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Aging, The Molecular Concepts


Reduced translational activity is a widely observed age-associated biochemical change in cells, tissues, organs and organisms. Although there is a considerable variability among different tissues and cell types in the extent of decline, the fact is that the bulk protein synthesis slows down during aging (1). Furthermore, it has been shown that the conditions, such as calorie-restriction, that are associated with an increase in the lifespan and which retard the aging process in many organisms, also slow down the age-related decline in protein synthesis (2). The consequences of slower rates of protein synthesis are manifold in the context of aging and age-related pathology. These include decreased availability of enzymes, inefficient removal of intracellular damaged products, inefficient intra- and intercellular communication, decreased production of hormones and growth factors, decreased production of antibodies, and altered nature of the extracellular matrix.

Eukaryotic protein synthesis is a highly complex process which requires a large number of components to function effectively and accurately in order to translate one mRNA molecule while using large quantities of cellular energy. Since the error frequency of amino acid misincorporation is generally considered to be quite high (10-3 to 10-4) compared with nucleotide misincorporation, the role of protein error feedback in aging has been a widely discussed issue.


At present, no direct estimates of protein error levels in any aging system have been made, primarily due to the lack of appropriate methods to determine spontaneous levels of errors in a normal situation. Studies on the accuracy of protein synthesis during aging that have been performed on animal tissues did not reveal any major age-related differences in the capacity and accuracy of ribosomes to translate poly(U) in cell-free extracts (3). However, these attempts to estimate the error frequencies during translation in vitro of poly(U) template were inconclusive because the error frequencies encountered in the assays were several times greater than the estimates of natural error frequencies (4). The accuracy of mouse liver ribosomes did not change with age in cell-free assays. However, using mRNA of tobacco mosaic virus coat protein (CcTMV) for translation by cell extracts prepared from young and old human fibroblasts, a sevenfold increase in cysteine misincorporation during cellular aging has been observed (5). Furthermore, an aminoglycoside antibiotic paromomycin (Pm), which is known to reduce ribosomal accuracy during translation in vivo and in vitro, induces more errors in the translation of CcTMV coat protein mRNA by cell extracts prepared from senescent human fibroblasts than those from young cells (5). Further indirect evidence indicating the role of protein errors in aging comes from studies on the increase in the sensitivity of human fibroblasts to the life-shortening and aging-inducing effects of Pm and another aminoglycoside, antibiotic G418 (6, 7).

Another indirect method that has been used to detect misincorporation of amino acids during aging is the method of two-dimensional (2D) gel electrophoresis of proteins, by which at least one kind of error, that is, the misincorporation of a charged amino acid for an uncharged one (or vice versa) can be demonstrated because of "stuttering" of the protein spot on 2D gels. Using this method, no age-related increase in amino acid misincorporation affecting the net charge on proteins was observed in histidine-starved human fibroblasts and in Caenorhabditis elegans (8). Although a global "error catastrophe" as a cause of aging, due to error in each and every macromolecule, is considered unlikely, it is not ruled out that some kind of error in various components of protein synthetic machinery including tRNA charging may have long-term effects on cellular stability and survival (9).

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