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Genetic instability

Database
Genetic instability

Authors:

Researches on this mechanism of aging are carrying out by M. B. Kastan, R. A. Beckman, K. Neveling etc.

History:

The role of this mechanism in aging process was evaluated due to investigations that were started in the majority in 1990s. Correlation between aging and genetic instability was analyzed on various biological systems.

Example:

The fact that genetic instability is the mark of aging is supported by the accelerated aging syndrome. It is caused by congenital mutations in genes controlling DNA repair. As the result of those mutations, young people or even children have signs of aging and even look like elderly people. Mutations induced in genes of DNA repair of mice under experimental conditions also result in accelerated aging.


Description:

The main functions of our body are under control of genes situated in nuclear chromosomes. Every cell has only two copies of each chromosome, and these copies are not identical — they can have different variants of the same gene (alleles). That is why damages of DNA molecules could badly affect cell functions. The surge of mutations that is observed during aging was called genetic instability. An example of genetic instability is telomere shortening. Telomeres are special areas at chromosome ends. They protect chromosomes so cells with defective telomeres cannot divide and even survive, but sometimes such cells begin to divide in an uncontrolled manner and become tumor ones. When we age chromosomes accumulate damage not only in telomere regions but also along the full length. The main reason of that phenomenon is that mechanisms of DNA repair cease to work effectively. Any damage of nucleotides that form genes or breaks in DNA strands cause mutations in aging cell with repair deficiency. The more mutations cell accumulates, the less viable it becomes and the high risk of its transformation into cancer one arises.

Another reason of genetic instability observed under aging is the activation of mobile genetic elements, also known as «jumping genes» or retrotransposons. Those are virus-like DNA fragments hiding in our chromosomes.

Normally, they are inactivated by addition of the methyl groups. When DNA breaks occur in a chromosome, such chromosome becomes less accessible for the methylation enzymes. This activates retrotransposones that start copy and jump to other places of chromosome. While jumping, they can take along fragments of some important genes, as well as switch some genes of and switch other genes on. That results in genome destabilization and cell aging.

Additions and Criticism:

For preventing telomeres shortening in germ and embryonal stem cells the special enzyme — telomerase — is activated in those cells. Telomerase elongates telomeres after every cell division. In the cells of most human tissues and organs, a gene responding for one of the telomerase components is switched off or works poorly. Accessory effect of that switching-off is so-called replicative aging — fading of the ability to divide. The nature took that step to protect an developing organism from a deadly disease — cancer. Ordinary cells can not divide more than certain number of times and that impede tumor formation.

Similar to retrotransposones, silent virus infections are activated in aging cells. That results in triggering of inflammatory response.

Publications:

  • Kastan, Michael B., ed. Genetic instability and tumorigenesis. Vol. 221. Springer Science & Business Media, 2012.
  • Strehler, Bernard L. «Genetic instability as the primary cause of human aging." Experimental gerontology 21.4 (1986): 283–319.
  • Slagboom, P. Eline, and Jan Vijg. «Genetic instability and aging: theories, facts, and future perspectives." Genome 31.1 (1989): 373–385.
  • Beckman, Robert A., and Lawrence A. Loeb. «Genetic instability in cancer: theory and experiment." Seminars in cancer biology. Vol. 15. No. 6. Academic Press, 2005.