Supercentenarians
are the rare individuals who have made it to the age of 110 and beyond.
At any given time, there are only 50 to 80 supercentenarians in the
entire world. In the U.S., an estimated 120,000 people make it to 100,
but only 20 of them make it to 110
What sets them
apart is that, up until the ages of 105 to 108, they’ve maintained the
health of someone in their 70s and 80s. They have no age-related
diseases, and typically die from sudden onset immune failure
In many
respects, supercentenarians age normally, while the rest of us age at an
accelerated rate. The basis of the book, “The Switch: Ignite Your
Metabolism With Intermittent Fasting, Protein Cycling, and Keto,” is
essentially how to normalize your aging rate, thus allowing you to
optimize your life span
Cyclically
activating and deactivating the mTOR pathway to intermittently trigger
autophagy is a key element that will increase your longevity.
Time-restricted eating and other fasting regimens accomplish this.
Fasted exercise can further boost results
NAD+ is one of
the most important longevity molecules that we know of. NAD+ is a
coenzyme needed by longevity-related enzymes called sirtuins. It’s also
required for DNA repair, but levels plummet with age, necessitating ways
to boost NAD+ levels. Strategies include time-restricted eating, fasted
exercise and supplementation
If you're interested in healthy living,
you won't want to miss this interview with anti-aging scientist James
Clement, author of "The Switch: Ignite Your Metabolism With Intermittent Fasting, Protein Cycling, and Keto,"
While a lawyer by trade, he has since transitioned into a full-time
research position, running his own antiaging research laboratory.
From Lawyer to Full-Time Researcher
Clement wrote "The Switch" because he saw that many still don't
understand the basics of health and longevity. The "switch" refers to
the switch between activating and deactivating the mammalian target of rapamycin (mTOR) pathway,
which is the central topic of discussion here. His book also covers how
to upregulate your mitochondrial function and other important pathways
for health and longevity, such as NAD+.
"For [as long as] I can remember, I've always been interested in longevity," Clement says.
"I just didn't know that there was a field that dealt with [longevity]
until Durk Pearson and Sandy Shaw's book, 'Life Extension: A Practical
Scientific Approach,' came out in 1982.
I happened to be a third-year law student at the time, married
to another law student. As soon as I read the book, which I did in like
two days, I said, 'I'm going to be a molecular biologist.' She
jokingly said, 'No. You aren't.' But I did start reading molecular
biology. I became very passionate about keeping up with antiaging
science.
I was lucky enough in 2009 to get on the board of the first
direct-to-consumer genome company called Knome that George Church had
co-founded. I had my own whole genome sequenced in 2009. George was the
scientist who read me my interpretation of my genome.
We started talking about aging. I found out that he had this
similar passion. We came up with a project called the Supercentenarian
Research Study. That sort of launched my becoming a full-time scientist
as opposed to a lawyer and entrepreneur that I've done previously …
We were a couple of years into the supercentenarian project. I
was starting to open my own lab. I started a vivarium and eventually
added 1,200 mice that I raised by myself with a couple of interns. At
that time, I approached George and asked him, 'Do you think it would be
beneficial to my credibility, career and knowledge to enroll in a Ph.D.
program?'
George kind of looked at me and said, 'You're doing projects that
grad students would give their right arm for. You're already reading 10
to 20 scientific papers a day. You're involved in writing up research
papers. This is what a scientist is. This is what they do. You don't
need to go work for someone else to learn these processes.' So, I stuck
with what I was doing."
60 Minutes Interview with Harvard Geneticist Professor George Church
What Sets Supercentenarians Apart?
Supercentenarians are the rare individuals who have made it to the
age of 110 and beyond. According to Clement, there are only 50 to 80
supercentenarians in the entire world at any given point. In the U.S.,
an estimated 120,000 people make it to 100, but only 20 of them make it
to 110.
As Clement began working with these supercentenarians, he realized
that what set them apart was the fact that, up until the age of 105 to
108, they'd really had the health of someone in their 70s and 80s. They
have no age-related diseases, and typically die from sudden onset immune
failure followed by pneumonia.
