DNA damage theory of aging

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damages. Damage in this context is a DNA alteration that has an abnormal structure. Although both and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly (by increasing apoptosis or cellular senescence) or directly (by increasing cell dysfunction).

In humans and other mammals, DNA damage occurs frequently and DNA repair processes have evolved to compensate. In estimates made for mice, on average approximately 1,500 to 7,000 DNA lesions occur per hour in each mouse cell, or about 36,000 to 160,000 per cell per day. In any cell some DNA damage may remain despite the action of repair processes. The accumulation of unrepaired DNA damage is more prevalent in certain types of cells, particularly in non-replicating or slowly replicating cells, such as cells in the brain, skeletal and cardiac muscle.

To understand the DNA damage theory of aging it is important to distinguish between DNA damage and mutation, the two major types of errors that occur in DNA. Damage and mutation are fundamentally different. DNA damage is any physical abnormality in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damage can be recognized by enzymes, and thus can be correctly repaired using the complementary undamaged sequence in a homologous chromosome if it is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die. Descriptions of reduced function, characteristic of aging and associated with accumulation of DNA damage, are given later in this article.

In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.

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