Life span extension by dietary restriction is reduced but not abolished by loss of both SIR2 and HST2 in Podospora anserina

Dietary restriction (DR) extends life span of many organisms, from yeast to mammals. The question of whether or not the SIR2 protein functions to mediate life span extension in response to DR remains debated. In this paper, we studied the relationship between SIR2 and DR in the filamentous fungus Podospora anserina. We show that the loss of PaSir2, PaHst2 or PaPnc1 does not alter life span under standard conditions. PaHst2 is the closest paralog of PaSir2 and the ortholog of yeast HST2 and PaPnc1 is the ortholog of the yeast PNC1 which encodes a nicotinamidase that deaminates nicotinamide, a natural inhibitor of SIR2. As observed for other organisms, overexpression of PaSir2 weakly increases life span under standard condition. Under DR conditions, deletion of the PaSir2 or PaHst2 genes induce a significant reduction in life span extension, while the double mutant strongly reduces life span extension. However, a clear response to DR subsists in the double mutant, demonstrating that DR acts through a SIR2/HST2 independent pathway.