In 2016, the Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for his pioneering work elucidating the mechanisms behind autophagy.1 Before this event, few people outside the medical and scientific communities had ever heard the term "autophagy," and even fewer understood its profound implications for human health. Read on to learn all about autophagy, its role in the prevention and development of chronic diseases, and how diet and lifestyle strategies optimize autophagic activity in the body to create lasting health and wellness.
What is Autophagy?
The term autophagy is derived from the Latin words for “self” (autos) and “eating” (phagia) and refers to the ancient, evolutionarily-conserved pathway by which cells regulate the turnover of cytosolic proteins and organelles. Essentially, autophagy is a form of “cellular quality control” that removes and recycles dysfunctional cellular components, keeping cells in tip-top shape so they can function optimally.2 Autophagy occurs in cells within a diverse array of body tissues and systems, including the brain, eye, heart, immune system, kidneys, liver, and skeletal muscle.
While there are several forms of autophagy, macroautophagy (hereafter referred to simply as “autophagy”) is the primary type that takes places in mammalian cells. Autophagy is a stepwise signaling pathway that culminates in the degradation and recycling of dysfunctional cellular components:
1. The process of autophagy is initiated by signals from within the complex cellular milieu that indicate a need for cellular “housekeeping.”
2. Next, a semicircular membrane called a “phagophore” forms and engulfs the portion of the cytoplasm containing misfolded, dysfunctional proteins and organelles. The new membrane-encapsulated structure containing damaged proteins and organelles is called an autophagosome.
3. The autophagosome fuses with a lysosome, an organelle that contains degradative enzymes. The resulting autolysosome uses lysosomal enzymes to break down the damaged proteins and organelles, “rejuvenating” the non-nuclear portions of the cell.
While autophagy is a crucial process, more is not better! A delicate balance must be maintained between activation and inhibition of autophagy for the human body to stay healthy. Various biochemical signaling pathways and molecules regulate the induction and inhibition of autophagy, ensuring that our cellular “waste disposal system” performs properly; the two primary signals are activation of AMPK and inhibition of mTOR.
Autophagy: Activated by AMPK, Inhibited by mTOR
The clearance of damaged proteins and organelles from cells via autophagy not only rejuvenates cells but also helps them adapt to environmental stressors. Beyond proceeding at baseline levels, autophagy can be activated by hormesis, the process by which exposure to low levels of toxins or stressors increases the resilience of the organism to future stress. Fasting, exercise, heat, and food-based phytochemicals offer biological cues that induce autophagy, improving long-term health.
The parent pathway that stimulates autophagy is AMPK. AMP-activated protein kinase (AMPK) is a nutrient-sensing enzyme that functions as a central regulator of metabolism and energy production in the body. It is activated by low cellular ATP levels, glucose, and insulin and inhibited by hyperinsulinemia, IGF-1 signaling, chronic overnutrition, and obesity.
Conversely, autophagy is inhibited by glucose consumption and insulin signaling, both of which activate mTOR (mechanistic target of rapamycin), an anabolic cellular pathway that opposes AMPK. mTOR is involved in beneficial processes such as cell growth and the response to exercise but, when overstimulated by factors such as nutrient excess, can promote hyperinsulinemia, obesity, and cancer.3
What Happens When Autophagy Goes Awry?
Efficient autophagy is crucial for the maintenance of optimal cellular health. When cells lose the ability to kick in their innate “waste disposal system,” they become dysfunctional and pathological processes result. In fact, dysfunctional autophagy is linked to many chronic diseases, including type 2 diabetes, Alzheimer’s disease, cardiovascular disease, macular degeneration, and cancer.
Type 2 diabetes
Research indicates that autophagy regulates the normal function of insulin-producing pancreatic beta cells and the insulin sensitivity of target tissues such as skeletal muscle, liver, and adipose tissue.4 Suppression of autophagy thus plays a pivotal role in the development of type 2 diabetes and its complications, such as diabetic neuropathy and retinopathy.
The human brain is uniquely susceptible to the harmful effects of misfolded proteins and mitochondrial dysfunction. Autophagy helps maintain protein homeostasis (“proteostasis”) and healthy mitochondrial function in the brain. Conversely, impaired autophagy disturbs brain mitochondrial function and proteostasis, promoting the development of amyloid-beta plaques, tau tangles, and alpha-synuclein, abnormal protein aggregates involved in Alzheimer's disease and Parkinson's disease, respectively.5,6
Autophagy helps maintain the health of numerous types of cardiovascular cells, including cardiomyocytes, endothelial cells, and arterial smooth muscle cells.7 In animal studies, the deletion of autophagy-related genes and administration of autophagy-blocking drugs increases the risk of cardiovascular disorders.
