Τόμος 9 (1991) – Τεύχος 3 – Άρθρο 2 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 9 (1991) – Issue 3 – Article 2 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

9: 167-173 (1991)

PHARMAKON-Press: Epitheorese Klin. Farmakol. Farmakokinet.

9: 167-173 (1991)

ageing, dna

Two conceptually different hypotheses have been proposed to explain the biological phenomenon of ageing:

1. The hypothesis of chance summation of defects in biomolecules important for cellular functions and
2. The hypothesis of programmed, genetically controlled loss of functions related to the cell cycle.

Concerning the first hypothesis, either ex­ternal factors, such as radiation and chemicals, or internal ones, such as superoxide and hydroxyl radicals, produced during cell meta­bolism, have been implicated as causing the molecular defects. Among the biomolecules affected are DNA, with consequences for replication, transcription and translation, lipids and proteins.

As regards proteins, particular attention has been given to their glycosylation, which results in the formation of “advanced glycosylation end products”, which can interact both with other proteins and DNA.

The effects of the various agents on mito­chondrial DNA, with its negative consequences for the energy status of the cell, have also received due attention.

As regards the second hypothesis, which is centered on the genetically programmed inter­vention on genes which regulate cell division, a basic role for its establishment was the demonstration of the limited replicative capa­city of cells and the correlation of the life span of an organism to the replicative capacity of its cells in culture. Particularly important in stu­dies on ageing, under the light of this hypo­thesis, was the introduction of the model of human diploid fibroblast (HDF). In senescent HDF, cell division is arrested in late G₁ or early S phase. Studies of hybrids between “old” and “young” HDF have shown the dominant nature of senescence, and with the use of inhibitors of protein synthesis it was shown that the effect of the “old” cells is an active one, due to the production of “dominant inhibitory protein”, inhibiting some event of the cell cycle.

In addition to activation of inhibitory genes, the possibility of inactivation of inhibitory genes has been also considered. Characteristic are the studies involving the expression of the c­fos, a gene activated soon after administration of mitogens. In “aging” cells, in contrast to “younger” ones, the c-fos gene is not activa­ted, either after serum addition, or after phorbol ester or epidermal growth factor administra­tion. Significance has also been ascribed to research dealing with the overexpression of oncosuppressor genes in senescent cells. How­ever the role and mechanism of action of oncosuppressor genes in senescent cells is still unresolved.

The need to confirm the in vitro experi­ments in the living organism has led to the introduction of many animal models, which combine short life span and the methodology of classical and molecular genetics. Such models showing promising results are, among others. Drosophila and the nematode, Caenorhabditis elegans.

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