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Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin. Elucidating the molecular mechanism of metformin regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases. As humans are living for longer, age-related diseases – including cancer, diabetes, cardiovascular diseases and cognitive disorders – are becoming more common. Many research groups are therefore trying to find drugs that might prevent these diseases or make them less harmful. A drug called metformin has been shown to extend the healthy lifespan of animals such as mice and the roundworm Caenorhabditis elegans. The drug is also currently used to treat type 2 diabetes in humans and may help to prevent some other age-related diseases. However, it is still not clear exactly what effects metformin has on cells. Healthy cells need to perform many ‘metabolic’ processes to produce the molecules necessary for survival. Cell compartments called lysosomes play a role in many of these processes because they digest unneeded biological molecules. Through a combination of biochemical and genetic experiments involving C. elegans and human cells, Chen, Ou et al. found that metformin coordinates two metabolic pathways that both depend on lysosomes. Metformin reduces the activity of a pathway (called mTOR) that boosts cell growth and the metabolic processes that build complex molecules. At the same time, the drug activates a metabolic pathway (called AMPK) that breaks down complex molecules. Overall, therefore, metformin organizes a switch from a more growth-promoting state to a more growth-restricting state. Before metformin can be used more widely to treat human aging and age-related diseases, we need to understand how it works in even more detail. Further studies are required to discover which proteins metformin acts on inside cells, and a clinical trial has also been proposed to measure metformin’s effects on healthy human aging and age-related diseases.

Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response （UPRmr） and the cell non-autonomous modulation of longevity. However, the mechanism by which the nervous system senses mitochondrial stress and communicates to the distal tissues to induce UPRmt remains unclear. Here we employ the tissue-specific CRISPR-Cas9 approach to disrupt mitochondrial function only in the nervous system of Caenorhabditis elegans, and reveal a cell non-autonomous induction of UPRmt in peripheral cells. We further show that a neural sub-circuit composed of three types of sensory neurons, and one interneuron is required for sensing and transducing neuronal mitochondrial stress. In addition, neuropeptide FLP-2 functions in this neural sub-circuit to signal the non-autonomous UPRmt. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress re- sponse in the nervous system.

The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPR mt ) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPR mt . HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPR mt , innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPR mt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPR mt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPR mt ). Here the authors show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC), coordinates with the genome organizer DVE-1 to activate UPR mt and modulate mitochondrial homeostasis.

N6-methyldeoxyadenine (6mA), a major type of DNA methylation in bacteria, represents a part of restriction-modification systems to discriminate host genome from invader DNA 1 . With the recent advent of more sensitive detection techniques, 6mA has also been detected in some eukaryotes 2 – 8 . However, the physiological function of this epigenetic mark in eukaryotes remains elusive. Heritable changes in DNA 5mC methylation have been associated with transgenerational inheritance of responses to a high-fat diet 9 , thus raising the exciting possibility that 6mA may also be transmitted across generations and serve as a carrier of inheritable information. Using Caenorhabditis elegans as a model, here we report that histone H3K4me3 and DNA 6mA modifications are required for the transmission of mitochondrial stress adaptations to progeny. Intriguingly, the global DNA 6mA level is significantly elevated following mitochondrial perturbation. N6-methyldeoxyadenine marks mitochondrial stress response genes and promotes their transcription to alleviate mitochondrial stress in progeny. These findings suggest that 6mA is a precisely regulated epigenetic mark that modulates stress response and signals transgenerational inheritance in C. elegans . Ma et al. show that exposure of Caenorhabditis elegans to mitochondrial stress triggers stress adaptation in offspring, which is mediated by 6mA DNA modification at mitochondrial unfolded-protein-response genes.

