Dr. Josh Mitteldorf is an evolutionary
biologist and a long-time contributor to the growing field of aging
science. His work in this field has focused on theories of aging. He
asks the basic question: why do we age and die? This can seem like a
silly question to people encountering it for the first time because most
of us would quickly respond, “Because that’s just how it is; all
creatures age and die eventually as their bodies wear out.”
Essentially, Josh is saying, “Not so
fast. In fact, a lot of creatures don’t age and die. Humans, as well as
most other animals that do age and die, are programmed to do so. So,
humans are programmed to die in much the same way that salmon are
programmed to die after spawning.”
Wait, what? Yes, Josh argues, we are not
that much different than salmon in this regard – we just have longer to
enjoy our inevitable fate than salmon do. However, our ultimate fate is
the same. This is important because an accurate understanding of how
and why we age will lead to more effective therapies and interventions
to mitigate or even eliminate aging.
I discussed my thoughts and reactions
upon learning about Josh’s ideas in his excellent 2016 book co-authored
with Dorian Sagan, Cracking the Aging Code, in this piece here.
What follows is an interview with Josh
about his ideas and his thoughts on the field of aging science more
generally. This interview was conducted by email in early 2018.
It seems like the field of aging
science has grown remarkably in the last decade or so, with many new
books and more research money and scientists devoted to the many
problems of aging. Given this growing interest are you optimistic that
we’re on the verge of real breakthroughs in longevity improvements?
I’m not as optimistic as I was a few
years ago. The Next Big Thing in the field is likely to be senolytic
drugs. These are able to selectively remove the body’s worn-out cells
that have become toxic, without poisoning our healthy cells. I think
they’ll add a decade or more to the human lifespan. The “exercise pills”
popularized by the New Yorker last fall will be another boost if they can be made safe.
After that, I think the big challenge will require taking control of our epigenetics
(heritable changes that don’t require changes to the genome itself).
Epigenetics, I believe, is in control of aging at a deep level.
Epigenetics is so complicated that 20 years into the age of epigenetics,
we’re still just beginning to understand how it works.
You have a Ph.D. in
astrophysics, and you work in mathematical modeling and evolutionary
biology – not exactly a set of credentials we’d expect for someone
focused on aging science. What was your personal path for becoming a
biologist who studies aging? And what is your preferred designation:
biogerontologist, “aging scientist,” or something else?
I was and still am fascinated by
cosmology, the study of the large-scale structure and the history of the
universe as a whole. However, I was frankly intimidated by how many
really, really smart people there are in the field. I came to doubt that
I would be able to see something that they missed and to make a really
fundamental contribution.
Then, in 1996, I figured out that the
whole biological community had missed the point about what aging is and
where it comes from. Here was a fundamental error that I might be able
to help correct, and it is about a question of interest to scientists
and non-scientists alike. Truly low-hanging fruit in the world of
research, waiting to be plucked. I found my calling.
What I didn’t realize is that science is
so well-defended against challenging ideas. Within five years, I had
worked out an understanding and a resolution of the basic paradox that
aging evolves despite the fact that it is the opposite of traditional
notions of evolutionary fitness. Here we are, 17 years later, and I’m
still working with the public relations aspects of this new science and
entrenched conservatism.
Is it indulgent for scientists
to focus on extending lifespans and healthspans when there are so many
diseases that still afflict kids and adults?
I don’t think so. Diseases of old age take the biggest toll on human health, by far.
Why are you less optimistic about the potential for major breakthroughs in aging science now in 2018 than you were previously?
Originally, my thinking went like this:
The conventional view has been that aging exists despite evolution’s
best efforts over hundreds of millions of years to eradicate it.
Evolution is already trying to make us live as long as possible, and for
humans to extend our lifespan, we’ll have to do some pretty fancy
thinking to come up with something that evolution hasn’t already tried.
However, this conventional view is
wrong. In fact, evolution has preferred defined lifespans to indefinite
lifespans. So, we might hope that we can eliminate aging entirely by
understanding the mechanisms of self-destruction that evolution has
built into our life history and biochemically disabling them. I had
thought that this could probably be done by blocking the signals,
jamming the works. Pharmaceutical companies are generally quite good at
turning off a hormone or a whole biochemical pathway once it’s been
identified.
The reason I’m less optimistic now is
that I believe that the evolved mechanism of self-destruction involves
gene expression, which is to say epigenetics. Different genes are turned
on at different stages of life (this is a big part of what epigenetics
is), and the genes turned on late in life turn the body against itself.
