Intestinal IRE1 Required for Calorie Restriction to Extend Life in Flies
Calorie restriction, also known as dietary restriction, improves health and extends life in near all species and lineages tested to date. The evidence for health benefits in humans is solid, those benefits being sizable in comparison to what today's medical technology can achieve for basically healthy people, but the effects on life span are thought to be modest in our case. Calorie restriction makes sweeping changes to near every aspect of cellular metabolism, which means that pinning down how exactly it works under the hood is a challenging problem. In order to fully understand calorie restriction, it is more or less necessary to fully understand cellular metabolism and its relationship with aging. That is an enormous project, one that will likely still be in progress with decades to go when the first SENS rejuvenation therapies are widely available. It is fortunate indeed that full understanding of our biochemistry isn't needed to produce effective medicine, and that researchers can make significant progress given what is known of the root causes of aging today.
For present investigations of calorie restriction, after two decades of increasing investment, many research teams are still at the stage of deleting specific genes and proteins one at a time to find those that are important. Theories have been sketched in at the high level, but at the low level of cellular biochemistry, the gaps in understanding are enormous. The research noted here is an example of the type, but since it involves intestinal function in flies, additional caution is warranted when considering possible relevance to human calorie restriction. In recent years, researchers have demonstrated that intestinal function occupies an central position in the processes of aging in flies, far more so than appears to be the case in higher animals such as mammals.
Dietary restriction (DR), defined as a regime of limited protein intake without malnutrition, leads to increased lifespan and health span in all tested model organisms. One of the conserved fundamental adaptations to DR, or to other low-nutrient conditions such as fasting, involves a metabolic shift toward increased triglyceride (TG) utilization. DR increases the conversion of dietary carbohydrates into lipids, elevates fat storage, and accelerates lipid turnover in flies, which appears to have a profound positive impact on longevity. Drosophila has emerged as an excellent model organism to explore the mechanisms driving diet- and/or age-related changes in lipid metabolism. Importantly, Drosophila provides critical technical advantages that allow characterizing tissue-tissue coordination during metabolic adaptation. While lipids are stored in the fat body and transferred to oenocytes for mobilization, the Drosophila intestine also contributes to lipid synthesis and cholesterol homeostasis. The Drosophila intestine plays a key role in modulating health span by modulation of immune responses, metabolic homeostasis, and stress signaling.
The adult intestine is regenerated by intestinal stem cells (ISCs), which divide to replace functional enterocytes (ECs) and enteroendocrine cells when needed. The intestine is also central to longevity in Drosophila, as gut function rapidly declines in aging flies. Furthermore, in old flies, the ability of the intestine to generate and store lipids is severely compromised, and restoring the adequate metabolic function of this tissue increases health span. The age-related decline in intestinal function in flies is a consequence of complex inflammatory conditions that are associated with increased protein misfolding. How endoplasmic reticulum (ER) stress and ER stress response pathways influence diet- and/or age-related metabolic function of the intestinal epithelium remains unclear.
The ER stress transducer IRE1 triggers one of the three signaling pathways engaged by ER stress. Interestingly, IRE1 also influences lipid homeostasis. IRE1 is also required for S6K- and HIF-1-mediated lifespan extension under DR in C. elegans, though the mechanisms mediating this effect remain unclear. During ER stress, IRE1 dimerizes and splices the mRNA of XBP1, leading to translation of a functional transcription factor that induces genes involved in ER biogenesis, protein folding, and degradation to restore ER homeostasis. The role of IRE1/XBP1 in the regulation of lipid homeostasis has not been explored in the context of a DR intervention or during conditions of obligatory lipid recruitment, such as prolonged fasting/starvation. Here, we identify IRE1 as a player in DR-induced lifespan extension in flies. Our data suggest that IRE1 is required for the metabolic shift toward elevated TG turnover occurring during DR and that the absence of IRE1 is detrimental under this dietary intervention. Moreover, we identify the transcription factor Sugarbabe as a downstream target of the IRE1/XBP1 module that is required for increased lipid turnover under DR. Our results provide insights into physiological mechanisms that link tissue-specific metabolic adaptation to lifespan extension under DR conditions.