summarize this "One goal of Medicine 3.0 is to help people live a life course more like the
centenarians—only better. The centenarians not only live longer but live
longer in a healthier state, meaning many of them get to enjoy one, or two, or
even three Bonus Decades. They are often healthier at ninety than the average
person in their sixties. And when they do decline, their decline is typically
brief. This is what we want for ourselves: to live longer with good function
and without chronic disease, and with a briefer period of morbidity at the end
of our lives.
The difference is that while most centenarians seem to get their longevity
and good health almost accidentally, thanks to genes and/or good luck, the
rest of us must try to achieve this intentionally. Which brings us to our next
two questions: How do centenarians delay or avoid chronic disease? And how
can we do the same?
—
This is where the genes likely come in—the longevity genes that most of us
don’t have because we failed to pick the right parents. But if we can identify
specific genes that give centenarians their edge, perhaps we can reverseengineer their phenotype, their effect.
This would seem to be a relatively straightforward task: sequence the
genomes of a few thousand centenarians and see which individual genes or
gene variants stand out as being more prevalent among this population than in
the general population. Those would be your candidate genes. But when
researchers did this, examining thousands of individuals via genome-wide
association studies, they came up almost empty-handed. These individuals
appeared to have very little in common with one another genetically. And
their longevity may be due to dumb luck after all.
Why are longevity genes so elusive? And why are centenarians so rare in
the first place? It comes down to natural selection.
Hold on a second, you might be saying. We’ve been taught all our lives
that evolution and natural selection have relentlessly optimized us for a billion
years, favoring beneficial genes and eliminating harmful ones—survival of the
fittest, and all that. So why don’t we all share these pro-longevity centenarian
genes, whatever they are? Why aren’t we all “fit” enough to live to be one
hundred?
The short answer is that evolution doesn’t really care if we live that long.
Natural selection has endowed us with genes that work beautifully to help us
develop, reproduce, and then raise our offspring, and perhaps help raise our
offspring’s offspring. Thus, most of us can coast into our fifth decade in
relatively good shape. After that, however, things start to go sideways. The
evolutionary reason for this is that after the age of reproduction, natural
selection loses much of its force. Genes that prove unfavorable or even
harmful in midlife and beyond are not weeded out because they have already
been passed on. To pick one obvious example: the gene (or genes) responsible
for male pattern baldness. When we are young, our hair is full and glorious,
helping us attract mates. But natural selection does not really care whether a
man in his fifties (or a woman, for that matter) has a full head of hair.
Hair loss is not terribly relevant to longevity, luckily for me. But this
general phenomenon also explains why genes that might predispose someone
to Alzheimer’s disease or some other illness, later in life, have not vanished
from our gene pool. In short, natural selection doesn’t care if we develop
Alzheimer’s disease (or baldness) in old age. It doesn’t affect our reproductive
fitness. By the time dementia would appear, we have likely already handed
down our genes. The same is true of genes that would accelerate our risk of
heart disease or cancer in midlife. Most of us still carry these lousy genes—
including some centenarians, by the way. Indeed, there is a chance that those
same genes may have conferred some sort of advantage earlier in life, a
phenomenon known as “antagonistic pleiotropy.”
One plausible theory holds that centenarians live so long because they also
possess certain other genes that protect them from the flaws in our typical
genome, by preventing or delaying cardiovascular disease and cancer and
maintaining their cognitive function decades after others lose it. But even as
natural selection allows harmful genes to flourish in older age, it does almost
nothing to promote these more helpful longevity-promoting genes, for the
reasons discussed above. Thus it appears that no two centenarians follow the
exact same genetic path to reaching extreme old age. There are many ways to
achieve longevity; not just one or two.
—
That said, a handful of potential longevity genes have emerged in various
studies, and it turns out that some of them are possibly relevant to our
strategy. One of the most potent individual genes yet discovered is related to
cholesterol metabolism, glucose metabolism—and Alzheimer’s disease risk.
You may have heard of this gene, which is called APOE, because of its
known effect on Alzheimer’s disease risk. It codes for a protein called APOE
(apolipoprotein E) that is involved in cholesterol transport and processing,
and it has three variants: e2, e3, and e4. Of these, e3 is the most common by
far, but having one or two copies of the e4 variant seems to multiply one’s
risk of developing Alzheimer’s disease by a factor of between two and twelve.
