Progerin and telomeres: a common link for premature and normal aging
Researchers at the US National Institute for Human Genome Research, working under the leadership of Francis S. Collins, have identified a new mechanism regulating the aging program of normal cells. The results of the study provide new information about the interaction between the toxic protein progerin and telomeres.
As it turned out, short or abnormally functioning telomeres activate the synthesis of progerin, the accumulation of which is associated with cell damage occurring during aging of the body. As telomeres shorten, progerin synthesis in the cell increases.
Telomeres – the end sections of chromosomes – shorten with each cell division, while reaching their critical length leads to the termination of division and cell death.
Progerin is an alternative version of the normal lamin A protein encoded by the LMNA gene. This protein is necessary to maintain the normal structure of the cell nucleus, which is a repository of genetic information.
In 2003, the authors established that a mutation of the LMNA gene is the cause of the development of premature aging syndrome, known as progeria or Guilford syndrome. With this very rare hereditary disease, children develop symptoms associated with old age, including hair loss, a decrease in the layer of subcutaneous fat, atherosclerosis and skeletal changes. Such children usually die from diseases of the cardiovascular system in adolescence.
According to Collins, the study of progeria can help to understand the biochemical and molecular mechanisms of normal aging. And indeed, the work that began with the study of this disease turned out to be very productive.
In 2007, researchers demonstrated that normal cells of healthy people, even in the absence of a corresponding mutation, can produce toxic protein progerin in small quantities, the synthesis of which is activated as the cell ages. However, the reason for launching this mechanism remained a mystery for a long time.
The progeria-causing mutation causes a strong activation of splicing (a mechanism for processing genetic information for subsequent protein synthesis) of lamin A. The result is the production of progerin and premature aging of the body. However, as it turned out, changes in lamin A splicing also occur in the presence of a normal LMNA gene.
Protein synthesis occurs according to the instructions encoded in the information RNA (mRNA), which transcribes (translates) the sequence of nucleotides in DNA into its alphabet, differing in one of the four letters – nucleotides. However, mRNA does not contain all the information recorded in DNA. Instead, it undergoes splicing – removal of the so-called introns (non-coding fragments) and subsequent crosslinking of the remaining exons (fragments in which the amino acid sequence of the protein is encoded). The first systematic analysis of the genome for the appearance of alternative splicing during cell aging, carried out by the authors using laboratory techniques for analyzing the sequence of RNA nucleotides, showed that the shortening of telomeres during cell division of individuals with a normal version of the LMNA gene somehow violates the mechanism of splicing of a number of mRNAs. These mRNAs encode proteins necessary to maintain the integrity of the cytoskeleton of the cell. And, more importantly, there is a violation of the splicing of lamin A mRNA, which leads to the appearance and accumulation of progerin in the cell.
To prove the existence of a relationship between telomeres and progerin, researchers have demonstrated that the so-called immortalized (immortal) cells produce very little progerin. Such cells (usually malignant) are capable of infinite division and have a constant telomere length maintained by the enzyme telomerase.
The scientists also conducted laboratory testing of normal cells of healthy individuals aged 10 to 92 years using biochemical markers indicating the presence of progerin mRNA in the cell. It turned out that, regardless of age, cells that have gone through many division cycles are characterized by higher progerin production. These same cells are characterized by shortened and abnormally functioning telomeres, which are an indicator of multiple cell division.
The data obtained indicate that the cell aging process is triggered by a combination of two factors: telomere shortening and progerin synthesis. They also shed light on the involvement of this toxic protein in the mechanisms of normal aging.
The article by Kan Cao et al. "Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts was published on June 13 in the preliminary on-line version of the Journal of Clinical Investigation.
Evgeniya Ryabtseva
Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of Medical Xpress – Researchers find new clues about aging.
15.06.2011