Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen. From this screen, we identified 30 novel regulators of post-reproductive longevity, including Through downstream analysis of, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as , strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.

Chromatin regulators play important roles in the safeguarding of cell identities by opposing the induction of ectopic cell fates and, thereby, preventing forced conversion of cell identities by reprogramming approaches. Our knowledge of chromatin regulators acting as reprogramming barriers in living organisms needs improvement as most studies use tissue culture. We used Caenorhabditis elegans as an in vivo gene discovery model and automated solid-phase RNA interference screening, by which we identified 10 chromatin-regulating factors that protect cells against ectopic fate induction. Specifically, the chromodomain protein MRG-1 safeguards germ cells against conversion into neurons. MRG-1 is the ortholog of mammalian MRG15 (MORF-related gene on chromosome 15) and is required during germline development in C. elegans. However, MRG-1’s function as a barrier for germ cell reprogramming has not been revealed previously. Here, we further provide protein-protein and genome interactions of MRG-1 to characterize its molecular functions. Conserved chromatin regulators may have similar functions in higher organisms, and therefore, understanding cell fate protection in C. elegans may also help to facilitate reprogramming of human cells.

Cell-fate reprograming is at the heart of development, yet very little is known about the molecular mechanisms promoting or inhibiting reprograming in intact organisms. In the C. elegans germline, reprograming germ cells into somatic cells requires chromatin perturbation. Here, we describe that such reprograming is facilitated by GLP-1/Notch signaling pathway. This is surprising, since this pathway is best known for maintaining undifferentiated germline stem cells/ progenitors. Through a combination of genetics, tissue-specific transcriptome analysis, and functional studies of candidate genes, we uncovered a possible explanation for this unexpected role of GLP-1/Notch. We propose that GLP-1/Notch promotes reprograming by activating specific genes, silenced by the Polycomb repressive complex 2 (PRC2), and identify the conserved histone demethylase UTX-1 as a crucial GLP-1/Notch target facilitating reprograming. These findings have wide implications, ranging from development to diseases associated with abnormal Notch signaling.

Asymmetric cell divisions produce daughter cells with distinct developmental fates, therefore representing a key mechanism of tissue and organ differentiation during animal development (Betschinger and Knoblich, 2004;Roegiers and Jan, 2004; Gönczy, 2008). Cell commitment to a particular fate depends on establishment of a polarity axis, orientation of mitotic spindle along this axis and asymmetric segregation of cell-fate determinants. These processes are ensured by precise spatial and temporal cellular signaling. The Caenorhabditis elegans model has been instrumental for understanding the genetics and molecular biology of cell-fate determination, because worm development relies heavily on asymmetric cell divisions (Sulston et al., 1983;Sulston and Horvitz, 1977). Signal-transduction pathways including Notch, Wnt/β-catenin and G-protein signaling regulate asymmetric cell divisions during early embryogenesis, differentiation of the epidermal stem cells, the somatic gonad and the germline, and morphogenesis of the vulva (Gönczy, 2008;Kimble and Crittenden, 2007;Mizumoto and Sawa, 2007b).The epidermal stem cells in C. elegans, known as the seam cells, provide an excellent system in which to study asymmetric cell divisions during postembryonic development. The seam cells divide asymmetrically to produce a copy of themselves and a differentiated cell, either a hypodermal cell or a neuron, depending on the seamcell position (Sulston and Horvitz, 1977). The posterior seam cells V5, V6 and T are extensively studied. Already at its first division the T seam cell generates anterior (T.a) and posterior (T.p) daughters with distinct fates. The T.a daughter assumes a hypodermal fate, whereas T.p gives rise to neural cells. Divisions of the T-seam-cell lineage differ between hermaphrodites and males. At the L2 stage in males, the T.ap (posterior daughter of T.a) cell together with posterior daughters of the V5 and V6 seam cells begins to generate male-specific sensory rays that are essential for mating.Differentiation of the T seam cell relies on proper establishment of its polarity, which is controlled by the Wnt/β-catenin asymmetry pathway (Herman, 2002;Herman and Wu, 2004;Mizumoto and Sawa, 2007b). A LIN-44/Wnt (C. elegans/ mammalian homolog) signal from the epidermal tail tip cells activates its receptor LIN-17/Frizzled, localized to the posterior membrane of the T seam cell (Wu and Herman, 2007). The signal ensures asymmetric distribution of APR-1/APC, PRY-1/Axin, LIT-1/NLK and WRM-1/β-catenin in the T seam cell (Mizumoto and Sawa, 2007a;Mizumoto and Sawa, 2007b), leading to uneven inheritance of these cell-fate determinants by the T.a and T.p daughters. In the T.p cell nucleus, abundant WRM-1/β-catenin and LIT-1/NLK facilitate export of the POP-1/TCF transcription factor from the nucleus. The remaining POP-1/TCF associates with its cofactor SYS-1/β-catenin (Kidd et al., 2005), which is enriched in the T.p nucleus, and activates neural-fate-promoting genes, exemplified by tlp-1. By contrast, the anterior T.a daughter is ...