This suggests that improving your immune function is an essential
criterion to make it past 100. Clement goes so far as to say that, in
many respects, supercentenarians age normally, while the rest of us age
at an accelerated rate. The basis of his book is essentially how to
normalize your aging, thus allowing you to optimize your life span.
It's worth noting that while your lifestyle plays a tremendous role,
there's also a strong genetic influence. Siblings of supercentenarians
have a 17 times greater chance of reaching 100 years old than the rest
of us, for example, and many female supercentenarians have a mutation in
the IGF-1 pathway.
This makes them short in stature, so 5 feet is about the size of the
normal supercentenarian woman. In men, it tends to be a growth hormone
mutation that similarly makes supercentenarian men somewhat shorter than
the average man. Importantly, these mutations limit mTOR and turns on
autophagy, which is what gives these people such a head-start on
longevity. But there are ways for the rest of us to limit mTOR and
increase autophagy as well.
Advertisement
The Switch
The target of rapamycin (TOR), from which mTOR derives, is an
evolutionary mechanism that started with bacteria. All organisms need
nutrition, and the ability to make proteins and reproduce. When
nutrition is scarce, as it tends to be from time to time in the natural
world, the organism must venture out to seek more resources.
"The organisms that developed ways to hunker down and protect
themselves during these times of scarcity are the ones that survived and
we evolved from," Clement explains.
"We evolved and carried with us those genes that protected
bacteria, yeast cells, C. elegans worms, drosophila, mice, primates, et
cetera. They all have a version of mTOR. They all go through this
metabolic switch called mTOR and have an anabolistic state, anabolism,
and a catabolic state, or catabolism."
Anabolism is what allows you to grow and increase muscle mass,
whereas catabolism is the process of breaking down, repairing and
removing old worn-out cells. Importantly, catabolism is the phase that
cells enter when resources are scarce.
The cells essentially slow down protein production and cell division at this time, and activate the process of autophagy, which gets rid of misfolded proteins and dysfunctional organelles.
These old, worn-out proteins and organelles are recycled by lysosome,
which breaks them down into their base component parts and then
releases them back into the cell. These components can then be used to
make new amino acids capable of rebuilding new proteins.
This natural clean-out and regeneration process is why activating
autophagy on a regular basis is key for health and longevity. The same
process occurs in your mitochondria, which is called mitophagy.
"Like all other organisms, humans, for most our evolutionary
history, encountered this feast-or-famine state. Only recently, like
literally the last 150 years, has food production, industrialization of
farming and livestock management and refrigeration made it possible … to
have a never-ending abundance, mostly of foods that we didn't evolve to
eat in the first place," Clement says.
Why Cycling Through Feast and Famine Is so Important
One common mistake, which I also made, is continuously inhibiting
mTOR. It's really important to cycle back and forth between inhibition
and activation of mTOR. The anabolic state triggers cell growth, and
that includes stem cells — cells that can become any cell needed,
anywhere in your body.
"If you learn about mTOR and you say, 'I don't want cancer, and
turning on mTOR full-time and keeping autophagy off leads to cancer, so
I'm going to do the reverse,' then what you end up doing is not having a
strong populating of stem cells, not replacing damaged tissue, and you
end up losing muscle mass through sarcopenia.
I experienced this myself. I was on a vegan version of the
ketogenic diet for five years. I was doing this as self-experimentation …
I ended up losing a lot of muscle mass.
But as soon as I recognized what was going on and really thought
about the literature and what this meant, I realized that I was
foregoing the thing that nature had previously required, which is that
you go through this feast [stage]," Clement says.
"We have a whole chapter describing the different ways that you
can implement this in your own life. There's no one plan. There are
basically guidelines. … You can still have your pizza, your cheese,
cake, ice cream, et cetera, but you can't do this day in and day out.
You can't leave mTOR on [activated] and the brakes on autophagy
full-time."
Meal Frequency and Timing
Based on the evidence, time-restricted feeding appears to be one of
the essential keys to optimal health and longevity, as there's no other
way, really, to cyclically activate and deactivate mTOR and autophagy.
