6 Things You Should Know about Autophagy

Autophagy is a cellular process that is necessary for life and longevity; however, people who have disruptions in autophagy are at increased risk of developing chronic diseases. It's been commonly analogized as being the housekeepers, the garbage men, or the recyclers of our bodies. Although that doesn't sound too glamorous, it's a crucial process and increasing autophagy is something we should all be thinking more about if we want to live long and healthy lives.

What is Autophagy? The Simplified Science

Literally meaning "self-eating" in Greek, autophagy is the natural, regulated mechanism of the cell that removes unnecessary or dysfunctional components. It allows the orderly degradation and recycling of cellular components, which enables our cells to maintain healthy functionality. In times of starvation, autophagy kicks into high gear to make sure you get some energy resulting from the breakdown and recycling of protein and fat.

While there are technically three types of autophagy, the focus here, and the one most often studied, is macroautophagy. But it's worth mentioning mitophagy, another form of autophagy that specifically works on the recycling and turnover of damaged mitochondria, the "powerhouses" of the cell. As mitochondrial dysfunction plays a critical role in disease development, research on increasing mitophagy may be promising for improving health.

Autophagy is a non-negotiable part of being a healthy human. If your cells aren't able to properly detoxify and get rid of the damage, your risk of developing diseases (both chronic and infectious) increases, and you're more likely to age faster. Disruptions in the autophagy process lead to a buildup of dysfunctional and damaged cells in the body. This has been linked to neurodegenerative diseases, metabolic-related disorders, and even intestinal diseases.

The main players in autophagy involve the autophagosome and the lysosome. When the cellular trash needs to be taken out, the dysfunctional components get sealed in the autophagosome, which is a sac-like membrane that resembles the garbage bag. From there, the garbage bag and its contents get transported to the lysosome, which could be considered the recycling center. Though previously thought to just be a trash can, the lysosome plays a bigger role in metabolism than just a place to dump old cellular materials.

The lysosome can adapt to environmental cues, such as abundant and scarce nutrition. When there's plenty of food available, and you're regularly eating your three square meals per day, lysosomes signal to the rest of your body that excess energy stores can be used for other important things, like reproduction or growth. But when there's starvation, or you're fasting, more lysosomes are made that contain fat-digesting enzymes to provide you with energy.

These periods of fasting upregulate autophagy. Although constantly working in the background in maintenance mode when our bodies are well-fed, when we go for prolonged periods of fasting, starting at about the 12-hour mark, the principal of hormesis, or hormetic stress, comes into play.

Hormesis occurs when we add a low dose of stressors to our bodies, but not too much. An example would be restricting calories for a short period of time, as opposed to fasting for weeks on end. The middle ground of hormetic stress leads to an uptick in autophagy, which then leads to the cellular turnover that we want to stay healthy. Let's looks at some ways to boost autophagy.

6 Simple Ways to Increase Autophagy

1. Intermittent Fasting or Caloric Restriction

The most researched dietary method to increase autophagy is through short-term fasting. Whether through intermittent fasting, alternate-day fasting, time-restricted eating, or caloric restriction, all of these options get the same job done: they trigger autophagy.

When you fast, your body will activate the AMPK (5′ AMP-activated protein kinase) signaling pathway, which then inhibits mTOR (mammalian target of rapamycin). The inhibition of mTOR allows autophagy to increase and start using your excess cellular fat for energy.

Another mechanism by which fasting promotes autophagy is through the production of sirtuins, which are a family of proteins that protect against aging and its associated diseases. Lastly, fasting can also increase levels of NAD+, a critical molecule that decreases with age, which is involved with repairing DNA and oxidative damage and increasing longevity.

The majority of studies on intermittent fasting and longevity have been done with animals, typically rats or mice. However, the results are promising: studies show that caloric restriction in rats led to multiple health benefits, including longer lives and improvements in inflammatory and metabolic markers.

2. Exercise

Aerobic exercise is another way to induce autophagy, especially in muscle tissues. A small study published in Physiology Reports looked at autophagy markers in males after an eight-week exercise program. Two hours after participating in either moderate-intensity cycling or moderate-intensity cycling interspersed with sprints (resembling a high-intensity interval training workout), skeletal muscle AMPK was increased in both groups, as well as other autophagy markers, including LC3I, LC3II, and BNIP3.

In a study on rats, researchers questioned whether high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) had more of a benefit on autophagy. The HIIT group saw higher mitochondrial biogenesis markers as well as muscular increases in autophagy markers, compared to the MICT group, indicating that HIIT may provide an additional cellular benefit that moderate-intensity exercise does not, likely due to the increased hormetic effect of the HIIT workout.

3. Restorative Sleep

One of the easiest ways to trigger autophagy is simply by getting enough sleep! Our circadian rhythms, which are our internal 24-hour body clocks, rely on the regulation of several pathways and markers of autophagy, including mTOR, AMPK and the sirtuin SIRT1.