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries and is characterized by degeneration of retinal pigment epithelial cells. Autophagy is critical in the maintenance of healthy vision, and autophagy dysfunction is linked to AMD pathogenesis.8
Autophagy plays dual roles in cancer suppression and promotion; defects in autophagy are linked to DNA damage and tumor growth, yet certain types of cancer demonstrate upregulated autophagy, with inhibition of increased autophagy decreasing cell proliferation.9 Whether or not autophagy should be induced depends on the specific type and stage of cancer.
Lifestyle Strategies and Nutraceuticals for Activating Autophagy
The scientific community has taken an intense interest in autophagy, exploring avenues through which autophagy can be activated to promote optimal health. One of the autophagy-promoting compounds that has garnered the most scientific attention is rapamycin, a drug traditionally used as an immunosuppressant in organ transplant patients that also inhibits autophagy through inactivation of mTOR. In fact, mTOR (mechanistic target of rapamycin) is so named because of its interactions with the drug.
However, our understanding of rapamycin and autophagy is limited to preclinical research, and we do not yet know whether it is safe or effective for inducing autophagy in humans. Fortunately, rapamycin is not your only option for enhancing autophagy; several lifestyle strategies and nutraceuticals have been found to naturally upregulate your body’s “cellular housecleaning” system, promoting robust health!
Insulin signaling, induced by the consumption of glucose and amino acids, triggers mTOR and inhibits autophagy. Conversely, fasting decreases insulin signaling and activates AMPK, inducing autophagy. By incorporating fasting into your lifestyle, you can enhance autophagy and keep your cells in tip-top shape!
The length of time required to upregulate autophagy in humans during a fast is not well-understood, but scientists suspect that longer fasting durations of 24 or more hours may be required.10 While a 24-hour fast may seem daunting, you can make the process easier by gradually easing into fasting. Start by incorporating one 24-hour fast per month, eventually working your way towards doing one per week. Animal studies also suggest that limiting food consumption to two meals a day, with extended periods of fasting between meals, can also modestly upregulate autophagy.11 In the long-run, your current health status and your level of physical fitness will determine how long you need to fast in order to initiate autophagy.12
Tea and coffee lovers rejoice – while food consumption generally inhibits autophagy, preclinical research suggests that green tea and coffee induce autophagy in the liver, heart, and skeletal muscle by deacetylating proteins, a process that mimics caloric restriction, and by inhibiting mTOR.13,14 These findings suggest that drinking green tea and coffee during your fast may enhance its health benefits! Since both decaffeinated and caffeinated coffee and tea induce autophagy, the pro-autophagic activity of these beverages is attributed to their unique polyphenols, rather than their caffeine content.
A growing body of fascinating research indicates that autophagy induction is one of the primary mechanisms by which exercise produces health benefits! Exercise induces autophagy in peripheral tissues and the brain, improves neurological function, and is even responsible for many of the health benefits of endurance training at altitude!15,16,17
While our understanding of the role of heat exposure on autophagy is still in its infancy, preclinical research indicates that extreme heat exposure produces heat shock proteins (HSPs), molecules that regulate protein folding, unfolding, and degradation. HSPs, in turn, induces autophagy, suggesting that sauna therapy may be a useful strategy for upregulating autophagy!18,19
Berberine, a bright yellow phytochemical found in Oregon grape, barberry, and goldenseal, is a potent activator of autophagy. It alleviates impaired autophagy by regulating cholesterol metabolism and inhibiting COX2 prostaglandin synthesis.20 It has also been found in vitro to induce autophagic cell death in cancer cells! 21
Resveratrol, a phytochemical found in red wine, berries, and peanuts, induces autophagy by inhibiting mTOR.22 Resveratrol is poorly absorbed on its own; packaging it in liposomes enhances its absorption and may thereby enhance its pro-autophagic activity.23 You can find liposomal berberine and resveratrol in Keto Before 6, our revolutionary formula that supports the health benefits of a ketogenic diet while allowing greater dietary freedom.
