White Paper by Madelyn Robinson
Reviewed by Kritika Pathak, Khushboo Verma
Background
Intermittent fasting has gained a lot of attention in recent years for helping with weight loss, but what many people don’t know is that it’s not quite as simple as just eating less to lose a few pounds. Intermittent fasting is an umbrella term that describes a variety of eating patterns in which no or few calories are consumed for 12 to 48 hours on a recurring basis (Anton et al., 2017). These eating patterns include time restricted feeding (restriction of food intake to a 8-12 hour period of the day), alternate day fasting (alternation between little to no caloric intake one day and unrestricted caloric intake the next), and periodic fasting (fasting twice a week with unrestricted consumption of food during the other five days, also known as the 5:2 diet) (Barnosky et al., 2014; Longo & Panda, 2016; Bjarnadottir, 2018). Fasting is an integral practice in many different religious disciplines including Islam, Christianity, Judaism, and Hinduism, and it has been safely practiced for centuries (Lessan & Ali, 2019). In more recent years, however, fasting has become known for its health benefits as well.
Obesity and Metabolic Syndrome
Obesity is a complex and largely preventable disease, but about 30% of the world is obese or significantly overweight (Hruby & Hu, 2015). It is defined as a condition of abnormal or excessive fat accumulation in adipose tissue to the extent that health is impaired (Ofei, 2005). Obesity greatly increases the risk of chronic diseases such as depression, type 2 diabetes, cardiovascular disease, certain cancers, and mortality (Hu, 2008; Keipert et al., 2010). Obesity is also closely associated with metabolic syndrome, which affects 30-40% of people by age 65 (Han & Lean, 2016). Metabolic syndrome is a condition characterized by hypertension, central obesity, insulin resistance, elevated triglyceride and low-density lipoprotein (LDL) levels, and low high-density lipoprotein (HDL) levels, and it is strongly associated with an increased risk for developing diabetes and cardiovascular disease (Rochlani et al., 2017). It is widely accepted that fasting is effective at decreasing obesity and helping individuals lose weight; therefore, fasting can alleviate the effects of obesity as well, including those related to metabolic syndrome (Li et al., 2017; Harris et al., 2018; Zubrzycki et al., 2018; Templeton, 2019).
Metabolic Markers and Longevity
One of the main benefits of fasting is that it can favorably alter glucose and lipid metabolism and promote beneficial hormonal changes. Fasting shifts fuel utilization toward free fatty-acid mobilization, fatty-acid oxidation, and ketogenesis as glucose is conserved (Antoni et al., 2017). In fact, 12 to 24 hours of fasting typically results in a 20% decrease in serum glucose and depletion of the hepatic glycogen due to this switch in metabolic mode (Longo & Mattson, 2014). Metabolic and hormonal changes such as lower glucose, insulin, glycated hemoglobin, cholesterol, and blood pressure levels serve as metabolic markers, and all of these were seen in a study regarding the effects of fasting on humans (Walford et al., 2002). Since effects on human longevity are difficult to study, many studies regarding the effect of fasting on longevity in rats have been conducted and compared to shorter human studies (de Cabo et al., 2014; Antoni et al., 2017). Many of these rat studies not only concluded that fasting increases the longevity of rats, but they also concluded that many of the aforementioned metabolic markers seen in human fasting studies were also seen in these rats (Badreh et al., 2020; Carlson & Hoelzel, 1946; Mager et al., 2006).
Figure 2: Major responses of various organ systems to intermittent fasting (Anton et al., 2017).
Insulin sensitivity
One of the key factors in metabolic syndrome is insulin resistance, which is characterized by impaired glucose uptake in muscle and fat cells, reduced glycogen synthesis/storage in the liver, and failure to suppress hepatic glucose production (Barzilai & Ferrucci, 2012). Most likely caused by a post-receptor defect in target tissue insulin action, insulin resistance often develops with the aging process and is a major feature of type-2 diabetes (Evans & Goldfine, 2013; Fink et al., 1983). To counter the harmful effects of insulin resistance, the body needs to increase insulin sensitivity. Fasting has been shown to be an acceptable way to increase insulin sensitivity since body weight loss has been proven to improve insulin sensitivity and glucose tolerance (Sutton et al., 2018; Ryan, 2000; Barnosky et al., 2014; Cho et al., 2019). Increased insulin sensitivity reduces the effects of type-2 diabetes, which means that fasting can reduce the risk of diabetic complications such as heart attack, stroke, peripheral artery disease, nerve damage, retina damage, and kidney damage (IQWiG, 2008).
