Oral Treatments for Autophagy

Housekeeping, cleaning-up, and recycling. These are all important in our daily lives to keep our environments clean and safe, but did you know that our cells also have a similar system? It’s called autophagy (pronounced ah-TAH-fah-gee and meaning “self-eating”) and it allows our bodies to “remove misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens” (Glick & Macleod, 2010). The parts of the cellular debris that can be recycled or upcycled are, and the rest are discarded. Additionally, the harmful viruses and bacteria are disposed of like garbage set outside of a house for the sanitation workers to pick up. If the cellular debris wasn’t cleared, it would slow down a cell, prevent it from functioning correctly, or make us sick. Autophagy cleans and repurposes the parts and debris so that everything works efficiently and pathogens are removed- both of which optimize cell health. Recently, researchers have found that “autophagy significantly controls immune responses by modulating the functions of immune cells and the production of cytokines [and] conversely, some cytokines and immune cells have a great effect on the function of autophagy” (Jiang et al., 2019).  This means that helping our bodies have healthy and regular autophagy is even more critical to our health than previously thought!

There are natural ways to induce autophagy, including the following as noted by The Cleveland Clinic (2022):

• Fasting
• Calorie restriction
• Switching to a high-fat, low-carb diet
• Exercise

Not all of these are right for all people all of the time. Especially if a person is sick or their body can’t handle caloric restriction. In this care, there are multiple oral treatments for autophagy, which include:

• Metformin (Bharath et al., 2020)
• Resveratrol, a precursor to metformin (Tianet et al., 2019)
• Berberine, a natural equivalent to metformin (Fu et al., 2023)
• B6 (Zhang et al., 2022)
• Curcumin (Forouzanfar et al., 2019)
• EGCG (Epigallocatechin Gallate) found in green tea (Zhang et al., 2020)
• Theaflavins (Xu et al., 2022)
• Gynostemma, an AMPK booster (Ke et al., 2022)
• Fisetin (Jia et al., 2019)
• Urolithin A (Ahsan et al, 2019)
• Rapamycin (Lin, 2018)
• NAD+ Infusions (Navas & Carnero, 2021)
• Hesperidin (Saiprasad et al., 2014)
• Quercetin (Guo et al., 2021)
• Dasatinib (Milano et al., 2009)

While maintaining a nutritious diet, exercising, lowering stress, and having community support all contribute to our overall health and wellness, autophagy is a common thread in all the cellular processes that help us lead a long and healthy life (Nakamura & Yoshimori, 2018). Problems with autophagy may be associated with the following as per the Cleveland Clinic (2022):

• Crohn’s disease
• Diabetes
• Heart disease
• Huntington’s disease
• Kidney disease
• Liver disease
• Parkinson’s disease

Therefore, people at high risk for these illnesses may wish to be proactive in helping their bodies’ natural autophagy process.

References

Ahsan, A., Zheng, Y. R., Wu, X. L., Tang, W. D., Liu, M. R., Ma, S. J., Jiang, L., Hu, W. W., Zhang, X. N., & Chen, Z. (2019). Urolithin A-activated autophagy but not mitophagy protects against ischemic neuronal injury by inhibiting ER stress in vitro and in vivo. CNS neuroscience & therapeutics, 25(9), 976–986. https://doi.org/10.1111/cns.13136

Bharath, L. P., Agrawal, M., McCambridge, G., Nicholas, D. A., Hasturk, H., Liu, J., Jiang, K., Liu, R., Guo, Z., Deeney, J., Apovian, C. M., Snyder-Cappione, J., Hawk, G. S., Fleeman, R. M., Pihl, R. M. F., Thompson, K., Belkina, A. C., Cui, L., Proctor, E. A., Kern, P. A., … Nikolajczyk, B. S. (2020). Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation. Cell metabolism, 32(1), 44–55.e6. https://doi.org/10.1016/j.cmet.2020.04.015

Cleveland Clinic. (Aug 23, 2022). Autophagy: Definition, process, fasting & signs. https://my.clevelandclinic.org/health/articles/24058-autophagy 

Forouzanfar, F., Read, M. I., Barreto, G. E., & Sahebkar, A. (2019). Neuroprotective effects of curcumin through autophagy modulation. IUBMB Life, 72(4), 652–664. https://doi.org/10.1002/iub.2209 

Fu, K., Chen, H., Mei, L., Wang, J., Gong, B., Li, Y., & Cao, R. (2023). Berberine enhances autophagic flux by activating the Nrf2 signaling pathway in bovine endometrial epithelial cells to resist lps‐induced apoptosis. Animal Science Journal, 94(1). https://doi.org/10.1111/asj.13847

Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. The Journal of pathology, 221(1), 3–12. https://doi.org/10.1002/path.2697

Guo, H., Ding, H., Tang, X., Liang, M., Li, S., Zhang, J., & Cao, J. (2021).Quercetin induces pro‐apoptotic autophagy via SIRT1/AMPK signaling pathway in human lung cancer cell lines A549 and H1299 in vitro. Thoracic Cancer, 12(9), 1415–1422. https://doi.org/10.1111/1759-7714.13925 

Jia, S., Xu, X., Zhou, S., Chen, Y., Ding, G., & Cao, L. (2019). Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways. Cell Death & Disease, 10(2). https://doi.org/10.1038/s41419-019-1366-y 

Jiang, GM., Tan, Y., Wang, H. et al. The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol Cancer 18, 17 (2019). https://doi.org/10.1186/s12943-019-0944-z

Ke, J. Y., Liu, Z. Y., Wang, Y. H., Chen, S. M., Lin, J., Hu, F., & Wang, Y. F. (2022). Gypenosides regulate autophagy through Sirt1 pathway and the anti-inflammatory mechanism of mitochondrial autophagy in systemic lupus erythematosus. Bioengineered, 13(5), 13384–13397. https://doi.org/10.1080/21655979.2022.2066749

Lin, X., Han, L., Weng, J., Wang, K., & Chen, T. (2018). Rapamycin inhibits proliferation and induces autophagy in human neuroblastoma cells. Bioscience reports, 38(6), BSR20181822. https://doi.org/10.1042/BSR20181822

Milano, V., Piao, Y., LaFortune, T., & de Groot, J. (2009). Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Molecular cancer therapeutics, 8(2), 394–406. https://doi.org/10.1158/1535-7163.MCT-08-0669

Nakamura, S., & Yoshimori, T. (2018). Autophagy and Longevity. Molecules and cells, 41(1), 65–72. https://doi.org/10.14348/molcells.2018.2333

Navas, L. E., & Carnero, A. (2021). NAD+ metabolism, stemness, the immune response, and cancer. Signal Transduction and Targeted Therapy, 6(1). https://doi.org/10.1038/s41392-020-00354-w 

Saiprasad, G., Chitra, P., Manikandan, R., & Sudhandiran, G. (2014). Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-a mediated phosphoinositide-3-kinase/AKT/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis. European Journal of Cancer, 50(14), 2489–2507. https://doi.org/10.1016/j.ejca.2014.06.013 

Tian Y, Song W, Li D, Cai L, Zhao Y. Resveratrol As A Natural Regulator Of Autophagy For Prevention And Treatment Of Cancer. Onco Targets Ther. 2019 Oct 17;12:8601-8609. doi: 10.2147/OTT.S213043. PMID: 31802896; PMCID: PMC6802539. 

Xu, J., Wang, S. J., Bu, S. S., Guo, X. Q., & Ge, H. (2022). Theaflavin promoted apoptosis in nasopharyngeal carcinoma unexpectedly via inducing autophagy in vitro. Iranian journal of basic medical sciences, 25(1), 68–74. https://doi.org/10.22038/IJBMS.2021.59190.13143

Zhang, S., Cao, M., & Fang, F. (2020). The Role of Epigallocatechin-3-Gallate in Autophagy and Endoplasmic Reticulum Stress (ERS)-Induced Apoptosis of Human Diseases. Medical science monitor : international medical journal of experimental and clinical research, 26, e924558. https://doi.org/10.12659/MSM.924558

Zhang Y, Zhou XA, Liu C, Shen Q, Wu Y. Vitamin B6 Inhibits High Glucose-Induced Islet β Cell Apoptosis by Upregulating Autophagy. Metabolites. 2022 Oct 31;12(11):1048. doi: 10.3390/metabo12111048. PMID: 36355132; PMCID: PMC9695582.

About the author: Mary Genevieve Carty, MS, MHEd holds Masters degrees in Complementary and Integrative Health as well as Higher Education and is currently a doctoral student in Health Science at George Washington University’s College of Medicine and Health Science.  She is passionate about holistic health and wellness, and has additional training in teaching, Reiki, and Tapping/ Emotional Freedom Technique. Her research interests include resiliency, psychoneuroimmunology, neuroplastic pain, placebo/ nocebo effect, and bioenergy therapies.  The views she expresses are her own, and do not reflect any affiliation.