A rare genetic disease that resembles a sped-up aging, progeria, may point to one of the keys to longevity for humans. Similar to normal aging, about which we know so little, it causes deterioration of blood vessels, resulting in major lethal cardiovascular diseases. The skin of children with progeria becomes less elastic, their joints become stiffer, and bones weaker, but they do not develop dementia.
In 2003, a point mutation was identified: the swapping of just one gene, LMNA. This gene encodes a protein, lamin A, which is a major part of the nuclear lamina on the inner side of the membrane of the cell. Most normal DNA is coiled tightly, except for the genes that are chemically switched on to produce proteins. People with progeria have cells with abnormally shaped nuclei, not smooth and spherical, and all DNA in it is uncoiled, regardless of the activity of the genes, plus there are many changes in their on or off determinations.
One consequence of the LMNA mutation is that it impacts the “transportation” of lamin A. During its production, normally a group of sticky molecule farnesyl is attached to it by an enzyme, to be removed after reaching the lamina and before joining it. The mutation prevents such removal, and the unusual form of the protein with the farnesyl group still connected, progerin, accumulates. Preventing the addition of farnesyl by blocking the enzyme that adds it, results in addition of another fatty group to lamin A on a later stage and in a similar agglomeration at the lamina. Blocking both additions by drags like statins or bisphosphonates can ease the symptoms without providing a cure. Progerin accumulation occurs in normal skin cells and increases with age. It rises in the blood vessels of healthy people by 3.3 percent each year of their lives. Similar to progerin prelamin A, increases in the muscle cells of blood vessel walls and facilitates calcification, because the enzyme that trims the farnesyl group is lacking.
The mutation in the LMNA gene also causes a splicing error while copying DNA into a coding string of RNA for the protein synthesis. Human DNA is organized into strings or chromosomes, 46 per cell, ending with protective sequences bound with protein, the telomeres. They shorten when cells divide. This could be a natural regulation of the number of possible cell divisions, and can explain tissue aging. In people with progeria, telomere shortening caused splicing errors with several genes.
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