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Fasting has been used in therapeutic, cultural, and religious practices and traditions for thousands of years and is described as an abstinence from some or all foods and drinks for a set period of time. When fasting, the body experiences ketosis and undergoes a metabolic switch in its fuel source, from stored glycogen to fatty acids.1 Fasting may not be optimal for all patients, such as those who are pregnant, who have type 1 diabetes, or who have or are at risk of developing an eating disorder.2,3 However, if appropriate for a patient’s personalized treatment strategy, fasting benefits may include improvements in a range of areas such as mental or cognitive performance, cardiovascular health, type 2 diabetes, obesity, and the effectiveness of cancer treatments.4-7 How does mitochondrial health relate to fasting and its potential benefits?
Mitochondrial Responses to Fasting
Mitochondria have multiple functions, from generation of reactive oxygen species (ROS) to energy metabolism and ATP synthesis. Mitochondrial quality impacts the health of multiple body systems and tissues, with mitochondrial biogenesis and performance impacting cardiovascular,8 immune,9 musculoskeletal,10,11 gut,12 and brain health.13,14 One of the suggested benefits of intermittent fasting is the optimization of mitochondrial health, potentially leading to improved energy production and overall function.4,15-17 While the long-term effects of intermittent fasting have not been fully established,18 mitochondrial and fasting-related research continues to evolve, with more clinical and observational studies demonstrating potential benefits of therapeutic fasting approaches to support health19,20 and with additional investigations clarifying the mitochondrial mechanisms that may be involved.
Mitochondrial MECHANISMS: homeostasis & biogenesis
Mitochondria are dynamic organelles undergoing continuous cycles of fusion and fission. While excessive division or fission has been associated with mitochondrial functional defects that may lead to multiple disease states,21 a recent study in nematode worms suggested that fasting may increase overall lifespan by promoting a balance between the fusion and fission states and homeostasis in mitochondrial networks.22
Mitochondrial biogenesis and function are mediated by different activators, regulators, and transcription factors such as PGC-1? and Nrf2. Research has suggested that fasting may enhance these mediators to promote mitochondrial biogenesis and improve mitochondrial function. For example:
- Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?) is a fasting-induced transcriptional coactivator23 that mediates mitochondrial biogenesis, activates when the body receives a signal that it needs more cellular energy, and increases in expression during fasting.24,25
- Nuclear factor (erythroid-derived 2) factor 2 (Nrf2) is a transcription factor that regulates ROS production by mitochondria.26 Studies suggest that Nrf2 is associated with mitochondrial biogenesis and may be involved in mitochondrial quality control systems.27 A 2019 study evaluated the impact of Ramadan intermittent fasting on the expression of antioxidant genes, including Nrf2, and results suggested that fasting improved the expression of the antioxidant regulatory genes.16
Nutrition + Fasting Interventions for Mitochondrial Health
Specific nutrients that support mitochondrial function may be part of a personalized nutrition strategy for some patients. In other cases, a form of fasting may be appropriate and blended with a food plan to create an individualized nutrition intervention. Examples include the following:
- Fasting: The willful abstinence from any caloric intake for an extended period of time that is greater than 24 hours. This practice usually includes water only, but some methods allow tea, coffee, and minerals. Of note, some experts only define fasting in this way and do not consider intermittent approaches as forms of fasting.
- Intermittent fasting: A broad term used to describe food consumption cycles that alternate between periods of restricting calories and periods of not restricting calories.
- Time-restricted eating/prolonged nightly fastingcalories from food and beverages only during a hortened window of time daily, ranging from four to 12 hours. This is also called “prolonged nightly fasting,” which eliminates or reduces a person’s caloric intake at night, with an extended overnight fast that is greater than 10 hours.
- Alternate-day fasting: A cycle of a complete fast on one day and eating freely on the next day.
- Intermittent energy restriction: Consecutive or non-consecutive days of alternating very low-calorie intake (as low as 400 to 500 kcal) with days of normal calorie intake.
- 5:2 diet: Two consecutive or non-consecutive days of low-calorie intake (no more than 25% of an individual’s daily caloric requirement) coupled with five days of unrestricted eating.28
- Calorie restriction: Daily caloric intake is reduced for an extended period of time without causing malnutrition and meal frequency is maintained.
- Fasting-mimicking diet: A periodic, multiple-day (typically followed for five days), very low-calorie, low carbohydrate food plan designed to mimic a fasting state.29,30
Research studies continue to investigate mitochondrial responses to the metabolic stress from fasting or reduced energy intake. As an example, in preclinical experiments and a few clinical studies, calorie restriction has been shown to promote mitochondrial function and to induce both mitochondrial biogenesis as well as mitophagy.31-35
IFM’s Mitochondrial Food Plan is an anti-inflammatory, low-glycemic, high-quality fat approach to eating that supports healthy mitochondria for improved energy production. Further, this food plan can be expanded with various levels of fasting. In the following video, IFM educator Monique Class, MS, APRN, BC, IFMCP, discusses the benefits of incorporating fasting with IFM’s Mitochondrial Food Plan.
Fasting approaches may be integrated into therapeutic nutritional strategies based on a patient’s needs. For example, patients with chronic conditions may already have elevated levels of inflammation and oxidative stress, and their current diet may need to be stabilized to reduce overall inflammation before introducing fasting. Functional medicine provides a framework within which practitioners may collaborate with patients to develop personalized therapeutic strategies that potentially include nutrition interventions incorporating different levels of fasting.
