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August 5, 2018

Autophagy - Your
Cellular Upgrade
We recently read Naomi Whittel’s
book, Glow15, which we highly
recommend for anyone wanting to
learn more about autophagy and
lifestyle changes for anti-aging.

The book piqued our interest in


autophagy and so we started looking
into it ourselves.

What we have learned is that there really is


no surface level understanding of how
autophagy is regulated and this diagram

can easily attest to that:


Source: Meijer AJ & Codogno P. 2005. Autophagy
and signaling: their role in cell survival and cell
death. Cell Death and Differentiation, 12:1509-1518.

BUT, we at least want to give you a basic


understanding of how the process works and
touch on some promising areas of research
that may translate into practical use.

WHAT IS AUTOPHAGY:

The word “autophagy” is Greek for “self-


eating”, and to no surprise that is its function.
It’s a normal mechanism inside each and
every one our cells where proteins or
whole organelles, that are damaged or
just not serving us anymore, are broken
down and any individual components
salvaged in the process are recycled as a
source of energy or to make new cellular
structures. The process is always running on
a basal level to ensure the quality and survival
of our cells. It’s the cellular equivalent to
“taking out the trash” so to speak, the only

difference is that if we don’t take out the trash


we still go on living our lives, whereas our cells
do not. Autophagy can be both, pro-survival
and pro-death, so it is important that we don’t
hold it on a pedestal and dedicate our lives to
having it activated at all times.
Take home message: Autophagy is the
cellular process that ensures protein and
organelle turnover by degrading what is no
longer needed and recycling materials to be
used again by the cell, either as energy or
synthesis of new structures.

PICTURE YOUR CELL AS YOUR KITCHEN

Naomi uses a great analogy in her book


comparing the cellular environment to your
kitchen. See when you’re working hard to
cook dinner, messes get left behind, things
drop on the floor, dishes pile up in the sink,
and that’s normal, no issues there. Our cells
are basically cooking dinner all the time,
working hard to perform all their functions,
but instead of dishes piling up and messes on
the counter tops, damaged proteins start to
accumulate and organelles start losing their
spunk. After dinner, the last thing we want to
do is clean up, but we do it anyways because a
clean kitchen makes things run smoothly when
the next meal time rolls around. Our cells are
doing the same, cleaning up after the messes

they’ve made by getting rid of these damaged


or dysfunctional components to make sure
things can continue to run smoothly.
Problems occur when this process slows,
and these messes don’t get cleaned up
properly, leading to the accumulation of
cellular garbage ultimately interfering
with our health.

A STEP BACK INTO

HIGH SCHOOL

BIOLOGY

Our cells contain a


nucleus and a
Source: https://www.thermofisher.com/us/en/home/life-
science/cell-analysis/cell-
structure.html variety of
membrane-bound
organelles all
enclosed by what’s
called the plasma
membrane.
Different organelles
carry out different
functions but there
is one that we are
particularly
interested in on the
topic of autophagy,
and that is the
lysosome.

Lysosomes contain all the enzymes needed to


breakdown proteins, nucleic acids,
carbohydrates and lipids, some people like to
refer to the lysosome as the stomach of the
cell. Not only do they contain the enzymes
needed to breakdown cellular waste, but their
membranes contain the transport proteins
needed to recycle anything that can be reused
by the cell. So, the lysosome is like a little
recycling plant, taking in useless
material, breaking it down and returning
the useable components. This is an
important action in autophagy, because not
only can we remove these damaged proteins
or structures but we provide the building
blocks to make new and better ones!

Take home message: The lysosome is the


organelle responsible for autophagy and
contains degradative enzymes to break down
cellular waste (aka the stomach of the cell).

AUTOPHAGY AT THE CELLULAR


LEVEL

In the cytoplasm, the proteins and organelles

that are ready to be removed, are sequestered


into a double membraned vesicle, called the
autophagosome. The autophagosome is
delivered to the lysosome where the
membranes fuse, making one large
compartment, exposing the materials to be
degraded to the lysosomal enzymes.

