On why decreasing protein synthesis can increase lifespan

doi:10.1016/j.mad.2007.03.002

Mechanisms of Ageing and Development

Volume 128, Issues 5–6, May–June 2007, Pages 412-414

https://doi.org/10.1016/j.mad.2007.03.002 Get rights and content

Abstract

An explanation is offered for the increased lifespan of Caenorhabditis elegans when mRNA translation is inhibited due to loss of the initiation factor IFE-2 [Hansen, M., Taubert, T., Crawford, D., Libina, N., Lee, S.-J., Kenyon, C., 2007. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Ageing Cell 6, 95–110; Pan, K.Z., Palter, J.E., Rogers, A.N., Olsen, A., Chen, D., Lithgow, G.J., Kapahi, P., 2007. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Ageing Cell 6, 111–119; Syntichaki, P., Troulinaki, K., Tavernarakis, N., 2007. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445, 922–926]. It is suggested that the general reduction of protein synthesis, due to the decreased frequency of mRNA translation, also lowers the cellular load of erroneously synthesized polypeptides which the constitutive protein homeostatic apparatus (proteases and chaperones proteins) normally eliminates. This situation results in “spare” proteolytic and chaperone function which can then deal with those proteins modified post-synthetically, e.g. by oxidation and/or glycation, which are thought to contribute to the senescent phenotype. This increased availability of proteolytic and chaperone functions may thereby contribute to the observed increase in organism stress resistance and lifespan.

Section snippets

The problem

Three recent papers (Hansen et al., 2007, Pan et al., 2007, Syntichaki et al., 2007) have described a phenomenon where loss of the initiation factor eIF4E (IFE-2), a principal regulator of protein biosynthesis, increases lifespan in the nematode Caenorhabditis elegans. As the mechanisms involved are at present unclear, one wonders whether a consideration of protein breakdown, as well as synthesis, could help to explain this observation.

Error proteins and their elimination

Protein biosynthesis is not perfect. Messenger RNA translation is the most error-prone step in gene expression as approximately 3 codons in 10,000 are mistranslated (Kirkwood et al., 1984). Normally the resultant error proteins are selectively degraded by constitutive cellular proteolytic activities, thereby maintaining protein quality. It is not unreasonable to expect that regulation of this homeostatic proteolytic activity is linked to the maximum protein biosynthetic activity of the cell (

Ageing and the fate of altered proteins

The most common molecular signal of ageing is an accumulation of altered proteins derived from both erroneous biosynthesis and post-synthetic modification, particularly oxidation/glycoxidation (Stadtman, 1992, Rosenberger, 1991, Rattan et al., 1992, Hipkiss, 2006). Importantly, not only are erroneously synthesized proteins more prone to oxidation than the normal gene products (Dunkan et al., 2000, Ballesteros et al., 2001) but error proteins and oxidized ones are degraded by the same proteases.

Reduced mRNA translation, less error protein and increased protease/chaperone availability

Consequently it can be argued that the decreased mRNA translation frequency, induced by the loss of the initiation factor IFE-2, decreases synthesis of both normal and erroneous polypeptide chains. This would reduce the biosynthetic component of the aberrant protein load which the constitutive proteolytic apparatus should eliminate, the excess spare capacity being available for degradation of proteins modified post-synthetically. Such a condition would increase the likelihood for destruction of

Error protein, folding and oxidation

Another possibility which should be considered is whether partial inhibition of translation increases the accuracy of amino acid incorporation into the growing polypeptide chain. It has been shown that treatment of yeast with erythromycin, an antibiotic which decreases the rate of protein biosynthesis but increases the accuracy of amino acid incorporation of mitochondrially synthesized polypeptides, also improves lifespan (Holbrook and Menninger, 2002). Furthermore partial inhibition of

Conclusion

It is suggested that decreasing mRNA translation lowers global synthesis of both normal and erroneous proteins. This decrease in error proteins creates, in effect, a phenotypic upregulation of homeostatic proteolytic and chaperone activities which may contribute to the observed increased stress resistance and extended lifespan of the organisms.

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CommentaryOn why decreasing protein synthesis can increase lifespan

Abstract

Section snippets

The problem

Error proteins and their elimination

Ageing and the fate of altered proteins

Reduced mRNA translation, less error protein and increased protease/chaperone availability

Error protein, folding and oxidation

Conclusion

Int. J. Biochem. Cell Biol.

Exp. Gerontol.

Exp. Gerontol.

Mech. Ageing Dev.

Int. Rev. Cytol.

Mech. Ageing Dev.

Mutat. Res.

FEMS Lett.

Cell Biol. Int.

FEBS Lett.

Protein homeostasis and molecular chaperones in aging

Biogerontology

Bacterial senescence: protein oxidation in non-proliferating cells is dictated by the accuracy of the ribosomes

EMBO J.

Commentary
On why decreasing protein synthesis can increase lifespan