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Intermittent Fasting, Autophagy and Parkinson's Disease:

The theory behind "Intermittent Fasting" (also known as "Time Restricted Eating") is that if you reduce your food intake to fewer hours and increase the duration of fasting, you will force your body into a mode known as "autophagy" during the fasting phase. It is while the body is in a state of autophagy that the body will begin cleaning-up neuron killing Lewy bodies, the mechanism of the neurodegeneration of Parkinson's disease.

The period of eating and digestion is called the "absorptive" or fed state. The tail end of the fasting portion of your day, called the "post-absorptive" state, will put your brain in a state of metabolic stress where the body's internal cellular mechanisms will consume the waste responsible for Parkinson's Disease (Lewy Bodies) and Alzheimer's (Beta-amyloid protein and plaque). The theory maintains that during the eating phase, the body feeds directly off of the glucose and carbohydrate nutrients consumed and available in your blood supply. This is called the metabolic state of glycolysis. In this state the blood glucose is elevated, inducing the body to produce more insulin which promotes the storage of body fat.

During the fasting period the body runs out of the easily available fuel and switches to other sources. During this fasting phase, nutrients are not available in the blood supply so the body enters a mode where it consumes excess fat found in the body and turns it into ketone bodies to fuel your body. This is a state known as ketosis where fat reserves of the body are released and consumed. Most cells in your body use ketones and glucose for fuel. For cells that can only process glucose, like parts of the brain, the glycerol derived from dietary fats is made into glucose by the liver in a process known as gluconeogenesis. During the fasting state, the body also enters a clean-up phase where the internal cellular mechanism for recycling, consumes plaque waste products. This catabolic break down and clean-up phase is referred to as Autophagy.

Autophagy is a non-specific degradation process involved in the clearance of unnecessary or dysfunctional proteins and cellular components. Autophagy (specifically macroautophagy) begins with cellular stress, such as limited nutrients, which influences the the cell's lysosomes (internal cell component responsible for recycling cellular proteins, carbohydrates and lipids) to come to action and fuse with autophagosomes (generated when a phagophore engulfs the protein material to be processed) to form autolysosomes containing everything required to degrade, recycle and process the material. Autophagy is a cell survival processes of consuming internal cell material during a period of nutrient deficiency. It is important that during the fasting phase that nutrition be held back from the blood supply otherwise the body will never reach Autophagy. It also must be pointed out that autophagy is the goal and that restricting a diet so much so that it becomes chronic starvation, can damage rather than protect neurons.

Research has also shown that the misfolded protein responsible for the generation of Lewy Bodies, alpha-synuclein, spreads via a cascade from neuron to neighboring neuron and that Intermittent Fasting mediates microglia (immune system macrophage cells in the brain which act as immune sentinels orchestrating an inflammatory response) to consume the alpha-synuclein. This has been termed "synucleinphagy".

Note that "intermittent fasting" and "calorie restriction" have become two ideological camps in the study of weight loss and dieting. The goal for one with Parkinson's is to reach a state autophagy in order to promote cell clean-up. This is more easily achieved with intermittent fasting. A calorie restricted diet may never reach a state of autophagy or ketosis for long eating cycles and may lead to muscle loss and a lack of essential nutrients. Intermittent fasting allows for weight or muscle gain or loss depending on the quantity of calories consumed, while still supporting the state of autophagy.

See references:
Clock

Stages of Fasting:

HoursDescription
4 - 8Food is digested and has left the stomach. Blood sugar levels fall.
12+Body enters state of Keytosis, burns body fat and lowers insulin and inflammation levels. Brain Derived Neurotrophic Factors (BDNF) generated.
References:
18+Significant fat burning and keytone generation. Signaling to reduce inflammation and cell DMA damage repair.
References:
24+Fasting activates the AMPK signaling pathway and inhibits mTOR activity, which in turn activates autophagy. Autophagy, cell recycling of misfolded alpha-synuclein and neuroprotective action. Insulin levels drop.
References:
48+Autophagy becomes more abundant. Growth hormone secretion becomes greater.
References:
54+Insulin drops to lower levels. Body becomes insulin sensitive. Lowers inflammation levels.
References:
72+Insulin drops to lowest levels. Regeneration of immune cells. Self-renewal and regeneration of hematopoietic or blood cell stem cells.
References:

Signaling:

The human body communicates by various methods. The brain commands muscles by sending a cascading signal along the nervous system. The immune system has sentry cells (macrophages) which release inflammasomes which attract killer cells to come and consume pathogens. The body also has glands and cells which can release proteins which represent a message to cells and organs. The body releases AMPK and mTor proteins to deliver the message that nutrition is abundant or scarce and to enter the state of autophagy when nutrition is scarce.