Reducing Cardiovascular Disease Risk Factors
Studies have suggested that alternate day fasting can reduce risk factors associated with cardiovascular disease (Tinsley & La Bounty, 2015). Many human clinical trials have resulted in the reduction of total cholesterol, LDL, and triglycerides, although not in every single case (Johnson et al., 2007; Varady et al., 2009; Varady et al., 2011; Klemel et al., 2013). Total cholesterol consists of LDL, HDL, and very low-density lipoprotein (VLDL), and maintaining cholesterol and triglyceride levels within healthy limits is critical for decreasing the risk of heart disease (Elshourbagy et al., 2013). While HDL is beneficial to the body, LDL drives the development of atherosclerosis, which can contribute to heart attacks and strokes (Ravnskov, 2002). Elevated triglyceride levels also contribute to cardiovascular disease by increasing inflammation and artherosclerotic plaque formation, and triglycerides have also been proven to be risk factors for cognitive decline as well (Singh & Singh, 2016; Parthasarathy et al., 2017). Therefore, fasting can very possibly reduce the negative cardiac and cognitive decline that is associated with aging by reducing LDL cholesterol and triglyceride levels.
Therapy in Neurodegeneration
Aging is associated with neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, and these disorders are linked to impaired glucose metabolism, neuron bioenergetics, insulin signaling, and neurotrophic signaling (Phillips, 2019; Mattson et al., 2017). Fasting has been shown to slow neurodegeneration in animal models of Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease by protecting neurons from mitochondrial toxins and kainic acid (Duan & Mattson, 1999; Anson et al., 2003). These rodents were seen to have improved cognition and slowed cognitive decline (Fontan-Lozano et al., 2007; Li et al., 2013). Fasting’s effects on neurodegeneration in humans are still largely untested, but many researchers hopefully await future research into the subject due to the strength of animal evidence (Phillips, 2019).
Anti-Cancer Effects
Furthermore, many clinical studies have concluded that fasting and caloric restriction reduces cancer incidence and inhibits tumor progression in rodents (Dirx et al., 2003; De Lorenzo et al., 2011; Lv et al., 2014; Mai et al., 2003), strongly reduces cancer incidence and mortality in primates (Colman et al., 2009), and reduces metabolic and hormonal factors linked to cancer risks in humans (Renehan et al., 2004; Ravussin et al., 2015). Of course, fasting alone is not an effective treatment or sole preventative measure against cancer, but it can be a useful supplement to mainstream treatment especially since fasting has also been shown to protect from chemotherapy’s toxic effects in numerous rodent studies (de Groot et al., 2019; Brandhorst et al., 2013; Tinkum et al., 2015; Huisman et al., 2015). This is largely because fasting reinforces the stress resistance of healthy cells while imposing extra stress on tumor cells; the stress on tumor cells results from the switch to oxidative metabolic phenotype that fasting encourages instead of the natural glycolytic metabolism that helps tumors resist radiation (Klement, 2015; Di Biase et al., 2017; de Groot et al., 2019).
Figure 3: Effects of short-term fasting on healthy and cancerous cells (de Groot et al., 2019).
Risks and Safety Concerns
However, intermittent fasting has also been shown to have a few risks and safety concerns. Firstly, it can lead to fatigue, dizziness, and difficulty concentrating in the long run, even though it might increase alertness short term, if the body is simply not getting the energy it needs (Meszaros, 2020). Furthermore, intermittent fasting can increase cortisol levels, the body’s stress hormone, which is often associated with increased stress, increased fat storage, and decreased insulin sensitivity, especially in overweight individuals (Adam et al., 2010; van der Valk et al., 2018). When taken to the extreme, fasting can even lead to ketoacidosis (Blanco et al., 2019). Fasting induces ketosis after about 12 hours, and this is considered harmless because few ketone bodies are generated (Masood, 2020). However, in ketoacidosis, the liver generates enough ketone bodies to lower blood pH and is life threatening; it generally takes about 3-14 days of complete fasting to reach the maximum severity of ketoacidosis (Nickson, 2019). Finally, intermittent fasting can lead to disordered eating behaviors such as orthorexia, which is the unhealthy obsession with eating healthy, or anorexia, which is compulsive fasting to lose weight (Petre, 2020). Despite these potential adverse effects, however, the majority of adverse effects of fasting are generally mild to moderate (Finnell et al., 2018).
Conclusion
Fasting, a practice in which little to no calories are consumed during a defined period of time, has been around for centuries, and it is no surprise that it has health benefits in addition to cultural importance. These health benefits include decreasing the effects of obesity and metabolic syndrome, producing beneficial metabolic and hormonal changes, increasing insulin sensitivity (and thus alleviating the effects of type-2 diabetes), reducing risk factors for cardiovascular disease, potentially slowing cognitive decline, and decreasing the toxicity while increasing the efficacy of cancer therapies. While largely considered safe, intermittent fasting does have some mild to moderate risks, so it is recommended to consult a health professional prior to starting to fast.
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