The ability to synthesize functional proteins is dependent on the fidelity of genetic information encoded in the DNA, its unimpaired transcription from DNA to RNA, and translation into peptides and proteins. As each of these processes is subject to inaccuracy, and during the life course of an organism the sequence of information transfer steps is continuously operational, the error potential is large. With increasing chronological age the probability of errors increases, resulting in the accumulation of deleterious mutations late in life.⁽⁶⁾ Since a number of the proteins synthesized may be involved as surveillance enzymes to maintain the accuracy of the entire system, feedback mechanisms could lead to its collapse, resulting in a phenomenon initially termed error catastrophe.

With the demonstration of an inverse correlation between the lifespan of mammalian species and the incidence of chromosome abnormalities, age-related physiological changes were originally ascribed to accumulated mutations in the nuclear DNA (nDNA) of somatic cells. Findings of this nature could, however, be explicable in terms of the ability of an organism to tolerate DNA damage via the repair of damaged molecules, with more than 130 human DNA repair genes identified.⁽⁷⁾ The capacity of nDNA to resist attack by endogenous reactive species and environmental agents is therefore considerable, which casts doubt on the general applicability of the theory.

Epigenetic errors, i.e. errors in the control of gene expression rather than mutations in DNA or protein, have been proposed as major primary causal factors in senescence.⁽⁸⁾ In promoter regions of genes, hypermethylation silences a gene whereas the hypomethylation of previously methylated sequences permits their expression. The pattern of DNA methylation is established during development and is cell type-specific, and changes in methylation can occur both during ageing and in cancer cells. The advantage of epigenetic models of ageing is their lack of requirement for the evolutionary preservation of genes encoding ageing, which in former generations would seldom have been expressed.

Mitochondria are subcellular organelles responsible for aerobic energy production in humans and many other species. The mitochondrial genome of ˜16.5 kb is characterized by its extremely compact organization, with no protective histones, a lack of excision or recombinational repair mechanisms, and a virtual absence of introns, all of which make it highly susceptible to mutation. Mitochondrial DNA (mtDNA) plays a central role in mitochondrial propagation and the maintenance of cellular respiration, but a majority of proteins involved in the regulation of mtDNA transcription, translation and replication, and the mitochondrial respiratory chain, are encoded in the nuclear genome. This design requires the operation of a highly coordinated mechanism for the expression of the nuclear and mitochondrial genomes. The central role of mitochondria in energy production means that defects may be of major metabolic significance, and the demonstration of increased levels of mtDNA deletions and base-substitutions in aged human neurones, heart, and skeletal muscle suggest a causative role for mtDNA mutations in ageing.⁽⁹⁾

Telomeres are specialized structures located at the terminus of the DNA helix and critical to the maintenance of DNA stability and replication. The enzyme telomerase which is responsible for telomere synthesis is active during early embryonic and foetal development but its activity is down-regulated in all human somatic cells before birth. As human diploid fibroblasts in culture were shown to progressively lose telomeres, it was hypothesized that telomere length could act as a predictor of the potential in vitro lifespan achievable by a cell strain.⁽¹⁰⁾ Humans have a common telomere profile found on lymphocytes, amniocytes, and fibroblasts which appears to be preserved throughout life. However, the rate of telomere loss with ageing varies between chromosomes and there is evidence that, in addition to the common human telomere profile, each person exhibits an individual profile.⁽¹¹⁾ Besides ageing, telomere loss has been implicated in a wide range of disease states, including heart disease, stroke, infection, long-term chronic stress, and obesity. Given the apparent relationship between telomere loss and both ageing and age-related pathologies, pharmacological activation of telomerase has been proposed as a potential treatment for chronic or degenerative diseases.⁽¹²⁾ As tumour tissue and transformed cells constitutively produce telomerase, any therapeutic intervention of this nature would require careful monitoring.