Dietary restriction but not rapamycin extends disease onset and survival of the H46R/H48Q mouse model of ALS

Abstract

Dietary restriction (DR) and rapamycin (Rapa) have been shown to increase the lifespan of a variety of organisms leading to the speculation that these interventions increase lifespan through related mechanisms. However, both these interventions have a detrimental effect in the G93A mutant mouse model of amyotrophic lateral sclerosis (ALS). Our previous work indicated that different ALS SOD1 mutant mouse models differ in disease pathogenesis; therefore in this study we measured the effect of DR and Rapa in a second ALS mutant mouse model (the H46R/H48Q mutant). Interestingly, in mice expressing this mutant SOD1 protein, DR significantly delays disease onset and extends lifespan, while Rapa has no effect. These findings suggest that: (1) the effect of DR in ALS is not mediated through pathways common with Rapa, (2) the deleterious effect of DR and Rapa in the G93A ALS mouse model may not be universal to disease caused by all SOD1 mutations, and (3) the results reinforce our previous conclusions that the pathogenic mechanisms in G93A and H46R/H48Q mice are distinct.