Mechanisms like apoptosis (cell death), autoimmunity, and inflammation
are all dialed up.
The reason my expectations are scaled
back now is that epigenetics has turned out to be enormously
complicated. We once thought that a few transcription factors controlled
a large number of genes, turning them on and off en masse. We now know
that there are thousands of different transcription factors, almost as
many as there are genes. And there is wide overlap between genes that
have transcriptional functions and genes that have metabolic functions.
Sigh.
There are more than 100 known mechanisms
of epigenetics, and the only one that we have a handle on is
methylation; that is, we can measure it and, clumsily with gene editing
tools like CRISPR, re-program methylation one site at a time.
In short, I think that turning aging
processes off completely will require a mastery of epigenetics, and we
have a long way to go before we even understand, let alone take control
of, epigenetics.
Could you flesh out a little
your contributions to aging science, in terms of the evolutionary theory
of programmed death in humans and most other species? I found your book
Cracking the Aging Code very interesting and enlightening on these
issues, but these ideas are hard for most people to get their heads
around.
Thank you, Tam. I do hope that this book
will turn around the way people think about the evolutionary origin of
aging, causing ripples that affect our understanding of the metabolism
of aging and leading to improved medical research. It’s gratifying that
my theory is receiving the recognition that was completely absent 20
years ago, but it’s also frustrating that the entrenched theory refuses
to die.
Briefly, the entrenched theory
is based on the “selfish gene” notion that Richard Dawkins and others
have made popular. Darwin had a broad and multifaceted view of what
constitutes fitness. He was appropriately vague. But in the 20th
century, “fitness” came to mean just one thing: fertility. How many
offspring can you produce, and how fast can you produce them?
In this picture of fitness, evolution is
highly motivated to make you live as long as possible, so long as you
are still churning out babies. So, where does aging come from? The
standard answer is that there are genes that tie fertility directly to
deterioration late in life, and evolution has not found a way around
this; it has not found a way to have lots of fertility early in life
without incurring damage later on, despite hundreds of millions of years
of trying to overcome this limitation.
In my book, I describe a great mass of
evidence against this picture. Much of it is common sense, but there is a
lot of technical, genomic evidence as well. The evidence strongly
points to the inference that natural selection has preferred shorter
lifespans to indefinite (or very long) lifespans.
Why might this be? My theory is that it
is about ecosystem stability. It’s not possible to construct a stable
ecosystem out of selfish individuals that are each trying to live as
long as possible and produce as many offspring as possible. In order to
have stable ecosystems, nature has had to accept limits to fertility and
to lifespan.
The reason that the evolutionary
community is so resistant to this idea is that it requires natural
selection to occur within entire ecosystems. In other words, this
ecosystem persisted because it was stable, while that one collapsed
because it was way out of balance.
So, stable ecosystems spread to take
over the territory of collapsed ecosystems, and all the species in the
stable ecosystem benefit. This is a much broader notion of how natural
selection works than the selfish gene model.
For largely historical reasons,
evolutionary theory grew up in a way that was committed to the selfish
gene. Most evolutionary biologists today believe that the selfish gene
is the only mode by which evolution operates, though they could not
articulate a reason why, if challenged.
If we are indeed programmed to
die, what does this insight suggest about the most promising pathways
for anti-aging breakthroughs?
The death program seems to operate
primarily through inflammation, apoptosis (programmed cell death),
autoimmunity, and cellular senescence through telomere shortening. My
understanding of aging suggests the following:
- Anti-inflammatories are already well-studied and represent the state of the art in anti-aging medicine.
- Apoptosis is trickier because the body needs apoptosis to get rid of cancer and infected cells. We can’t just dial down apoptosis; we need to make it smarter and more discriminating.
- Autoimmunity occurs when the thymus gland shrinks throughout a person’s lifetime. The most promising therapies to restore the thymus involve FOXN1.
- Telomere maintenance will have to be part of any full-spectrum anti-aging program.
How many additional years of
healthspan and/or lifespan do you think good nutrition, exercise,
attitude, supportive social bonds, etc. can contribute?
Look around you. The people who are
doing everything right live about 10 extra years. However, after age 90
or maybe 95, the genes take over. If you don’t have centenarian genes in
your family, all the healthy habits in the world won’t get you to age
100.
