Premature Senescence of Primary Fibroblasts From Patients with Ataxia-Telangiectasia (A-T): A Major Feature of A-T

Genome stability suppresses the development of aging phenotypes, and genome instability syndromes can give rise to segmental premature aging. Genome stability and integrity are maintained primarily by the DNA damage response (DDR) – a complex signaling network that is induced by DNA damage. Loss of the ATM protein kinase – the chief DDR mobilizer in response to double-strand breaks in the DNA – leads to ataxia-telangiectasia (A-T), a multisystem genome instability syndrome that includes premature aging signs. Early studies demonstrated decreased colony forming ability of primary skin fibroblasts from A-T patients, which was presumed due to premature senescence. Here, we show that human A-T skin fibroblasts do indeed undergo premature senescence, under either ambient or 3% oxygen pressure. This conclusion is corroborated by several cellular senescence readouts. Importantly, fibroblasts from A-T carriers exhibit senescence rates that are intermediate between those of A-T fibroblasts and fibroblasts from unrelated, healthy individuals. This finding provides additional evidence for the segmental premature aging observed in A-T patients and further substantiates the link between genome instability, cellular senescence and aging. Additional molecular aspects of this cellular phenotype are being studied.