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Be sure to check out An Introduction to Autophagy, Autophagy: When, What, Where, and Why, and Autophagy: When Things Go Wrong.

Congratulations! You’ve made it to the fun part. Now we get to discuss how we might harness autophagy to our (healthspan) advantage. As a quick debrief, autophagy is a form of cellular housekeeping whereby damaged cells or organelles are eliminated and their useful components are degraded and recycled. This evolutionary process has enabled us to continue to thrive in times of low nutrition availability by improving efficiency and supplying the most critical cells with necessary energy (1). The ability to maintain homeostasis in response to a number of external stimuli is pivotal to our survival, and any disruption to this system can breed a state of disease or illness. Understanding how we might support autophagy throughout our lifespan may serve to enhance and extend our healthspan. 

While a number of pharmaceuticals are being investigated for their potential to regulate autophagy, I am going to focus on lifestyle choices and natural compounds that have been implicated in driving healthy autophagic processes. As always, you will want to work with your healthcare team to determine what is the best option for you in your particular situation. Our bodies are so very complex, and our environments so specific, that one approach absolutely cannot and should not be applied to all. You do you! 

The two broad categories of autophagy inducers that I will be covering are related to diet and lifestyle. Diet includes caloric restriction and fasting as well as micronutrients that have been shown to play a role in autophagy. Lifestyle includes physical activity and sleep. Let’s dive in! 

Fasting and caloric restriction

We now know, assuming you have read the previous posts in this series, that autophagy changes in response to stress (2). Fasting and caloric restriction both involve a certain amount of temporary or chronic nutritional insufficiency that is a potent modulator of autophagy. To be clear, this nutritional insufficiency is in relation to calories, not micronutrients. It is absolutely vital that we continue to furnish our bodies with adequate nutrients. Assuming we have the requisite nutrients but energy is lacking, an operation is deployed whereby the cells gear up for a hard winter by chopping down old or dead trees for firewood, preserving fresh produce that is on the verge of rotting, slaughtering cattle that won’t make it through the famine, and otherwise scouring the land for supplies. Our bodies are truly incredible at hunkering down and holding onto what serves us while recycling and reusing what doesn’t. Research has elucidated that these stresses do truly help us grow stronger and even younger as the body prioritizes and protects the ‘best’ tissue. This is something we have evolved to do and is fundamental to our health. 

Fasting and caloric restriction are relatively loose terms with no consistent definition. Caloric restriction is typically defined as a reduction of 10-40% in caloric intake (2). Fasting most commonly incorporates a 16 hr window of not eating, but can extend into days, weeks, or even months. How you choose to fast will greatly depend on your underlying activity level, weight, health status, and many other factors. A key side effect of fasting is an inadvertent yet invariable tendency to diminish energy intake. Either way, by forcing the cells to experience low energy, the autophagic machinery is induced along with a number of other favorable outcomes, such as mitochondrial biogenesis (increasing the mitochondrial count), diminished inflammation brought about by elimination of toxic proteins and organelles, and a robust metabolism as a result of better energy utilization (2). Caloric restriction and autophagy collectively seem to enhance the function of most tissues and organs, from the heart and skeletal muscle to the liver, kidney, and pancreas. This improvement is purported to arise due to the eradication of old, injured cellular components and a subsequent ‘youthful glow’ from enhanced energy production and usage as well as heightened efficiency and functionality of the preserved cells. 

Physical activity

Physical activity may work through similar pathways as caloric restriction and fasting to elicit an upregulation in autophagy (3). Autophagy is not only increased in skeletal muscle with physical activity as one would believe, but a rise in autophagic flux is also seen in the heart, liver, pancreas, adipose, and brain. Oh boy, do our brains love exercise! But that’s for another post. Exercise provokes a decline in energy in addition to damage to the proteins that make up muscle tissue as well as the mitochondria that supply the energy to exercising muscles. While this sounds like it might be a net negative, injury to the muscle tissue is necessary to promote adaptations that augment tissue function (3). The autophagic machinery is called to order to deal with this damage, leaving fitter and more powerful proteins and organelles behind. Notice the presence of this low-nutrient status similar to caloric restriction. Exercise depletes our energy stores, including glycogen and triglycerides that reside within the muscle tissue, and autophagy sprints to the rescue! As you might imagine, the longer and harder we work out, the more autophagy is stimulated (3). However, an exact exercise prescription for maximizing autophagy is lacking.