Learn more about tailoring nutrition-based treatments through IFM’s course Therapeutic Food Plans: A Component of Personalized Nutrition and gain additional evaluation insights and tools on fasting and optimal mitochondrial function at the Bioenergetics Advanced Practice Module.
Related Articles & Podcasts
- Anton SD, Moehl K, Donahoo WT, et al. Flipping the metabolic switch: understanding and applying the health benefits of fasting. Obesity (Silver Spring). 2018;26(2):254-268. doi:10.1002/oby.22065
- Kanikarla-Marie P, Jain SK. Hyperketonemia and ketosis increase risk of complications in type 1 diabetes. Free Radic Biol Med. 2016;95:268-277. doi:10.1016/j.freeradbiomed.2016.03.020
- Glazier JD, Hayes DJL, Hussain S. The effect of Ramadan fasting during pregnancy on perinatal outcomes: a systemic review and meta-analysis. BMC Pregnancy Childbirth. 2018;18:421. doi:10.1186/s12884-018-2048-y
- de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease [published corrections appear in: N Engl J Med. 2020;382(3):298; N Engl J Med. 2020;382(10):978]. N Engl J Med. 2019;381(26):2541-2551. doi:10.1056/NEJMra1905136
- Carter S, Clifton PM, Keogh JB. Effect of intermittent compared with continuous energy restricted diet on glycemic control in patients with type 2 diabetes: a randomized noninferiority trial. JAMA Netw Open. 2018;1(3):e180756. doi:10.1001/jamanetworkopen.2018.0756
- Zubrzycki A, Cierpka-Kmiec K, Kmiec Z, Wronska A. The role of low-calorie diets and intermittent fasting in the treatment of obesity and type-2 diabetes. J Physiol Pharmacol. 2018;69(5):663-683. doi:10.26402/jpp.2018.5.02
- 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
- Zhou H, He L, Xu G, Chen L. Mitophagy in cardiovascular disease. Clin Chim Acta. 2020;507:210-218. doi:10.1016/j.cca.2020.04.033
- Breda CNS, Davanzo GG, Basso PJ, Saraiva Câmara NO, Moraes-Vieira PMM. Mitochondria as central hub of the immune system. Redox Biol. 2019;26:101255. doi:10.1016/j.redox.2019.101255
- Wang S, Deng Z, Ma Y, et al. The role of autophagy and mitophagy in bone metabolic disorders. Int J Biol Sci. 2020;16(14):2675-2691. doi:10.7150/ijbs.46627
- Ferri E, Marzetti E, Calvani R, Picca A, Cesari M, Arosio B. Role of age-related mitochondrial dysfunction in sarcopenia. Int J Mol Sci. 2020;21(15):5236. doi:10.3390/ijms21155236
- Ballard JWO, Towarnicki SG. Mitochondria, the gut microbiome and ROS. Cell Signal. 2020;75:109737. doi:10.1016/j.cellsig.2020.109737
- Belenguer P, Duarte JMN, Schuck PF, Ferreira GC. Mitochondria and the brain: bioenergetics and beyond. Neurotox Res. 2019;36(2):219-238. doi:10.1007/s12640-019-00061-7
- Lejri I, Agapouda A, Grimm A, Eckert A. Mitochondria- and oxidative stress-targeting substances in cognitive decline-related disorders: from molecular mechanisms to clinical evidence. Oxid Med Cell Longev. 2019;2019:9695412. doi:10.1155/2019/9695412
- Lettieri-Barbato D, Cannata SM, Casagrande V, Ciriolo MR, Aquilano K. Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle. PLoS One. 2018;13(5):e0195912. doi:10.1371/journal.pone.0195912
- Madkour MI, T El-Serafi A, Jahrami HA, et al. Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT 1, SIRT3) gene expressions in subjects with overweight and obesity. Diabetes Res Clin Pract. 2019;155:107801. doi:10.1016/j.diabres.2019.107801
- Zhao Y, Jia M, Chen W, Liu Z. The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function. Free Radic Biol Med. 2022;182:206-218. doi:10.1016/j.freeradbiomed.2022.02.021
- National Institute on Aging. Research on intermittent fasting shows health benefits. Published February 27, 2020. Accessed July 12, 2022. https://www.nia.nih.gov/news/research-intermittent-fasting-shows-health-benefits
- Currenti W, Godos J, Castellano S, et al. Association between time restricted feeding and cognitive status in older Italian adults. Nutrients. 2021;13(1):191. doi:10.3390/nu13010191
- Maniaci G, La Cascia C, Giammanco A, et al. Efficacy of a fasting-mimicking diet in functional therapy for depression: a randomised controlled pilot trial. J Clin Psychol. 2020;76(10):1807-1817. doi:10.1002/jclp.22971
- Serasinghe MN, Chipuk JE. Mitochondrial fission in human diseases. Handb Exp Pharmacol. 2017;240:159-188. doi:10.1007/164_2016_38
- Weir HJ, Yao P, Huynh FK, et al. Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab. 2017;26(6):884-896.e5. doi:10.1016/j.cmet.2017.09.024
- Besse-Patin A, Jeromson A, Levesque-Damphousse P, Secco B, Laplante M, Estall JL. PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin. Proc Natl Acad Sci U S A. 2019;116(10):4285-4290. doi:10.1073/pnas.1815150116
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