Modulation of caveolae by insulin/IGF-1 signaling regulates aging of Caenorhabditis 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. Here, we report 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.

Neuropeptide signaling and SKN-1 orchestrate differential responses of the proteostasis network to dissimilar proteotoxic insults.

The protein homeostasis (proteostasis) network (PN) encompasses mechanisms that maintain proteome integrity by controlling various biological functions. Loss of proteostasis leads to toxic protein aggregation (proteotoxicity), which underlies the manifestation of neurodegeneration. How the PN responds to dissimilar proteotoxic challenges and how these responses are regulated at the organismal level are largely unknown. Here, we report that, while torsin chaperones protect from the toxicity of neurodegeneration-causing polyglutamine stretches, they exacerbate the toxicity of the Alzheimer's disease-causing Aß peptide in neurons and muscles. These opposing effects are accompanied by differential modulations of gene expression, including that of three neuropeptides that are involved in tailoring the organismal response to dissimilar proteotoxic insults. This mechanism is regulated by insulin/IGF signaling and the transcription factor SKN-1/NRF. Our work delineates a mechanism by which the PN orchestrates differential responses to dissimilar proteotoxic challenges and points at potential targets for therapeutic interventions.

The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans.

Although aging-regulating pathways were discovered a few decades ago, it is not entirely clear how their activities are orchestrated, to govern lifespan and proteostasis at the organismal level. Here, we utilized the nematode Caenorhabditis elegans to examine whether the alteration of aging, by reducing the activity of the Insulin/IGF signaling (IIS) cascade, affects protein SUMOylation. We found that IIS activity promotes the SUMOylation of the germline protein, CAR-1, thereby shortening lifespan and impairing proteostasis. In contrast, the expression of mutated CAR-1, that cannot be SUMOylated at residue 185, extends lifespan and enhances proteostasis. A mechanistic analysis indicated that CAR-1 mediates its aging-altering functions, at least partially, through the notch-like receptor glp-1. Our findings unveil a novel regulatory axis in which SUMOylation is utilized to integrate the aging-controlling functions of the IIS and of the germline and provide new insights into the roles of SUMOylation in the regulation of organismal aging.