Sleep and melatonin

Both sleep and melatonin are intricately linked with proper house-keeping in the brain (4). Melatonin is a neurohormone that is commonly associated with inducing sleep. It exhibits several other functions, including promoting autophagic flux in the brain and preserving mitochondrial function in part via mitophagy (mitochondrial recycling). Our brains are extremely energetically demanding organs, and mitochondrial function is imperative to their long-term health. Poor sleep habits can impair melatonin secretion and subsequently autophagy (4). Autophagy is most active during sleep, and thus inadequate sleep will impact autophagic housekeeping. Unfortunately, as autophagy is hindered, toxic proteins are inadequately cleared in the brain causing inflammation and neuron damage, leading to further sleep loss, melatonin synthesis disruption, and perpetually diminished autophagy. This is an ugly, feed-forward process that can promote neurodegeneration if not corrected. Yet another reason to prioritize good sleep hygiene and quality shut-eye! 

Diet

Polyphenols are natural compounds found ubiquitously amongst fresh, whole foods, especially fruits, vegetables, herbs, and spices (5). Flavonoids are a specific group of polyphenols that have shown to be especially strong inducers of autophagy. Intriguingly, these compounds work through some of the same pathways as nutrient depletion, triggering a switch from a state of high energy to one of low energy availability. Both AMPK and the AKT/mTOR signaling pathway influence autophagy as they function as energy sensors within the cell (5). When energy declines, AMPK is activated and the AKT/mTOR pathway is inhibited, driving autophagy to create a novel energy source. By acting as a mild stress, polyphenols and more specifically flavonoids trigger autophagy by acting on AMPK and the AKT/mTOR signaling pathway. Other plant molecules that have been implicated in autophagy modulation include terpenoids, saponins, alkaloids, isoprenoids, and phytosterols (5, 6). Just some fun words to throw into your next party conversation! A side benefit of these plant compounds is their ability to act as protectors against reactive oxygen species, which can cause significant tissue assault if not properly extinguished.

Several micronutrients, such as vitamins A, B, C, and E, along with a few select minerals, have been studied for their role in autophagy (6). These compounds exert their effects in a similar fashion to polyphenols by instigating a mild stress response in the body that causes an upregulation of autophagy. Vitamin and mineral content of natural foods can vary widely based on the soil content, state of maturation, and preparation method. It is subsequently important to incorporate a wide variety of foods in the diet, from grass-fed meats to organic produce, and to switch up your preparation methods to include raw, steamed, and cooked foods. 

Finally, we have omega-3 fatty acids, located most prevalently in fatty fish (5). Omega-3 fatty acids are woefully minimal in the typical American diet despite their numerous health benefits. Omega-3 fatty acids are critical components of cell membranes, and are especially concentrated in the brain. Omega-3 fatty acids are touted for their anti-inflammatory properties, but also preserve autophagic processes. 

What now?

What am I going to do with this information? Well, as best I can, I am going to prioritize my sleep, activity, and mood, and enjoy lots of fresh, delicious foods prepared in all kinds of different ways. I will reach for beautiful, colorful, whole food sources and experiment with the addition of spices and herbs to add bang for my buck to each meal. I’ll choose ways to move that make me happy, no matter how unconventional they might be. And most importantly, I’m not going to worry about optimizing every little detail. That is NOT a productive source of stress! The best part is that I can absolutely tailor these components to fit my lifestyle. There is no one-size-fits-all approach, and that is so liberating and empowering! I don’t have to follow some super regimented protocol that is unsustainable for me and negatively impacts my outlook on life. Feel free to embrace your idiosyncrasies, biases, and preferences, and treat yourself with grace, kindness, and compassion. I think that might be the most crucial health advice of all. 

Let me know what you thought of this series. I hope it will be the first of many! 

References

1. Giampieri F, Afrin S, Forbes-Hernandez TY, et al. Autophagy in Human Health and Disease: Novel Therapeutic Opportunities. Antioxid Redox Signal. 2019;30(4):577-634. doi:10.1089/ars.2017.7234
2. Bagherniya M, Butler AE, Barreto GE, Sahebkar A. The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Res Rev. 2018;47:183-197. doi:10.1016/j.arr.2018.08.004
3. Escobar KA, Cole NH, Mermier CM, VanDusseldorp TA. Autophagy and aging: Maintaining the proteome through exercise and caloric restriction. Aging Cell. 2019;18(1):e12876. doi:10.1111/acel.12876
4. Hossain MF, Wang N, Chen R, et al. Exploring the multifunctional role of melatonin in regulating autophagy and sleep to mitigate Alzheimer’s disease neuropathology. Ageing Res Rev. 2021;67:101304. doi:10.1016/j.arr.2021.101304
5. Al-Bari MAA, Ito Y, Ahmed S, Radwan N, Ahmed HS, Eid N. Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer. Int J Mol Sci. 2021;22(18):9807. Published 2021 Sep 10. doi:10.3390/ijms22189807
6. Giampieri F, Afrin S, Forbes-Hernandez TY, et al. Autophagy in Human Health and Disease: Novel Therapeutic Opportunities. Antioxid Redox Signal. 2019;30(4):577-634. doi:10.1089/ars.2017.7234