Let’s dive into what you
identify above as perhaps the most promising area of research: senolytic
drugs and apoptosis. What are these drugs, and how do they work? Are
there over-the-counter or prescription options available yet?
Senolytic drugs kill senescent (old)
cells without harming normal cells. The best evidence we have about the
potential for this therapy is that when senescent cells are efficiently
eliminated in mice, the mice live 25% longer. However, the catch is that
the way this is accomplished in mice is to genetically engineer the
mice before they are born, giving them a self-destruct mechanism built
only into their senescent cells. Then, the lab scientists can administer
a drug that doesn’t directly kill the cells but only signals them to
kill themselves.
Without genetic engineering, human cells
don’t have these self-destruct mechanisms built-in. Genetic engineering
has to start with the fertilized egg; it’s way too late for you and me
under this approach. So, for senolytics to be implemented in humans, we
need a really smart poison that only affects senescent cells without
harming normal cells. There are several pharmaceutical companies working
on this idea. The record-holder so far is FOXO4-DRI, and it is about 10
times more toxic to senescent cells than to normal cells. That factor
of 10 isn’t enough margin of error for a practical drug. To get rid of
all your senescent cells, you’d have to take too many healthy cells as
collateral damage.
A combination of dasatinib and quercetin
has been suggested for senolytics. Quercetin is found in fruits and
berries, but by itself it doesn’t extend lifespan (in mice). Dasatinib
is a chemotherapy drug that is far too toxic to be a practical life
extension medicine.
The best senolytic treatment we have now
is fasting. When we go without food for three days at a time or more,
senescent cells start to die off, but normal cells dial up their
resistance and become healthier during a fast. Valter Longo has
experimented with fasting and has designed a low-cal, low-protein
“fasting-mimicking diet” that allows you to get a lot of the benefits of
fasting with much less hunger.
David Sinclair, a geneticist at Harvard, has made waves
recently with his research on nicotinamide (a type of vitamin B3) and
its potential to rejuvenate circulation and increase energy, among many
other benefits. He’s talked about his 78-year-old father taking
nicotinamide and feeling like a 30-year-old again–with the adventurous
lifestyle to prove it. Sinclair’s recent paper
found a strong association between nicotinamide and reversing vascular
aging. Do you agree that nicotinamide and other methods of increasing
NAD+ are promising for significant rejuvenation?
I’ve been behind the curve with the
science of NAD all along. There may be evidence I haven’t seen. From
what I know now, I’m not impressed with the idea that NAD or its
precursors are a significant anti-aging tonic, though I don’t doubt that
there are some people who have benefited from these supplements. Our
metabolisms are so different, one person from the other, and I believe
that individualized anti-aging programs will ride a wave of
individualized medicine over the coming decades.
What researchers do you see as being mostly on the right track for major breakthroughs?
Recently, I’ve been much enchanted by Horvath’s aging clock.
But isn’t the “Horvath clock” a measurement tool rather than an anti-aging treatment?
Exactly so. What I believe is that our
development of anti-aging technologies has far outpaced our program of
testing, so, at present, we don’t know what works. For example, we now
have something in the neighborhood of over 20 treatments that have been
found to extend lifespan in mice by 5% to 15%, with a few up in the 20%
area.
The biggest unknown of all is how all
these technologies interact. I take about 20 different pills, plus
intermittent fasting, a low-carb vegetarian diet, yoga, endurance
exercise and interval training. All these things have been shown to have
some benefit, but we know almost nothing about how they interact with
one another. The great majority are likely to be redundant. That is, the
benefit of taking two supplements is barely better than taking one, if
at all; and with 20 different supplements, we can guess that most of
them are doing the same thing, but not all. There are some combinations
that actually synergize: 1 + 1 = 3.
How can we test all these
hundreds of different combinations, when a single life extension trial
in humans takes 10-20 years and costs hundreds of millions of dollars?
This is where the Horvath clock is a
real breakthrough. The standard test at present would be to try a
combination on 3,000 subjects and 3,000 controls, then wait and wait for
50 of them to die in the control group and only 40 in the test group,
and we have a positive result that’s barely significant, statistically.
However, the new Horvath clock, just out this spring, is so accurate
that you can see the results in a single human in the course of a year
or two. I predict that testing with the Horvath clock is going to be 10
times faster and 100 times cheaper than the present protocol.
