Saturday, January 16, 2010

Error Catastrophe Theory of Biological Aging

The error catastrophe theory of aging was proposed by Leslie Orgel in 1963 and it was originally a very popular theory because it made a great deal of sense. Although the theory per se has by now been largely discarded due to a lack of experimental supporting evidence, elements of the theory are still being investigated as possible factors in aging.

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Error catastrophe is a term used to describe the extinction of an organism (often in the context of microorganisms such as viruses) as a result of excessive RNA mutations. The term specifically refers to the predictions of mathematical models.
The genetic blueprint for each biological species occurs in the deoxyribonucleic acid (DNA) in the nucleus of each cell. When the cell divides, an enzyme known as DNA polymerase makes a new copy of the DNA by combining the appropriate building blocks known as deoxyribonucleotides in the correct sequence in a process known as DNA replication. The genetic sequences in the DNA are then transcribed by another kind of copying enzyme, known as RNA polymerase, into a ribonucleic acid (RNA) molecule called messenger RNA. Specific messenger RNAs contain the instructions for synthesizing individual proteins of the correct amino acid sequence, corresponding to the original blueprint in the DNA. This final protein synthesizing process is called translation.

The original theory posited that low levels of mistakes in the form of misincorporation of amino acids into proteins occur during protein synthesis, although this misincorporation may actually be due to copying mistakes made during DNA replication or messenger RNA synthesis. Although these mistakes can occur in any protein made by the cell, when these mistakes occur in the enzymes and other proteins responsible for synthesizing DNA and RNA, or in the protein synthesizing machinery itself, this could lead to an increasing cascade of errors, referred to as an error catastrophe. This escalating process could turn what is initially a very low error rate in young individuals into a significant rate of accumulation of errors in older individuals, and one would predict that the rate of error accumulation might continue to increase exponentially throughout the life of the individual.

The importance of maintaining high fidelity in biological replicating systems has long been recognized. This is particularly true during DNA replication, as many DNA polymerases possess the ability to recognize mismatched bases, then back up and correct their own mistakes. In addition, very robust DNA repair systems are present to correct mistakes made during synthesis, or afterward by chemicals able to damage DNA. Thus, the error frequency in DNA replication is usually extremely low, perhaps less than one in a million bases. Studies to demonstrate age-related changes in the copying fidelity of polymerases or DNA repair capacity have not provided convincing support for the error catastrophe theory.

In general, RNA polymerases also combine ribonucleotide building blocks to make RNA with high sequence fidelity, but lower than that exhibited by DNA polymerases. However, the overall instability and turnover of messenger RNA tends to attenuate the impact of any mistakes made during messenger RNA synthesis. Protein synthesis is also generally carried out with high fidelity, and there is little evidence to suggest that this changes with age.

Research trying to prove the error catastrophe theory has focused primarily on identifying differences in either amino acid sequence or the 3-dimensional structure of specific proteins. Attempts to detect errors in sequence as a function of aging have generally failed, but it is thought that sequencing procedures are only sensitive enough to pick up fairly gross sequence errors. However, it has been possible to demonstrate significant changes in physical properties of proteins, suggesting that the 3-dimension structure of old proteins differs from that of young proteins due to differences in protein folding.

These differences have mainly been indirectly identified through studies of heat sensitivity of proteins, although very sophisticated biophysical methodologies were employed beginning in the 1990s. The general conclusion has been that aging of proteins is due to changes in the way proteins fold up to form 3-dimensional structures, rather than accumulation of proteins with an incorrect sequence of amino acids. Both kinds of altered proteins tend to aggregate and/or become better substrates for protein-degrading enzymes, thereby, removing the altered protein from the cell. Thus, the rate of accumulation of altered proteins in a cell is a balance between rates of generation and degradation of altered proteins, so the actual rate of generation of altered proteins is difficult to determine with great accuracy.

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A related question is whether modification of existing proteins plays a role in aging. Several lines of evidence indicate that proteins do become randomly altered after they are synthesized; a variety of such processes is collectively referred to as post-translational modification because it occurs after synthesis of the protein using the messenger RNA as a template has been completed. Although distinct from the damage hypothesized in the original error catastrophe theory, post-translational modification of proteins could functionally resemble an error catastrophe. These modifications include oxidation of amino acid sidechains, racemization of certain amino acids, and condensation of the lysine side chain amino group with aldehyde groups such as those found in glucose. This latter process is known as non-enzymatic glycation. Biochemical mechanisms exist to repair the damage caused during some of these processes, suggesting they could have biological significance with implications for aging. However, there is a dearth of evidence unequivocally indicating that damage-inducing processes, damage accumulation, or repair processes are casually related to aging in mammalian species.

In summary, although altered proteins do accumulate with increasing age in mammals, the error catastrophe theory itself is no longer regarded as a viable theory. Nevertheless, there remains a healthy research interest in determining what roles damaged proteins, and the processes that either destroy the damaged protein or repair the damage, might play as casual factors in aging.

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