CARTA: Anthropogeny for Medicine and Health – Michael Gurven: Heart Disease in Hunter-Gatherers?

CARTA: Anthropogeny for Medicine and Health – Michael Gurven: Heart Disease in Hunter-Gatherers?


– [Announcer] This UCSD-TV
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us on Facebook and Twitter to keep up with the latest programs. (piano music) – [Man] We are the paradoxical ape. Bipedal, naked, large brain. Long the master of fire,
tools, and language, but still trying to understand ourselves. Aware that death is inevitable, yet, filled with optimism. We grow up slowly. We hand down knowledge. We empathize and deceive. We shape the future from
our shared understanding of the past. Carta brings together experts
from diverse disciplines to exchange insights on who
we are, and how we got here. An exploration made possible
by the generosity of humans, like you. (soft piano music) – One out of every four deaths, basically, in the US and the UK,
are from heart disease, so it’s basically the number one killer, not just in the industrialized world, and a major source of cost
burning our healthcare system, but also, around the world, including in the developing world,
that heart disease and its more insidious form
of it, atherosclerosis, is the source of every
three out of 10 deaths around the world today. So it’s so familiar to us
that the obvious question is, well, is atherosclerosis
really a universal aspect of just human aging, it’s
sort of an inevitable aspect, by the time you’re 20,
you probably already have some of the fatty streaks
that will later go on to become more complicated lesions and create problems for us,
or is that not the case? And so, maybe atherosclerosis is some, the process is universal,
but maybe it does or does not always present clinical manifestations that will affect our morbidity, and ultimately, mortality. So, a standard story is
that if we could zoom back into the past and look
at hunter-gatherers, that hunter-gatherers wouldn’t have these types of heart disease,
or other types of problems, and that it’s modern
features of our lifestyle that is making us ill,
that there’s a mismatch between our genetic adaptions, and modern features of lifestyle. So, changes in our nutrition, our diet, our physical activity, our
bad habits, as Barbara said, like cigarette smoking,
and alcohol consumption, that these are maybe
what create the problem, and that hunter-gatherers
would have little or no coronary heart disease. And the evidence for this is often focused on some risk factors, so, cholesterol, type 2
diabetes, low prevalence, that their risk factors seem
to suggest a healthy heart. But there’s some problems here, is that, we don’t really know, that in
these types of populations, that heart disease is fairly
absent, there could be, first of all, the
numbers are fairly small, and often, there’d be a
medical team like in the 1950s or ’60s that would
sweep through a village, but fairly quickly, and so, it could be that people who have heart disease die fairly quickly from it,
and so unless you’ve spent a long time in an area,
you might not actually see the real cases, if the case
fatality rate is quite high, and it could be that those people get weeded out of the population early, and so if you looked at
people over the age of 60, no one has heart disease,
maybe because they died earlier on in life. But also, the assessment
is fairly indirect, as I mentioned, it’s easy to
take someone’s blood pressure, to measure how much cholesterol they have, to measure their BMI, but it’s much harder to get a direct assessment, and of course, if certain risk factors work differently in different human populations, then it might not be a 1:1 relationship that the risk factors tell you about the actual underlying heart disease. And one good example, from the ’70s, it became established fact, almost, that the Inuit of the arctic north, in Alaska and Greenland, in particular, that they don’t have atherosclerosis, and they don’t have heart disease, and that, in particular,
their marine-rich diet, and particularly omega-3s,
was one good reason why, despite a very meat-based diet, that they would not have heart disease, but it actually turns out, there was some unreliable mortality statistics that some of those earlier
inferences were based on, and further x-ray and ultrasound studies actually showed the
opposite, that there is quite a decent amount of atherosclerosis, and that heart disease didn’t
really look that different from near surrounding populations, and that stroke might even be higher, and also, more recent meta-analyses show no effect of omega-3 fish
oils on heart-related deaths, heart attacks and strokes,
so the standard story is actually a little bit different when you look into it in more detail. And also, The Horus Group, which we’ll see a little bit more further in the talk, looked at a unique sample of 137 mummies across four world regions, so, Ancient Egypt, Ancient Peru,
