05/03/2019 Fasting, Longevity and the Mitochondrial Connection

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Mitochondrial Connection
Dr. Jason Fung Follow
Jan 25, 2018 · 7 min read

To understand a disease properly, you need to focus on nding the right

level. This is a ‘forest for the trees’ problem. Think about Google Maps.
If you zoom in too closely, you will miss what you are looking for. If you
look at a map of your neighborhood, you can’t see where Greenland is.
Similarly, if you zoom out too far, the same problem exists. Suppose I
am looking for my house, but I look at a map of the world. Good idea.
But where’s my city? Where is my street? Where is my house? It’s
impossible to tell, because we are not looking at the right scale or level.

Where’s my house?

The same problem exists in medicine, as human diseases occur at

di erent levels. For example, if we are examining a gun shot wound
and zoom in too closely to look at the genetic makeup of the victim, we
will miss the sucking chest wound that is obviously killing our patient.
By the same token, if we are dealing with a genetic disease such as
Fabry’s disease, looking at the chest wall will not give us much clue as
to what is going on. We must zoom in to the genetic level in order to get
a clue.

There are diseases involving the entire body, e.g. hemorrhage, sepsis.
There are diseases speci c to the level of individual organs — heart
failure, strokes, kidney failure, blindness. There are diseases at the
cellular level — myeloma, leukemia etc. There are diseases at the
genetic level — Duchenne muscular dystrophy, Fabry’s disease. In all
cases, nding the right ‘level’ to zoom in is vital to nding the ultimate
cause of disease. But there is one level that has been virtually ignored,

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until recently — the sub cellular level that exists between the cellular
and genetic levels.

Di erent Levels of Human Disease:

• Whole Body

• Individual Organs

• Individual Cells of each organ

• Subcellular (Organelles)

• Genes

Our body is composed of multiple organs and other connective tissue.

Each organ is composed of di erent cells. Within the cells there are
organelles (mini-organs) such as the mitochondrion and endoplasmic
reticulum. These sub-cellular mini organs do various functions for the
cell such as generate energy (mitochondrion) and remove waste
products (lysosomes) and make proteins (endoplasmic reticulum).
Within the nucleus of the cell lies the genetic material including
chromosomes and DNA.

We have de ned diseases for every level except the sub-cellular,

organelle level. Is it possible that organelles never become diseased?
That hardly seems possible. At every level, things can go wrong, and
the organelles are no di erent. Increasing attention is being paid to
mitochondrial dysfunction as a contributor to many chronic diseases

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because these organelles lie at the cross roads of sensing and

integrating cues from the environment to trigger adaptive and
compensatory cellular responses. That is, they serve a key role in
sensing the outside environment and optimizing the cell’s appropriate
response. Mitochondrial disease seems to be linked to many of the
diseases of excessive growth, including Alzheimer’s disease and cancer.
This makes sense because mitochondria are the power producers of the
cell.

Consider an engine, your car’s power producer. What part of the car
breaks down the most often? Usually it is the part that has the most
moving parts, is the most complex and does the most work. So, the
engine requires constant maintenance in order to run acceptably. By
contrast, a part of the car that is not complex, gets no usage and has no
moving parts like the back seat cushion requires little maintenance and
almost never breaks down. You change the oil every few months, but
don’t worry about the back seat cushion much. Mitochondria are your
cell’s little engines and are just as prone to breakdown as other body
part. Keeping mitochondria functioning well may be a hidden key to
good health.

So let’s talk mitochondria.

Mitochondrial Dynamics

The most well recognized role of mitochondrion is as the cell’s

powerhouse, or energy producer. It generates energy in the form of ATP
using oxidative phosphorylation (OxPhos). Organs (heart is #1, and
kidney is #2 in terms of ATP usage) that use a lot of oxygen, or have
high energy demands are particularly rich in mitochondria. These
organelles are constantly changing in size and number by the processes
of ssion (breaking apart) or fusion (putting together). This is called
mitochondrial dynamics. A mitochondrion may divide into two
daughter organelles, or two mitochondria may fuse into a single larger
one.

