Condition-dependent effects of knockdown of autophagy on C. elegans longevity

Autophagy is thought to clear damaged cellular constituents that contribute to aging, and several life-extending interventions in model organisms show some degree of autophagy dependence. In C. elegans, inhibiting autophagy can shorten, lengthen or have no effect on lifespan. Differences between published findings likely reflect variability in experimental conditions. Here we investigate the condition dependence of effects on lifespan of RNA-mediated interference (RNAi) knockdown of autophagy pathway components. Effects on several interventions causing a strong Age (increased lifespan) phenotype were examined, including mutation of daf-2 (insulin/IGF-1 receptor). Factors varied included daf-2 mutant allele class, atg gene, temperature and presence of 5-fluoro-2'-deoxyuridine (FUDR). Effects on lifespan of atg RNAi proved to be highly condition dependent. Notably, for most atg genes tested lifespan was not usually reduced more in the long-lived mutant than in the wild-type control. This occurred at 20°C for certain atg genes with daf-2(e1368) but not daf-2(e1370). At 25°C, little reduction in lifespan was seen. However, atg-18 knockdown behaved differently, suppressing daf-2 Age under all conditions, suggesting possible pleiotropic action. Presence of high concentration FUDR caused knockdown of several atg genes to increase lifespan. Thus, depending on experimental conditions, atg knockdown can increase, decrease or have no effect on daf-2 Age. The lack of suppression of Age by atg RNAi in most cases raises questions about the importance of autophagy in daf-2 Age. Moreover, condition dependence of effects creates a risk of possible condition selection bias.