Home Learn Apps About Contact

THE 5 STAGES OF INTERMITTENT

FASTING
FEBRUARY 26, 2019 | IN BRAIN, FASTING | BY PAIGE JARREAU

Intermittent fasting isn’t just a weight loss strategy or a hack that bodybuilders

use to lose fat quickly while maintaining lean muscle mass. It is at its best a

healthy lifestyle informed by human evolution and the study of metabolism. It

asks the human body to be much more ef cient and self-protective than it is

accustomed to being in modern times.

There are many things that happen when we fast that either don’t happen when

we are always in a fed state, or that happen very slowly in the background of

glucose metabolism. Scroll down to learn more about the ve stages of

intermittent fasting!

The 5 Stages of Intermittent Fasting with the LIFE Fasting Tracker app: 1) Ketosis and heavy ketosis, 2) Autophagy, 3)
Growth hormone, 4) Insulin reduction, 5) Immune cell rejuvenation!
In a well-fed state, the individual cell in your body is in “growth” mode. Its insulin

signaling and mTOR pathways that tell the cell to grow, divide and synthesize

proteins are active. By the way, these pathways, when overactive, have

implications in cancer growth.

The “mammalian target of rapamycin” or mTOR loves having plentiful nutrients

around, especially carbohydrates and proteins. When active, mTOR tells the cell

not to bother with autophagy (literally cellular “self-eating”), a recycling and

cleanup process that rids your body of damaged and misfolded proteins for

example. The well-fed cell isn’t worried about being ef cient and recycling its

components – it’s too busy growing and dividing.

In a well-fed state, your cells and their components are also highly acetylated.

This means that various molecules in your cells, including the “packaging”

proteins called histones that wrap your DNA up nicely within the core of your

cells, are “decorated” with acetyl groups on their lysine (amino acid) residues.

Don’t worry if you don’t understand the jargon in that last sentence. What you

really need to know is that the well-fed cell has many genes, including those

associated with cellular survival and proliferation, turned on. This is because

acetylation tends to loosen the packaging proteins that normally keep your DNA

wrapped up, and lets your DNA be read for protein production.

While your cells turn on cellular growth and proliferation genes when you aren’t

fasting, they also turn other genes off. These include genes related to fat

metabolism, stress resistance and damage repair. Actually, when you fast some

of your fat gets turned into ketone bodies that appear to reactivate these genes,

leading to lowered in ammation and stress resistance in the brain for example.

But during starvation, things are very different. When you are fasting, your body

reacts to what it sees as a environmental stress (low food availability) by

changing the expression of genes are important in protecting you from, well,

stress.

We have a well-preserved starvation “program” that kicks our cell into a

completely different state when food, particularly glucose or sugar, isn’t around.

When you fast, and when you exercise, you activate the AMPK signaling pathway.

AMPK or 5′ AMP-activated protein kinase is the brake to mTOR’s gas pedal. AMPK

signals the cell to go into self-protective mode, activating autophagy and fat

breakdown. It inhibits mTOR. At the same time, while you are fasting the levels of

a molecule called NAD+ begin to rise because you don’t have the dietary proteins

and sugars around that normally convert NAD+ to NADH through the Krebs

cycle. NAD+, a molecule whose precursor is Vitamin B3, activates the sirtuins,

SIRT1 and SIRT3. (Have you heard of the “longevity” molecule is wine called

resveratrol? Yep, it became famous as being a potential activator of the sirtuins).

These sirtuins are proteins that remove the acetyl groups we talked about above

from histones and other proteins. In this process, the sirtuins silence genes

related to cell proliferation and activate proteins involved in creating new

mitochondria (the power-generating factories of your cells) and cleaning up

reactive oxygen species.

Ketones, also produced during fasting, work as deacetylase inhibitors (in other

words, keeping acetyl groups in place). This turns on genes related to antioxidant

processes and damage repair.

Whew, that’s a lot happening while your body isn’t taking in any calories. But

when exactly do these things happen? We’ve helped you visualize the timeline

below and in the LIFE Fasting Tracker app, with a series of icons on the LIFE

Fasting arc that represent the ve stages of fasting!

The Five Stages of Intermittent (and

Prolonged) Fasting

By 12 hours, you’ve entered the metabolic state called ketosis

(Anton et al., Obesity 2018). In this state, you body starts to break

down and burn fat.

