Fasting, Caloric Restriction and Longevity

A question from Ms. Josephine Wong was posted to me on a video claim that frequent eating with short intervals between meals is more health-protective and contributes towards longevity than those who eat less and less often.

Thank you for your question.

Caloric Restriction and Longevity:

First of all I want to quote a very famous study by Clive McCay of Cornell University as far back as in 1935 that when rats were put on a caloric restriction diet, it considerably prolongs their life span.

This study was repeated many times on other animals showing the same result. Even before all these well-established studies, Hippocrates of Kos, circa 460 – c. 370 BC, now considered the Father of Medicine and Nutrition, and later Galen have all advocated eating less.

Avicenna c. 980 –1037) a Persian physician, astronomer, thinker and writer of the Islamic Golden Age also taught the same advice  that we should eat less for longevity and freedom from disease.

Let me now elaborate on their thinking as well as giving probable explanations what modern scientists found when we eat little, and less often. We will begin by seeing what happens when food is consumed  

However, we will not go into the physiology of food consumption, its digestion, absorption, transportation and distribution as discussion on these are very lengthy, unnecessary, and irrelevant within the scope of answering your enquiry.

We will instead go straight away into metabolism of food using simple biochemistry  and the role of the liver and kidneys as these are the only two organs that have to deal with the nutrients absorbed (the liver), and the chemical fate of the nutrients (metabolism), and the kidneys that has to deal with the metabolic wastes like urea.

Metabolism:

Once food has been digested, absorbed and transported to the liver by the portal vein, the nutrients are either metabolized or stored. The body is continuously undertaking a series of complicated chemical reactions called metabolism to empower the body to continue to exist, provide the energy the body needs, and the cells to divide and grow.

Metabolic reactions are divided into catabolism by obtaining energy derived from the nutrients, and anabolism for the development of new cells that necessitates energy from the catabolism.

There are hundreds of thousands of chemical reactions going on and their pathways in the body at any moment in time, but we shall not deal with biochemistry here.  

In order to keep this answer short and neat and within the scope of the question, we shall only give some examples of major sources of energy the body derives from the metabolism of nutrients. These are:

1.   Glycolysis which is the oxidation of glucose that empowers  the synthesis of energy-rich ATP

2.   Krebs' cycle or citric acid cycle (CAC), sometimes also called the tricarboxylic acid cycle (TCA) is a chain of chemical reactions used by the body to release stored energy through the oxidation of acetyl-CoA acquired from carbohydrates, fats, and proteins.  

Acetyl-CoA is a molecule that participates in many biochemical reactions involving protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for energy production.

They then give off carbon dioxide and the release of chemical energy and other intermediary products. The Kreb’s Cycles requires the B group of vitamins to proceed.

The oxidative phosphorylation encompasses the disposal of the electrons released by glycolysis and citric acid cycle. Much of the energy released in this activity is subsequently stored as adenosine triphosphate (ATP), an energy-rich phosphate bond.

The discharge of electrons in a metabolic or in any chemical reactions generates destructive free radicals to the cells, tissues and body systems, and more crucially to the DNA. We shall deal with this later.

3.   The pentose phosphate pathway is the synthesis of pentose, and the release of reducing energy needed for anabolic reactions

4.   The urea cycle comprises of the disposal of NH4+ in less toxic forms

5.   Fatty acid beta-oxidation activates fatty acids breakdown into acetyl-CoA. This then enters into the Krebs' cycle once again.

6.   Gluconeogenesis that involves in glucose synthesis is used by the brain for energy.

The Liver:

One of the major functions of the liver is the maintenance a fairly balanced concentration of glucose in the blood. This is accomplished through gluconeogenesis and glycogen synthesis and degradation. It synthesizes ketone bodies when acetyl-CoA is adequate.

It is also the site of urea synthesis. There are hundreds if not thousands of chemical reactions and various pathways taking place in the liver. But we shall not go into all the liver chemistry

It is estimated the liver has to deal with over 500 – 700 functions. Many of these include assimilating and storing fat-soluble vitamins, producing bile, filtering blood, metabolizing fats, proteins, and carbohydrates, and endogenous hormones, dealing with wastes, and detoxifying  alien chemicals,  toxins and drugs, changing ammonia into urea through the urea  or ornithine cycle.

