Progeria and life extension

Progeria is a rare disease that causes children to show severe signs of ageing very early in their short lives. A full description can be found at:

http://www.progeriaresearch.org/index.shtml

With support from the Progeria Research Foundation, Francis Collins of human genome fame identified the gene that is defective in afflicted individuals. It was a surprise. Instead of being a gene in energy metabolism, DNA repair, or autoimmune disease, the mutant gene turned out to be a gene for a structural protein found in the nucleus of the cell LMNA which produces a protein called Lamin A. In afflicted individuals the defective gene product or protein clumps on the nuclear cell membrane and distorts the nucleus impeding normal function. Just how this situation causes advanced aging in young individuals is not known but the defective protein, progerin, has been found to accumulate in cells of blood vessel walls in affected children’s. However, it may be that a pharmaceutical that can reverse some or all of the symptoms already exists!

Once formed many proteins undergo modification before they take on their normal function. The LMNA gene produces a protein called prelamin A that is subsequently modified by the addition of the lipid farnesyl, removal of some amino acids and the addition of a carboxymethyl group These modifications are subsequently removed by an enzyme, Ste24 (Zmpste24) that requires a specific binding site to do its thing. After all this modification the protein is ready to go to work stabilizing the cell nucleus. Because the mutant protein lacks the binding site that the Zlmpste24 enzyme requires, the modifications cannot be removed and the progerin clumps on the nuclear membrane.

This all sounds complicated but one can consider that the normal protein is packaged for transport to the nuclear membrane and once there unpackaged so that it can function normally. The mutant protein, progerin, is never taken out of the box.



A PNAS paper, (http://www.pnas.org_cgi_doi_10.1073_pnas.0503712102/ ), discusses what happens to mutant cells in culture when the addition of the lipid farnesyl is blocked. Farnesyl is added to the protein by the enzyme farnesyl transferase. Inhibitors of this enzyme have been developed as treatments for certain types of cancer. Application of enzyme inhibitor rac-R115777 significantly reversed abnormal nuclear morphology suggesting that they could be useful in treating Progeria.

In a subsequent study mice with Progeria were treated with a farnesyl transferase inhibitor and found to improve significantly. This provides significant hope for a treatment for children with Progeria.

The big question is whether these farnesyl transferase inhibitors will be useful in life extension in general. It may be that Progeria mimics aging but is caused by a different mechanism so that farnesyl transferase inhibitors will be of little utility for the rest of us. However, these finding points toward the status of these structural proteins as key factors in the aging process.