Aging and DNA polymerase alpha: modulation by dietary restriction.

Aging is an inevitable characteristic of biological processes in living organisms. For the last several years, investigators have proposed numerous mechanisms to explain the basic understanding of aging and its intervention and have provided many insights into the molecular bases and the biological events that contribute to the progressive decline in function observed during cellular aging. It is probable that a number of interacting factors, such as increased somatic mutations, changes in genetic expression, and decreased efficiency of protein synthesis, may contribute to the age-dependent deterioration of physiological processes. One cellular function involved in all of the above factors is that of normal DNA synthesis required for maintaining genomic integrity. This suggests that changes in function of DNA replicative enzymes are almost certain to be a factor in one or more of the negative cellular phenomena associated with aging. This is a particularly attractive hypothesis, since the accumulation of inactive or error-prone DNA polymerases during aging would be expected to initiate a sequence of events leading to synthesis of altered proteins and the general dysfunction of a wide range of cellular processes. Dietary restriction is the only anti-aging regimen uniquely suited to identifying these cellular processes and could play a significant role in maintaining cellular mechanisms necessary to reduce the rate at which mutations accumulate during aging. The observation that dietary restriction may impede the age-related decline in the activity and fidelity of DNA polymerases and in the decline of repair DNA synthesis, suggests potential mechanisms by which dietary restriction could extend the lifespan of animals, including humans.