The liver also syntheses blood proteins, depositing nutrients like glucose into glycogen, as well as storing fat soluble vitamins, and minerals.

The Liver and Free Radicals:

Since the liver is the site of most of the synthesis and metabolic breakdown, and since these biochemical reactions involve the transfer of elections; either to lose or to capture them, it generates free radicals.  Any atoms, molecules or molecular fragments that lose an election become a highly destructive free radical.

The simplest free radical is an electron. A hydrogen atom is also the simplest free radical

A hydrogen molecule has an electron pair, and hence, it is not a free radical. But when hydrogen is irritated with UV light without oxygen, a hydrogen molecule (H-H) may be fragmented evenly (homolytic cleavage) it produces two hydrogen atoms or two free radicals:

H2 → 2H•

A very good example of a free radical production in chemical reactions in the liver, or elsewhere in the body, and in the environment outside the body, is production of the hydroxyl radical (HO•)

Since free radicals are highly unstable chemically they can only exist for just a fraction of a second in the presence of an electron recipient   

However even their very short existence is long enough to cause untold damage to the DNA, cells, tissues, organs and systems of the body. We shall go more into free radicals a little later, and how they can damage the DNA in the body.

Unfortunately, the more food we eat, the more toxic wastes and metabolites we produce, and the more destructive free radicals are generated in the process of anabolism and catabolism. After the liver have broken down the toxic waste of metabolism, most of them are handed over to the kidneys for excretion 

The Kidneys:

The kidneys besides being an excretory organ can also carry out gluconeogenesis to release glucose into the bloodstream.  But its main role is the excretion of urea, electrolytes, and other excretory metabolites.

There is a condition called metabolic acidosis that occurs when the body produces excessive amounts of acid or when the kidneys are not clearing sufficient acid from the body.

However, metabolic acidosis may be increased during the ornithine (urea) cycle, since urea synthesis executed in the liver uses HCO3-, and in so doing further lowers the blood pH. Under these conditions, nitrogen may be removed by the combined action of kidney and liver.

Any surplus nitrogen is first integrated in glutamine by glutamine synthetase. The renal enzyme glutaminase then splits glutamine in glutamate NH3, which the kidneys directly excrete. This procedure permits nitrogen excretion without affecting blood bicarbonate levels.  

This process involves lots of excretory products of metabolism from the food consumed giving neither the liver nor the kidneys physiological or biochemical rest 

Hormone Regulator:

Hormone regulations are principally performed through the action of two hormones synthesized by the pancreas via its insulin and glucagon.

Insulin is released by the beta cells in the pancreas when blood glucose levels are elevated primarily after food.  Insulin stimulates glucose uptake by the muscle, glycogen synthesis, and triglyceride production by the adipose tissue.

Insulin blocks gluconeogenesis and glycogen degradation. Glucagon is then released by the pancreas when blood glucose levels drops significantly.

This biochemical event is the reversal of the action of insulin.  In the liver, glucagon excites glycogen breakdown, and the absorption of amino acids. It inhibits glycogen synthesis and stimulates the release of fatty acids by adipose tissue.

All these biochemical events snowballed when more and more food are consumed at libitum. More and more excess nutrients are stored, old cells including cancer cells and tissues cannot be disposed of until the excess sugars, triglycerides (fats) and amino acids (proteins) from over eating are metabolized (burnt)  first.

Once again keep in mind free radicals are produced in all these above metabolic process.

However, if the body is put on a caloric restricted diet, or on a prolonged and frequent fasting,  it  will start to break down its stored sugars (glycogen) first,  than the body stored fats, and lastly its own  body tissues and muscle to supply it with energy. That is where a biological event called autophagy kicks in by digesting its own old and unwanted cells first.

 

Autophagy:

Autophagy is a normal physiological function the body performs in the destruction of old and degenerated cells in the body. Its function is to maintain a homeostatic check and balance for normal cellular functioning by inducing protein degradation for the birth of new healthy cells.  