This is why I test all my patients for their APOE genotype, as we’ll discuss in
chapter 9.
The e2 variant of APOE, on the other hand, seems to protect its carriers
against dementia—and it also turns out to be very highly associated with
longevity. According to a large 2019 meta-analysis of seven separate
longevity studies, with a total of nearly thirty thousand participants, people
who carried at least one copy of APOE e2 (and no e4) were about 30 percent
more likely to reach extreme old age (defined as ninety-seven for men, one
hundred for women) than people with the standard e3/e3 combination.
Meanwhile, those with two copies of e4, one from each parent, were
81 percent less likely to live that long, according to the analysis. That’s a
pretty big swing.
We will explore the function of APOE in more detail in chapter 9, but it
is likely relevant to our strategy on multiple levels. First and most obviously, it
appears to play a role in delaying (or not delaying) the onset of Alzheimer’s
disease, depending on the variant. This is likely not a coincidence, because as
we’ll see, APOE plays an important role in shuttling cholesterol around the
body, particularly in the brain; one’s APOE variant also has a large influence
on glucose metabolism. Its potent correlation with longevity suggests that we
should focus our efforts on cognitive health and pay special attention to issues
around cholesterol and lipoproteins (the particles that carry cholesterol, which
we’ll discuss in chapter 7), as well as glucose metabolism (chapter 6).
Researchers have identified two other cholesterol-related genes, known as
CETP and APOC3, that are also correlated with extreme longevity (and may
explain why centenarians rarely die from heart disease). But one individual
gene, or even three dozen genes, is unlikely to be responsible for centenarians’
extreme longevity and healthspan. Broader genetic studies suggest that
hundreds, if not thousands, of genes could be involved, each making its own
small contribution—and that there is no such thing as a “perfect” centenarian
genome.
This is actually good news for those of us without centenarians in our
family tree, because it suggests that even on this genetic level there may be no
magic bullet; even for centenarians, longevity may be a game of inches, where
relatively small interventions, with cumulative effect, could help us replicate
the centenarians’ longer lifespan and healthspan. Put another way, if we want
to outlive our life expectancy and live better longer, we will have to work
hard to earn it—through small, incremental changes.
—
One other possible longevity gene that has emerged, in multiple studies of
centenarians worldwide, also provides some possible clues to inform our
strategy. These are variants in a particular gene called FOXO3 that seem to be
directly relevant to human longevity.
In 2008, Bradley Willcox of the University of Hawaii and colleagues
reported that a genetic analysis of participants in a long-running study of
health and longevity in Hawaiian men of Japanese ancestry had identified
three SNPs (or variants) in FOXO3 that were strongly associated with healthy
aging and longevity. Since then, several other studies have found that various
other long-lived populations also appear to have FOXO3 mutations, including
Californians, New Englanders, Danes, Germans, Italians, French, Chinese,
and American Ashkenazi Jews—making FOXO3 one of the very few
longevity-related genes to be found across multiple different ethnic groups
and geographical locations.
FOXO3 belongs to a family of “transcription factors,” which regulate how
other genes are expressed—meaning whether they are activated or “silenced.”
I think of it as rather like the cellular maintenance department. Its
responsibilities are vast, encompassing a variety of cellular repair tasks,
regulating metabolism, caring for stem cells, and various other kinds of
housekeeping, including helping with disposal of cellular waste or junk. But it
doesn’t do the heavy lifting itself, like the mopping, the scrubbing, the minor
drywall repairs, and so on. Rather, it delegates the work to other, more
specialized genes—its subcontractors, if you will. When FOXO3 is activated,
it in turn activates genes that generally keep our cells healthier. It seems to
play an important role in preventing cells from becoming cancerous as well.
Here’s where we start to see some hope, because FOXO3 can be activated
or suppressed by our own behaviors. For example, when we are slightly
deprived of nutrients, or when we are exercising, FOXO3 tends to be more
activated, which is what we want.
Beyond FOXO3, gene expression itself seems to play an important but still
poorly understood role in longevity. A genetic analysis of Spanish
centenarians found that they displayed extremely youthful patterns of gene
expression, more closely resembling a control group of people in their
twenties than an older control group of octogenarians. Precisely how these
centenarians achieved this is not clear, but it may have something to do with
FOXO3—or some other, as yet unknown, governor of gene expression.
