Xbp1 Upregulation Extends Life in Flies
The fly transcription factor xbp1 has been connected to improved cell maintenance resulting from calorie restriction and similar interventions. Researchers here dig into some of the biochemistry, finding that xbp1 upregulation produces different positive effects in different tissues, but overall acts to modestly slow aging and extend life span. This research is characteristic of the sort of exploration of biochemistry that results from studies of calorie restriction, as the changes produced in cell function are extensive. There is a great deal of ground to cover and only so many researchers. We might expect a full understanding of the response to calorie restriction to remain a work in progress even as we move into a world in which rejuvenation therapies of various sorts result from other lines of research and development.
Transcription factors (TFs) regulate gene expression and impact on a number of aging drivers, thus playing a crucial role in molding the longevity of an animal. Xbp1 is an evolutionary conserved TF that acts in the IRE1 branch of the endoplasmic reticulum unfolded protein response pathway (UPRER) and has a key role in maintaining cellular proteostasis.
Cellular ability to maintain the health of the proteome (proteostasis) declines with age, in part due to blunted activation and compromised capacity of the proteostasis-ensuring pathways, such as UPRER. Indeed, studies in worms have shown that Xbp1s overexpression solely in the intestine or pan-neuronally can increase lifespan. In both cases, Xbp1s stimulates the activation of UPRER in older animals. The lifespan extension is coupled with a metabolic shift and increased lysosomal activity in the intestine, which acts in concert with UPRER activation to maintain proteostasis. Indeed, Xbp1 is also required for the longevity and improved ER stress resistance of a daf2 mutant. Hence, Xbp1 with its canonical UPRER role contributes to longevity in worms.
Our recent work identified a pro-longevity effect of Xbp1 in Drosophila, where we found that Xbp1s overexpression in the gut and fat body can extend lifespan. In the current study we further characterize the role of Xbp1 in fly longevity. Surprisingly, Xbp1s induction triggered distinct gene expression programs in the two organs. Xbp1s's activity in the gut aligned with its canonical role in activating UPRER, and the activation of Xbp1s solely in the intestinal stem cells was sufficient to increase lifespan. In the fat body, Xbp1s regulated genes involved in metabolism and this activity was also sufficient to promote longevity.