Another key concept to keep in mind is that there are two basic types of DNA: nuclear DNA and mitochondrial DNA. Gerontologists such as Doctors Lee, Weindruch and Aiken6 believe that “one of the central features of biological aging is the alteration of mitochondrial function that occurs as a consequence of ‘free radical’ damage” (Diagram IV-6).
One of the key features of DNA is the ability of nuclear DNA to repair itself as it suffers damage from the environment and free radicals.
Nuclear DNA is also different from mitochondrial DNA in that it has a protective coat, or layer of proteins called histones, that absorb much of the free radical damage, which protects its essential genetic structure and codes. In fact, at the level of the nucleus, there are a number of DNA repair mechanisms that have evolutionarily evolved to prevent severe permanent genetic damage.7 The amount of DNA repair activity correlates directly with life span across different species.8a–8c
Mitochondrial DNA is 2,000 times more susceptible to oxidative damage from free radicals than is nuclear DNA. It contains no (known) DNA repair systems and does not replicate itself. It also has no protective histone coat. Mitochondrial DNA is also unique in that it is a ring-shaped structure rather than a double helix, as is present in the nuclear DNA compartment.
Mitochondrial DNA is also much more susceptible to damage than nuclear DNA because mitochondria are at the site where most free radicals are formed. This occurs during the process of energy production for the cell. This energy process, which is the formation of adenosine triphosphate (ATP), is essential for all cellular functions, as well as cell replication (Diagram IV-7). Without ATP, cell repair slows down or stops (Diagram IV-8).
In the more recent analogies, mitochondria are compared to “semiconductors,” or “chemical transducers,” that convert the potential chemical energy in food to potential metabolic energy. Mitochondria accomplish this by stripping off the electrons found in the molecules of food and causing them to move through a complex compartment of cellular membranes, as well as through the genes themselves.
In essence, mitochondria may be viewed as quantum energy devices that remove energy from matter—that is, the food we eat—and transfer this energy to different components of the cells, including the nucleus, in order to create new matter such as proteins and enzymes. The proteins then allow cells and organs to grow, reproduce and maintain health and youthful function.
Mechanisms of DNA Repair and DNA Damage: The Fundamental Concept of the New Aging Paradigm
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 strand10,11 (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.
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