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Both processes are necessary for mitochondria to stay healthy. Too

much ssion and there is fragmentation. Too much fusion is called
mitochodrial hypertabulation. As in life, the proper balance is
necessary (good and bad, feeding and fasting, yin and yang, resting
and activity). The molecular machinery of mitochondrial dynamics was
rst described in yeast and then the corresponding pathways found in
mammals and humans. Defective mitochondrial dynamics have been
implicated in cancer, cardiovascular disease, neurodegenerative
diseases, diabetes and chronic kidney disease. In kidney disease,
speci cally, too much fragmentation seems to be the issue.

Mitochondrion were rst described as ‘bioblasts’ by Altmann and in

1898, Benda observed that these organelles had various shapes,
sometimes long, like a thread, and sometime round, like a ball. Hence
the name mitochondrion is derived from the Greek words mitos
(thread) and chondrion (granule). Lewis, in 1914 observed that “Any
one type of mitochondria such as a granule, rod or thread may at times

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change into any other type” through the processes now known as
mitochondrial dynamics.

The numbers of mitochondria are regulated by biogenesis to meet the

energy needs of the organ. Just as they are ‘born’, they can also be
culled through the process of mitophagy, which also maintains quality
control. This mitophagy process is closely related to autophagy which
we have discussed previously.

The sirtuins (SIRT1–7) (previously discussed here) yet another type of

cellular nutrient sensor also regulates several aspects of mitochondrial
biogenesis. Increased AMPK (low cellular energy status) also acts
through several intermediaries to increase mitochondria.

Fission and fusion imbalances of mitochondria result in reduced

function. Mitochonria, other than just being the powerhouse of the cell,
also play an integral role in programmed cell death or apoptosis. When
the body decides that a cell is no longer necessary, the cell does not
simply die. If that happened, then the cellular contents would spill out,
causing all kinds of in ammation and damage. It’s just like when you
decide that you no longer need an old can of paint. You don’t simply
pour the paint out wherever you happened to store it. You would get
paint all over your dining room, and then your wife/husband would kill
you. Nice. No, instead, you need to carefully dispose of its contents.

The same is true for cells. When the cell is damaged or no longer
necessary, it undergoes an orderly disposal of its cellular contents,
which are reabsorbed and its components may be reused for other
purposes. This process is called apoptosis and is a major mechanism for
the precise regulation of cell numbers. It is also a major defence
strategy for the removal of unwanted or potentially dangerous cells

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(hello — cancer). So, if the process of apoptosis (a sort of cellular clean-

up crew) is impaired, then the result is too much growth.

There are two main pathways for the activation of apoptosis — the
extrinsic and intrinsic. The intrinsic pathway responds to cellular stress.
The cell, for some reason, is not working well, and should really be
eliminated like that excess can of paint. The other name for the
intrinsic? The mitochondrial pathway. So, all of these diseases of
excessive growth — atherosclerosis (causing heart attacks and stroke),
cancer, Alzheimer’s disease, where lack of a cellular clean up crew may
play a role, all link back to mitochondrial functioning.

So how to keep the mitochondria healthy? The key is AMPK, a sort of

reverse fuel gauge of the cell. When energy stores are low, AMPK goes
up. AMPK is a phylogenetically ancient sensor triggered by high cellular
energy demands. If energy demand is high and energy stores are low,
then AMPK goes up and stimulates new mitochondrial growth. As
mentioned in our last post, AMPK goes up with decreased nutrient
sensing, which is tightly correlated to longevity. Certain drugs (hello —
metformin) can also activate AMPK which explains how metformin
may have some role in cancer prevention. It also explains its popularity
in wellness circles. But you can do better.

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Fasting also stimulates autophagy and mitophagy, the process of culling

the old, dysfunctional mitochondria. So the ancient wellness practice of
intermittent fasting essentially gets rid of the old mitochondria and at
the same time stimulates new growth. This process of renewing your
mitochondria may play a huge role in the prevention of many of the
diseases we currently have no acceptable treatment — diseases of excess
growth. While metformin may stimulate AMPK, it does not reduce the
other nutrient sensors (insulin, mTOR), and does not stimulate
mitophagy. So, instead of taking a prescription medication o label
with its bothersome side e ect of diarrhea (don’t wear white pants),
you can simply fast for free, and get double the e ect. Intermittent
fasting. Boom.

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