Disruption of both circadian rhythms and autophagy has been seen in neurodegenerative diseases and cognitive decline. In studies done on flies, the protein aggregates in the brain that are hallmarks of cognitive problems have been linked to a reduction in autophagy, which was then resolved once neural autophagy pathways were improved.

Melatonin, our main sleep-related hormone, also depends on autophagy pathways, which in turn controls aging processes, especially in the brain. It's important to underscore that not all sleep will increase autophagy; it has to be deep and restorative sleep. When sleep is fragmented, autophagy proteins are decreased and memory and cognition can decline.

4. Green Tea

The most often studied compound in green tea is epigallocatechin gallate (EGCG), which is a polyphenol and antioxidant in the catechin family. Green tea and EGCG have both been associated with increased longevity and reducing inflammation and oxidative damage.

Dietary polyphenols, including EGCG, promote longevity by upregulating autophagy pathways in a similar way that caloric restriction does. EGCG can increase autophagy in the liver by increasing the AMPK pathway, as well as improving lipid clearance, which could be beneficial for those with fatty liver.

In an in vitro model, EGCG was able to increase cellular survival and balance out the pathways of mTOR and AMPK to promote autophagy during times of stress, showing a cytoprotective effect.

5. Resveratrol

Resveratrol, the beneficial compound found primarily in red wine and grape skins, has been shown to induce autophagy in cellular models as well as animal studies. Similar to EGCG, the polyphenol provides anti-inflammatory benefits and may increase longevity.

In a human study, 119 individuals received either a resveratrol supplement (up to one gram twice per day) for 52 weeks or a placebo. After the year, those in the resveratrol group saw significant decreases in neuroinflammatory markers.

Resveratrol induces autophagy by directly inhibiting the mTOR pathway and activating SIRT1. Research has indicated that these processes may prevent cognitive decline and provide a neuroprotective effect.

Something to be aware of is the low bioavailability of resveratrol, so choosing a trans-resveratrol supplement may provide more of the autophagy benefits.

6. Curcumin

Curcumin, another polyphenol compound that acts as an antioxidant, is the active ingredient in the spice turmeric, which gives its bright yellow coloring. Curcumin has anti-inflammatory properties and can activate the AMPK signaling pathway and inhibit mTOR, which, in turn, can increase autophagy. Curcumin supplementation may be an important herb in the quest to maintain cellular health.

Your Takeaway

• Autophagy is the method in which our bodies recycle and reuse damaged or dysfunctional proteins or compounds, which is essential for longevity and prevention of chronic diseases.
• Intermittent fasting or caloric restriction is the most well-known way to induce autophagy, which can involve either time-restricted eating, alternate-day fasting, or restricting calories.
• Other lifestyle factors that can increase autophagy are exercise (especially high-intensity interval training) and getting restorative, deep sleep.
• Supplements that may trigger autophagy include EGCG from green tea, resveratrol, and curcumin.

References:

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Galluzzi L, Baehrecke EH, Ballabio A, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36(13):1811–1836. doi: 10.15252/embj.201796697

Holczer M, Besze B, Zámbó V, Csala M, Bánhegyi G, Kapuy O. Epigallocatechin-3-Gallate (EGCG) Promotes Autophagy-Dependent Survival via Influencing the Balance of mTOR-AMPK Pathways upon Endoplasmic Reticulum Stress. Oxidative Medicine and Cellular Longevity. 2018; 2018(15). doi: 10.1155/2018/6721530

Kou X, Chen N. Resveratrol as a Natural Autophagy Regulator for Prevention and Treatment of Alzheimer's Disease. Nutrients. 2017;9(9):927. doi:10.3390/nu9090927

Li FH, Li T, Ai JY, et al. Beneficial Autophagic Activities, Mitochondrial Function, and Metabolic Phenotype Adaptations Promoted by High-Intensity Interval Training in a Rat Model. Front Physiol. 2018;9:571. doi:10.3389/fphys.2018.00571

Maiese K. Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer. Curr Neurovasc Res. 2017;14(3):299–304. doi:10.2174/1567202614666170718092010

Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46–58. doi:10.1016/j.arr.2016.10.005

Moussa C, Hebron M, Huang X, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease. J Neuroinflammation. 2017;14(1):1. Jan 3. doi:10.1186/s12974-016-0779-0

Perrone L, Squillaro T, Napolitano F, Terracciano C, Sampaolo S, Melone MAB. The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases. Nutrients. 2019;11(8):1881. doi:10.3390/nu11081881

Ratliff EP, Mauntz RE, Kotzebue RW, et al. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors. PLoS ONE. 10(7): e0132768. doi: 10.1371/journal.pone.0132768