Aging looks and feels like it is multifactorial: everything falls apart independently. But now Paola Scaffidi and Tom Misteli (National Cancer Institute, Bethesda, MD) report that multiple hallmarks of cellular aging can be reversed by eliminating one aberrant splicing product of lamin A.

The lamins form a structural cage on the interior surface of the nucleus. Lamin A has a long tail that is first farnesylated and then chopped off. In the 50 or so patients known to have the premature aging syndrome Hutchinson-Gilford Progeria (HGPS), an aberrant splicing event creates a lamin A that gets farnesylated but not cleaved.

The NCI team now shows that normal cells also have a small amount of this aberrant splice product. Although neither the splice product nor its protein product accumulate to higher levels with age, their effects do. As in HGPS cells, older cells have decreased heterochromatin and other nuclear markers, and increased markers of unrepaired DNA damage. Many of these changes were reversed by an oligonucleotide that eliminated the aberrant splice product.

Normal lamin A is found both at the nuclear periphery and within the nucleoplasm. But the aberrant splice product retains its farnesylation, and therefore gloms itself, and normal lamin A, onto the nuclear envelope. It is not clear how this leads to the many problems, although another group has suggested that lamin defects trigger a checkpoint that assesses nuclear envelope integrity. This, or some other mechanism that deals with the presence of the aberrant lamin product, must somehow be more sensitive in older cells.


Scaffidi, P., and T. Misteli.