BRIEF HISTORY OF AUTOPHAGY

Scientists knew early on that our cells had


some sort of degradation system after
observing cellular content, and even whole
organelles, inside the lysosome. It wasn’t until
Yoshinori Ohsumi, a Japanese biologist, ran a
series of experiments in yeast cells that lacked
the enzymes needed to digest these materials
in order to observe the buildup of
autophagosomes. He then induced genetic
mutations, and tested multiple cell lines to
identify which genes were responsible for the
process of autophagy in which he was
successful [1]. This won him the 2016 Nobel
Prize in Physiology or Medicine. Scientists are
building on Ohsumi’s research and uncovering
more on what genes, and their respective
proteins, are governing the process of
autophagy with attention on its role in health
and disease.

AUTOPHAGY’S 4 PRIMARY ROLES:

Housekeeping: This is autophagy at a basal


level, ridding the cells of damaged or
misfolded proteins that may be hanging
around and the same for damaged or
dysfunctional organelles.

Immunity: Autophagy is a host defence


mechanisms, meaning it helps rid the body of
pathogenic foreign invaders such as bacteria,
viruses, and toxins.

Stress response: Autophagy is triggered in


face of cellular stresses such as nutrient
deprivation where, in this case, it will
breakdown its own cellular components for
energy (hint hint… fasting). In the stress
response, autophagy is also a cytoprotective
(cyto = cell) mechanism to prevent the
accumulation of damaged proteins and
organelles that could be causing even more
harm to the cell.

Embryonic development and cell


differentiation: Autophagy plays a role
where major tissue remodelling processes are
taking place, such as creating a baby!

WHY IS AUTOPHAGY IMPORTANT?

When autophagy stops working, things can go


downhill very quickly. Think of the kitchen
scenario again, if we just stopped cleaning our
kitchens, eventually it would become a
massive garbage dump, foods will rot and the

place will start to smell. Now picture the


inside of our cells with piles of misfolded
proteins, and aged organelles, such as old
mitochondria, releasing damaging molecules.
When misfolded proteins are not cleared from
our cells, they form aggregates and lead to the
development of amyloids. Amyloids are found
in the brain of patience with Alzheimer’s,
Parkinson’s, in the arteries of diabetics, and
other amyloid diseases. Autophagy is the
mechanism that prevents this from happening
and autophagy deficiencies have been linked
to accelerated aging. Unfortunately,
autophagy slows as we age, and this is
likely connected to practically all age-
related diseases, with emphasis on
neurodegenerative diseases. It is therefore
important for us to understand how we can
optimize this mechanism, turn it on in times
of need, and possibly use it as another tool to
prevent or mitigate some of the effects of such
diseases.

Take home message: Autophagy is essential


for the health of our cells and deficient
autophagy has been linked to various age-
related diseases, due to the inability to clear
damaged cellular components that ultimately
contribute to disease progression. Autophagy
slows as we age, but we may have the power to

control it, and that’s why it’s an important


topic.

THE MITOCHONDRIA AND


“MITOPHAGY”

There are organelle specific autophagy


pathways and they are conveniently named
after the organelle at hand. Mitochondrial
specific autophagy is referred to as mitophagy.
The mitochondria are commonly called the
powerhouse of the cell, and if you landed on
this page because of your interest in the
ketogenic diet, you may already know how
incredibly sacred the mitochondria are to our
cells.