During cellular stress and trauma such as attacked by free radicals released in metabolic pathways, and in their breakdown, the rate of autophagy is increased.  Autography is also increased in prolonged fasting

Autophagy hence can be achievable through intermittent fasting or by longer fasts. This biological event is initiated when liver glycogen is depleted. This takes place around 12-16 hours into a fast. Studies showed the rate of autophagy peaks during this period, and then fall off after about 2 days.

This also takes place when cells in a healthy human body are continuously being damaged as a normal part of metabolic processes.

However, as we age, or endure any kind of physiological, psychological or chemical stress such as from the food and medicine we take, we have to  deal with more and more free radical damage, resulting in more and more cellular damage  at an increased rate.

Autophagy also comes in by clearing damaged and senescent cells that serve no more functional role in the body. The reason why it is so important to remove senescent and damaged cells is because they can trigger damaging inflammatory pathways that contribute to various diseases including cancers.

Autophagy and Longevity:

It is only in very recent animal studies that researchers have shown how autophagy can promote longevity by conferring benefit to the nervous and immune systems, as well as the cardiovascular system.

Naturopathic (Natural) Medicine:

While scientific research only over the last two decades has demonstrated the medical and health benefits of autophagy or autophagocytosis induced during fasting, this piece of evidence is not new.

Doctors of naturopathic medicine have already known this, and have put this principle into their clinical practice or the science of clinical autophagy through physiological fast on fruit juice. They have already practiced this on their patients for almost 10 decades already.

Prize in Medicine or Physiology:

It was only in 2016 that a Japanese medical researcher Dr. Yoshinori Ohsumi won the prestigious Nobel Prize in Medicine or Physiology for his work on the mechanism of autophagy when doctors of naturopathic medicine have already put that mechanism into their practice almost 100 years earlier.

Autophagy is a non-specific term for the degradation of cytoplasmic components within lysosomes as shown by several workers (Cuervo 2004; Levine and Klionsky 2004; Shintani and Klionsky 2004; Klionsky 2005, 2007; Mizushima and Klionsky 2007).

This process is quite separate from endocytosis-mediated lysosomal degradation of extracellular and plasma membrane proteins.

There are actually three types of autophagy (macroautophagy, microautophagy, and chaperone-mediated autophagy). We shall not go into all of them. However, “autophagy” usually signifies macroautophagy.

Autophagy is mediated by a unique organelle called the autophagosome. Organelles are specialized cellular parts such as lysosome, mitochondrion, chloroplast, or nucleus inside a cell.  

As autophagosomes swamp around a portion of cytoplasm, autophagy becomes part of a nonselective degradation system.

Its role can be beneficial or bad. For instance it can switch on tumor suppressors to prevent the onset of cancer, but it can also promote cancer cell survival among many other pathophysiological functions.

Recent Studies:

However, recent studies have clearly demonstrated that autophagy has a greater function other than its pathophysiological roles of destroying old, damaged and non-functional cells.  They are also mediated during starvation adaptation, intracellular protein and organelle clearance, development of new healthy cells, anti-aging function, the destruction  of pathogens and microorganisms,  promotes cell death, cancer suppression, and antigen production among others (Mizushima 2005).

Nonetheless, its mechanisms can be very complex such as its role in cancer suppression or promotion or in cell death.  Autophagocytosis is thus a double-edged sword much like the double personalities of Dr. Jekyll and Mr. Hyde.

Autophagocytosis Fasting:

The  best and easiest way to induce autophagy or sometimes called autophagocytosis  (meaning "self-devouring")  is through intermittent fasting  using plain drinking water with added minerals, or on fruit juice to maintain fluid and electrolyte balance. This is recently termed as autophagocytosis fasting or physiological fasting has already been put into clinical practice as one of the therapeutic modalities by doctors of naturopathic medicine.

Free Radicals and Cellular Damage:

The human body is mainly made up of 65 % oxygen, 18 % carbon and about 10 %hydrogen. The presence of carbon with other elements made up the organic compounds.  Hence the body consists mainly of organic compounds.  Most of the biochemical reactions in the body involve organic molecules such as sugars, amino acids, fatty acids, enzymes and hormones

In almost all chemical reactions, free radicals are generated during the transfer and exchange of electrons from one atom to the other among the donor and recipient molecules. These are free radical reactions. This type of reactions occurs very often in organic reactions.