Some of this fat is used by the liver to produce ketone bodies. Ketone bodies, or

ketones, serve as an alternative energy source for your brain cells and cells in

other tissues when glucose isn’t readily available. Did you know that your brain

uses up some 60% of your glucose when your body is in the resting state? When

you are fasting, ketone bodies generated by your liver partly replace glucose as

fuel for your brain as well as other organs. This ketone usage by your brain is one

of the reasons that fasting is often claimed to promote mental clarity and

positive mood – ketones produce less in ammatory products as they are being

metabolized that does glucose, and they can even kick-start production of the

brain growth factor BDNF!

By 18 hours, you’ve switched to fat-burning mode and are

generating signi cant ketones (Anton et al., Obesity 2018). You

can now begin to measure blood ketone levels above your baseline

values (for example, around a value of 0.6 to 1.0).

As their level in your bloodstream rises, ketones can act as signaling molecules,

similar to hormones, to tell your body to ramp up stress-busting pathways that

reduce in ammation and repair damaged DNA for example.

 Within 24 hours, your cells are increasingly recycling old

components and breaking down misfolded proteins linked to

Alzheimer’s and other diseases (Alirezaei et al., Autophagy 2010).

This is a process called autophagy.

When your cells can’t or don’t initiate autophagy, bad things happen, including

neurodegenerative diseases. Autophagy is an important process for cellular and

tissue rejuvenation – it removes damaged cellular components including

misfolded proteins. Fasting activates the AMPK signaling pathway and inhibits

mTOR activity, which in turn activate autophagy. This only begins to happen

naturally, however, when you substantially deplete your glucose stores and your

insulin levels begin to drop.

By 48 hours without calories or with very few calories, carbs or

protein, your growth hormone level is up to ve times as high as

when you started your fast (Hartman et al.,1992).

Part of the reason for this is that ketone bodies produced during fasting promote

growth hormone secretion, for example in the brain. Ghrelin, the hunger

hormone, also promotes growth hormone secretion. Growth hormone helps

preserve lean muscle mass and reduces fat tissue accumulation, particularly as

we age. It also appears to play a role in mammalian longevity and can promote

wound healing and cardiovascular health.

By 58 hours, your insulin has dropped to its lowest level point

since you started fasting and your body is becoming increasingly

insulin-sensitive (Klein et al., 1993).

Lowering your insulin levels has a range of health bene ts both short term and

long term. Lowered insulin levels put a break on the insulin and mTOR signaling

pathways, activating autophagy. Lowered insulin levels can reduce in ammation,

make you more insulin sensitive (and/or less insulin resistant, which is especially

a good thing if you have a high risk of developing diabetes) and protect you from

chronic diseases of aging including cancer.

By 72 hours, your body is breaking down old immune cells and

generating new ones (Cheng et al., 2014).

Prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell

populations. IGF-1, or insulin-like growth factor 1, looks a lot like insulin and has

growth-promoting effects on almost every cell in the body. IGF-1 activates

signaling pathways including the PI3K-Akt pathway that promotes cell survival

and growth. PKA can also activate the mTOR pathway (and, of interest, too much

caffeine during a fast may promote activation of PKA).

 You might see where this is leading – pressing the brakes on IGF-1 and PKA

through nutrient restriction and fasting can turn down cellular survival pathways

and lead to breakdown and recycling of old cells and proteins. Studies in mice

have shown that prolonged fasting (greater than 48 hours), by reducing IGF-1

and PKA, leads to stress resistance, self-renewal and regeneration of

hematopoietic or blood cell stem cells. Through this same mechanism,

prolonged fasting for 72 hours has been shown to preserve healthy white blood

cell or lymphocyte counts in patients undergoing chemotherapy.

Bonus stage: Refeeding!

We almost forgot about the last and perhaps most important stage of

intermittent fasting – the refeeding stage! It’s important to break your fast with a

nutritious, balanced meal that will further improve the function of cells and

tissues that went through cleanup while you were fasting. From Mark Mattson

and colleagues at the National Institute on Aging: “Upon refeeding, ingested

carbohydrates and glucose stimulate release into the blood of the incretin

hormone glucagon-like peptide 1 (GLP1) from enteroendocrine cells in the gut.

GLP1 enhances clearance of glucose from the blood by stimulating insulin

release from the pancreas and increases the insulin sensitivity of cells. GLP1

crosses the blood–brain barrier and can act directly on neurons to promote

synaptic plasticity, enhance cognition and bolster cellular stress resistance.”