As with anything that is overused, things start


to age and breakdown, and the mitochondria
are no exception. The issue is however, that
having damaged mitochondria hanging
around our cells can be very detrimental. Not
only is our energy supply insufficient, but
damaged mitochondria increase their
production of reactive oxygen species (ROS),
and release harmful inflammatory cytokines,
both in which wreak havoc on our bodies. In
fact, mitochondrial dysfunction is
characteristic of practically all metabolic
diseases such as diabetes, Parkinson’s,
Alzheimer’s, cancer, and many more. Why
autophagy, or mitophagy in this case, is such

an important preventative and anti-aging


mechanism may be becoming evident right
about now. It is suggested that mitophagy is
regulated by the generation of ROS as a signal
to the cell that the mitochondrion is defective
and it needs to be replaced [2]. As we age,
two major issues arise: autophagy slows
and mitochondria are damaged at an
increased rate, so if you’re entering your
later stages in life, autophagy becomes
even more important. Through increased
mitophagy, aging may decline at a slower rate
and the onset of age-related disease could be
delayed.

Take home message: Removing


old/damaged mitochondria and replacing
them with newer/better is crucial to the health
of our cells because they release damaging
molecules that contribute to many age-related
diseases.

WHAT IS CONTROLLING
AUTOPHAGY?

The initial figure in this post already


demonstrated the sheer madness when it
comes to the regulation of autophagy, and it is
something scientists are still working on. What
we do know, however, is that deficient
autophagy = shorter life span and that calorie
restriction = increased life span, in a range of

organisms from yeast to mammals.


Autophagy has also been shown to be a
required for the life-extension effects of
calorie restriction [3]. During periods of
starvation, autophagy is activated to provide
starving cells with primarily amino acids, to
be used for the synthesis of new proteins and
other molecules, but also as an energy source
by undergoing gluconeogenesis (conversion to
glucose).

Calorie restriction and fasting downregulate


the insulin/IGF-1 (Insulin-like Growth Factor)
and mTOR (mammalian Target of
Rapamycin) pathways, both in which have
been linked to autophagy. Low insulin levels
induce autophagy and high levels, you guessed
it, suppress it. That is not the whole story
though. A downstream target of insulin is
mTOR, which is considered one of the
primary regulators of autophagy [4]. mTOR
is activated in response to growth factors,
amino acids (e.g. dietary protein), and energy
status of the cell, so this makes sense why
calorie restriction would activate autophagy.
Since both of these pathways, insulin/IGF-1
and mTOR, are downregulated during fasting
or calorie restriction, it is through their
inhibition that autophagy can be activated.
There is undoubtedly more to the story which

involves AMPK, Beclin-1, tissue-specific


regulation, and many other players, but for
the sake of your time and your sanity we are
going to leave it at that.

Take home message: Autophagy is a multi-


regulated process, so there is no one pathway
that turns it on or off. Calorie restriction has
been proven to activate autophagy, and it is
believed that the downregulation of
insulin/IGF-1 and mTOR pathways are
playing a major role in this.

WHAT YOU CAN DO ABOUT IT

FASTING

Fasting is a very cut and dry approach to


activate autophagy, there’s no questioning
which foods to eat and what to abstain from to
keep these inhibitory pathways at bay. So, in
some ways, fasting is the easiest approach,
although I’m sure easy is not what you were
thinking since generally speaking, no food =
no fun. Multiple studies have demonstrated
the neuroprotective effects of calorie
restriction and fasting as means of removing
toxic molecules and damaged mitochondria
from neurons [5], and autophagy is the key
player. In one particular study using an
animal model, autophagy was upregulated
after a 24 hour fast, and results were even
more dramatic after 48 hours [6]. With that

being said, this was done in a rat model, and


fasting hours cannot directly translate to
humans, so this information is more
informative than practical. They also did not
test prior to 24 hours, so it is unknown after
what amount of hours autophagy begins
activation. The “minimum dose required”
would be great to know, because I’m sure we
can all agree that reaping the benefits of a 24
hour fast in something closer to 12 hours
sounds a lot better than going an entire day, or
maybe 3, without eating. As of right now
prolong fasts (~3-5 days) are likely what is
needed to really enhance autophagy. We
believe the research on that forefront will soon
be available, due to the current interest in
autophagy.

