Mechanisms of Aging: DNA Damage and Repair

DNA (deoxyribonucleic acid) is a pivotal molecule of life; it contains the blueprint of the organism encoded in genes. DNA is the most indispensable part of the cell. Other structures, such as RNA, proteins and lipids, can be completely replaced according to the instructions in the genes. DNA, on the other hand, cannot be replaced if lost or damaged beyond repair.

Damage to the DNA can have two main outcomes: the cell dies or the cell mutates. The latter means that one or more genes lose or change their properties. The vast majority of mutations are either harmful or neutral (no effect). The substances that can damage DNA and cause mutations are called mutagens. Free radicals are the most common mutagens; other examples are N-nitroso compounds, aldehydes, asbestos and coal tar. Most mutagens are also carcinogens (cancer-causing substances).

DNA is constantly bombarded with mutagens. Most mutagens, like oxygen free radicals or some aldehydes, are normal products of metabolism and cannot be avoided; others, like cigarette smoke or acetaldehyde (a product of alcohol breakdown in the body) are self-inflicted; yet others can come from environmental pollution. Different types of radiation also cause mutations; the damage produces by UV-radiation is limited mainly to the skin, cornea and retina, whereas high-energy radiation, such as X-rays, can cause mutations anywhere in the body.

Cells have many enzymes involved in DNA repair; most of the damage gets repaired without any adverse consequences. However, a few lesions always slip by and turn into permanent mutations.

The idea that the accumulation of mutations may be an important mechanism of aging is not new. It was convincingly demonstrated in many studies that the maximal life span (the longest a species can live) correlates with the efficiency of DNA repair, and, therefore, with the frequency of mutations. In particular, humans have the best repair system and the longest life span among mammals. It was found that the frequency of mutations rises with age. One probable reason is that over time the repair system itself becomes affected by mutations, so less damage is correctly repaired. Also, as we age, our bodies generate more free radicals, and, therefore, there are more mutations and other DNA lesions in the first place. In fact, free radical theory and DNA damage theory of aging are closely related because DNA is one of the primary victims of free radicals.

Are there ways to reduce DNA damage and improve DNA repair? The first step is to try to avoid environmental damage, such as cigarette smoking and overexposure to the sun. Those who have trouble quitting should at least try to switch to low tar brands because tar is the main source of the mutagens in the tobacco smoke. Make sure to follow basic sun protection guidelines. Another step to reduce DNA damage is keeping your antioxidant defenses in shape (see our article on free radicals).

At present, there is no practical way to improve the efficiency of cellular DNA repair. These systems are rather complex and involve many different enzymes. In each species, DNA repair system has a particular standard of quality, i.e. it is allowed a certain error margin. Incorrect or incomplete repair leads to mutations, which are the driving force of genetic change and, therefore, of evolution. The increase in the rate of mutations causes the species to evolve faster, but also shortens the life span of an individual organism. The reverse is also true. That is why an organism with a perfect repair system, if such is possible, is extremely unlikely to appear in the natural course of evolution.

Humans have more effective DNA repair system than most other species. We suffer relatively few mutations, so we age slowly. Paradoxically, our fairly good repair system is an obstacle on our way to evolving into an even longer-lived species -- that is if we want to do it in an all-natural manner. Humans are much more likely to find a way to improve their DNA repair through science, than by natural evolution. In fact, there is some promising research in that direction. All key DNA repair enzymes need to use special DNA precursors, called deoxyribonucleotides, as building blocks. Deoxyribonucleotides are synthesized from other precursors, ribonucleotides, by the enzyme ribonucleotide reductase (RR). If the activity of RR is increased, the level of deoxyribonucleotides rises and DNA repair system begins to work faster. Preliminary studies indicate that the substances that activate RR can partly protect animals from high doses of radiation, presumably by improving the quality of DNA repair. It is conceivable that a similar approach could work to retard normal aging.