Haplotype-resolved 3D chromatin architecture of the hybrid pig.

In diploid mammals, allele-specific three-dimensional (3D) genome architecture may lead to imbalanced gene expression. Through ultradeep in situ Hi-C sequencing of three representative somatic tissues (liver, skeletal muscle, and brain) from hybrid pigs generated by reciprocal crosses of phenotypically and physiologically divergent Berkshire and Tibetan pigs, we uncover extensive chromatin reorganization between homologous chromosomes across multiple scales. Haplotype-based interrogation of multi-omic data revealed the tissue dependence of 3D chromatin conformation, suggesting that parent-of-origin-specific conformation may drive gene imprinting. We quantify the effects of genetic variations and histone modifications on allelic differences of long-range promoter-enhancer contacts, which likely contribute to the phenotypic differences between the parental pig breeds. We also observe the fine structure of somatically paired homologous chromosomes in the pig genome, which has a functional implication genome-wide. This work illustrates how allele-specific chromatin architecture facilitates concomitant shifts in allele-biased gene expression, as well as the possible consequential phenotypic changes in mammals.

Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence.

Aging is a gradual process of natural change that occurs after reaching sexual maturity. It is also a known risk factor for many chronic diseases. Recent research has shown that senolytics can extend the lifespans and health spans of model organisms, and they have also been demonstrated effective in treating age-related diseases. In this study, we conducted a high-throughput screening of 156 drugs that targeted the PI3K/AKT/mTOR pathway to identify potential senolytic medications. Among these drugs, PF-04691502 was selected for further investigation to understand its molecular mechanism of action. Our findings indicate that PF-04691502, a dual inhibitor of PI3K/AKT and mTOR, specifically eliminates senescent cells. It reduces the expression levels of key markers of cellular senescence, such as SA-ß-Gal, senescence-associated secretory phenotypes (SASPs) and p16INK4a. Additionally, PF-04691502 inhibits the phosphorylation of S6K and AKT, leading to the apoptosis of senescent cells. These results suggest that PF-04691502 holds promise as a new senolytic drug. This paper provides important insights into the potential application of PF-04691502 in the study of cell senescence.

Transcriptomic and metabolomic analyses reveal that lemon extract prolongs Drosophila lifespan by affecting metabolism.

Ageing is an evolutionarily conserved and irreversible biological process in different species. Numerous studies have reported that taking medicine is an effective approach to slow ageing. Lemon extract (LE) is a natural extract of lemon fruit that contains a variety of bioactive phytochemicals. Various forms of LE have been shown to play a role in anti-ageing and improving ageing-related diseases. However, studies on the molecular mechanism of LE in Drosophila ageing have not been reported. In this study, we found that 0.05 g/L LE could significantly extend Drosophila lifespan and greatly improve antioxidative and anti-heat stress abilities. Furthermore, transcriptome and metabolome analyses of 10 d flies between the LE-fed and control groups suggested that the differentially expressed gene ppo1 (Prophenoloxidase 1) and metabolite L-DOPA (Levodopa) were co-enriched in the tyrosine metabolism pathway. Overall, our results indicate that affecting metabolism was the main reason for LE extending Drosophila lifespan.

Regulatory mechanism of circular RNAs in neurodegenerative diseases.

BACKGROUND: Neurodegenerative disease is a collective term for a category of diseases that are caused by neuronal dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Circular RNAs (circRNAs) are a class of non-coding RNAs without the 3' cap and 5' poly(A) and are linked by covalent bonds. CircRNAs are highly expressed in brain neurons and can regulate the pathological process of neurodegenerative diseases by affecting the levels of various deposition proteins. AIMS: This review is aiming to suggest that the majority of circRNAs influence neurodegenerative pathologies mainly by affecting the abnormal deposition of proteins in neurodegenerative diseases. METHODS: We systematically summarized the pathological features of neurodegenerative diseases and the regulatory mechanisms of circRNAs in various types of neurodegenerative diseases. RESULTS: Neurodegenerative disease main features include intercellular ubiquitin-proteasome system abnormalities, changes in cytoskeletal proteins, and the continuous deposition of insoluble protein fragments and inclusion bodies in the cytoplasm or nucleus, resulting in impairment of the normal physiological processes of the neuronal system. CircRNAs have multiple mechanisms, such as acting as microRNA sponges, binding to proteins, and regulating transcription. CircRNAs, which are highly stable molecules, are expected to be potential biomarkers for the pathological detection of neurodegenerative diseases such as AD and PD. CONCLUSIONS: In this review, we describe the regulatory roles and mechanisms of circRNAs in neurodegenerative diseases and aim to employ circRNAs as biomarkers for the diagnosis and treatment of neurodegenerative diseases.

