#059 Aliquot #3: Q&A Mashup - Fasting
This FoundMyFitness Aliquot mashup, hosted by Dr. Rhonda Patrick, explores fasting's health benefits, mechanisms for healthspan/longevity, and how to break a fast. It covers different fasting types, effects on gut microbiome and immune system, caloric restriction mimetics, and exercise while fasting.
Deep Dive Analysis
13 Topic Outline
Fasting's Impact on Gut Microbiome and Autoimmunity
Fasting, Autophagy, and Immune Cell Regeneration
Translating Animal Fasting Studies to Humans
Fasting Duration Required to Activate Autophagy in Humans
Biomarkers for Measuring Autophagy Sensitivity
Caloric Restriction Mimetics: Resveratrol and Spermidine
Spermidine's Mechanism of Action and Health Effects
Fasted Exercise and its Effect on Autophagy
Comparing Fasting Mimicking Diet to Water-Only Fast
Challenges in Human Autophagy Research and Clinical Translation
Long-Term Caloric Restriction and Autophagy Markers
Indirect Markers of Autophagy: Blood Glucose and Ketosis
Ketogenic Diet vs. Fasting for Autophagy Induction
7 Key Concepts
Autophagy
Autophagy is a cellular process that involves clearing out damaged organelles, protein aggregates, and other dysfunctional components within a cell. It is a major mechanism for cellular cleanup and recycling, activated by stressors like fasting or exercise.
Apoptosis
Apoptosis is programmed cell death, a process where an entire cell that is sufficiently damaged will die off. This can occur when a stressor, such as prolonged fasting, is strong enough to cause widespread cellular damage beyond what autophagy can repair.
T-regulatory cells
T-regulatory cells are a type of immune cell that plays a crucial role in regulating the immune system and preventing autoimmunity. Fasting has been shown to increase the production of these cells, potentially through changes in the gut microbiome.
Protein Acetylation
Protein acetylation is a biochemical modification where acetyl groups are added to proteins, a process that increases when food is consumed. A decrease in protein acetylation is a strong signal for autophagy to occur, requiring a caloric deficit.
Caloric Restriction Mimetics
These are substances, also called fasting mimetics, that can induce similar cellular responses to caloric restriction or fasting, such as activating autophagy. Examples include resveratrol and spermidine, which work through different mechanisms to decrease protein acetylation.
Sirtuins
Sirtuins are a group of enzymes that act as histone deacetylases, meaning they remove acetyl groups from proteins. Activating sirtuins, for example with resveratrol, can indirectly decrease protein acetylation, thereby mimicking the effects of not eating food and promoting autophagy.
Mitophagy
Mitophagy is a specific type of autophagy focused on the selective degradation and recycling of damaged or dysfunctional mitochondria within a cell. It is crucial for maintaining cellular health, especially in energy-intensive organs like the heart.
6 Questions Answered
Intermittent fasting for 15 days (with 500 calories on fasting days) was shown in a pilot study to increase bacterial richness in the gut, specifically lactobacilli and Prevotella, which promote T-regulatory cell production and may reduce autoimmunity. Fasting also induces ketone body metabolism that facilitates microbiome growth.
One preliminary clinical study found that biomarkers of autophagy, specifically a decrease in protein acetylation on lysine residues, were detectable in humans after 24 hours of a water fast. However, this doesn't mean autophagy isn't occurring earlier, just that current biomarkers lack the sensitivity to detect it at shorter durations.
Resveratrol indirectly lowers protein acetylation by activating sirtuins, enzymes that remove acetyl groups from proteins. Spermidine directly inhibits protein acetylation by preventing the transfer of acetyl groups to proteins in the first place, both mimicking the effects of caloric restriction.
Spermidine has been shown in lower organisms (yeast, flies, nematode worms) to extend lifespan in an autophagy-dependent manner. In mice, dietary spermidine can prolong lifespan in accelerated aging strains, improve heart function in older animals by enhancing mitophagy, and brain concentration correlates with memory capacity in flies.
Many studies suggest that doing aerobic exercise in a fasted state leads to better and more robust mitochondrial adaptations compared to a fed state, which can induce autophagy more easily. However, most 'fed state' studies used simple sugars, which might not represent all fed conditions.
