Manipulation of Behavioral Decline in Caenorhabditis elegans with the Rag GTPase raga-1

Abstract

Normal aging leads to an inexorable decline in motor performance, contributing to medical morbidity and decreased quality of life. While much has been discovered about genetic determinants of lifespan, less is known about modifiers of age-related behavioral decline and whether new gene targets may be found which extend vigorous activity, with or without extending lifespan. Using Caenorhabditis elegans, we have developed a model of declining neuromuscular function and conducted a screen for increased behavioral activity in aged animals. In this model, behavioral function suffers from profound reductions in locomotory frequency, but coordination is strikingly preserved until very old age. By screening for enhancers of locomotion at advanced ages we identified the ras-related Rag GTPase raga-1 as a novel modifier of behavioral aging. raga-1 loss of function mutants showed vigorous swimming late in life. Genetic manipulations revealed that a gain of function raga-1 curtailed behavioral vitality and shortened lifespan, while a dominant negative raga-1 lengthened lifespan. Dietary restriction results indicated that a raga-1 mutant is relatively protected from the life-shortening effects of highly concentrated food, while RNAi experiments suggested that raga-1 acts in the highly conserved target of rapamycin (TOR) pathway in C. elegans. Rag GTPases were recently shown to mediate nutrient-dependent activation of TOR. This is the first demonstration of their dramatic effects on behavior and aging. This work indicates that novel modulators of behavioral function can be identified in screens, with implications for future study of the clinical amelioration of age-related decline.

Author Summary

As humans and animals age, there is an inevitable decrease in functional capacity. Elderly individuals can suffer from a decline in motor function, or the ability to move. Genetic studies in model organisms have led to the identification of genes that can prolong lifespan. Elongation of lifespan is less appealing, however, if there is not also an extension of vitality or enhanced functionality. Here, we have used a genetic model organism, the nematode worm Caenorhabditis elegans, to screen for mutations that result in enhanced vitality in older animals. We identified a new modifier of the aging of motor function, RAGA-1, a protein present in species from worms and fruit flies to humans. Animals with a raga-1 mutation move more vigorously at advanced ages and also live longer, on average, than wild-type. In contrast, animals engineered with an excessively active version of RAGA-1 show decreases in behavioral activity earlier in life than wild-type and a strikingly shortened lifespan. This offers the possibility that manipulating raga-1 could also produce beneficial effects, such as enhanced vitality, in aging humans.