We still have more questions than answers when it comes to the genetics
behind extreme longevity, but this at least points in a more hopeful direction.
While your genome is immutable, at least for the near future, gene expression
can be influenced by your environment and your behaviors. For example, a
2007 study found that older people who were put on a regular exercise
program shifted to a more youthful pattern of gene expression after six
months. This suggests that genetics and environment both play a role in
longevity and that it may be possible to implement interventions that replicate
at least some of the centenarians’ good genetic luck.
—
I find it useful to think of centenarians as the results of a natural experiment
that tells us something important about living longer and living better. Only in
this case, Darwin and Mendel, the Russian geneticist, are the scientists. The
experiment entails taking a random collection of human genomes and
exposing them to a variety of environments and behaviors. The centenarians
possess the correct combination of genome X required to survive in
environment Y (perhaps with help from behaviors Z). The experiment is not
simple; there are likely many pathways to longevity, genetic and otherwise.
Most of us, obviously, cannot expect to get away with some of the
centenarians’ naughty behaviors, such as smoking and drinking for decades.
But even if we don’t (and in many cases, shouldn’t) imitate their “tactics,” the
centenarians can nevertheless help inform our strategy. Their superpower is
their ability to resist or delay the onset of chronic disease by one or two or
even three decades, while also maintaining relatively good healthspan.
It’s this phase shift that we want to emulate. But Medicine 2.0, which is
almost solely focused on helping us live longer with disease, is not going to
get us there. Its interventions almost always come too late, when disease is
already established. We have to look at the other end of the time line, trying
to slow or stop diseases before they start. We must focus on delaying the onset
rather than extending the duration of disease—and not just one disease but
all chronic diseases. Our goal is to live longer without disease.
This points to another flaw of Medicine 2.0, which is that it generally
looks at these diseases as entirely separate from one another. We treat
diabetes as if it were unrelated to cancer and Alzheimer’s, for example, even
though it is a major risk factor for both. This disease-by-disease approach is
reflected in the “silo” structure of the National Institutes of Health, with
separate institutions dedicated to cancer, heart disease, and so on. We treat
them as distinct when we should be looking for their commonalities.
“We’re trying to attack heart disease, cancer, stroke, and Alzheimer’s one
disease at a time, as if somehow these diseases are all unrelated to each
other,” says S. Jay Olshansky, who studies the demography of aging at the
University of Illinois–Chicago, “when in fact the underlying risk factor for
almost everything that goes wrong with us as we grow older, both in terms of
diseases we experience, and of the frailty and disability associated with it, is
related to the underlying biological process of aging.”
In the next chapter, we will look at one particular intervention, a drug that
likely slows or delays that underlying biological process of aging at a
mechanistic level. It may become relevant to our strategy as well, but for now
this means pursuing two approaches in parallel. We need to think about very
early disease-specific prevention, which we will explore in detail in the next
few chapters dedicated to the Horsemen diseases. And we need to think
about very early general prevention, targeting all the Horsemen at once, via
common drivers and risk factors.
These approaches overlap, as we’ll see: reducing cardiovascular risk by
targeting specific lipoproteins (cholesterol) may also reduce Alzheimer’s
disease risk, for example, though not cancer. The steps we take to improve
metabolic health and prevent type 2 diabetes almost certainly reduce the risk
of cardiovascular disease, cancer, and Alzheimer’s simultaneously. Some
types of exercise reduce risk for all chronic diseases, while others help
maintain the physical and cognitive resilience that centenarians largely get via
their genes. This level of prevention and intervention may seem excessive by
the standards of Medicine 2.0, but I would argue that it is necessary.
In the end, I think that the centenarians’ secret comes down to one word:
resilience. They are able to resist and avoid cancer and cardiovascular disease,
even when they have smoked for decades. They are able to maintain ideal
metabolic health, often despite a lousy diet. And they resist cognitive and
physical decline long after their peers succumb. It is this resilience that we
want to cultivate, just as Ali prepared himself to withstand and ultimately
outlast Foreman. He prepared intelligently and thoroughly, he trained for a
long time before the match, and he deployed his tactics from the opening bell.
He could not have lasted forever, but he made it through enough rounds that
he was able to fulfill his objective and win the fight."