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It is obvious that, if you don't eat, you'll lose weight but this is easier said than done.  Many people have not had success by restricting calories because the glucose-adapted body responds to a reduced calorie intake by reducing its basal metabolic rate through the Starvation (Famine) ResponseFasting is voluntary form of starvation, which has been commonly practiced throughout history.  Intermittent Fasting is often done today for therapeutic reasons - often to treat or prevent Metabolic Syndrome but there are other benefits as well.  Intermittent fasting shifts the body from using glucose as its main source of fuel to ketones and ketone usage tends to maintain or increase the basal metabolic rate (eg, though the uncoupling of adipose tissue mitochonria) while also suppressing appetite, likely because fasting affects the timing of caloric consumption rather than the amount.

The key to avoiding Metabolic Syndrome is keeping insulin levels low and constant.  Because insulin is produced by the pancreas in response to serum glucose, the obvious thing to do is restrict carbohydrate intake.  Excess dietary carbohydrates are stored in the liver and muscle tissue as glycogen and, since these tissues have a limited storage capacity, the remaining are then stored in adipose (fat) tissue.  It normally takes a few hours of fasting to deplete the body's glycogen stores and, as this happens, insulin levels will fall and glucagon levels will rise.  With a low Insulin to Glucagon Ratio (IGR), ketone levels will increase and the body will be in fat-burning mode. This reality means that are essentially two metabolic states: FED (high IGR) and FASTED (low IGR).  A low carb diet tends to keep glycogen stores low, which in turn allows the body to return to a fasted state much quicker.

Rapamycin is a macrolide first isolated in 1972 and was initially found to inhibit fungal activity.  In the early 1990s, several researchers (including Dr David Sabatini) found a biological process that is sensitive to Rapamycin, which was eventually named Target of Rapamycin (TOR) and the process specific to mammals was named Mammalian Target of Rapamycin (mTOR). mTOR is a protein kinase that regulates cellular pathways (including cell, organ, and body growth) in mammals and has many inputs and outputs - basically any process that consumes or produces large amounts of energy/nutrients.  One of the inputs is metabolic state (fed or fasted) and some of the outputs are Autophagy (recycling of proteins) and Mitophagy (recycling of mitochondria).  The human body contains an mTOR (mechanistic Target Of Rapamycin) gene.  Being in fasted state inhibits mTOR with the beneficial effect of increased lifespan and decreased tumor growth.  Increased mTOR activity has been implicated in central nervous system disorders (eg, Autism, Alzheimer's Disease, Parkinson's Disease).  Although there are no tests for autophagy, autophagy is the mechanism that enables the body to absorb excess skin tissue so that extreme weight loss does not result in flabby loose skin.

Dr. Valter Longo's research found that prolonged fasting can remove damaged cells and regenerate new cells.  Research on the Little Women of Loja, Ecuador found that their growth hormone-receptor deficiency (IGF-1) gave them a long lifespan and low risk of cancer and diabetes.  Research into starved organisms found that amino acids activate the TOR pathway related to IGF-1 and glucose activates the PKA pathway to accelerate aging.  A normal diet causes IGF-1 and PKA genes to stall stem cell production.  Fasting causes old and dysfunctional cells to be recycled through autophagy and refeeding activates stem cell growth, thereby causing a rejuvenating effect.

Dr Longo developed the Fasting Mimicking Diet (FMD) to treat a variety of diseases, including cancer, neurodegenerative, autoimmune, and metabolic.  Both amino acids (from proteins) and glucose (from carbohydrates) have pathways to activate mTOR.  The FMD effectively causes the body to function in a fasted state with minimal nutritional restrictions (800-1100 calories/day) by reducing the body's glucose levels while increasing its ketone levels. The FMD restricts calories for 5 days of a month with reduced carbohydrates & proteins and increased plant-based fats.  According to Dr Longo, people can go as long as 60 days without food so 5 days is doable without much difficulty.  However, Virta Health's Dr. Stephen Phinney cautions against zero-calorie fasts that are longer than 48 hours due to re-feeding syndrome and the risk of permanent metabolic rate reduction. 

It appears that the closest thing to drinking from the fountain of youth is to inhibit mTOR activity via regular intermittent caloric restriction.  There are several ways to inhibit mTOR activity, including:

  • Long Fasts: Water-only
    • 2-day fast every month
    • 2-week fast twice a year
  • Intermittent Fasting
    • Alternate Day Fasts: eat 0-600 calories/day
    • 5-2 fasts: eat normally for 5 days and then 0-600 calories/day for 2 days
    • Daily Time-Restricted Fasting: consume normal amount of food within 4-8 hours/day
  • Fasting Mimicking Diet - low carb & protein diet 5 days/month

For most of my life, I believed the common wisdom that breakfast was the most important meal of the day, which is inconsistent with intermittent fasting and completely untrue.  This notion was invented by General Foods in 1944 in order to sell more Grape Nuts cereal. Similarly, Sunkist (formerly, California Fruit Growers Exchange) hired marketer Albert Lasker to influence North Americans to consume more oranges, which is how orange juice became a breakfast staple.  See How Breakfast Became a Thing and Meet the man who influenced your entire breakfast this morning.

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