
for 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 people
who are maximally suited for responsiveness to
the Mediterranean diet, and other people who are
gonna respond very easily to even minimally ketogenic diet. And perhaps, not the other. I will say, though, that a couple of things
are relatively common for humans overall. One is that, all people
do enter into ketosis. If you fast for a
substantial amount of time, we all generate ketone bodies. So that's a physiology that is present and essentially all of us, unless you have a
specific genetic mutation that prevents that from
happening very aggressively, and that's very rare. But most people will generate ketones and so you could play on that
mammalian physiology dietarily and get at least some benefit
for just about everybody. The question is whether you
can get a lot of benefit, and it's clinically
relevant for that person. The Mediterranean diet on the other hand, again, it plays on multiple factors, we don't really know what the
specific only major factor that determines the beneficial
effects of that diet, 'cause you're doing lots of things in the Mediterranean diet. But if you just stick to the mono unsaturated fat
consumption 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, or
a monkey, or a person. So it's exceptionally
basic and fundamental in terms of its response. And so, again, we don't know whether
someone 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 can
get some modicum of benefit from a Mediterranean diet. I think the more fundamental
point I would make, though, is that, if you look
at 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, two
weeks, three weeks, four weeks, for example, where the
diets are really different from one another. If you take those acute
phases 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 with
palatability over the long term, the ability to people stay on the diet and really take it to heart, versus what's actually
sustainable physiologically over the long haul. Maybe you need to be in ketosis. Steve ketosis for only a
couple 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's
saying don't eat vegetables. So, there's lots of similarities. And I think, patients
and people in general should see past the acute phase. That is what leads the book
to have the title it has, and look at the maintenance phase and ask how similar these
diets are to one another, and then maybe aspire to
those common principles. 'Cause those principles in books, oftentimes really mirror like
American Diabetes Association, or American Heart Association recommendations relatively closely. (gentle music)
Nice presentation about obesity & T2DM and genetics, precision medicine, dietary impact, fructose etc
also talks about ketones around minute 41