Protein turnover plays a key role in aging

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Abstract

Although the molecular mechanism of aging is unknown, a progressive increase with age in the concentration of damaged macromolecules, especially proteins, is likely to play a central role in senescent decline. In this paper, we discuss evidence that the progressive decrease in protein synthesis and turnover can be the primary cause of the increase in the concentration of damaged proteins with age. Conversely, protein damage itself is likely to be the cause of the decrease in protein turnover. This could establish a positive feedback loop where the increase in protein damage decreases the protein turnover rate, leading to a further increase in the concentration of damaged proteins. The establishment of such a feedback loop should result in an exponential increase in the amount of protein damage—a protein damage catastrophe—that could be the basis of the general deterioration observed in senescent organisms.

Section snippets

Increase in the concentration of damaged proteins during aging

Various genes have been identified in worms, flies and mammals whose mutation can drastically affect life span. For example, mutations in the insulin signaling pathway, such as age-1 and daf-2, can double life span in Caenorhabditis elegans (Friedman and Johnson, 1988, Kenyon et al., 1993), the Methuselah mutation can significantly increase life span in Drosophila (Lin et al., 1998), and mutation of p66shc can increase life span in mice (Migliaccio et al., 1999). However, the molecular

Protein turnover in aging

The rate of protein turnover is determined by the combined rates of protein synthesis and degradation. Once growth is complete, organisms reach a steady state in which the rate of protein synthesis equals the rate of protein degradation. Most studies of protein metabolism in aging were focused on protein synthesis, and there is overwhelming evidence that the rate of protein synthesis declines with age. This decrease in protein synthesis appears to be a universal phenomenon (reviewed in

Protein damage catastrophe

Although the age-dependent decrease in protein turnover is well-documented, the mechanism responsible for this decrease is unclear. Analysis of the literature suggests that the activities of various components of both the protein synthesis and degradation machinery decline with age (reviewed in Van Remmen et al., 1995, Cuervo and Dice, 2000, Grune, 2000, Friguet et al., 2000, Keller et al., 2000). A possible cause of such age-dependent decline in protein turnover can be the cumulative effect of

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