Epithelial homeostasis in the posterior midgut of Drosophila is maintained by multipotent intestinal stem cells (ISCs). ISCs self-renew and produce enteroblasts (EBs) that differentiate into either enterocytes (ECs) or enteroendocrine cells (EEs) in response to differential Notch (N) activation. Various environmental and growth signals dynamically regulate ISC activity, but their integration with differentiation cues in the ISC lineage remains unclear. Here we identify Notch-mediated repression of Tuberous Sclerosis Complex 2 (TSC2) in EBs as a required step in the commitment of EBs into the EC fate. The TSC1/2 complex inhibits TOR signaling, acting as a tumor suppressor in vertebrates and regulating cell growth. We find that TSC2 is expressed highly in ISCs, where it maintains stem cell identity, and that N-mediated repression of TSC2 in EBs is required and sufficient to promote EC differentiation. Regulation of TSC/TOR activity by N signaling thus emerges as critical for maintenance and differentiation in somatic stem cell lineages.

Cellular responses to extrinsic and intrinsic insults have to be carefully regulated to properly coordinate cytoprotection, repair processes, cell proliferation and apoptosis. Stress signaling pathways, most prominently the Jun-N-terminal Kinase (JNK) pathway, are critical regulators of such cellular responses and have accordingly been implicated in the regulation of lifespan in various organisms. JNK signaling promotes cytoprotective gene expression, but also interacts with the Insulin signaling pathway to influence growth, metabolism, stress tolerance and regeneration. Here, we review recent studies in Drosophila that elucidate the tissue-specific and systemic consequences of JNK activation that ultimately impact lifespan of the organism.

Genetic and pharmacological interventions have successfully extended healthspan and lifespan in animals, but their genetic interventions are not appropriate options for human applications and pharmacological intervention needs more solid clinical evidence. Consequently, dietary manipulations are the only practical and probable strategies to promote health and longevity in humans. Caloric restriction (CR), reduction of calorie intake to a level that does not compromise overall health, has been considered as being one of the most promising dietary interventions to extend lifespan in humans. Although it is straightforward, continuous reduction of calorie or food intake is not easy to practice in real lives of humans. Recently, fasting-related interventions such as intermittent fasting (IF) and time-restricted feeding (TRF) have emerged as alternatives of CR. Here, we review the history of CR and fasting-related strategies in animal models, discuss the molecular mechanisms underlying these interventions, and propose future directions that can fill the missing gaps in the current understanding of these dietary interventions. CR and fasting appear to extend lifespan by both partially overlapping common mechanisms such as the target of rapamycin (TOR) pathway and circadian clock, and distinct independent mechanisms that remain to be discovered. We propose that a systems approach combining global transcriptomic, metabolomic, and proteomic analyses followed by genetic perturbation studies targeting multiple candidate pathways will allow us to better understand how CR and fasting interact with each other to promote longevity.

Regulated Apoptosis (Programmed Cell Death, PCD) maintains tissue homeostasis in adults, and ensures proper growth and morphogenesis of tissues during development of metazoans. Accordingly, defects in cellular processes triggering or executing apoptotic programs have been implicated in a variety of degenerative and neoplastic diseases. Here, we report the identification of DCAF12, an evolutionary conserved member of the WD40-motif repeat family of proteins, as a new regulator of apoptosis in Drosophila. We find that DCAF12 is required for Diap1 cleavage in response to pro-apoptotic signals, and is thus necessary and sufficient for RHG (Reaper, Hid, and Grim)-mediated apoptosis. Loss of DCAF12 perturbs the elimination of supernumerary or proliferation-impaired cells during development, and enhances tumor growth induced by loss of neoplastic tumor suppressors, highlighting the wide requirement for DCAF12 in PCD.

To adapt to and anticipate rhythmic changes in the environment such as daily light-dark and temperature cycles, internal timekeeping mechanisms called biological clocks evolved in a diverse set of organisms, from unicellular bacteria to humans. These biological clocks play critical roles in organisms' fitness and survival by temporally aligning physiological and behavioral processes to the external cues. The central clock is located in a small subset of neurons in the brain and drives daily activity rhythms, whereas most peripheral tissues harbor their own clock systems, which generate metabolic and physiological rhythms. Since the discovery of Drosophila melanogaster clock mutants in the early 1970s, the fruit fly has become an extensively studied model organism to investigate the mechanism and functions of circadian clocks. In this review, we primarily focus on D. melanogaster to survey key discoveries and progresses made over the past two decades in our understanding of peripheral clocks. We discuss physiological roles and molecular mechanisms of peripheral clocks in several different peripheral tissues of the fly.