Lamin A-Dependent Nuclear Defects in Human Aging

TLDR

Lamin A mutations cause Hutchinson‑Gilford progeria, but its role in normal aging is unclear. We demonstrate that the same cryptic splice site in lamin A that drives HGPS is sporadically activated in healthy aging cells, leading to nuclear defects and DNA damage, and that inhibiting this splice site reverses these defects, implicating lamin A in physiological aging.

Abstract

Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays any role in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging. These observations implicate lamin A in physiological aging.