You have to have a period of famine, a restriction of nutrients, to
enter into a catabolic state.
The question then becomes, just how long does this famine need to be?
To be sure, eating throughout the whole day is a prescription for
metabolic disaster. Research by Dr, Satchinanda Panda
suggests 90% of people eat across a span of 12 hours a day, and many
across even longer timespans, which clearly is not doing them any
favors.
"I personally have gone now to a four-hour window," Clement says.
"I never was a big breakfast eater. I have a couple cups of coffee in
the morning. But historically, breakfast didn't exist until the Middle
Ages. We didn't evolve as cavemen eating at 6 a.m. or 7 a.m. a
breakfast of eggs, toast, jam and milk.
It's literally in the English version of the name, 'break-fast.'
It's the period in which you're breaking your overnight fast. This is
essential to keeping mTOR down and autophagy on as long as possible.
I would argue that people evolved to have autophagy turned on
every single night of their life, not just on occasions when they once a
year would go on a fast or try a ketogenic diet for a month and then go
back to the normal lifestyle."
I too was on a four-hour eating window for many months, but I'm now
starting to think that perhaps this window also needs to change from
time to time. Four to eight hours is probably the sweet-spot, and I now
think shrinking the eating window down to four hours a few times a week
is enough.
How to Incorporate Exercise for Optimal Results
The timing of exercise can also play a role. If you're fasting for 20
hours and eating within a four-hour window, aggressively working out
about two hours before you break your fast will suppress mTOR and
activate autophagy even further, increasing metabolic markers such as 5
AMP-activated protein kinase (AMPK) and decreasing insulin-like growth
factor (IGF), at least in your muscle.
As noted by Clement, this strategy will actually allow you to achieve the benefits of a two- to three-day long fast.
"By and large, the average person, who is obese and on seven
medications by the time they're 70 years old and has hypertension and
all these problems, those people got there because they weren't paying
attention to this switch," Clement says.
"These discussions about autophagy tell people essentially what
to do to turn it on, but hasn't really focused much on the balance — the
fact that we need both sides of this. I've also concentrated on the
triggers that turn on mTOR, because if we want it on, then we want to
make sure we aren't taking supplements or doing something else that
tends to inhibit it …
A branched-chain amino acid named leucine, which is four times
higher in dairy than it is in human breast milk, essentially locks on
mTOR … Leucine is almost like a key that, alone, without any help from
anything else, in sufficient quantities, will trigger mTOR activation
and turn off autophagy …
Generally speaking, if you are consuming dairy or animal meat,
you will likely have sufficient levels of leucine. Now, the cell also
needs, for mTOR to be working fully, insulin … which means you need
certain levels of blood sugar that will essentially trigger insulin to
be relatively high …
Without leucine or sufficient amino acids, mTOR is going to
essentially wait. That's what autophagy is actually meant to do — it's
to create more amino acids by breaking down organelles and misfolded
proteins to supply the cell [raw material to reuse].
It's got the sugar. It's got the energy. The insulin receptor is
turned on but it lacks the amino acids. So, through a short bout of
autophagy, the cell would most likely have enough to go through with
cell division or protein production."
Generalized Rules of Thumb
So, to summarize, having large amounts of dairy and/or animal
proteins for 12 hours a day or more is a prescription for metabolic
disaster, as it prevents the suppression of mTOR and activation of
autophagy.
One of the easiest solutions is to restrict your eating window to
four to eight hours each day, fasting the remaining 16 to 20 hours and,
ideally, exercising a couple of hours before your first meal.
"If you look at the diets of people who don't have the diseases
of civilization, which include the centenarians in Okinawa, Greece [and]
Loma Linda, California, you see that what's really happening is that
they're running through their glycogen stores in their liver and their
muscles overnight.
We only carry about 800 calories worth of energy in our glycogen
stores. It doesn't really take that much [to deplete them] … In a
deficit state, insulin drops, glucagon goes up, and you enter this
catabolic state. That can happen every day. I think it's probably how
humans evolved and probably we want to have happen most of the year …
This balance is what people have to find. I personally think that
it's going to be somewhere along the ratio of 8 to 4. [You could] make
that eight days in a row of turning down mTOR and two days of turning it
up, consecutively, or four months on of autophagy and then two months
off in a repeated cycle. There are lots of different ways to do this.
