Mitogen-activated protein kinases, Fus3 and Kss1, regulate chronological lifespan in yeast

Using a systems-based approach, we have identified several genes not previously evaluated for a role(s) in chronological aging. Here, we have thoroughly investigated the chronological lifespan (CLS) of three of these genes (FUS3, KSS1 and HOG1) and their protein products, each of which have well-defined cell signaling roles in young cells. The importance of FUS3 and KSS1 in CLS are largely unknown and analyzed here for the first time. Using both qualitative and quantitative CLS assays, we show that deletion of any of the three MAPK's increases yeast lifespan. Furthermore, combined deletion of any MAPK and TOR1, most prominently fus3Δ/tor1Δ, produces a two-stage CLS response ending in lifespan increase greater than that of tor1Δ. Similar effects are achieved upon endogenous expression of a non-activatable form of Fus3. We speculate that the autophagy-promoting role of FUS3, which is inherently antagonistic to the role of TOR1, may in part be responsible for the differential aging phenotype of fus3Δ/tor1Δ. Consistent with this notion we show that nitrogen starvation, which promotes autophagy by deactivating Tor1, results in decreased CLS if FUS3 is deleted. Taken together, these results reveal a previously unrealized effect of mating-specific MAPKs in the chronological lifespan of yeast.