Does transcription-associated DNA damage limit lifespan?

• Transcription causes DNA damage in non-dividing cells.
• DNA damage in non-dividing cells can accelerate aging in humans and mice.
• The transcription rate correlates with the rate of aging in mammals.
• Caloric restriction reduces the rate of transcription and increases lifespan.
• Transcription is reduced in long-lived mutants.

Small mammals undergo an aging process similar to that of larger mammals, but aging occurs at a dramatically faster rate. This phenomenon is often assumed to be the result of damage caused by reactive oxygen species generated in mitochondria. An alternative explanation for the phenomenon is suggested here. The rate of RNA synthesis is dramatically elevated in small mammals and correlates quantitatively with the rate of aging among different mammalian species. The rate of RNA synthesis is reduced by caloric restriction and inhibition of TOR pathway signaling, two perturbations that increase lifespan in multiple metazoan species. From bacteria to man, the transcription of a gene has been found to increase the rate at which it is damaged, and a number of lines of evidence suggest that DNA damage is sufficient to induce multiple symptoms associated with normal aging. Thus, the correlations frequently found between the rate of RNA synthesis and the rate of aging could potentially reflect an important role for transcription-associated DNA damage in the aging process.