In the long run, I don't think we know what's absolutely optimal.
We just know that cycling back and forth is the way to do it. Probably,
if we keep those periods relatively shorter, especially as we get
older, the chance that you're inhibiting mTOR too long goes down … On
the whole, we want [mTOR] off more than we want it on, because that's
what all the long-lived people have. They all have mTOR more suppressed
than normal people."
At present, I'm experimenting with an updated cyclical time-restricted eating strategy that can be summarized as follows:
Two days a week, I eat all my meals within a four-hour window
One day a week, my meal window is eight hours
The remaining five days, my meal window is somewhere between four and eight hours
Each day, right before I eat my first meal, I will do a really hard blood flow restriction (BFR) training
workout. Knowing how the body loves variability and uses that to
optimizing the whole system, avoiding anything that is too monotonous
makes sense to me. Clement is a proponent of BFR as well.
"I'm a big fan of walking," he says. "I go out on 4- to
8-mile walks about once a day. It's really hard to get a power workout
in a walk … But with the [BFR], it has an amazing ability to actually
stress my muscles in a way that makes them grow and get stronger and
larger without having to do heavy weight presses and those kinds of
exercises."
The Importance of NAD+
Overall, NAD+ may be one of the most important longevity molecules
that we know of. As explained by Clement, NAD+ is a coenzyme needed by
longevity-related enzymes called sirtuins. It's also required for DNA
repair.
Finding data on NAD+ sorely lacking, Clement began his own research,
starting with a clinical trial testing intravenous (IV) NAD+ in elderly
people, in collaboration with Dr. John Sturges. Clement also underwent
the treatment, which involved an infusion of 1,000 milligrams of NAD+
per day for six straight days, finding it remarkably effective for
tremors he'd had since he was 20 years old.
"My hands would shake … It was just some neurological problem. It
wasn't the onset of Parkinson's at 20 years old or anything else that
anyone could point to. But surprisingly, within an hour or two of
starting the IV infusion, my tremors went away completely, which I had
had for the previous 40 years.
I noticed later that evening that I fell asleep and didn't wake
up during the middle of the night … I woke up way earlier than I
normally would, completely refreshed and ready to get back to work. This
was the same kind of experiences all of our elderly patients were
telling us as well. We had several people who had tremors that went
away.
I think [1,000 mg of NAD+] is too much for people who don't have
issues that would cause incredibly severe NAD+ depletion … Your body
uses copious amounts of NAD+ to detoxify alcohol, for example. In and of
itself, drinking every single night of your life will drastically
deplete your NAD+ levels.
There are other things that people do that can deplete their NAD+
levels. We've seen that in teenagers who get an infection, influenza or
something and then all of a sudden start getting migraines.
NAD+ will totally prevent the onset of migraines for periods of
two or three months at a time. People who have had multiple migraines a
month who get on these iontophoresis NAD+ patches can go years without
having migraines.
There are many, many symptoms of NAD+ depletion that we're just
now learning. We're finding that restoring the NAD+ to healthy levels
gets rid of these symptoms almost immediately."
NAD Plummets With Age
NAD+ levels plummet by the time you're 60 years old, and is nearly
undetectable by the time you're 80. NAD+ is a crucial part of the
longevity puzzle, as it's essential for repairing broken DNA. Broken DNA
is not something that occurs once in a while.
Single-stranded DNA breaks occur about 125 times an hour in every
cell of your body, and double-stranded breaks occur about 25 times per
day in every cell. DNA breaks are further accelerated if you're exposed
to high levels of electromagnetic fields, which virtually everyone in
the developed world are.
"There are lots of lifestyle practices and exposures that will
increase [DNA breaks] dramatically, and you need NAD+ in order to turn
on gene repair," Clement says.