Free radicals are highly reactive when molecules lose their electrons. They become highly unstable, and in order to stabilize themselves, they snatch an electron from the next molecule or molecular fragment such as a DNA, damaging it and causing it to be unstable.

The amount of damage done to the body by free radicals by excessive eating is horrendous. This has already being earlier explained in our brief discussions of metabolisms and the role of the liver and kidney.

Even at rest and on fasting, free radicals are also continuously being generated by untold number of chemical reactions of metabolism throughout the body. The more we eat, or the more frequent we eat in between meals, the more free radical reactions occur to process the excess nutrients. This event causes a lot of damage to the cells which the body tries to repair or replace. In doing so we do not even allow a chance for the body to have bowel, physiological and biochemical rest. We treat it like whipping a tired horse.

Cellular Repairs:

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Normally cells will try to repair themselves. But when a cell cannot be repaired, the body will substitute it with stromal connective tissue to maintain tissue and organ function 

Metabolic activities and environmental factors such as radiation resulting in free radicals can also cause DNA damage, and there may be about as many as 1 million individual molecular lesions per cell per day.

Many of these lesions initiate structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes.

Other lesions generate potentially unsafe mutations in the cell's genome. This affects the survival of its daughter cells after it undergoes mitosis. As an after-effect, the DNA repair process is continuously active as it responds to damage in the DNA structure.

The rate of DNA repair is dependent on various factors, including the cell type, the age of the cell, and the extracellular environment.  

A cell that has amassed a large degree of DNA damage, or one that can no longer effectively repair the damage to its DNA, it then enters into one of four possible events:

1.   Go into senescence which is an irreversible state of dormancy

2.   Induce autophagocytosis

3.   Commit apoptosis or programmed cell death which is cellular suicide

4.   Uncontrollable cellular dissection which may lead to the formation of a cancerous tumor

Number of Cells in the Body:

Scientists are not very sure how many cells are there in the human body, because this depends on the age, the  body weight, growth rates, aging, degenerations of old cells, etc.

Our current estimate is at 37 to 38 trillion. This number fluctuates over time and varies from individual to individual, but about 37.5 trillion cells should be a close estimate for an average adult.

Cellular Molecular Damage:

Within the structure of each cell, untold numbers of molecular lesions occurs at any point in time each day, and as already estimated, it could be as many as 1 million individual molecular lesions per cell per day.

Even if we put the number of cells of a small child at just ten million, million (10¹³) the child would have been bombarded with tens of thousands of DNA lesions per day

Scientists estimate the human body is injured by no less than 1 million individual molecular lesions per cell per day even during physiological and metabolic rest.

Many of these lesions cause structural damage to the DNA and can change or eliminate the cell's ability to transcribe the gene that the affected DNA encodes.

Other lesions induce potentially injurious mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis.

All these destructive factors affect human health, the onset of degenerative diseases and cut short life span

All these destructive biochemical events cause a lot of stress to the liver and other organs brought about by free radicals generated during the exchange of free elections in their chemical reactions, causing uncountable damage to all the cells involved. All these events are the result of over eating or eating too often.

We estimate there are about  37 thousand billion,  billion chemical reactions per second taking place in the human body at any moment in time, and this biochemical scenarios occurs throughout 24 hours even when we are at rest or sleeping.

This is chemically a disaster by shortening our programmed longevity drastically through damaging lifestyle and over nutrition that promote these destructive chemical events.

Summary:

In summary we can see the benefits of intermittent fasting to allow autophagocytosis to take its course through bowel rest and metabolic clearance via the liver and kidneys

This would be contrary to a video claim you sent to me for comment  that frequent eating  is more health protective than a longer delay between small feeds. I do not know where that American lady in her U-tube video claim got that belief from?

Best of all to my understanding, to ensure a disease-free life and longevity go on regular physiological fasts on low-sugar fruit or vegetable juice, or go on a  caloric restricted diet as demonstrated in countless studies, subsequent to the famous and classical study of  Clive McCay of Cornell University in 1935

Thank you once again Ms. Josephine Wong for your question. I hope my brief and easy to understand explanation helps

Lim ju boo