The study by Paola Scaffidi and Tom Misteli investigates the role of lamin A in the normal aging process. Mutations in the lamin A gene cause Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease. However, the authors found that healthy cells also exhibit nuclear defects similar to those seen in HGPS patients, including changes in histone modifications and increased DNA damage. These defects are caused by the sporadic use of a cryptic splice site in lamin A, which leads to the production of a truncated, dominant-gain-of-function lamin A isoform (Δ50 lamin A). Inhibition of this splice site reversed the nuclear defects associated with aging, suggesting that lamin A plays a role in physiological aging. The findings indicate that HGPS and physiological aging share a common molecular basis, and that Δ50 lamin A accumulation at the nuclear periphery contributes to age-related nuclear abnormalities.The study by Paola Scaffidi and Tom Misteli investigates the role of lamin A in the normal aging process. Mutations in the lamin A gene cause Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease. However, the authors found that healthy cells also exhibit nuclear defects similar to those seen in HGPS patients, including changes in histone modifications and increased DNA damage. These defects are caused by the sporadic use of a cryptic splice site in lamin A, which leads to the production of a truncated, dominant-gain-of-function lamin A isoform (Δ50 lamin A). Inhibition of this splice site reversed the nuclear defects associated with aging, suggesting that lamin A plays a role in physiological aging. The findings indicate that HGPS and physiological aging share a common molecular basis, and that Δ50 lamin A accumulation at the nuclear periphery contributes to age-related nuclear abnormalities.