Читать книгу The Principles and Practice of Antiaging Medicine for the Clinical Physician - Dr. Vincent C. Giampapa - Страница 27

According to this new aging paradigm, humans are not programmed to age and die; instead, they are programmed, genetically, for cell repair and longevity. In other words, humans are programmed to live longer than they actually do, if they can use their full potential. That potential is related directly to the ratio of DNA repair to DNA damage.^8a–8c,9 Within each of the 46 chromosomes that make up the human body, there is a series of proteins that the DNA is wound about. These proteins, called histones, help stabilize the three-dimensional structure of the double helix but also, more important, protect the genetic content of each chromosome from free radical damage and other sources of damage as well. The initial process of damage to DNA begins when there is a break in the DNA strand^10,11 (Diagram IV-9). This event occurs most commonly because free radicals penetrate the protective his-tone coating and cause a break in the double helix structure. Damage to the underlying DNA strand causes the release of adenosine diphosphate ribosyl transferase (ADPRT). The break in the DNA strand caused by the free radicals causes this compound to be released suddenly. ADPRT then reacts with DNA and opens the protective coating of chromatin surrounding the chromosome. The chromatin layer resembles a Slinky (toy). When the coils open up, the genes are exposed to the fluid within the cell and, more specifically, within the nucleus. When ADPRT opens up this protective coating, a number of other events occur: the damaged segments of DNA are attacked by endonucleases and exonucleases that can enter into the damaged segment of the chromosome. The exonucleases cut out other damaged base pairs of the DNA. At this stage of DNA repair, DNA polymerase and DNA ligase replace the damaged base pairs with new ones from the cell fluid-like environment. Therefore, ADPRT is essential in order to open up the chromatin to allow the damaged base pairs of DNA to be exposed and then be fixed by the whole sequence of DNA stitching and repairing enzymes mentioned earlier, the endonucleases.

Also residing in the intracellular fluid is a very important compound called nuclear transcription factor kappa B. NF-κB which is activated by a series of events already described: glycation, inflammation, methylation and oxidative stress. NF-κB inhibits ADPRT from opening up the chromatin so that DNA repair can commence and be completed (see Diagram IV-9). Hence, in this specific situation it is important to understand that NF-κB controls DNA repair. It also results in a series of other molecular responses that interfere with DNA repair. The consequences of poor DNA repair and excessive DNA damage are summarized throughout the rest of this chapter (Diagrams IV-10, IV-11 and IV-12).

It has been discovered that if NF-κB can be inhibited, the rate of DNA repair can be markedly improved; this would help maintain genetic codes and the aging blueprint in optimal condition.^12–16

Within the ADPRT enzyme complex, there is an important zinc region. Attached to the zinc region is a thiol group, which is a chemical structure with sulfur containing bonds. This thiol group is what bonds to the damaged DNA sites, allowing ADPRT to be activated (see Diagram IV-9). When a high level of free radicals are present, the thiol group cannot bond to damaged DNA segments and it becomes oxidized. It is therefore inhibited directly by high levels of free radicals.

The consequences of this are far-reaching. In essence, if the body is depleted of zinc or antioxidants and there are many free radicals, this key complex is directly inhibited from binding to DNA to initiate the whole repair sequence.

A number of substances will stimulate DNA repair according to new research. One of them is niacinamide, and another is zinc. Both of these compounds help the ADPRT complex link up to the damaged DNA sites so that DNA repair can commence and be completed at a faster rate and more efficiently. The next two chapters show that the inhibition of NF-kB is one of the key therapeutic approaches within the science of anti-aging medicine; this includes aging of both the interior body and the external skin.

Of major importance is a compound, isolated and tested, that is a direct NF-κB inhibitor. This compound, called C-MED-100, is an isolated fraction of a water extract of the herb cat’s-claw.^14–16 It will be a key anti-aging therapeutic nutraceutical in the immediate future. It belongs to the chemical group called carboxy alkyl estors.

So, what happens if DNA repair is poor? DNA damage could cause two possible categories of health consequences (see Diagram IV-11). One includes toxic disease and inflammation, inhibition of methylation and creation of more glycation, as well as more free radicals. The other potential outcome, aside from chronic disease processes, is the creation of mutagenic disease, or cancer, a common occurrence during aging.

Another key consequence of poor DNA repair is poor DNA replication. This results in poor copies of future generations of cells and can result in more mutations and further alteration of DNA expression. More important, this process directly affects stem cell pool reserves. The adult stem cells that all humans possess, although small in number, constitute one of the key reservoirs of new cell growth and cell repair during aging. The preservation and restoration of stem cell reserves and stem cell function in the adult will also take on paramount importance in the field of anti-aging medicine in the immediate future.

The measure of DNA damage and free radical levels are the two most easily obtained biomarkers that are clinically useful. These measurements are easily obtained from a small urine or blood sample and supply the key information necessary to document the effectiveness of an age-management program. The next few chapters discuss how these measurements can be used. They should be considered the two core laboratory tests for aesthetic surgeons and physicians as they begin to incorporate anti-aging medicine into their practice.