SIR4-42 suppresses aging at the rDNA by preventing rDNA instability, which leads to rDNA circles that kill cells, and SIR2 can suppress this instability.

“The extra chromosomal circles (ERCs) that cause aging, we discovered in 1996-1997, that stay within the mother cell and don’t get passed on, are an example of how the daughter DNA can stay immortal”

“ERCs are pieces of ribosomal DNA that pop out of the genome and form self-replicating circles. As yeast mother cells age, these circles accumulate dramatically, clogging the nucleus and eventually limiting how many times the cell can divide”

“In this 1997 Cell paper, Lenny and I hypothesized that SIR4-42 was suppressing a process of aging at the rDNA (nucleolus), which we showed was rDNA instability, leading to rDNA circles that amplify and kill cells. SIR2 could suppress that instability...”