Spatiotemporal regulation of autophagy during <i>Caenorhabditis elegans</i> aging.

Abstract

Autophagy has been linked to longevity in many species, but the underlying mechanisms are unclear. Using a GFP-tagged and a new tandem-tagged Atg8/LGG-1 reporter, we quantified autophagic vesicles and performed autophagic flux assays in multiple tissues of wild-type <i>Caenorhabditis elegans</i> and long-lived <i>daf-2</i>/insulin/IGF-1 and <i>glp-1</i>/Notch mutants throughout adulthood. Our data are consistent with an age-related decline in autophagic activity in the intestine, body-wall muscle, pharynx, and neurons of wild-type animals. In contrast, <i>daf-2</i> and <i>glp-1</i> mutants displayed unique age- and tissue-specific changes in autophagic activity, indicating that the two longevity paradigms have distinct effects on autophagy during aging. Although autophagy appeared active in the intestine of both long-lived mutants, inhibition of intestinal autophagy significantly abrogated lifespan extension only in <i>glp-1</i> mutants. Collectively, our data suggest that autophagic activity normally decreases with age in <i>C. elegans,</i> whereas <i>daf-2</i> and <i>glp-1</i> long-lived mutants regulate autophagy in distinct spatiotemporal-specific manners to extend lifespan.