AMPK:

Adenosine 5' monophosphate-activated protein kinase is an enzyme, known more simply as AMPK, that plays a central role in cell energy metabolism with an ability to regulate a wide variety of metabolic processes. It also plays an important role for intermittent fasting and the activation of autophagy for cells under stress. AMPK is found in the brain, liver, fat and muscle tissue and regulates cellular energy usage, improves physical performance, decreases inflammation and supports autophagy and cellular renewal. AMPK production is activated with high intensity exercise and the production of nitric oxide, intermittent fasting, consumption of antioxidants high in polyphenols and certain foods and supplements. Foods and supplements which boost AMPK are fresh vegetables, green tea, berries, resveratrol, quercetin, berberine, ALA, zinc, omega-3, Aspirin, etc. When energy (ATP) levels are low in the cell, AMPK is activated to restore energy to equilibrium by triggering energy-producing metabolic processes such as glycolysis and fatty acid oxidation, while simultaneously inhibiting energy-consuming metabolic pathways such as protein and fatty acid synthesis (ref). AMPK also has an anti-inflammatory effect and promotes the production of antioxidant proteins including NRF2 and dismutase. A similar mechanism is used by the type II diabetes drug Metformin which increases AMPK and activates autophagy (see drugs in trials and the repurposing of type II diabetes drugs to treat Parkinson's). In contrast, a "bad" diet high in sugar and fat will decrease AMPK activity.

See references:

The World Anti-Doping Agency (WADA) banned metabolic modulators designed to increase AMPK. This includes AICAR (AICA ribonucleotide) a medication used to tread cardiac ischemic injury. Studies showed that the AMPK activator, AICAR, boosted the athletic performance of mice by increasing glucose uptake and fatty acid oxidation during exercise.
See:

There are vendors who claim to have supplements to boost AMPK and thus induce a greater period of autophagy. Claims include support for normal glucose levels and insulin activity, energy production and a healthy inflammmatory response.
See:

Warning: inhibition of AMPK signaling in the aged brain will cause a concomitant increase in hippocampal neurogenesis. This research shows that for those over 60 years of age, AMPK may have adverse effects. This research makes it very unclear as to the benefits of AMPK evangelized by so many in the nutrition industry. Thus one may want to activate AMPK in your liver, fat, and muscle cells and inhibit it in your hypothalamus. Exercise and calorie restriction may be preferred over AMPK activator medications or supplements.
See: AMPK Signaling Regulates the Age-Related Decline of Hippocampal Neurogenesis (2019)
DOI: 10.14336/AD.2019.0102

AMPK supplement
AMPK Charge+: AMPK boosting supplement (vendor claim)

mTOR:

Studies have shown that there are a number of signaling pathways involved in the regulation of autophagy, one is AMPK and another is mTOR. The mammalian target of rapamycin (mTOR) is a protein which regulates cell growth, proliferation, protein synthesis and autophagy. Rapamycin can induce autophagy by blocking mTOR which indicates to the body that no nutrients are being consumed. There are a number of rapamycin based drugs in development to promote autophagy or one can pursue the natural approach of time restricted eating.

See references:
mTOR protein (FRAP1)
mTOR protein (FRAP1)
This image file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

AMPK and mTOR are the signaling mechanisms used by the body to let it know if there is nutrient availability and signal growth or if there is low nutrient availability and signal the body to stop growing and to invoke the self cleansing pathway of autophagy. Growth mode in fully grown adults leads to diseases such as obesity, type 2 diabetes, cancer, atherosclerosis and neurological ailments such as Parkinson's disease.

Also see Reported effects of autophagy-enhancing agents in preclinical PD models - table of agents which induce autophagy

Fasting App:

In the modern world of the smart phone, it's not surprising to find out that there is a mobile app to help with intermittant fasting. The app Zero, named for the amount of food you consume while fasting, will track one's daily fasting. It also can support the circadian rythm fast guiding one to eat as close to sunset as possible by using GPS to calculate the phone's location and derive the local sunset time. This function supports research by Dr. Satchin Panda showing that eating late at night can be detrimental to your health.
Reference: Fasting, circadian rhythms, and time restricted feeding in healthy lifespan Panda 2016
DOI: 10.1016/j.cmet.2016.06.001

See: Zero fasting app

Fasting mobile app screenshot: Zero

Conclusion:

Restrict one's eating to fast for a 48 hr period once during the week to promote cellular clean-up and counter the generation of Parkinson's pathogens. A supporting daily regiment of "Time Restricted Fasting" schedules eating once a day with a 22 to 23 hour fast.


Pros:
  • Cellular level restoration, reduced hypertension, anti-inflammatory, circadian rhythm stability and improved sucrose regulation are all potential benefits. No negative side effects of autophagy except some potential weight loss.

Cons:
  • Not likely to make a huge difference if the root cause (eg neurotoxins) which is causing neuron dysfunction and the creation of Lewy bodies and causing Parkinson's disease is not addressed. It will be important to counter the root cause (toxins, inflammation, etc) in order to have the effects of Intermittent Fasting dominate and win. Extreme fasting will lead to malnurishment and muscle loss (more susceptible as we age).