It is not clear if a ketogenic diet induces autophagy as effectively as fasting because a strong signal for autophagy is a decrease in protein acetylation, which requires a decrease in overall food intake. While fasting mobilizes fatty acids for energy, a ketogenic diet still involves consuming fat, which can be used to make acetyl-CoA and acetylate proteins, potentially counteracting the autophagy signal.
15 Actionable Insights
1. Dietary Approaches for Autoimmunity
Explore fasting, a fasting-mimicking diet, or a ketogenic diet, especially if dealing with autoimmune disorders like multiple sclerosis, as pilot studies and animal research suggest these can improve clinical measures and affect immune regulation.
2. Prolonged Fasting for Immune Renewal
Consider prolonged fasting (e.g., 48 hours for mice, longer for humans to achieve similar IGF-1 reduction) to potentially clear dysfunctional immune cells and stimulate the production of new, healthy immune cells.
3. Five-Day Water Fast for IGF-1
To significantly lower IGF-1 levels by 50% in humans, a five-day water-only fast is typically required.
4. Water-Only Fast for Max Autophagy
For potentially faster and more pronounced effects on autophagy and IGF-1 reduction, prioritize water-only fasts, as consuming some calories (even in a fasting-mimicking diet) may slow these processes.
5. 24-Hour Water Fast for Autophagy
Consider a 24-hour water fast, as this is the earliest time point where specific biomarkers for autophagy have been empirically detectable in humans.
6. Fasted Aerobic Exercise for Autophagy
Engage in aerobic exercise while in a fasted state, as this can more easily induce autophagy and lead to more robust mitochondrial adaptations compared to exercising in a fed state.
7. Fasting Activates Autophagy
Engage in fasting as a major activator of autophagy, the cellular process that clears out damaged organelles and dysfunctional components, promoting cellular health.
8. Exercise & Polyphenols for Autophagy
Incorporate regular exercise and consume plant polyphenols found in coffee, tea, blueberry skins, grape skins, or resveratrol, as these are known activators of autophagy.
9. Consume Spermidine-Rich Foods
Increase intake of spermidine, found in high concentrations in natto (fermented soybeans), as it directly inhibits protein acetylation, a key signal for autophagy, and has been shown to extend lifespan in lower organisms.
10. Resveratrol for Autophagy Activation
Consider supplementing with resveratrol, which activates sirtuins to remove acetyl groups from proteins, thereby mimicking fasting’s effect on protein acetylation and promoting autophagy.
11. Intermittent Fasting for Gut Health
Practice intermittent fasting, potentially allowing up to 500 calories on fasting days (as in a pilot study of 7 fasting days over 15 days), to increase beneficial gut bacteria and T-regulatory cells.
12. FMD as Fasting Alternative
If full water fasting is not feasible, consider a fasting-mimicking diet as an alternative option, which can still offer some benefits, though potentially at a slower rate.
13. Long-Term Caloric Restriction
Consider practicing long-term caloric restriction (e.g., for six years or longer), as studies have shown increased markers of autophagy in individuals maintaining this lifestyle.
14. Monitor Glucose & Ketones
Monitor your blood glucose levels (aiming for a decrease) and ketone levels (aiming for ketosis) as potential indirect indicators that autophagy might be occurring, due to their link with caloric deficit and protein acetylation.
15. Discuss Fasting Research with Doctor
If you have an autoimmune disease, share emerging research on fasting and fasting-mimicking diets with your physician to help them become more familiar with potential benefits.
4 Key Quotes
As a fast becomes more prolonged, autophagy starts to happen. And autophagy is basically clearing out damaged stuff within a cell. But as the stressor becomes stronger, if the entire cell is actually damaged enough, the cell will die via apoptosis.
Rhonda Patrick
Your biomarkers are only as good as the sensitivity of them.
Rhonda Patrick
Doesn't mean that autophagy doesn't happen after a six or after a 12-hour fast. It just means that you're not detecting it.
Rhonda Patrick
The heart... is basically primarily using what's called beta oxidation as the energy source, meaning it's using fatty acids, which require beta oxidation occurs within the mitochondria. So it's not using glucose.
Rhonda Patrick