(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)