the southwest of the US, and the Aleutian Islands, and
across 4,000 years of history, and they looked at different arterial beds for evidence of calcification, so a more direct measure, using CT scans, whole-body CT scans of these mummies, so for example, here you’ve got, these are both two Unangan
women from the Aleutian Islands, up here it’s woman about
50, here, a woman about 30, and you can see some
evidence of calcification in the aortic arch up on the top, and in the carotid artery
down here on the bottom, and what they found was
evidence of calcification across all arterial beds,
across all four populations. And so they argued that,
their conclusion was that, “We found that heart
disease is a serial killer “that has been stalking
mankind for thousands of years. “The presence of atherosclerosis
in premodern human beings “suggests that the disease
is an inherent component “of human aging, and not characteristic “of any specific diet or lifestyle.” So now, the paleo diet
people hated this, right? Because they were basically saying, “Look, it’s all over, it
doesn’t matter what you eat, “we find evidence of this everywhere.” But of course, all the
mummies had been long dead, so it’s hard to know what
they actually died of, and whether that atherosclerosis might’ve been relevant
to their daily lives. Now, also, free-riding off of Ajit’s talk, we now know that chimpanzees,
while the number one cause of death in captives is heart attacks, it’s not exactly coming
from the same ideology as human heart attacks. That chimpanzees do not seem to have the same kind of atherosclerosis, coronary artery disease is rare, but the heart failure instead
is diffused interstitial myocardial fibrosis, often
triggered by arrhythmias. You can see the fused
fibrosis in the heart tissue in chimpanzees, the kind
of subendothelial plaques in the human interior lumen,
that this is very different, and in captive chimpanzees,
despite the fact that they have higher cholesterol levels, they’re homozygous for
alleles in the ApoE4 that are higher risk of
atherosclerosis in humans, and less physical activity, so,
quite remarkable difference. So, now the standard evolutionary story brought to us by some
evolutionary biologists made critical foundational
contributions, Medawar, as well as Haldane and Hamilton, that basically, that
the force of selection declines with age, as
fertility is dropping, so, the relative contributions for future generations are declining, and so you can have
mutations that exert effects late in life, that might be somewhat blind to the effects of natural selection, especially if they have
beneficial effects early in life. So what that means is that
you’ve got deleterious effects that manifest, say, later in life, fall under the selection shadow, and it actually turns out,
when you actually look at the cases, this is from US data, the actual incidence of heart attacks and fatal coronary heart disease, that those cases do fall
into this selection shadow, so one knee-jerk response
is, well, maybe, again, these things have always been with us, but in hunter-gatherers,
if you’re not gonna live to this kind of age range,
then you’re not gonna see these types of ailments,
and so death might be the end of story, and
that our longer lives in modern society’s why we
see so much more of it today. But that doesn’t really
seem to be the case. If we take some of the best
demographic data out there in hunter-gatherers, as kind of a key, obviously, living hunter-gatherers are not the same as our ancestors, but it’s the closest thing we have to try to understand what life
and mortality might be like, without all the modern amenities. And so, in hunter-gatherers,
where the average life expectancy at birth
is in the either high 20s or low 30s, compared to
what we’re used to in the US and other first world countries,
is a dramatic difference! But if you notice, this is
the ratio of the mortality in hunter-gatherers, to
say the American mortality, and it’s quite high, the difference, but most of those differences
are early in life, and that by the time
you get to, say, age 15, the mortality differences drop
from, say, 200 early in life, to 14 times higher in hunter-gatherers, to about age 40, seven times
higher in hunter-gatherers, and by age 60, that mortality difference is only three times higher. Now, so if you live past this early period of high mortality, and
you survive to age 15, the modal age of adult death is actually, it ranges from 68 to 78,
in these hunter-gatherer populations. So, it’s not probably the case that the absence of older people is why we don’t see
these types of problems presenting these kinds of populations. So I wanted to move beyond mortality, and actually look at living bodies to see, well, okay, do people actually have some more direct evidence? And so since I mentioned, since 1999, we’ve been working in
central lowland Bolivia, with the Tsimane, so again,
