Sci. Aging Knowl. Environ., 3 May 2006
A Shared Splice Site?
Defect behind "premature aging" disorder might foster normal aging
Slicing messenger RNA molecules in the wrong position cuts short the lives of children with a disease that resembles speedy aging, and new research suggests that cells from old people make the same mistake. The finding implies that normal aging shares a mechanism with the rare genetic ailment.
Children with Hutchinson-Gilford progeria syndrome (HGPS) seem to age rapidly in some ways (see "Of Hyperaging and Methuselah Genes"). They lose their hair, develop arthritis, and usually die in their teens from a heart attack or stroke. The culprit is a faulty version of the protein lamin A, which reinforces the membrane around the nucleus, among other cellular jobs. Most individuals with HGPS carry a mutation that mucks up the maturation of lamin A messenger RNA molecules (see "Lamin-tation"). After a cell makes an RNA copy of the gene, enzymes snip segments from this rough draft and stitch the remaining fragments together; this trimmed strand encodes the protein. The HGPS mutation creates a so-called splice site in the wrong position, generating an abbreviated messenger RNA that spawns a stubby version of lamin A. Some research implicates lamin A in aging: Rodents appear to get old swiftly if they lack an enzyme that helps activate the protein (see "Nuclear Fallout").
To probe lamin A's role in aging, cell biologist Tom Misteli and colleague Paola Scaffidi of the National Cancer Institute in Bethesda, Maryland, studied cultured connective tissue cells from healthy people in their 80s and 90s. Cell nuclei of HGPS patients sport telltale flaws. They become lopsided, for instance, and DNA accrues extra damage. Also, histone H3--a protein that DNA strands wrap around--sheds some of its methyl groups, and the alteration might flip on genes at inopportune times (see "Loose Chromosomes Sink Cells"). The researchers detected these faults in some cells from the oldsters. Compared with cells from healthy children, cells from the older patients were more than twice as likely to show reduced methylation of histone H3, for example.
Elderly and youthful cells squeezed out small amounts of the defective lamin A, the researchers found. Its presence indicates that even cells lacking the HGPS mutation sometimes use the abnormal splice site. Seniors and youngsters produced about the same amount of abnormal lamin A, but the protein clustered at the edge of the nucleus in cells from the older individuals. The same clumping occurs in HGPS cells. To test whether truncated lamin triggers faults in older cells, the team added a small RNA chain that covers the incorrect splice site. The molecule restored the normal pattern of methyl groups. The splice blocker also prevented older cells from entering a nondividing state called senescence. Abnormal lamin A prods cells into this state, which might play a role in aging (see "More Than a Sum of Our Cells"). Overall, the results suggest that imperfections in lamin A could contribute to bodily decay, says Misteli.
The work uncovers a relationship between HGPS and normal aging, at least at the cellular level, says human geneticist Thomas Glover of the University of Michigan, Ann Arbor. This advance is significant, he adds, because researchers have been cautious about claiming that such a connection exists. Molecular biologist Anthony Weiss of the University of Sydney in Australia says that the observations imply that the cell's tolerance for faulty lamin A declines with age. Researchers need to determine whether the results hold for other cell types and how damage to the nucleus leads to changes such as altered gene activity. Future work might reveal how to keep older cells from making the wrong cut.
May 3, 2006
Science of Aging Knowledge Environment. ISSN 1539-6150