Autophagy is key for longevity. We can all agree on that.

We should all fast to maximize autophagy!! Now that’s where I disagree. Whether it be intermittent fasting or long-term fasting, it shouldn’t be a must.

I do get that in some circumstances fasting can be beneficial. But the way I see it, fasting is like disassembling something. If you assemble a car and you have a few bolts left and it doesn’t start, you might have to disassemble parts to find the problem and fix it. But do you really have to disassemble the whole car on a frequent basis if it just needs a service once in a while?

Also, did you know that you can induce autophagy via alternative mechanisms than fasting?

Autophagy

The Wikipedia definition:

“Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components.“

They make it sound like a good thing. It removes the damaged cells and stuff. That’s what you want right?

Actually, autophagy induced by calorie restriction or fasting upregulates non-selective/non-specific autophagy. So it doesn’t just clear the broken pieces, but working pieces as well. Now that doesn’t seem so good anymore, especially if done in excess.

There are at least three types of autophagy: microautophagy, chaperone-mediated autophagy (CMA) and macroautophagy.

“Both microautophagy and macroautophagy can be further divided into non-selective autophagy and selective autophagy (Yang et al., 2019). Non-selective autophagy is applied to the turnover of bulk cytoplasm under starvation conditions, whereas selective autophagy is employed in targeting redundant proteins and damaged or aged organelles, including mitochondria, lipid droplets, peroxisomes and so on (Wang et al., 2019). Depending on the cargo being targeted for destruction, selective autophagy can be further categorized into mitophagy (mitochondria), pexophagy (peroxisomes), lipophagy (lipid dropts), ribophagy (ribosomes), aggrephagy (aggregated proteins), and xenophagy (pathogens).“

So basically, fasting-induced autophagy (non-selective) degrades proteins, glycogen, triglycerides, etc., to provide amino acids, lipids and glucose for survival. In the process, it also clears off the damaged cells.

Specific autophagy on the other hand will degrade only the damaged tissue.

This kind of autophagy is mainly upregulated by oxidative stress and inflammation.

Too much oxidative stress and inflammation will result in excess tissue damage which can (unnecessarily) increase the requirement for autophagy and overwhelm autophagy capacity, leading to autophagy stress.

What we want is proper autophagy

Proper autophagy is when cellular damage is minimized, thus reducing the requirement for autophagy. And when cellular cleanup is required, the machinery doesn’t become overwhelmed. Also, the entire process is optimally executed, without a hiccup or buildup at one point.

As a side note, autophagy becomes dysfunctional with aging. Atm, we don’t know if it’s due to aging or if aging is due to dysfunctional autophagy.

But does this enhance the requirement for autophagy?

No, it only enhances the requirement for proper autophagy.

Here is what we need to do to get proper autophagy

• Minimize oxidative stress and inflammation
• Optimize cellular energy production
• Improve thyroid function
• Improve androgen levels
• Maximize sleep quality

Minimize oxidative stress and inflammation

Oxidative stress is important for a variety of reasons, but excess production, especially if it overwhelms the body’s ability to cope with it, will lead to inflammation and problems.

Excess oxidative stress and inflammation can be caused by excess iron and other heavy metals, excess PUFA (oxidized or not), poor sleep quality, terrible environmental hygiene, etc.

Too much free radical production will damage proteins, DNA, lipids, etc., which enhances autophagy requirement. Autophagy is good, but if there aren’t damaged cells to clear, it’s not necessary (unless it’s starvation-induced ofc, but that’s different). If you only have to dig a 6 feet deep hole, why dig it 12 feet deep, every day for the rest of your life?

Optimize cellular energy production

One of the main functions of the mitochondria is to produce energy via the electron transport chain.

The inability to do so not only creates unnecessary free radicals but also inhibits lysosomal hydrolysis, which is the breakdown process of the damaged tissue (R). Without proper lysosomal hydrolysis, the autophagosome and autophagolysosome will accumulate and lead to autophagy stress.

The electron transport chain consists of complexes (complex 1 to 5), held stable by a lipid structure called cardiolipin. CoQ10 is a fundamental piece of complex 1. Without sufficient CoQ10, NADH will accumulate in the cell, leading to reductive stress (the opposite of oxidative stress, but just as harmful).

Consuming more CoQ10 through the diet leads to an increase in the NAD to NADH ratio, which increases SIRT1, and indirectly increases AMPK and autophagy (R).