Primordial germ cells (PGCs) play a crucial role in transmitting genetic information to the next-generation. In chickens, genetically edited PGCs can be propagated in vitro and subsequently transplanted into recipient embryos to produce offspring with desired genetic traits. However, during early embryogenesis, the effects of external conditions on PGC migration through the vascular system to the gonads have yet to be explored, which may affect the efficiency of preparing gene-edited chickens. In this study, we investigated the effects of hyperthermia on the biological characteristics and migration of chicken PGCs. A gonad-derived PGC line of White Leghorn (WLH) chicken was established and verified through PAS staining and immunofluorescence of PGC-specific proteins. To visually observe PGC migration in vivo , GFP-positive PGCs were prepared and locations of chimeras were validated. Cell viability, glycogen granule contents, and mRNA expression levels of pluripotency markers ( NANOG and POUV ), germ cell-specific markers ( DAZL and CVH ), and telomerase reverse transcriptase ( TERT ) were reduced in PGCs cultured under high temperatures (43°C for 12, 24, and 48 h). After the heat treatment of donor PGCs (43°C) or recipient embryos (39.5°C), GFP-positive PGCs in gonads were rarely observed. Taken together, our results underscore the negative effects of hyperthermia on the biological characteristics and migration of chicken PGCs, which provides valuable insights for the implementation of PGC-based gene editing techniques in chickens.

A set of high-quality pan-genomes would help identify important genes that are still hidden/incomplete in bird reference genomes. In an attempt to address these issues, we have assembled a de novo chromosome-level reference genome of the Silkie ( Gallus gallus domesticus ), which is an important avian model for unique traits, like fibromelanosis, with unclear genetic foundation. This Silkie genome includes the complete genomic sequences of well-known, but unresolved, evolutionarily, endocrinologically, and immunologically important genes, including leptin , ovocleidin-17, and tumor-necrosis factor -α . The gap-less and manually annotated MHC (major histocompatibility complex) region possesses 38 recently identified genes, with differentially regulated genes recovered in response to pathogen challenges. We also provide whole-genome methylation and genetic variation maps, and resolve a complex genetic region that may contribute to fibromelanosis in these animals. Finally, we experimentally show leptin binding to the identified leptin receptor in chicken, confirming an active leptin ligand-receptor system. The Silkie genome assembly not only provides a rich data resource for avian genome studies, but also lays a foundation for further functional validation of resolved genes. A chromosome-level genome for the Silkie chicken ( Gallus gallus domesticus ) provides insight into both the basis of fibromelanosis in these animals and, more broadly, unresolved genes in genome assemblies for related chicken subspecies.

Background Fabry disease (FD) is an X-linked, hereditary dysfunction of glycosphingolipid storage caused by mutations in the GLA gene encoding alpha-galactosidase A enzyme. In rare cases, FD may coexist with immunoglobulin A nephropathy (IgAN). We describe a case of concurrent FD, IgAN, and dilated cardiomyopathy-causing mutations in the TTN and BAG 3 genes, which has not been reported previously. Case presentation A 60-year-old female patient was admitted with a one-week history of facial and lower-limb edema, two-year history of left ventricular hypertrophy and sinus bradycardia, and recurring numbness and pain in three lateral digits with bilateral thenar muscle atrophy. Renal biopsy revealed concurrent FD (confirmed via an alpha-galactosidase A enzyme assay, Lyso-GL-3 quantification, and GLA gene sequencing) and IgAN. Heterozygous mutations in the TTN (c.30,484 C > A;p.P10162T) and BAG 3 (c.88 A > G;p.I30V) genes were observed. The patient reported that two of her brothers had undergone kidney transplantation; one died suddenly at 60 years of age, and the other required a cardiac pacemaker. The 35-year-old son of the patient was screened for the GLA gene mutation and found to be positive for the same mutation as the patient. The patient was administered oral losartan (50 mg/day). Enzyme replacement therapy was refused due to financial reasons. Her renal and cardiac functions were stable yet worth closely monitoring during follow-up. Conclusion The family history of patients with concurrent heart and renal diseases should be assessed in detail. Genetic testing and histological examinations are essential for diagnosing FD with IgAN.