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Fasting vs. Keto: The Science of Caloric restriction.

Updated: Mar 13, 2022

Have you noticed how hard it is to get rid of sugar-ants at home?

No matter where food specks are in the home, one will find them and beckon others.

Throughout evolution and in research laboratories, all living things, including unicellular organisms, gravitate toward any identifiable source of nutrients.

This is because the energy management or metabolic systems responsible for life depend on molecules from nutrition.

Like ants, all living cells crave nutrients and would do anything to get to them. It is a basic need that the human cells have come to develop intricate systems to fulfill.

Therefore, the biology of living things, including humans, devoted significant molecular, cellular, tissue, and organic resources to manage this vital need and function.

Furthermore, it is a part of the growth of organisms, and the intricately organized, as well as monitored and maintained pathways in human cells show the level of importance and hence the value in the hierarchy of the functional imperatives of our health and existence.,

In any energy system, there is always an excellent consideration for the source of energy, the type of energy, the quality of energy, the storage, and usage has to be optimized for efficiency.

Nutrient Sensing?

The craving for food that we all have is not unique and should not elicit any sense of guilt because that is human. Human cellular metabolic physiology is designed to drive from the acquisition of the raw material to the complex utilization process, including the currency of storage in batteries known as mitochondria and the use for activities in the form of Adenosine Triphosphate or ATP.

Nutrient sensing is the total sum of organisms' need for efficient acquisition and utilization of usable energy. Hence one of the most critical factors that directly interact with the DNA genes to maintain optimal health is nutrient sensing and regulation. Nutrients also affect the metabolic variables that are the vital forces of cellular biology, from mitochondrial health to functional/structural protein clearance.

The regulation of nutrient-sensing by any organism, including humans, impacts other aspects of a healthy homeostatic mechanism through its linkage with metabolism; hence, the principles of nutrient-sensing is one of the most studied aspects of aging. It has been noted that the genetic determinants are well preserved across millions of years of species' evolutionary timeline. It is therefore not difficult to draw inferences from studies on lower animals.

The sensing of a nutrient usually involves the molecule's binding directly to the sensor, or sometimes due to indirect mechanisms that would detect surrogate molecule that reflects either nutrient abundance or depletion. However, irrespective of how nutrient-sensing occurs, the affinity constant has to be within the range of physiological fluctuations of the blood level of the nutrient or its surrogate for it to be considered a sensor. This is akin to the gas tank of contemporary automobiles, with a sensor detecting the quality and amount of gas and valves controlling the exact amount needed for optimal engine performance.

Ultimately, the overall evolutional objective of nutrient-sensing pathways is to ensure that the body takes just enough nutrients for optimal health, not too little and not too much. This is because metabolism, which is the process of nutrient utilization in itself, puts cells under stress. By implication, excessive metabolic activity due to an unwarranted increase in nutrient availability and composition cause accelerates the aging of cells.

The observation that 'less is better' is profound from logical reasoning, though from the surface appear challenging to appreciate. In business transactions, marginal profit is the objective of trade, and the best strategy is to minimize the cost of production. In the cell, the cost of producing usable energy currency increases with the availability of excess nutrients, especially 'cheap' sources.

In the last thirty years or so, health research laboratories around the world noted that in laboratory animals, the response to caloric restriction, occasionally termed the ‘longevity response,’ led to improved parameters of enhanced healthspan and improved lifespan; the underlying mechanism was found to be that caloric restriction is regulated by a series of interconnected nutrient-sensing pathways all leading to epigenetic confluence on genes known as the FOXO transcription genetic complex leading to the upregulation of factors that lead to improved healthspan and longevity.

This opened the flood gates and revolutionized the consideration of dietary ration as a fundamental consideration, in addition to quality and content when considering the optimization of health.

The Insulin-IGF-1 signaling (IIS) pathway

The evolutionary importance of carbohydrates as metabolic fuel is remarkably expressed with the dedication of the entire digestive system to mechanisms that break down complex food sources toward the molecular skeleton of glucose. The carboxylic or citric acid cycle was dedicated to completing this catabolism in the cell.

On a systemic level, the Somatotrophic axis of the anterior pituitary produces Growth Hormone (GH), and the intracellular secondary mediator, known as the Insulin-like growth factor 1 (IGF-1), all dedicated to the management of acquisition and utilization of glucose. The sensors on the extracellular aspect of this axis are devoted to responding to the glucose level using Insulin receptors connected to a feedback loop akin to the thermostat in physical systems.

The change in presenting levels of glucose (and any digestive end molecules including fatty acids and amino acids) in the blood triggers the release of insulin by the beta cells of the pancreas; this, in turn, leads to the induction of insulin receptors in muscle, liver and various tissue to move glucose into the intracellular space where it is intended to be stored or converted to usable energy.

However, continuous sustained Insulin release suppresses the signaling system for Growth Hormone in the feedback loop and hence interferes with the repair mechanisms mediated by GH. These intricately connected metabolic interactions are known as the Insulin-Insulin-like growth factor or IIS systems, responsible for the anabolic component of cell metabolism, modulating energy storage, repair, and regeneration.