It’s not only CoQ10 that’s necessary but all vitamins and minerals and beneficial compounds found in food. I prefer animal foods since the nutrients are found in large amounts, it’s in a more usable form, there aren’t any anti-nutrients to inhibit their absorption, plus animal foods are easier to digest. And on top of that, animal foods contain beneficial nutrients that plant foods don’t contain, such as CoQ10, anserine, carnosine, 4-hydroxyproline, carnitine, etc.

Be sure to eat a nutrient-dense diet to optimize cellular function.

Improve thyroid function

One would think that thyroid hormones induce the opposite of autophagy. It speeds up the metabolism, whereas fasting slows it down so that autophagy can occur. Right?

The thing is, thyroid hormone, T3, is a potent inducer of autophagy.

Thyroid hormone’s induction of autophagy involves activation of the AMPK pathway via mitochondrial ROS production (R). In particular, T3 induced ROS generation in a time- and dose-dependent manner, which was accompanied by increased autophagosome formation (R).

Just look at someone that is hyperthyroid. They are almost never overweight and they struggle to build muscle. Why is that? Excess autophagy.

What is key here is that thyroid hormone not only promotes autophagy but proper cellular turnover, which is the most important.

T3 increased fatty acid oxidation and mitochondrial respiration as well as autophagic flux, mitophagy, and mitochondrial biogenesis (R).

If you only have autophagy, you’ll end up with too few mitochondria for example. If you have only mitochondrial biogenesis, you’ll replicate defective mitochondria. The balance is key and thyroid promotes this proper cycle.

Also, thyroid hormones are crucial for improving mitochondrial function, especially the electron transport chain, which improves electron flow, uncoupling (which lowers inflammation) and ATP production.

Thus, thyroid hormone isn’t just catabolic, but also anabolic. Recycling. Regeneration. Improvement. Healing.

Someone that is hypothyroid produces less energy, clears defective tissue slower, regenerates slower, and remains in a suboptimal state.

Hypothyroidism speeds up aging. Check out this example.

Hypothyroid on the left, euthyroid on the right. Hypothyroidism speeds up aging.

Here are just a few examples of thyroid hormone and regeneration. Thyroid hormones:

• are essential for skeletal development, linear growth, maintenance of bone mass, and efficient fracture healing (R).
• lead to better muscle function, therefore successfully overcoming the imbalance of homeostatic and entropic processes involved in muscle aging (R).
• are key regulators of the development, regeneration and metabolism of skeletal muscle. T3 enhances fast-twitch muscle fibers, mitochondrial biogenesis, muscle regeneration, muscle strength and the relaxation–contraction rate (R).

Additionally, not only does T3 increase autophagy, but also increases mitochondrial protein
ubiquitination (R). Ubiquitination is a specific form of clean-up. It regulates the degradation of proteins (via the proteasome and lysosome), coordinating the cellular localization of proteins, activating and inactivating proteins, and modulating protein-protein interactions.

If you want to optimize autophagy, cellular turnover and health, optimizing thyroid function should be a big part of that.

And this is where intermittent fasting, calorie restriction or long-term fasting is non-ideal since they reduce thyroid hormone production and conversion.

Improve androgen levels

Androgens, specifically testosterone and DHT, are crucial for muscle health and proper autophagy.

“…genetic and pharmacological inhibition of the HPG (hypothalamic-pituitary-gonadal) axis recapitulates the progressive aging process of MuSCs (muscle stem cells). Mechanistically, the ablation of sex hormone signalling reduced the expression of transcription factor EB (Tfeb) and Tfeb target gene in MuSCs, suggesting that sex hormones directly induce the expression of Tfeb, a master regulator of the autophagy–lysosome pathway, and consequently autophagosome clearance.” (R)

“We show here that increased and sustained levels of sex hormones at adulthood prevent MuSC senescence by maintaining autophagosome clearance through Tfeb, and their decline at old age results in the reduction of Tfeb that leads to accumulation of autophagosome and eventual induction of senescence at geriatric age. As organism ages, MuSCs become defective in autophagy flux leading to the accumulation of autophagosome. In this study, genetic and pharmacological inhibition of the HPG axis recapitulates progressive aging progress of MuSCs: at early stage, decrease of Tfeb, autophagy, and lysosomal genes leads to impaired autophagosome clearance, which is similar to those of old MuSCs.” (R)

Low androgens lead to low TFEB, which leads to defective autophagy and the accumulation of autophagosomes, causing poor muscle quality and autophagic stress.

