How might a loss of silencing cause aging?
Models relating loss of silencing to aging have been described in yeast (Kennedy et al. 1995) and in mammalian cells (Howard 1996;Villeponteau 1997; Imai and Kitano 1998). In yeast, one effect of Sir2-mediated silencing is a repression of recombination in the rDNA (Fig. 4). This repression of genome instability delays the formation of ERCs, which will ultimately lead to the demise of aging mother cells. However, there is no good evidence that ERCs, or for that matter any extra DNA, accumulates in aging metazoan cells. Does this mean that the yeast model for aging bears no relevance to aging in higher organisms? Not necessarily. The generation and accumulation of ERCs may be viewed as the molecular read-out of a breach in genomic silencing that leads to aging in yeast. However, I imagine that in other organisms different read-outs are possible. The most obvious of these is the inappropriate gene expression that would result from a loss of silencing (Fig. 4).