a horticulturalist population that share many similarities
with hunter-gatherers, their fertility’s quite
high, they’re fairly high pathogen load, most of their diet, if not all their diet, is
basically coming from the land, from fish, from their fields,
and also, from wild game. And so, taking advantage
of the French government donating a 16-slice CT scanner, just a mere 10 hours and
several days in a canoe away, we brought people to the CT scanner to get a more direct
measure of atherosclerosis, through looking at coronary
arterial calcification, based on thoracic CT scans. And, what we found, so
using the exact same methods for scoring as in US studies,
when we compared Americans to the Tsimane, it
actually turns out that, well, the Tsimanes, these are here in red, there is evidence of
atherosclerosis, of calcification, but the levels are much lower
than what we see in the US. Now, the MESA, this is
the Multi-Ethnic Study of Atherosclerosis, these
are asymptomatic people without heart disease or
diabetes that are in the sample, so compared to those, the levels
of the percentage of people with any calcification
is much, much lower, and in fact, the Tsimane reach a level that the Americans have, that’s
a gap of over 20, 25 years. And so, one easier way
of thinking about this than just kind of obscure
calcification scoring, is what’s called the arterial age, and this is basically what
age, based on the CAC score you have, what’s that the equivalent of someone in the MESA study. And compared to what you would expect based on just the calcification score, that the Tsimane show
evidence that, basically, estimated arterial ages that
are about 20, 25 years younger than their chronological age. But the great thing about
working with living people, if the story ended there, we might say, well, look, just like we
found with the mummies, there’s atherosclerosis in the Tsimane, but, here, the clinical
findings really suggest minimal manifestations of atherosclerosis, so, over the past decade,
we found minimal obesity, hypertension, cigarette smoking, moderate-high physical activity, low cholesterol levels, your bad, your low-density lipoprotein cholesterol, low blood glucose, so the risk
factors are fairly minimal, and then if we actually
look based on EKGs, if we look for evidence of past infarcts, over 1,100 EKGs we’ve looked
at of people 40 and up, maybe one case of an infarct, looked at by our team of
cardiologists, and even that, some people, a couple of the cardiologists think it’s dubious, and
also, based on other evidence with EKGs, and also with ultrasound, evidence of preserved systolic
and diastolic function, and it’s not the case
that the young people that have these conditions,
then, are dying at early ages, or that these people have
high case fatality rates, so, based on verbal autopsies,
over the past 15 years, we don’t see very much evidence at all, in fact, maybe one case of
someone who may have died of a heart attack, so
it really doesn’t seem like there’s evidence
of mortality selection that is explaining these differences away. Now, this is in spite of the fact, they have some protective factors, but they also have very
high levels of inflammation, and in the past 20 years or so, it’s well known that inflammation
is a major risk factor, in fact, it’s a fundamental to the process of what we know about atherosclerosis, and by a number of
biomarkers, C-reactive protein is the one many of you
might be familiar with, because you often get it
done by your own clinician. They have very high levels
and cumulative levels over their life course, levels that would basically associate with
having heart disease amongst ourselves. They also have low levels of
the high-density lipoproteins, or good cholesterol. So a few take-home messages for
the larger biomedical field, first of all, it doesn’t seem
like the inflammation story is very complete, that the
same kind of risk factor might not exert the same
types of effects everywhere, and we probably would not have known that if we didn’t look at
populations that are, I guess, as Katy brought up, looking
at non-weird populations, and particularly,
populations that experience lots of infection and have
very different lifestyles than we have. And in fact, not only do they have high levels of inflammation,
but biomarkers of inflammation are either unrelated, or in some ways, oppositely associated with our measures of arterial calcification,
and other indicators of atherosclerosis, and it could be that inflammation that we experience
from cigarette smoking, from obesity, so-called
sterile inflammation, might have different effects than inflammation that is
induced under the conditions more representative of the past, which would be more from infection. But also that, that other
types of infections, particularly helminths, these
are our intestinal worms, our old friends that we’ve carried with us for long, long periods of
our evolutionary history, that they exert regulatory
