The Orgel's Error Catastrophe Theory of Aging and Longevity

The Orgel's error catastrophe theory of aging and longevity was published and developed in:

 [In the 3rd article published in 1973, Dr. Leslie E. Orgel had further generalized his theory to the level of the DNA and the proteins that repair damage to it.  He realized that a general breakdown in the accuracy of information transfer (predicted by his theory) would also affect DNA synthesis and repair, so that mutations would be expected to increase exponentially during aging]

Here are some excerpts from the recent scientific publications, which describe the essence of this theory:

"Maintenance of the structural integrity of DNA is critical not only for cell survival but also for the transfer of correct genetic information to daughter cells. Alterations in the fidelity of DNA polymerase alpha could result in a progressive degradation in information transfer during DNA synthesis, which would eventually affect a wide range of cellular components during ageing. [Orgel, 1963 and Orgel, 1973] suggested that cellular ageing involves accumulation of error-containing enzymes as a result of an inherent inaccuracy of the protein synthesizing machinery. One mechanism for the introduction of such errors would be decreased fidelity of DNA polymerases during repair activity or cell division. Furthermore [Burnet, 1974] has proposed that a main cause of cellular deterioration during ageing may be the accumulation of somatic mutations that are the product of error prone DNA repair and replication machinery. Support for these proposals has been derived mainly from experiments in which polydeoxynucleotide templates were utilized and incorporation of noncomplementary bases was determined in vitro. Various DNA polymerases isolated from fibroblasts aged in culture are less faithful in copying synthetic polynucleotide than the same DNA polymerases isolated from early passage cells ( [Linn et al., 1976, Murray and Holliday, 1981 and Krauss and Linn, 1982]). Similarly, DNA polymerase alpha isolated from MRC-5 human male fetal lung fibroblasts showed a decrease in activity and fidelity in late passage cells compared to early passage cells ( [Linn et al., 1976]). In a similar study [Murray, 1981] demonstrated reduced DNA polymerase alpha activity and fidelity in senescent MRC-5 fetal lung fibroblasts compared with DNA polymerase alpha from young cells. Additionally, several in vivo studies have shown lower fidelity of DNA polymerase alpha from old animals compared with enzyme from young animals ( [Srivastava et al., 1992, Taguchi and Ohashi, 1996 and Taguchi and Ohashi, 1997]). These data indicate that ageing has significant effects on the fidelity of DNA polymerase alpha and provides evidence to support the error catastrophe theory ( [Orgel, 1973]). This hypothesis is not, however, supported by some reports that failed to demonstrate decreased fidelity with increased age ( [Rao et al., 1985, Fry et al., 1981 and Silber et al., 1985])."

Cited from page 1293 in:

Replicative enzymes, DNA polymerase alpha (pol alpha), and in vitro ageing
Srivastava VK, Busbee DL
38 (11-12): 1285-1297 NOV-DEC 2003

"Positive feed-back loops are also found in biological systems. Many `snowball' effects fall into this category. Each time, the rate of change of a parameter P at a given time is function of the level reached by the parameter at this time, Eq. (2), i.e. a growing exponential is obtained (this results from the integration of dP/dt --:-- P). All cases of defects accumulation fall into this category. Mutations, which are harmless in a first time, may become deleterious when their effect is combined with other insignificant changes in the internal organisation of a living entity, just because, for instance, there is a threshold in the number of these mutations and changes, from which a metabolic function is impaired. An example is given by the monistic theory of Orgel (Orgel, 1963). This author based the whole ageing process on the fact that it results from errors in translation of mRNA into protein. There will, then, be more defective proteins, which will increase the number of errors in translation of mRNA, and so on until an error catastrophe occurs."

Cited from page 283 in:

A system approach modelling of the three-stage non-linear kinetics in biological ageing
Crevecoeur GU
122 (3): 271-290 MAR 2001

Our comments on the Orgel's  Error Catastrophe Theory

and its possible link to the Gompertz law of mortality

It is no brainier to link an exponential increase in error frequency of macromolecular biosynthesis (predicted by the Orgel's error catastrophe theory) to exponential increase in death rates (Gompertz function) for aging cells. The main problem here is that it is the multicellular organisms, rather than their cells, that die out exponentially.