Calorie restriction and fasting lower androgens.

Maximize sleep quality

A significant amount of autophagy occurs during sleep. Poor sleep can cause autophagy dysregulation (R). Poor sleep includes light sleep, unrefreshed sleep, frequent wakings, bad dreams, etc. The better the quality of your sleep, the better cellular clearance can occur. Read more here on how to improve your sleep quality.

DNA damage activates the PARP enzymes, which are responsible for DNA repair. PARP activation induces fatigue and a desire to sleep. So if you’re tired all the time, it could indicate excess oxidative stress, PARP activation, ineffective autophagy or autophagy overwhelm.

Hypothyroidism, endotoxin, excess serotonin, high cortisol, inadequate sunlight exposure, etc., are known to induce poor sleep quality.

Exercise

Exercise has been shown to induce autophagy as well as upregulate mitochondrial biogenesis, thus improving muscle quality.

“Exercise-induced autophagy has been associated with increased muscle mass, enhanced contractility, and muscle fiber type shifting (2). Therefore, modulating autophagy has been suggested as a key strategy for improving muscle performance as well as treating sarcopenia and several dystrophic muscle diseases (3, 4). On the other hand, autophagic overactivity or overinhibition leads to significant skeletal muscle mass loss, myopathy, muscle injury, and impaired performance (5–9). Therefore, balanced autophagy is critical for maintaining appropriate mitochondrial number and function in skeletal muscle.” (R)

And yes, mTOR actually plays a beneficial role in autophagy. Autophagy activation following high-resistance electrically stimulated contraction of rat skeletal muscle correlated with mTOR activity. “Together, this suggests that it may be the increased amino acid turnover per se that regulates autophagy through mTOR signaling in response to resistance exercise potentially allowing further stimulation of protein synthesis at later timepoints.” (R)

Exercise induces TFEB (the master gene for lysosomal biogenesis; a crucial part of proper autophagy) translocation to the nucleus which regulates exercise training-induced long-term adaptations in the autophagy and lysosome pathways (R).

Physical exercise regulates mitochondrial quality control allowing the repair/elimination of damaged mitochondria and synthesizing new ones, thus recovering the metabolic state (R). Proper autophagy/cellular recycling.

Induce uncoupling

Uncoupling is induced by proteins in the mitochondrial membrane that pumps proton into the mitochondria to make heat instead of ATP.

Uncoupling can unclog the mitochondria to improve proper fat and glucose oxidation, reduce oxidative stress and enhance autophagy.

Uncoupling reduces ATP production, which leads to an increase in the AMP/ADP to ATP ratio, which activates AMPK, a driver of autophagy.

Niclosamide is an inducer of mild uncoupling and it also inhibits mTOR1, both of which lead to better autophagy. Check out my vid about niclosamide vs rapamycin and autophagy here.

But not all kinds of autophagy is good. Niclosamide has been shown to reduce the overexpression of autophagy-related proteins, including p-AMPK, FoxO3a, p-ULK1, LC3B II, and p-p38 in gastrocnemius muscle of the type 1 diabetes mice, thus preventing muscle wasting (R).

Summary

Proper autophagy and cellular turnover are desired. A balance between mTOR and autophagy.

The elderly lose muscle and strength and experience a decline in thyroid hormone and androgen production. Do you think that doing caloric restriction, fasting, low protein diets, plant-based diets, or other catabolic activities will optimize muscle mass, thyroid function and androgen production? I hope you said no, because that would have been the right answer.

There is a balance between catabolism and anabolism. Too much of either can be bad. As you age you need to maximize proper autophagy as best possible, via thyroid and androgens. This makes the importance of proper diet and lifestyle so much more significant.

Anything that causes inflammation will upregulate autophagy, which can be dysregulated. It will lead to excessive catabolism and not enough proper turnover. Fasting can “fix” it because it lowers oxidative stress due to the removal of the offensive substance and most people start to eat less and healthier as well. But that’s the opposite direction you should go in. If catabolism/wasting happens with age, why speed it up with fasting or calorie restriction?

Someone with metabolic syndrome, hyperinsulinemia, excess ROS, will have excessive and dysfunctional autophagy. Fix that to fix autophagy.

If you want to maximize proper autophagy, check out my Alpha Energy Male course, where I teach you how to optimize your diet, thyroid, sleep, activity and androgens and minimize inflammation.