Melatonin, a sleep-inducing hormone produced in the brain that regulates our circadian rhythms and acts as a potent antioxidant, has recently demonstrated an essential role in the regulation of autophagy.24
You can optimize your melatonin production by limiting blue light exposure at night with blue-light-blocking glasses, by maintaining a consistent sleep-wake schedule, and by sleeping in a completely dark room. If, after implementing these strategies, you still need a melatonin boost, consider supplementing with our Liposomal Melatonin, a highly bioavailable melatonin formula that gently eases your body into a deep, restful sleep.
The significance of autophagy for promoting optimal health cannot be overemphasized! With the help of fasting, exercise, heat therapy, and potent natural compounds, you can enhance your body's autophagic activity and create vibrant whole-body health!
1. Ke PY. Horning cell self-digestion: Autophagy wins the 2016 Nobel Prize in Physiology or Medicine. Biomed J. 2017; 40(1): 5-8.
2. Yoshii SR, Mizushima N. Monitoring and measuring autophagy. Int J Mol Sci. 2017; 18(9): 1865.
3. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015; 125(1): 25-32.
4. Bhattacharya D, et al. Is autophagy associated with diabetes mellitus and its complications? A review. EXCLI J. 2018; 17: 709-720.
5. Uddin MS, et al. Autophagic dysfunction in Alzheimer's disease: Cellular and molecular mechanistic approaches to halt Alzheimer's pathogenesis. J Cell Physiol. 2019; 234(6): 8094-8112.
6. Zhang G, et al. New perspectives on roles of alpha-synuclein in Parkinson’s disease. Front Aging Neurosci. 2018; 10: 370.
7. Bravo-San Pedro JM, et al. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017; 120(11): 1812-1824.
8. Kivinen N. The role of autophagy in age‐related macular degeneration. Acta Opthalmol. 2018; 96: 1-50.
9. Yun CW, Lee SH. The roles of autophagy in cancer. Int J Mol Sci. 2018; 19(11): 3466.
10. Anton SD, et al. Flipping the metabolic switch: Understanding and applying health benefits of fasting. Obesity (Silver Spring). 2018; 26(2): 254-268.
11. Martinez-Lopez N, et al. System-wide benefits of intermeal fasting by autophagy. Cell Metab. 2017; 26(6): 856-871.
12. Dethlefsen MM, et al. Training state and skeletal muscle autophagy in response to 36 h of fasting. J Appl Physiol. 2018; 125(5): 1609-1619.
13. Holczer M, et al. Epigallocatechin-3-Gallate (EGCG) promotes autophagy-dependent survival via influencing the balance of mTOR-AMPK pathways upon endoplasmic reticulum stress. Oxid Med Cell Longev. 2018; 2018: 6721530.
14. Pietrocola F, et al. Coffee induces autophagy in vivo. Cell Cycle. 2014; 13(12): 1987-1994.
15. He C, et al. Exercise induces autophagy in peripheral tissues and in the brain. Autophagy. 2012; 8(10): 1548-1551.
16. Xing Y, et al. The beneficial roles of exercise training via autophagy in neurological diseases and possible mechanisms. Life Sci. 2019; 221: 130-134.
17. Zhang Y, Chen N. Autophagy is a promoter for aerobic exercise performance during high altitude training. Oxid Med Cell Longev. 2018; 2018: 3617508.
18. Hussain J, Cohen M. Clinical effects of regular dry sauna bathing: A systematic review. Evid Based Complement Alternat Med. 2018; 2018: 1857413.
19. Penke B, et al. Heat shock proteins and autophagy pathways in neuroprotection: From molecular bases to pharmacological interventions. Int J Mol Sci. 2018; 19(1): 325.
20. Sun H, et al. Berberine ameliorates blockade of autophagic flux in the liver by regulating cholesterol metabolism and inhibiting COX2-prostaglandin synthesis. Cell Death and Dis. 2018; 9: 824.
21. La X, et al. Berberine-induced autophagic cell death by elevating GRP78 levels in cancer cells. Oncotarget. 2017; 8(13): 20909-20924.
22. Park D, et al. Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Sci Rep. 2016; 6: 21772.
23. Balanc BD, et al. Resveratrol‐loaded liposomes: Interaction of resveratrol with phospholipids. Eur J Lipid Sci Tech. 2015; 117(10): 1615-1626.
24. Boga JA, et al. Therapeutic potential of melatonin related to its role as an autophagy regulator: A review. Pineal Res. 2019; 66(1): e12534.