Essential Cell Signaling


The changes in calorie restriction science over the past 20 years can be likened to the changes in the game of chess. Twenty years ago, there were lots of ideas about how certain chess openings should be played. But the use of computers to analyze chess play ended many speculative, imprecise ways of playing. These days much more precision is required at high levels of play, or checkmate comes early.

 

Twenty years ago there were many ideas about what constituted an effective CR diet and, indeed,  a number of approaches are still valid. Anyone following The CR Way, for example, finds CR protocols, developed for the most serious, for dabblers, for cancer survivors, and for optimal performers.

 

But two themes are present in all CR Way-recommended diets:

  • less energy availability (fewer calories and lower glucose)
  • less anabolic substrate (less protein)

When energy availability drops – adenosine triphosphate (ATP), the preferred energy molecule of cells, drops too. And a red alert goes out: Cells must have energy to power their actions. So the body turns to adenosine monophosphate (AMP) for its energy source.

 

However, the difference between adenosine triphosphate and adenosine monophosphate is huge. AMP has only one phosphate (phosphorus-and-oxygen) molecule to be broken apart for energy release, and that molecule is fairly stable, making it hard to break apart. But this must happen to yield energy, so AMP needs help.

 

This is when the master metabolic regulator, AMP Kinase (AMPK stands for AMP phosphokinase, an enzyme that facilitates phosphorylation) becomes active. Like an emergency medical technician, AMPK rushes into the fray, making energy transfer easier and shutting down growth, so energy is less likely to be expended.

 

The benefits are marvelous. AMPK works in concert with AMP to regulate hundreds of cell signals that make CR benefits possible.

 

Take a look: AMP Kinase - master metabolic regulator

 

AMPK Signaling diagram explained

 

To facilitate looking at the PDF above, printing out the following explanation maybe helpful: 

 

    Center

 

 As In biology, huge molecules often occur with domains (parts) that act differently. So, indeed, AMP Kinase has separate domains: AMPKα (alpha), AMPKβ (beta), and AMPKγ (gamma). This complex is pictured in the center of the diagram and is responsible for the far-reaching actions of AMP Kinase.

    From Left to Right on the Cell Surface

 

As we proceed from left to right, the implementers of CR's beneficial actions within the cell are listed.

 

Glucose Transporter (GLUT4) an energy-transfer molecule that facilitates transport of circulating glucose into the cell

 

Adiponectin a fat hormone that protects heart function and activates cell-preserving SIRT1 genes

 

Leptin – a fat-secreted hormone that inhibits appetite when food is not plentiful

 

α-Adrenergic receptor – a target of norepinephrine and epinephrine, which raises glucose levels when energy is low

 

Histamine & Thrombin – Histamine dilates blood vessels by making vessel walls abnormally permeable. Thrombin facilitates blood vessel dilation by activating nitric oxide production. 

Low glucose, hypoxia, ischemia, heat shock – all of these stressors activate AMP and AMPK. This beneficial stress is the hormesis that characterizes CR.

Metformin – an oral anti-diabetic drug that activates AMPK

Exercise – Muscular contractions activate AMPK.

Insulin/IGF-IActivation of this pathway drives growth, which silences AMPK.

 

Biology affected by AMPK

Protein metabolism – down-regulation of protein synthesis

Cell growth – slowed cell growth with possible protection against cell damage and cancerous mutations

Apoptosis – upregulation or down-regulation, depending on the tissue – another protection mechanism against mutations

Lipid metabolism – switch from fat storage to fat burning with decreased formation of triglycerides and cholesterol

Carbohydrate metabolism – down-regulation of glycogen synthesis: lower glucose levels and less ATP

 

 

The actions of AMP Kinase provide a blueprint for applying CR biochemistry to practical lifestyle decisions such as what supplements to take: Any supplement or lifestyle practice that counters activation of AMPK will likely negate some or all CR benefits.

 

AMP Kinase and Cancer

One of the most important actions of AMP Kinase is initiated by the cancer protection gene p53. P53 helps destroy mutant cells by killing them through a normal physiological process called apoptosis. To facilitate cell death, p53 activates AMP Kinase*, which logically downregulates IGF1 – AKT – mTOR, cell signals that act to preserve cells, increase growth, and cancer incidence and metastasis.

 

Related to this is the need of cancer cells to power their activities through the ancient energy production method of glycolysis, (at its base -- the cellular degradation of the simple sugar, glucose, to yield ATP as an energy source). This supplies necessary energy, which is often unavailable through their defective mitochondria.  The linked PDF, shows the dramatic increase of apoptosis as glucose starvation increases. This is vital knowledge for cancer patients who have better chances of recovery and slowing metastasis by following regimens that keep blood glucose low.

 

Coordinate communication between p53 and IGF-1-AKT-mTOR pathways.pdf

*The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways.

Cancer Res. 2007 Apr 1;67(7):3043-53.

Feng Z, et al.

The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal-specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways.

PMID: 17409411

Also see: Insulin/IGF-1

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