Age-associated and tissue-specific decline in autophagic activity in the nematode C. elegans

Abstract

Macroautophagy/autophagy is a cellular recycling process that is required for the extended life span observed in many longevity paradigms, including in the nematode C. elegans. However, little is known regarding the spatiotemporal changes in autophagic activity in such long-lived mutants as well as in wild-type animals during normal aging. In a recent study, we report that autophagic activity decreases with age in several major tissues of wild-type C. elegans, including the intestine, body-wall muscle, pharynx, and nerve-ring neurons. Moreover, long-lived daf-2/insulin-signaling mutants and glp-1/Notch receptor mutants display increased autophagic activity, yet with different time- and tissue-specific differences. Notably, the intestine appears to be a critical tissue in which autophagy contributes to longevity in glp-1, but not in daf-2 mutants. Our findings indicate that autophagic degradation is reduced with age, possibly with distinct kinetics in different tissues, and that long-lived mutants increase autophagy in a tissue-specific manner, resulting in increased life span.

Keywords: Atg8/LC3/LGG-1; C. elegans; aging; autophagy; daf-2; glp-1; tissue-specificity.

Figure 1.

Spatiotemporal analysis of autophagic activity in C. elegans. (A) Different LGG-1/Atg8 reporters were used in combination with bafilomycin A₁ (BafA) to quantify fluorescent puncta as a readout for autophagosomes (AP) and/or autolysosomes (AL) to assess autophagic activity in tissues of C. elegans (i.e., intestine, pharynx [the foregut], body-wall muscle, and neurons. (B) Assessment of autophagic activity in young (top) and old wild-type (bottom) animals shows an age-associated decline. This trend was seen in all tissues, albeit with different kinetics. (C) Assessment of autophagic activity in long-lived mutants (i.e., in DAF-2/insulin/IGF-1 receptor daf-2(e1370) and GLP-1/Notch receptor glp-1(e2144) mutants) indicate a general increase in autophagic activity in young (top) and old (bottom) animals, compared to wild-type, and showed age- and tissue-specific differences between the 2 long-lived mutants. Future experiments are needed to directly test autophagic activity in C. elegans. See text for details. PG, phagophore.