Autophagy- Exercise and Fasting

Intro

In the last of the Metabolism Certification Lectures, we cover the process of autophagy, and how we can induce this process through fasting and exercise. We also discuss the pro’s and cons of each approach to inducing this critical biological process.

At a detailed level, we’ll cover what the term autophagy means, how the process works and how it is regulated at a protein-based level.

From there we’ll cover the two major ways to induce autophagy from a nutrition and lifestyle perspective: exercise and fasting. We’ll discuss animal model and human studies, and whether or not a 24 hour fast in a mouse is the same thing metabolically in a human.

Finally, we’ll end with a discussion of time-restricted feeding and it’s potential impacts on health, fitness and obesity.

Key take-aways

At the end of this lecture, you should be able to:

Define and describe autophagy
Know what activates autophagy
Know what suppresses autophagy
Describe how endurance and strength training differ in their inductions of autophagy
Explain several of the benefits of fasting from animal models
Explain the difference in metabolisms from mice to humans as it relates to fasting (Hint: How long can a mouse or human live without food?)

Key terms

Key terms we will cover:

Autophagy/Macroautophagy mTOR AMPK Fasting Time restricted feeding

What is autophagy

literally means ‘self eating’

clears out cellular waste, recycles cellular units

shown to be critical for overall health. during homeostasis and infection

induced by fasting and exercise

areas of importance

cancer - improving aspects related to DNA damage, inflammation, genetic instability exercise induces damage to cellular proteins. Improves the structure and function of muscle proteins/fibers misfolded proteins are thought to contribute to neurological diseases helps fight bacterial and viral infections helps with aging, effects on growth hormone and telomere length mitochondria can be damaged - enhances metabolism

3 types of autophagy

Macro Autophagy
microautophagy less selectivity
chaperone-mediated autophagy high levels of selectivity, only cells that are damaged

Macro autophagy

gets most of the attention

alt-1 protein in a set of proteins initiates the process

Steps of macro Autophagy

initiate
nucleation
elongation brings mytochondria into the structure
maturation once the structure has matured it mixes with a lysosome. Lysosome - ph is lower enzymes like sepsin break down damaged proteins and structures that were captured

Subtypes of macro autophagy

Mitophagy
Reticulophagy
Nucleophagy
Lipophagy

Inhibitors

growth proliferation when
energy insulin
mTOR pathway induced by resistance training

activation

starvation
cellular stress infection
ampk pathway endurance exercise

Results

nutrient recycling
proteo-statsis
organelle regeneration
infection control

energy rich states

inhibits the initiation of macro autophagy regulates the liposome and down regulates atg associated genes (autophagy genes)

low energy state

low amounts of ATP ATP -> processed down to AMP -> AMPK which blocks mTOR

Induce autophagy thru lifestyle

Exercise

Activates a ton of proteins which induces autophagy

mTORC1 -> protein synthesis hypertrophy AMPK -> Mitochondria biosynthesis -> TSC1/2 blocks mTORC1

Resistance exercise induces increased expression of several key autophagy proteins
Mice that lack key autophagy genes accumulate dysfunctional mitochondria, altered muscle fiber generation and decreased overall strength
Autophagy may ultimately be a myoprotective process

exercise -> Oxidative stress -> energetic imbalance -> increased calcium -> protein misfolding

---> autophagy -> mitochondrial turnover -> protein turnover -> metobolic adaptions -> angiogenesis

---> results in -> enhanced endurance performance -> improved glucose and lipid homeostasis -> stronger muscle fibers

Endurance training -> energy depletion -> high amp levels -> ampk activation -> autophagy -> atp generation

Resistance training -> metabolic damage, protein misfolding, mitochondrial damage, -> Autophagy -> muscle homeostasis

Studies

critical for manti-agin effects of exercise especially upon muscle loss

aging leads to more misfolded proteins as well as less autophagy which means they stick around increased apoptosis (bad!)

exercise leads to more autophagy

exercise leads to more autophagy in the brain as well

improve your neurological state

Fasting

if your exercising, you are inducing a lot of autophagy already

Mice who were fed every other day out performed mice who were fed regularly in regards to treadmill training
After 11 months, mice who were fed every other day had better memory and exercise tolerance than the control or high fat groups
Mice who fasted longer between meals were shown to live longer than mice that were free fed and had delayed disease development
Effects on mouse immunity were mixed, with some very negative effects, and some positive ones
Fasting improved the composition and diversity of the gut bacteria in mice

fasting in humans

The general take home point is that not eating for large parts of the day/week is a good way to reduce calorie intake
When total calories are controlled for, IF does not produce improved weight loss

are fasting and exercise synergistic

not sure quite yet. some positive studies but a study on high fat diet in mice had no results

fasting guidelines

While mouse studies are clearly beneficial, human data is still lacking
Not everyone should fast for health
- Men versus women
- Age differences
- Pregnancy
- Post Partum
If you wish to try fasting…
- Start by simply extending the time between dinner and breakfast
- Make sure you’re “harvesting the low hanging fruit” first
  - Sleeping 8 hours, managing stress, eating a high quality diet, exercising

Time restricted feeding

Differs from Fasting or Intermittent Fasting in that:

With time-restriction eating you have anywhere from a 9-12 hour window to eat, as opposed to fasting which prescribes windows of less than 8 hours
Your goal is to time the eating window into the the normal waking hours, with the goal of aligning your dietary intake with your circadian rhythms

Summary

Autophagy is a critical biological process for overall health and to maintain a healthy metabolism
Exercise clearly induces autophagy, both through endurance and resistance training
Fasting also strongly induces autophagy
- Mouse studies are equivocal
- Human studies need additional work to determine how long one must fast to reproduce similar effects
Time restricted feeding, a cousin of fasting, may provide similar benefits with less restriction