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Resveratrol: A Real Anti-aging Product
By: Peter T. Pugliese, MD
Posted: November 25, 2008, from the December 2008 issue of Skin Inc. magazine.
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The first concept to understand is that sirtuins remove acetyl groupsb from proteins. They do this in the presence of nicotinamide adenine dinucleotide (NAD+); that is how it gets its name as a NAD+-dependent deacetylases. Now it must do something with this acetyl group, so the sirtuins then take the acetyl group from the protein and add it to the ADP-ribose part of NAD+ to form adenosine diphosphate (O-acetyl-ADP), a lower energy form of the high energy form known as adenosine triphosphate (ATP), a major source of energy in biology. Here is the key phrase: energy-linked. When you see sirtuins and ADP, you know ATP—or energy—is not far behind. This is how it works. This tells you that sirtuins are linked in some manner to the generation of ATP. That is the first key concept.
The hydrolysisc of this protein, whatever it may be, yields three compounds: O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide. The dependence of sirtuins on NAD links their enzymatic activity to the energy state of the cell through the cellular NAD:NADH ratio.d You can see this reaction that shows the acetylation process. (See Figure 2.) Due to this relationship with energy, sirtuins have been associated in the regulation of aging, transcription, apoptosis and stress-resistance. The regulation of many metabolic processes and cellular defense mechanisms could easily be the key to a possible lifespan-extending role for sirtuins in mammals. This reaction ties in with the histones and deacetylation and finally, resveratrol. I shall take you on a walk through this minefield and hopefully we shall not step on a mine. Keep in mind that all this discussion relates to turning on a cell’s metabolic mechanisms, as well as turning them off. It is very similar to a traffic light that has green for go, red for stop and yellow for caution.
A brief cell review
A cell consists of a membrane, cytoplasm, a nucleus and organelles, such as the mitochondria. Deoxyribose nucleic acid (DNA) is the body’s master template. Any time a protein—or any complex substance in the body—is made, DNA must open its two strands and expose the code for that substance. The code is copied in a process called transcription, and the copy is sent to the reticuloendothelium, an organelle in the cytoplasm, which then translates the copied code into the substance or protein. So transcription and translation are the two key words in molecular biology. All of this is written in many basic textbooks in biology, and also in Advanced Professional Skin Care, Medical Edition (The Topical Agent, LLC, 2005).3 If you are rusty in this area, please review it before you read further in order to have a better understanding of this article. If you can remember the acts of transcription and translation, you have a grasp on biology. The DNA code can only be initiated by transcription.
Histones and deacetylation
This concept is critical to understanding resveratrol action. DNAe, which is the genetic-containing molecule in every body cell, is a very large, very complex and very long molecule. In each cell, it is 1.8 m long when unwound. Think about that: A cell is only about 80–100 microns in diameter, while a strand of DNA is 1,800 mm, or 1,800,000 microns long. That is 18,000 times longer than the cell. Now, to get the DNA into the cell, it needs to be wound up to fit into a very tiny space. The cell uses tiny protein balls called histones to serve as the surface on which to wind the DNA. Figure 3 shows a segment of DNA wrapped around some histones. Actually, they assemble to form one nucleosome core particle by wrapping 146 base pairsf of DNA around the protein spool in a spiral. These histones with DNA wrapped around them form a string of beads with some space between, called linker DNA. It looks much like a very long rosary and is called chromatin. (See Figure 4.) Before any message can be transmitted to the DNA, this giant molecule must open up, unwind and expose the code. If the DNA does not unwind, there can be no cellular action. Now here is where the deacetylation comes in.
Acetic acid can be added to a molecule under certain circumstances and this is called acetylation. If it is removed, this is called deacetylation. It is known that when DNA is active, the histones are acetylated; if they are deacetylated, they become less active. Following is a short explanation for this phenomenon. Histones have positive ends due to amine groups present on their lysine and arginine amino acids. The positive charges help the amines to interact with and bind to the negatively charged phosphate groups on the DNA back. Being acetylated, which is the normal state in a cell, they neutralize these positive charges on the histone and change the amines into amides, thereby decreasing the ability of the histones to bind to DNA. What this action does is to allow chromatin expansion, causing more genetic transcription to occur. Enter histone deacetylase. This enzyme removes those acetyl groups, increases positive charges to the histone and causes it to bind tightly to the histones and DNA structure. Net result: condensing of the DNA structure, which prevents transcription of DNA.g With all of that background, how does resveratrol fit into the picture?