The idea that translation fidelity might play a role in aging dates back at least as far as 1963, when Leslie Orgel proposed the “error catastrophe” theory of aging: in this model, mistranslation of the translational machinery creates a feedback loop that leads to further translation errors, ultimately causing loss of cell viability. From the Science of Aging Timeline:
Orgel considers two types of proteins: those involved in metabolism, and those involved in information processing. For metabolic proteins, translational error isn’t a long-term problem for the cell, since a malfunctioning protein is simply one of many. Likewise, for translational errors causing loss of function in information processing proteins: the error isn’t heritable, and a small decrease in the efficiency of gene expression is unlikely to pose a serious problem.
However, information processing proteins can be altered in another way: by mutations that decrease the fidelity with which they process or propagate genetic information. Lower-fidelity transcription and translation will result in more mutations. This is the core of Orgel’s idea: “errors which lead to a reduced specificity of an information-handling enzyme lead to an increasing error frequency. Such processes are clearly cumulative and…in the absence of an imposed selection for “accurate” protein-synthesizing units, must lead ultimately to an error catastrophe; that is, the error frequency must reach a value at which one of the processes necessary for the existence of viable cell becomes critically inefficient.”
The logic of the feedback loop is compelling, but the theory suffered for lack of experimental verification. While there is still some controversy over whether error catastrophe has received a full and fair experimental test, the consensus appears to be that while error catastrophe can take place under some systems (e.g., viral replication in the presence of drugs that reduce polymerase fidelity), this phenomenon does not play a role in mammalian aging: the measured values of the relevant parameters (basal translation error rates; the likelihood that a given error will result in further alteration to translation fidelity; protein lifetimes; etc.) appear to be such that the feedback loop doesn’t actually occur.
The error catastrophe theory is still an important waypoint in the evolution of theories of aging, and it has had tremendous influence in other areas within biogerontology. For example, similar logic has been applied to the role of autophagy in aging, where the feedback loop is called the garbage catastrophe.
And even if the feedback-loop logic doesn’t hold up to experimental scrutiny, recent findings have revealed that there may nonetheless be a relationship between protein translation fidelity and aging. Writing in PLoS ONE, Silva et al. report that in yeast, increasing the rate of translation errors might increase the activity of the longevity assurance gene SIR2:
The Yeast PNC1 Longevity Gene Is Up-Regulated by mRNA Mistranslation
Translation fidelity is critical for protein synthesis and to ensure correct cell functioning. Mutations in the protein synthesis machinery or environmental factors that increase synthesis of mistranslated proteins result in cell death and degeneration and are associated with neurodegenerative diseases, cancer and with an increasing number of mitochondrial disorders. Remarkably, mRNA mistranslation plays critical roles in the evolution of the genetic code, can be beneficial under stress conditions in yeast and in Escherichia coli and is an important source of peptides for MHC class I complex in dendritic cells. Despite this, its biology has been overlooked over the years due to technical difficulties in its detection and quantification. In order to shed new light on the biological relevance of mistranslation we have generated codon misreading in Saccharomyces cerevisiae using drugs and tRNA engineering methodologies. Surprisingly, such mistranslation up-regulated the longevity gene PNC1. Similar results were also obtained in cells grown in the presence of amino acid analogues that promote protein misfolding. The overall data showed that PNC1 is a biomarker of mRNA mistranslation and protein misfolding and that PNC1-GFP fusions can be used to monitor these two important biological phenomena in vivo in an easy manner, thus opening new avenues to understand their biological relevance.
PNC1 is a longevity gene because its biochemical activity feeds into the sirtuin pathway: Pnc1p synthesizes nicotinic acid from nicotinamide, which is an inhibitor of Sir2p, one of the canonical longevity factors in S. cerevisiae. Overexpression of PNC1 increases lifespan, presumably by increasing the activity of Sir2p. (The authors show that Sir2p silencing activity is elevated under conditions that cause mistranslation, and that this is inhibited by exogenous nicotinamide. Missing, as far as I can tell, is the same experiment in ∆pnc1 cells, which according to the authors’ model would not induce silencing during mistranslation.)
Is this simply an example of a general stressor activating a general stress response, whose constitutive activation in turn makes cells more stress-resistant and therefore longer-lived? For example, one could imagine a translation fidelity problem resulting in synthesis of lots of poorly folded proteins, leading to activation of the heat shock response and expression of chaperones (indeed, in the worm, heat shock transcription factor HSF-1 is required for life extension by daf-2 mutations). This doesn’t appear to be that. Instead, loss of protein fidelity causes upregulation of a major longevity assurance pathway, which acts primarily at the level of transcriptional silencing.
A couple of questions:
- What is the relevant molecular correlate of translation infidelity? Unfolded proteins would be the most likely culprit (prediction: whether or not it’s involved in the lifespan extension, there should be some heat shock response under these conditions), but one can imagine more elaborate scenarios: Suppose an inhibitor of PNC1 translation is encoded by an mRNA that is particularly likely to be mistranslated under normal conditions (e.g., because of weird codon usage, secondary structure, or some other quirk) and is now translated so poorly that it loses its inhibitory activity altogether (or acquires a new activity).
- How is the translational upregulation of PNC1 mediated? This is particularly curious given that, by assumption, a cell with a high rate of translation infidelity is having difficulty with translation. Teleologically, there’s no reason not to regulate gene expression at this level — if the gene were upregulated transcriptionally, the mRNA would still have to be translated — but it still strikes me as odd. If this is a bona fide evolved response to translation problems, wouldn’t it be better to pre-synthesize PNC1 and then activate it post-translationally (e.g. by proteolysis)?
- Is SIR2 involved in translation fidelity? Looking at this story as a straightforward stress response, one would expect some action of SIR2 to help mitigate the stress that started the whole process. So I’d be curious to know whether SIR2 mutants have lower translation fidelity, and if so, how it is that SIR2 is involved in improving the accuracy of translation?
Silva, R., Duarte, I., Paredes, J., Lima-Costa, T., Perrot, M., Boucherie, H., Goodfellow, B., Gomes, A., Mateus, D., Moura, G., & Santos, M. (2009). The Yeast PNC1 Longevity Gene Is Up-Regulated by mRNA Mistranslation PLoS ONE, 4 (4) DOI: 10.1371/journal.pone.0005212