Fasting is voluntarily refraining from eating for a set period of time and has been used for many years for therapeutic and spiritual purposes. Intermittent fasting (IF) is defined as a variety of eating patterns where no or few calories are consumed for periods of time than can span 12 hours to several days, on a recurring basis, and can result in a number of different physiological responses. Time restricted fasting (TRF) is a specific type of IF in which food intake is restricted to specific time periods of the day, typically between 13 and 18 hours. TRF has been shown to improve glycemic control, increase fat oxidation, and has the potential to improve insulin signaling. This is all due in part to the increased levels of ketone bodies produced when fasting.

Ketones - otherwise known as ketone bodies, are mainly produced by the liver when glycogen storage (your stored carbohydrates) is low in order to provide energy for the heart and brain. They’re consistently present in the blood but are elevated during fasting and prolonged periods of exercise. Ketones have been shown to counteract the effects of hypoglycemia and hypometabolism as well as generate lower levels of oxidative stress and increase antioxidant protein levels. Research suggests that the increase in these ketone bodies result in metabolic and cardiovascular benefits, improvements in migraines and headaches, and has also been shown to have many cancer benefits in recent studies.

As part of a second 4-day crossover study, the effects of early time restricted feeding (eTRF) on energy metabolism in adults who were overweight found that eTRF increased fat oxidation, reduced the hunger hormone ghrelin, and improved appetite. TRF improved glycemic control by lowering 24-hour glucose levels, and reduced sudden spikes in glucose, most likely due to eating earlier in the day and also having a short meal interval (only eating between 8am and 2pm vs eating between 8am and 8pm). eTRF was found to increase ketone levels in the morning and improve cortisol rhythm. Many hormonal and metabolic rhythms involving cortisol, growth hormone, insulin and plasma lipids peak in the morning and are downregulated in the evening, suggesting the morning is better for optimal food intake. TRF interventions show that food intake limited to the early part of the day is effective at improving cardiometabolic health and works in relation with the circadian system.

Metabolic Benefits
Metabolically, beneficial effects stem from the “switch” of using glucose from glycogenolysis to utilizing fatty acids and fatty acid derived ketones consistent with IF. IF improves cardiometabolic risk factors like insulin resistance, dyslipidemia, and inflammatory cytokines. And given that insulin levels impact cancer risk, these improvements may be clinically significant, Additionally, IF decreases visceral fat mass and has shown improvements in osteoarthritis, lipid profiles and the healing of skin ulcers. In many studies, traditional cardiovascular risk factors, including levels of total cholesterol, LDL cholesterol, and triglycerides were decreased from 6-21%, 7-32% and 16-42%, respectively. Furthermore, TRF has been found to decrease fasting glucose levels by 3-6% in people with pre-diabetes.

Improvements in Migraines/Headaches
In a one-month observational study in 96 migraine patients found a reduction of up to 80% in migraine frequency, severity and acute medication use while following a ketogenic diet. These effects are seen due to the increased blood concentration of ketone bodies, which are produced in higher amounts from TRF. The prevalence of migraines among patients with mitochondrial disorders is 29-35% of patients. Therefore, the efficacy of increased ketone body production on decreased migraine frequency and severity could be related to enhanced mitochondria energy metabolism and the ability to counteract neural inflammation. In addition to enhancing mitochondrial functioning, ketone bodies have been shown to have anti-inflammatory effects, combat the negative effects of oxidative stress, enhance cerebral excitability, and may beneficially alter the gut microbiome, all of which may significantly impact migraines.

Cancer Benefits
While more studies on humans are needed in this area, nutritional restriction is a promising approach designed to modulate autophagy and enhance anti-cancer therapies while protecting normal cells. What is autophagy you ask? Autophagy maintains homeostasis and cellular health by slowing the rapid increase of mutated cells and also by recycling damaged cells from the body. Inflammation promotes tumorigenesis, the forming of a tumor, and is suppressed through autophagy. Autophagy suppresses initiation and progression of tumors by limiting inflammation and genome mutations. By sustaining normal physiology and regulating metabolic pathways, autophagy is needed for normal physiological processes, particularly to fight against different disease states and their progression.

Recent pre-clinical and animal studies have shown that IF improved chemotherapeutic response to 10 different chemotherapy drugs in models of glioma, neuroblastoma, melanoma, fibrosarcoma, breast cancer, colon cancer, pancreatic cancer, hepatocellular cancer and lung cancer. Studies combining IF and chemotherapy showed slowed tumor growth and overall prolonged survival in breast cancer, melanoma, and neuroblastoma in animal models. Furthermore, in a small pilot study consisting of 10 patients diagnosed with breast, prostate, esophageal or lung cancer suggested that periods of IF before and after chemotherapy reduced the self-reported side effects of therapy, particularly weakness, fatigue, nausea and vomiting. In the Women’s Healthy Eating & Living Study, early-stage breast cancer survivors who fasted for less than 13 hours overnight had a 36% greater risk of breast cancer recurrence and a 22% increased mortality risk compared with those who fasted for more than 13 hours overnight. Additionally, longer fasting duration was associated with a significantly lower hemoglobin A1C, a marker that assesses blood sugar over the previous 2-3 months. Elevated A1C values have been associated with poorer survivorship.

Overall, IF has demonstrated improvements in migraines/headaches, cardio metabolic risk factor such as glucose levels, insulin resistance, and lipid values. It has shown promise in a variety cancers with reduced patient side effects to chemotherapy and significantly lower hemoglobin A1C markers in those fasting for longer durations. Time of day and duration clearly play a large role in the beneficial effects of fasting and should be studied further.

Take Home Messages:
- Consider fasting overnight for 13 hours or more.
- Aim to stop eating for the day by 7pm or 8pm.
- If you’re undergoing chemotherapy, consider fasting or avoiding carbohydrates the day prior, day of, and day following your treatment. Be sure to discuss with your healthcare team.
- Nourish yourself with colorful vegetables and fruits.
- Include protein with every meal; plant protein at least once daily.
- Opt for healthy fats, such as cold-water fish, nuts & seeds, avocados, and olive oil.
- Avoid processed and refined grains/flours/sugars. Choose sweet potatoes, winter squash, and whole grains.

** Written & edited by Kelly Drane Gomez, dietetic intern with the University of Alabama at Birmingham and Natalie Ledesma

Be well,

Natalie