"If [NAD+] is naturally going down — by the time you're 60 it's
maybe 50% of what it was when you were in your 20s and 30s, and then by
the time you're 70, it's 10% and then at 80, there's almost none — you
can see how this huge build-up of damaged DNA in every cell of your body
is potentially one of the driving forces of these morbidities that you
see with aging, heart disease, cancer [and] Alzheimer's …"
While IV NAD+ is available, it's cost prohibitive at $1,000 per IV.
Fortunately, there are less expensive ways to raise your NAD+. Two
precursors to NAD+ are nicotinamide riboside (NR) and nicotinamide
mononucleotide (NMN), both of which are available in supplement form.
NAD+ patches are also available, and all of these are far more
economical than IV.
A 1,000-milligram dose of NR has been shown to double your NAD+
level. The problem is that for the elderly, doubling a grossly deficient
level is not enough. In people with near-undetectable levels, the NAD+
levels need to be increased by 10 to 100 times.
So, while taking an NR or NMN precursor for six months will double
your level, you may still be depleted. Clement's study revealed many
older people need 4 or 5 grams a day for a period of time to restore
more youthful levels, which could end up being costly at today's price
of NAD supplements.
To circle back to exercise and time-restricted eating,
both of these strategies will increase nicotinamide phosphoribosyl
transferase (NAMPT) by about 30%, and NAMPT is the rate-limiting enzyme
for the recovery of NAD+ from its metabolic breakdown product,
nicotinamide. In other words, implementing time-restricted eating and
fasted exercise will naturally increase your NAD+ levels even without
taking any NAD+ supplements.
More Information
Clement also reviews the possibilities of using CRISPR technology for
gene editing, so for additional information, please listen to the
interview in its entirety, or read through the transcript. He also
discusses how his laboratory is pushing the limits to minimize the
transitional period from discovery to integration into clinical
medicine.
"[Many] for-profit companies that have gone into the antiaging
field … have one particular target, one arrow in their quiver,
essentially, to aim at [antiaging].
Most … get locked into spending the next four or five years
working on a particular antiaging pathway that may or may not turn out
to be all that important, whereas as a nonprofit and supported by
donors who really want to foster anti-aging, I can say that we're
looking at dozens of different completely independent pathways for
antiaging," Clement says.
"I've read between 18,000 and 20,000 scientific papers on aging.
I've made long notes about the things that were working on model
organisms, like flies and mice, for example. In many cases, we know
that these same things should work in humans, but the molecules or the
techniques used are generic drugs or compounds that you can't patent
for various reasons …
Therefore, there's just not a financial incentive for a venture
capital company to fund someone researching metformin, let's say, and
rapamycin, both of which are generic drugs, specifically for antiaging.
What you see is the venture capital companies are putting money
into companies that want to create novel compounds that mimic compounds
we already know about.
But no one's really studied or optimized those compounds … and
because anybody can knock that off, you might see a pharma company
trying to create a synthetic molecule that takes attributes of those and
has a particular molecular benefit similar to what they do.
But my parents, my elderly friends, they don't have 10 years to
wait. And then, often, these drugs are really powerful. For a lot of
people, they aren't appropriate anyway. The natural compound or the
generic drug that we already knew about would have probably been a
better choice.
What we want to do is take a lot of these compounds that are
already proven to work in other organisms, try them on humans, and then
if they do seem to work, then we go through a process of optimizing
them.
If they don't work, we just simply drop it and move on. Because
no one's counting on us turning this particular thing into a product, so
we don't have that weight over us that somehow the one and only thing
that we chose now has to be [profitable] …
Everything that we've talked about today is a result of decades'
worth of very intense research by hundreds and hundreds of scientists
that are focused on anti-aging and who are not specifically trying to
make a profit from a single molecule or cell line or therapy, but merely
doing the hard work of telling us what seems to work and what doesn't.
And then testing those in model organisms, from C. elegans, worms, drosophila, fruit flies and rodents, like mice and rats.
Much of this is already known that we can rapidly, I think,
qualify these things in humans using these clinical trials and know,
'OK. This is worth spending more time on because it has profound
antiaging effects or it helps one particular morbidity pathology.'"
No comments:
Post a Comment