If we are only focused on insulin and mTOR


then intermittent fasting is a more realistic
strategy. The most common forms of
intermittent fasting studied include alternate-
day fasting and time restricted feeding, where
you alternate between eating normally one
day and restrict to ~500 calories or less the
next, or eat all of your daily calories in a 6-8
hour window and fast the remaining,
respectively. These methods may have some
benefit on autophagy by giving our bodies
periods of time without food and therefore

downregulating our nutrient sensing pathways


that, when activated, inhibit autophagy.

Take home message: It is clear that fasting


activates autophagy in animal models, it is
unclear however how long humans need to
fast to activate autophagy. ~3-5 days likely
guarantees some autophagy action, but
prolong fasting is not for everyone and
intermittent fasting may be an alternative.

KETOGENIC DIET

CAN WE INDUCE AUTOPHAGY WITHOUT

S T A R V I N G O U R S E LV E S ?

Of course, fasting is the simplest way to turn


off these nutrient sensing pathways, but
fasting is not for everyone (although you could
argue, periodic fasting should be for
everyone). Nonetheless, a lot of the
physiological responses of a ketogenic
diet mimic fasting and the reduction in
insulin that accompanies the diet and
sequential downstream signalling is likely, in
part, responsible. In an animal model, the
ketogenic diet was shown to upregulate
autophagy in the brain and showed a
reduction in the release of the highly
inflammatory molecule, cytochrome C [8],
eluting to the neuroprotective mechanisms of
the ketogenic diet. If done properly, the
ketogenic diet will induce the metabolic state

of ketosis where blood ketones are elevated (>


0.5 mmol/L). Beta-hydroxybutyrate, the
primary ketone body, has been shown to
stimulate chaperone-mediated autophagy (a
type of autophagy that does not require the
formation of the autophagosome) in vitro,
however this was in the context of nutrient
deprivation [9]. There is plenty of other
research demonstrating the neuroprotective
effects of the ketogenic diet, and how the diet
could replace the need for fasting and this
could be tied to the activation of autophagy.
Thus, we believe the ketogenic diet could be
used to, at least moderately, induce autophagy.

Take home message: The ketogenic diet


mimics fasting in a lot of ways, and has been
shown to induce autophagy in animal models.
It is a promising alternative to fasting.

BETTER YET, COMBINE THE TWO!

Using one of the two intermittent fasting


protocols mentioned above, in
combination with the ketogenic diet is
most likely the best alternative to fasting
cold turkey. The reduction in insulin
signalling and other nutrient sensing pathways
during these periodic fasts in combination
with the ketogenic diet, may activate
autophagy better than what they may

individually, but this is based on speculation


and more human data is needed!

SAUNA

Some studies have suggested that heat stress


such as that associated with sauna use
can activate autophagy, since autophagy is
a stress response in and of itself. Research in
C. elegans (worms), a commonly used model
organism, demonstrated the use of heat stress
to induce autophagy and extend life-span.
Worms, deficient in autophagy did not
experience the beneficial effects of the heat
stress, indicating that autophagy was
responsible for these results. In this study,
using a worm model of Huntington’s disease, a
reduction of protein aggregation in the brain
was observed in, which as previously
mentioned, contributes to other
neurodegenerative diseases such as
Alzheimer’s and Parkinson’s [10]. So, next
time you hit the gym, maybe stick around an
extra 20 minutes and treat yourself to a sauna
session.

Take home message: Mild heat stress could


be used as a way to activate autophagy and in
worms was shown to reduce toxic protein
aggregation in the brain.

EXERCISE

Speaking of hitting the gym, exercise has


also been shown to induce autophagy, and
fasted exercise may be even more beneficial.
In a mouse model, it was shown that treadmill
exercise induced autophagy in the brain [11].
Exercise-induced AMPK and sirtuin 1 could
be responsible for these effects, as both are
linked to the activation of autophagy, however
as always, more research is needed! The many
benefits of exercise are actually in response to
acute stressors, and this is likely how
autophagy is working in this regard.

