Dietary restriction (DR) is a robust means of extending adult lifespan and postponing age-related disease in many species, including yeast, worms, flies and rodents1,2. Studies of the genetic requirements for lifespan extension by DR in the nematode Caenorhabditis elegans (C. elegans) have implicated a number of key players in this process3–5, including the nutrient-sensing target of rapamycin (TOR) pathway6 and the Foxa transcription factor PHA-47. However, little is known about the metabolic signals that coordinate the organismal response to DR and maintain homeostasis when nutrients are limited. The endocannabinoid (EC) system is an excellent candidate to play such a role given its involvement in regulating nutrient intake and energy balance8. Despite this, a direct role for EC signaling in DR or lifespan determination has yet to be demonstrated, in part due to the apparent absence of EC signaling pathways in model organisms that are amenable to lifespan analysis9. N-acylethanolamines (NAEs) are lipid-derived signaling molecules, which include the mammalian EC arachidonoyl ethanolamide (AEA). Here we identify NAEs in C. elegans, show that NAE abundance is reduced under DR and that NAE deficiency is sufficient to extend lifespan through a DR mechanism requiring PHA-4. Conversely, dietary supplementation with the nematode NAE eicosapentaenoyl ethanolamide (EPEA) not only inhibits DR-induced lifespan extension in wild type animals, but also suppresses lifespan extension in a TOR pathway mutant. This demonstrates a role for NAE signaling in aging and suggests that NAEs represent a signal that coordinates nutrient status with metabolic changes that ultimately determine lifespan.

Helenius and colleagues proposed over twenty-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new type of molecular chaperone- the carbohydrate binding chaperones, calnexin and calreticulin. While the originally established basics for this lectin chaperone binding cycle holds true today, there has been a number of important advances that have expanded our understanding of its mechanisms of action, role in protein homeostasis, and its connection to disease states that are highlighted in this review.

Background:The ER is organized into subdomains containing large protein complexes that help to perform a variety of functions. Results: TMTC1 and TMTC2 are ER membrane proteins with large TPR-containing adapter domains that mediate associations with SERCA2B. Conclusion: TMTC1 and TMTC2 are ER adapter proteins that influence intracellular calcium levels. Significance: TMTC1 and TMTC2 are regulators of calcium homeostasis.

The C. elegans germline and somatic gonad are actively developing until the animal reaches adulthood, and then continue to undergo striking changes as the animal ages. Reported changes include a depletion of available sperm, a decrease in oocyte quality up till mid-life, a reduction in germline nuclei, a decrease in fertility, and an accumulation of DNA in the midbody of aging C. elegans. Here, we have focused on the aging gonad in old animals, and show in detail that the aging gonad undergoes a massive uterine growth composed of endoreduplicating oocytes, yolk, and expanses of chromatin. We use a novel series of imaging techniques in combination with histological methodology for reconstructing aged worms in 3-dimensions, and show in old animals growing masses swelling inside the uterus to occupy most of the diameter of the worm. We link this accelerated growth to the cep-1/p53 tumor suppressor. Because cep-1 is required for DNA damage induced apoptosis, and daf-2 limits longevity, these results suggest a role for age-related DNA damage in dysplastic uterine growths, which in some respects resemble premalignant changes that can occur in aging mammals.

Here we characterize TMTC3 as an ER, polytopic membrane protein with C-terminal luminal-facing TPRs, and an O-mannosyltransferase of E-cadherin. O-mannosylation of cadherins by TMTC3 affects cellular adherence, E-cadherin homophilic binding, and embryonic gastrulation, helping to explain the basis of a number of TMTC3-associated disease variants.