Another great benefit is that early
adopters and self-hackers are going to start testing themselves, trying
an intervention and testing again the next year. If they do this with
some discipline, they can learn not just what works in general but what
works for their particular metabolisms. The Horvath clock will be a huge
boon for individualized medicine.
That’s an inspiring development. Who else has captured your imagination with their research?
I’m a fan of Irina and Mike Conboy.
Starting with parabiosis experiments (hooking the blood circulation of
two mice together), they have progressed toward blood draws and blood
infusions to study what factors in the blood are responsible for
rejuvenation. I think that this is a very promising line of research. On
the other hand, they haven’t published a major new finding in several
years, and privately, they’ve told me that rejuvenation may be
complicated, requiring a rebalancing of many different blood factors.
Dario Valenzano at the Max Planck
Institute published a stunning finding last year, linking intestinal
flora to rejuvenation in fish. Translated to humans, a 60-year-old might
be able to add a dozen years to his life with rectal transplants of
feces from his 30-year-old son or daughter. I don’t know of anyone who
is trying this yet, but that’s a simple, cheap procedure. You don’t need
a lot of money or even a doctor. Combine it with the Horvath clock, and
see if it is working.
Of course, I’m a fan of what Nir
Barzilai is doing with human trials of metformin. I’d like to see
someone do the same with rapamycin. The Russian labs of Anisimov and
Skulachev are doing remarkable work, but without proper controls or
replication. I’d like to see some Western labs pick up on their
technologies. Elissa Epel, Barry Sears, and P.D. Mangan are among many
people getting the word out about pro-longevity lifestyles that people
can adopt right now.
In the debate over telomerase
and telomeres, you’ve previously seemed to side with the more optimistic
thinkers like Michael Fossel and Bill Andrews. Aubrey de Grey, another
prominent researcher, has downplayed the potential for telomerase due to
fears about increasing cancer, and more generally because de Grey’s
approach is about simply cleaning up the detritus of the various aging
processes rather than stopping the aging processes. Are you shifting
over more to the de Grey camp now that your optimism about telomerase
therapy is fading?
I’m less enthusiastic than I was about
the potential of telomerase activators (which boost telomerase and thus
telomere length). I’m not afraid of cancer, but the very recent results
associating telomerase with an acceleration of the Horvath aging clock
are a big warning sign for me.
Fossel has stated in his book The Telomerase Revolution
that we should have affordable (about $100) IV drip treatments for
telomerase therapy that rejuvenate the whole body by 2025 or so. Is this
wildly optimistic, or is Fossel onto something that most others just
aren’t recognizing yet? He’s an M.D./Ph.D. with over thirty years of
aging research behind him, so he’s hard to dismiss, but this kind of
statement may seem over the top to many.
I like Michael and have enormous respect
for him. He saw the potential for telomerase technology more than 20
years ago, when it wasn’t on anyone else’s radar, except Michael West’s
and maybe Bill Andrews’. Now, we have so much more data, and I believe
the data is telling us that the potential life extension from telomerase
therapy is limited to a few years–maybe five at most. I’m glad that
Fossel and Andrews are doing what they’re doing, and we should know
before long if there are dramatic benefits from telomerase therapies.
What do you think of using de
Grey’s approach to clean up the detritus of aging while using things
like telomerase therapy, stem cell therapy, and gene therapy to prevent
future aging, combining them into a promising “big picture” approach to
rejuvenation?
I’ve always said that Aubrey’s
repair-based program is going to turn out to be unnecessary. The body
knows how to repair itself if we can just adjust the signaling
environment appropriately. We shouldn’t have to engineer all these
workarounds. However, this is just my theory versus Aubrey’s theory, and
time will tell how much can be done with signaling and how much needs
engineered repair. (Actually, Aubrey’s view and mine have been
converging from both ends in recent years. He is much more aware of the
potential for signaling approaches, and I’m coming around to believing
that some things will have to be repaired.)
What is your personal balance
between “aging gracefully” (accepting the aging process and all that it
entails) and staying abreast of all the aging science over the years as
well as making original contributions in this area, as you have?
I’m no believer in “aging gracefully.”
I’m much more in the camp of “Do not go gentle into that good
night–rage, rage against the dying of the light!” (Dylan Thomas). Or
Edna St. Vincent Millay: “Down, down into the darkness of the grave they
go… I know. But I do not approve. And I am not resigned.”
At age 68, I’m starting a new career,
learning new things not just in the sense of adding to my knowledge; I’m
revising old theories as new evidence comes in and overturning the way I
see the world.