CONCLUSION

Autophagy is not as simple as we’d like it to


be, but we think with the current
understanding of how it is regulated, there are
life-style practices that at least wouldn’t hurt to
try. The caveat to all of this is that we don’t
want these processes on or off at all times and
we certainly don’t always want to be in a
catabolic state. These growth factors that
inhibit autophagy are also what allow us to
increase muscle mass, heal our wounds, and
regulate many cellular processes for growth
and development. It’s also important to
recognize that most of this research is done in
animal models and in terms of the practical
implementation not all data is directly
translatable to humans. We still believe

autophagy can play a significant role in the


prevention and management of many age-
related diseases and that knowing how to
activate autophagy is another tool in our tool
box, just how we think of the ketogenic diet is
as well. All in all, autophagy is an
extremely important cellular process that
is absolutely required for the health of
our cells and should be given close
attention as we age. Hopefully this article
breaks down everything you wanted to know
about this hot topic and your leaving with
some actionable tips on using temporary
stressors to activate autophagy. Now go eat
yourself!

References:

1. Tsukada M, and Ohsumi, Y. Isolation


and characterization of autophagy-defective
mutants of Saccharomyces cerevisiae. FEBS
Lett. 1993;333(1-2):169-174.

2. Zhang J. Autophagy and mitophagy in


cellular damage control. Redox Biology.
2013;1:19-23.

3. Moselli, et al. Calorie restriction and


resveratrol promote longevity through the
Sirtuin-1-dependent induction of autophagy.

Cell Death Dis. 2010;1(1):e10.

4. Naito T, Kuma, A, and Mizushima N.


Differential contribution of insulin and amino
acids to the mTORC1-autophagy pathway in
the liver and muscle. J Biol Chem.
2013;288:21074-21081.
5. Jaeger PA, Wyss-Coray T. All-you-can-
eat: autophagy in neurodegeneration and
neuroprotection. Molecular Neurodegeneration.
2009;4:16.

6. Alirezaei M, Kemball CC, Flynn CT,


Wood MR, Whitton JL, Kiosses WB. Short-
term fasting induces profound neuronal
autophagy. Autophagy. 2010;6(6):702-710.

7. Wang et al. Ketogenic diet attenuates


neuronal injury via autophagy and
mitochondrial pathways in pentylenetetrazol-
kindled seizures. Brain Res. 2018;1678:106-
115.

8. Finn PF and Dice JF. Ketone bodies


stimulate chaperone-mediated autophagy. J
Biol Chem. 2005;280(27):25864-25870.

9. Kumsta C, Chang JT, Schmalz J, and


Hansen M. Hormetic heat stress and HSF-1
induce autophagy to improve survival and
proteostasis in C. elegans. Nature
Communications. 2017;8:14337.

10. He C, Sumpter, Jr. R, Levine B. Exercise


induces autophagy in peripheral tissues and in
the brain. Autophagy. 2012;8(10):1548-1551.

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COMMENTS (4)

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Sherri
2 months ago · 0 Likes

Thank you SO much for publishing


such an understandable, entertaining
and thorough explanation of autofagy!
I am very happy to have read your
article which actually uses scientific
and scholarly (read VALID and not just
anecdotal) articles. I have read so much
garbage that talks about autofagy as if
they are experts and they don't know
the first thing about it. "It's a great idea
- trust me!" And list benefits as truths
when they have never been
experimentally proven. Again,
THANK YOU! You have earned my
respect. (Sharryn and Kahlil are right,
though - there are several grammatical
errors. Lol)

Sharryn
3 months ago · 0 Likes

Great article. Sorry to be the grammar


police but (under ‘Why is Autophagy
important’) patients and patience are
not interchangeable...

Brandy
11 months ago · 0 Likes

very informative! Thanks!

Kahlil
11 months ago · 0 Likes

@Dom - I'm a huge fan. Sorry for


being a grammar nazi: I think you
mean "this book piqued our interest"
instead of "peaked"
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