DNA Damage and Aging

Abstract

DNA, the carrier of genetic information, is constantly damaged by radiation and numerous agents from the environment and cellular metabolic processes. Genome maintenance pathways are important to ensure DNA integrity. Impairments in genome maintenance can result in the development of cancer as well as aging, as exemplified by a variety of cancer-prone and accelerated aging syndromes that result from defects in DNA repair pathways. We have investigated genome-wide expression patterns after UV-induced DNA damage in cell culture and during aging in mice. This has led to the identification of common expression patterns between these conditions. Detailed studies have shown that, in response to lesions that block ongoing transcription, a “survival response” is elicited as a direct consequence of DNA damage. This response seems to induce a shift from growth to maintenance in order to prevent further accumulation of damage and extend lifespan. In addition, we have studied the consequences of several different types of DNA damage on the development of age-related pathology in a variety of cell types and tissues. With the use of various mouse models that suffer from segmental progeria (accelerated aging) due to genome maintenance defects, we have shown that DNA damage may elicit different responses and aging characteristics, depending on the cellular processes it interferes with. Each different DNA repair defect represents only a partial, but accelerated, contribution to the natural aging process. Combining molecular and cellular studies on various DNA repair deficiencies will contribute towards elucidating the mechanisms that underlie the process of natural aging and the onset of aging-related diseases.