effects on the immune system, and also, anti-inflammatory
effects that might perhaps protect against the
otherwise destructive effects of inflammation. And the other take-home is that what we consider average
might not be really normal. So, James O’Keefe, a physician
back in the early 2000s, argued the case, based on randomized placebo-controlled studies with statins that if you looked at
the chronic LDL levels, and you looked at a whole bunch of things, this is just a decrease over time in the luminal diameter, so
the interior of the artery, but you can change the y-axis
and make it heart attacks and other cardiac events,
that when you actually looked at how the occurrence of these things in relation to the chronic LDL levels, it seems to be a somewhat
linear relationship, to the point where, if you draw the line, that you would expect to
get almost zero events, in this particular graph,
it would mean, basically, a slowing of atherosclerosis
to the point of stopping, at a level of about 70,
or just less than 70, and so they were arguing
in a series of papers, that the optimal LDL should
be something between 50 to 70, whereas your typical recommendations, at least up until 2013,
when the statin-based recommendations changed
so that we’re not reaching a target level, but it used
to be that 100 was a level, but it actually turns out,
there’s a decent amount of heart attacks in the
region between 70 to 100, and this is just from the Tsimane, but if we looked at other populations, it would be a similar case, the
distribution of the LDL here in the Tsimane, compared to Americans, and it might be a little hard,
sorry, to see the numbers, but the mode and the average there is about 70 for the
Tsimane, whereas about 85% of Americans have LDL higher than that, and that what’s yellow there
is in that 70 to 100 region that basically, many of
Americans would fall into, even if they were taking statins. So, less than 70 is a
hunter-gatherer level of LDL that might be more extreme,
but probably very difficult for us, as omnivores, to reach, unless, perhaps, you’re taking statins. So, just to summarize and conclude, atherosclerosis is present, just like we observed in the mummies,
but it’s less pervasive than we see in the West. So, certain features
of cardiovascular aging may be universal, so you
might see some calcifications and stiffening of the arteries, there’s some declines, even
though they might be delayed, in systolic and diastolic function, but they occur nonetheless,
yet the clinical manifestation, so whether it’s heart
attacks, hypertension, peripheral arterial disease, strokes, that those themselves
may not be universal, and were likely very rare throughout human evolutionary
history, despite the fact that we can observe
calcifications in these mummies. And also, I think it
behooves us to revisit the common risk factors, that
inflammation might be high in hunter-gatherer populations, but immune function
might be better regulated in a very different
environment, particularly in the presence of a more
diverse set of pathogens, and also, it raises the
question of what is normal? What are the target levels of
different biomarkers like LDL that we should be reaching,
and what might they have been like, over the
course of evolutionary history? And to take advantage of the fact, if we hadn’t looked at a
population like she Tsimane, these non-weird populations,
that we can actually learn quite a bit about our own
health in, say, the US, by focusing on people that
are more likely to have certain types of infections
that could be cardioprotective, even a lot of our standard
model organisms in the lab are infection-free, and so
there might be some limitations of what can be gained, and also, taking advantage of the fact, well, and the horror of the fact,
that all indigenous populations around the world are in
different states of flux, and so it’s a kind of
quasi-natural laboratory for looking at the changes
in lifestyle and environment, on how that shapes increases
in type 2 diabetes risk, and in heart disease, and so
it’s sort of untapped territory that very, in fact, I don’t know any biomedically-oriented
folks that are working in these populations, to
try to learn more about the underlying ideology. And so, for the future, I think, one thing that a take-home message, is if the story was just
that, look, exercise more, eat well, don’t smoke, we already knew, those are your standard
Framingham study risk factors, and I think those do
make a big difference, but also, regulated immune function in the presence of certain parasites might also have some protective
aspects on the heart, and that maybe, in the
future, we might see that the hygiene
hypothesis, this idea that we are not exposed to
the same type of critters as we would’ve in the past,
that not only helps explains autoimmune-type disease currently, but also, maybe extend
it to heart disease. Thank you very much for your time. (piano music)