So what are you waiting for? Try out a 12-hour,

16-hour or even a 48-hour hour or longer fast

(but talk to your physician rst before

prolonged fasting) with the LIFE Fasting

Tracker app! You’ll be rewarded with badges

on your fasting arc that give you updates on

your progress toward autophagy and cellular

renewal!

Glossary

AMPK = a protein and cellular energy sensor that is activated in response to

stresses that deplete supplies of cellular ATP (the cell’s energy currency) such as

low glucose, hypoxia and exposure to toxins. It activates autophagy. It is AMPK is

“considered to be a major therapeutic target for the treatment of metabolic

diseases including type 2 diabetes and obesity.”

Autophagy = a process by which components inside of cells (including proteins)

are degraded and recycled. Autophagy can protect brain cells against
 accumulation of “bad” proteins that cause neurodegeneration.

Gene = “basic physical and functional unit of heredity”. Genes are made up of
DNA and some genes act as instructions to make molecules called proteins.

Glucose = simple sugar with the molecular formula C₆H₁₂O₆. Glucose is the most

abundant monosaccharide, a subcategory of carbohydrates.

Insulin = “a hormone made by the pancreas that helps glucose in your blood
enter cells in your muscle, fat, and liver, where it’s used for energy.” – via NIDDK

Ketone bodies / Ketones = organic compounds produced by the liver and used

as an energy source when glucose is not readily available

mTOR = a protein, originally discovered in yeast, that “controls cell growth and
metabolism in response to nutrients, growth factors, cellular energy, and stress”.

“As a central controller of cell growth, TOR plays a key role in development and
aging and has been implicated in disorders such as cancer, cardiovascular

disease, obesity, and diabetes.”

NAD+ = nicotinamide adenine dinucleotide, a cosubstrate (an activating

substance) for other enzymes such as the sirtuins. “Cellular NAD+ concentrations

change [decrease] during aging” and increased NAD+ concentrations, for

example through supplementation, may promote longevity.

Sirtuins = anti-aging genes and proteins that require NAD to function. SIRT1

activates the production of new mitochondrial (the cell’s power-generating

organs) and cleanup of damaging reactive oxygen species

References

1. Klein et al. (1993) Progressive alterations in lipid and glucose metabolism during short-term
fasting in young adult men.
2. Alirezaei et al. (2010) Short-term fasting induces profound neuronal autophagy
3. Walsh et al. (2015) Fasting and exercise differentially regulate BDNF mRNA expression in
human skeletal muscle.
4. Cheng et al. (2014) Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-
Cell-Based Regeneration and Reverse Immunosuppression.
5. Natalucci et al. (2005) Spontaneous 24-h ghrelin secretion pattern in fasting subjects:
maintenance of a meal-related pattern.
6. Sinturel et al. (2017) Diurnal Oscillations in Liver Mass and Cell Size Accompany Ribosome
Assembly Cycles.
7. Hartman et al. (1992) Augmented growth hormone (GH) secretory burst frequency and
amplitude mediate enhanced GH secretion during a two-day fast in normal men.
8. Anton et al. (2018) Flipping the Metabolic Switch: Understanding and Applying the Health
Bene ts of Fasting.
AGING AUTOPHAGY DIABETES FASTING HEALTH HEALTHSPAN INTERMITTENT FASTING LONGEVITY

RENEWAL

Paige Jarreau

I am the Director of Social Media and Science Communication for LifeOmic and an avid blogger. I'm interested in

how scientists use social media to promote public engagement and health behaviors.

 

      

2 COMMENTS

Resh REPLY

March 5, 2019, 3:20 am

Loving the app n the latest icon!

Thank you.

Paige Jarreau REPLY

March 5, 2019, 11:27 am

Awesome, thank you for the feedback!

ADD COMMENT

Name *

Email *

Website
 P O ST CO M M E N T

 PR EV N EXT 

EXPLORE LOCATIONS CONTACT US

LifeOmic is the software company that LIFE Fasting Tracker Headquarters: 855-LIFEOMIC

leverages the cloud, machine learning and LIFE Extend 351 W. 10th St (855-543-3664)
Support Indianapolis, IN 46202
mobile devices to offer disruptive solutions
Learn info@lifeomic.com
to healthcare providers, researchers,
Videos North Carolina Of ce:
health IT companies and patients.
Blog for us 3800 Paramount Pkwy,
About Ste 150
Morrisville, NC 27560

Utah Of ce:

615 S Arapeen Dr, Ste 204

Salt Lake City, UT 84108

© 2019 LifeOmic Health, LLC