Supplementary Figure 1: Additional examples of tissue-specific CRISPR mutagenesis in wing disc and abdomen. (A) CRISPR mutagenesis of smo in the posterior compartment of the wing imaginal disc. Smo protein was detected by immunohistochemistry. Smo is normally expressed in all wing disc cells, but protein levels are higher in the posterior compartment (see Control (hh-Gal4 UAS-cas9.P2)). In hh-Gal4 UAS-cas9.P2 pCFD6-smo 2x wing discs cells in the posterior compartment express no or reduced levels of Smo, presumably reflecting cells containing only one or no functional smo alleles. (B) CRISPR mutagenesis of sens in the dorsal compartment of wing imaginal discs with ap-Gal4 leads to a loss of Sens expression in most, but not all cells. (C) Mutagenesis of y in the dorsal abdomen.In pnr-Gal4 UAS-cas9.P2 pCFD6-y 2x animals cuticle coloration is uniformly changed in a broad stripe centred around the dorsal midline, compared to control animals ). Note that the strong phenotype mediated by pCFD6-y 2x is in line with the high levels of mutagenesis with this construct reported in Figure 4a. Control hh-Gal4 UAS-cas9.P2 pCFD6-smo 2x

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The intestinal epithelium serves as a dynamic barrier to the environment and integrates a variety of signals, including those from metabolites, commensal microbiota, immune responses and stressors upon ageing. The intestine is constantly challenged and requires a high renewal rate to replace damaged cells in order to maintain its barrier function. Essential for its renewal capacity are intestinal stem cells, which constantly give rise to progenitor cells that differentiate into the multiple cell types present in the epithelium. Here, we review the current state of research of how metabolism and ageing control intestinal stem cell function and epithelial homeostasis. We focus on recent insights gained from model organisms that indicate how changes in metabolic signalling during ageing are a major driver for the loss of stem cell plasticity and epithelial homeostasis, ultimately affecting the resilience of an organism and limiting its lifespan. We compare findings made in mouse and Drosophila and discuss differences and commonalities in the underlying signalling pathways and mechanisms in the context of ageing.

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