Hence, low blood glucose, as in calorie-restricted diets or fasting, discourages this mechanism and triggers reduced insulin and IGF-1, leading to mTOR inhibition (mammalian target of rapamycin) complexes and upregulating FOXO transcriptional factors whose activities epigenetically are linked to longevity.

A paradox in research findings shows that whereas low levels of activity of the IIS are found during caloric scarcity or induced restriction as in fasting, improved healthspan, and longevity, there is also a constitutive reduction in the operation of the IIS in old age.

However, this paradox is resolved by understanding that the constitutive reduction of the IIS activity with aging is a deliberate attempt by the cell to conserve its regenerative rate concerning limitations of telomerase availability and the Hayflick limit.

However, concurrently in the aging process, factors like mitochondrial dysfunction, oxidative, and cytoplasmic organelle stress, over time, gradually damage cells leading to aging, cellular degeneration, and senescence.

One of the victims of this insult is also the disruption of nutrient-sensing factors described above, which invariably lead to a progressive breakdown at the cellular level and, consequently, metabolic syndromes and accelerated aging.

Therefore, considerable scientific research conclusively shows that caloric restriction improves healthspan and longevity by reducing the activity of the IIS through other pathways like mTOR, FOXO, and other kinase activities, leading to the overall increase in energy expenditure optimal mitochondrial metabolism of oxidative phosphorylation.

What is mTOR?

The mechanistic (or mammalian)Target of Rapamycin- mTOR was discovered as one of the nutrient-sensing and signaling pathways conserved in evolution that integrates nutrient and caloric availability with anabolism to control cell repair growth and regeneration. It is hence the ultimate contractor, coordinating the relevant pathways toward building cells, tissues, and organs.

Credits: Children's Research Institute | Dallas Texas

It regulates many cellular processes such as epigenetic transcription, mRNA translation, autophagy, and stress resistance.

It is a complex kinase that controls the phosphorylation of proteins with conformational cascades that regulate numerous anabolic processes. It is inhibited by limited caloric availability but is activated by nitrogen and amino acid availability, thereby upregulating the process of protein synthesis, as stated above.

The complexes of mTOR Complex 1 and Complex 2 control almost all aspects of metabolism.

Inactivating mTOR signaling by caloric restriction and rapamycin disrupts cellular growth activates autophagy processes and cleansing, extending lifespan and healthspan.

It works with the low energy sensing by Adenosine monophosphate kinase or AMPK to detect high AMP levels.

Sirtuins are the new kids in the block.

The Sirtuins are another group of the nutrient-sensing complex which derives their name from the yeast gene (silent mating-type information regulation SIR), which regulates yeast cellular metabolism. Paralogous genes have been identified in mammals and humans.

The Sirtuins were unraveled by various research findings showing that they sense lowered metabolic energy state by detecting high Nicotinamide adenosine dinucleotide NAD+, a coenzyme found in all living cells as the product of citric acid cycle metabolism. Increased availability of nutrients increases the input of acetyl Co-A into the cycle, which increases the oxidation of NAD to NADH, so low NAD indicates the inefficiency of this system which happens with aging.

Aging is known to reduce the metabolic vibrancy that produces NAD+, and hence its levels decrease with age and consequently result in the reduced ability of cells to regenerate.

The Sirtuins function as NAD-dependent deacetylases of proteins. They hence provide a vital element for discouraging unwanted epigenetic modification and infidelity of DNA sequence that adversely affect transcription and repair. So increasing NAD+ levels increases the activity of Sirtuins and thus improves the efficiency of these mechanisms leading to better healthspan and longevity.

AMPK pathway your way

The AMP-activated protein kinase AMPK, like the Sirtuins, acts in the opposite direction to the IIS and mTOR by being sensitive to low nutrient and low energy availability while mTOR and IIS sense abundance of glucose and Amino acids.

So any fall in energy levels, which swings the ratio of ATP to ADP in favor of ADP, usually due to reduced availability (fasting) of ATP or consumption of ATP (exercise), leads to increased activity of AMPK. Activated AMPK switches on the catabolic pathways while at the same time switching off processes that use up ATP.

Therefore, the upregulation of AMPK and Sirtuins mimic caloric restriction, just as inhibition of IIS and mTOR. It is also known that they are connected to AMPK activation and its effect on metabolism as it inhibits mTORC1.

Caloric Restriction: Fasting or Keto, your choice

There is a bi-directional relationship between nutrient sensing and metabolic control with aging. The aging process negatively affects the efficiency of the nutrient-sensing mechanism and metabolic signaling, which, on the other loop, leads to deregulated metabolic pathways and further acceleration of aging.

One notable instance is that age-induced deficiency in the activity of the IIS pathway results in insulin resistance and metabolic syndrome. Then the resulting hyperglycemia, from relative lack of insulin activity, cause the formation of advanced glycation end products or AGEs, which is responsible for most tissue damage, including further deterioration in the aberration and dysregulation of metabolic processes the acceleration of the aging process.

Therefore based on science, an established pathway that conjoins all the determined processes of preventing metabolic syndromes and delaying the aging process is sustained, continuous Caloric restriction in any way you can make it your lifestyle.

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