IIS-mediated modulation of DIGs proteome in C. elegans.

Reducing insulin/IGF-1 signaling (IIS) extends lifespan, promotes protein homeostasis (proteostasis) and elevates stress resistance of worms, flies and mammals. How these functions are orchestrated across the organism is only partially understood. One prominent group of IIS-regulated encode for lipid metabolizing enzymes. Thus, we asked whether IIS reduction modulates the protein content and functionality of membranal lipid assemblies. We discovered that in the nematode Caenorhabditis elegans, the IIS positively regulates the expression of caveolin-1 (cav-1), a gene which is primarily expressed in neurons of the adult worm and underlies the formation of caveolae, a subtype of lipid microdomains that serve as platforms for signaling complexes. Accordingly, IIS reduction lowers cav-1 expression and lessens the quantity of neuronal caveolae. Reduced cav-1 expression extends lifespan and mitigates toxic protein aggregation by modulating the expression of aging-regulating and signaling-promoting genes. Our findings define caveolae as aging-governing signaling centers and underscore the potential for cav-1 as a novel therapeutic target for the promotion of healthy aging.