The maintenance of the accuracy of protein synthesis and its relevance to ageing: a correction.
01 Nov 1970-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 67, Iss: 3, pp 1476-1476
TL;DR: A simpler model is considered in which successive generations of the protein-synthetic apparatus are discrete and distinguishable, and it is deduced that the error frequency would increase exponentially.
Abstract: An argument1 purporting to show that the accuracy of protein synthesis would deteriorate in the absence of cellular selection, thus leading to an "error catastrophe," contains a hidden assumption that no longer seems justified. I supposed that the error frequency in protein synthesis could be approximated as the sum of a residual error frequency (applicable where the protein-synthetic apparatus contains no errors) and a term dependent linearly on the number of errors already present in the protein-synthetic apparatus. I deduced that the error frequency would increase exponentially. To clarify the nature of the hidden assumption I now consider a simpler model in which successive generations of the protein-synthetic apparatus are discrete and distinguishable. Let c, be the error frequency in the nth generation, R the residual error frequency, and a the proportionality constant between errors in the synthetic apparatus and errors in freshly synthesized protein. Then
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TL;DR: This work has shown that mortality may be due to an energy-saving strategy of reduced error regulation in somatic cells, which supports Orgel's ‘error catastrophe’ hypothesis and offers a new basis for the study of normal and abnormal ageing syndromes and of apparently immortal transformed cell lines.
Abstract: An evolutionary view of ageing suggests that mortality may be due to an energy-saving strategy of reduced error regulation in somatic cells. This supports Orgel's ‘error catastrophe’ hypothesis and offers a new basis for the study of normal and abnormal ageing syndromes and of apparently immortal transformed cell lines.
1,513 citations
TL;DR: It is proposed that epigenetic defects in germline cells due to loss of methylation can be repaired by recombination at meiosis but that some are transmitted to offspring.
Abstract: Evidence from many sources shows that the control of gene expression in higher organisms is related to the methylation of cytosine in DNA, and that the pattern of methylation is inherited. Loss of methylation, which can result from DNA damage, will lead to heritable abnormalities in gene expression, and these may be important in oncogenesis and aging. Transformed permanent lines often lose gene activity through de novo methylation. It is proposed that epigenetic defects in germline cells due to loss of methylation can be repaired by recombination at meiosis but that some are transmitted to offspring.
1,021 citations
TL;DR: This ‘disposable soma’ theory of the evolution of ageing also proposes that a high level of accuracy is maintained in immortal germ line cells, or alternatively, that any defective germ cells are eliminated.
Abstract: Ageing is not adaptive since it reduces reproductive potential, and the argument that it evolved to provide offspring with living space is hard to sustain for most species. An alternative theory is based on the recognition that the force of natural selection declines with age, since in most environments individuals die from predation, disease or starvation. Ageing could therefore be the combined result of late-expressed deleterious genes which are beyond the reach of effective negative selection. However, this argument is circular, since the concept of 'late expression' itself implies the prior existence of adult age-related physiological processes. Organisms that do not age are essentially in a steady state in which chronologically young and old individuals are physiologically the same. In this situation the synthesis of macromolecules must be sufficiently accurate to prevent error feedback and the development of lethal 'error catastrophes'. This involves the expenditure of energy, which is required for both kinetic proof-reading and other accuracy promoting devices. It may be selectively advantageous for higher organisms to adopt an energy saving strategy of reduced accuracy in somatic cells to accelerate development and reproduction, but the consequence will be eventual deterioration and death. This 'disposable soma' theory of the evolution of ageing also proposes that a high level of accuracy is maintained in immortal germ line cells, or alternatively, that any defective germ cells are eliminated. The evolution of an increase in longevity in mammals may be due to a concomitant reduction in the rates of growth and reproduction and an increase in the accuracy of synthesis of macromolecules. The theory can be tested by measuring accuracy in germ line and somatic cells and also by comparing somatic cells from mammals with different longevities.
788 citations
465 citations
TL;DR: The chief purpose of this article is to review some recent work on the ageing of mammalian cells and to comment on the theoretical interpretation of the experimental findings.
Abstract: The chief purpose of this article is to review some recent work on the ageing of mammalian cells and to comment on the theoretical interpretation of the experimental findings. No claim will be made that cellular ageing is a primary cause of the ageing changes observed in whole animals; the evidence supporting such a causal connexion is inconclusive.
398 citations