The adaptor protein 14-3-3zeta modulates intestinal immunity and aging in Drosophila.

The proteins that coordinate the complex transcriptional networks of aging have not been completely documented. Protein 14-3-3zeta is an adaptor protein that coordinates signaling and transcription factor networks, but its function in aging is not fully understood. Here, we showed that the protein expression of 14-3-3zeta gradually increased during aging. High levels of 14-3-3zeta led to shortened lifespan and imbalance of intestinal immune homeostasis in Drosophila, but the decrease in 14-3-3zeta protein levels by RNAi was able to significantly promote the longevity and intestinal immune homeostasis of fruit flies. Importantly, we demonstrate that adult-onset administration of TIC10, a compound that reduces the aging-related AKT and extracellular signal-regulated kinase (ERK) signaling pathways, rescues the shortened lifespan of 14-3-3zeta-overexpressing flies. This finding suggests that 14-3-3zeta plays a critical role in regulating the aging process. Our study elucidates the role of 14-3-3zeta in natural aging and provides the rationale for subsequent 14-3-3zeta-based antiaging research.

Dynamic chromatin architecture of the porcine adipose tissues with weight gain and loss.

Using an adult female miniature pig model with diet-induced weight gain/weight loss, we investigated the regulatory mechanisms of three-dimensional (3D) genome architecture in adipose tissues (ATs) associated with obesity. We generated 249 high-resolution in situ Hi-C chromatin contact maps of subcutaneous AT and three visceral ATs, analyzing transcriptomic and chromatin architectural changes under different nutritional treatments. We find that chromatin architecture remodeling underpins transcriptomic divergence in ATs, potentially linked to metabolic risks in obesity development. Analysis of chromatin architecture among subcutaneous ATs of different mammals suggests the presence of transcriptional regulatory divergence that could explain phenotypic, physiological, and functional differences in ATs. Regulatory element conservation analysis in pigs and humans reveals similarities in the regulatory circuitry of genes responsible for the obesity phenotype and identified non-conserved elements in species-specific gene sets that underpin AT specialization. This work provides a data-rich tool for discovering obesity-related regulatory elements in humans and pigs.

Nutritional Programming of the Lifespan of Male Drosophila by Activating FOXO on Larval Low-Nutrient Diet.

Nutrition during the developmental stages has long-term effects on adult physiology, disease and lifespan, and is termed nutritional programming. However, the underlying molecular mechanisms of nutritional programming are not yet well understood. In this study, we showed that developmental diets could regulate the lifespan of adult Drosophila in a way that interacts with various adult diets during development and adulthood. Importantly, we demonstrated that a developmental low-yeast diet (0.2SY) extended both the health span and lifespan of male flies under nutrient-replete conditions in adulthood through nutritional programming. Males with a low-yeast diets during developmental stages had a better resistance to starvation and lessened decline of climbing ability with age in adulthood. Critically, we revealed that the activity of the Drosophila transcription factor FOXO (dFOXO) was upregulated in adult males under developmental low-nutrient conditions. The knockdown of dFOXO, with both ubiquitous and fat-body-specific patterns, can completely abolish the lifespan-extending effect from the larval low-yeast diet. Ultimately, we identify that the developmental diet achieved the nutritional programming of the lifespan of adult males by modulating the activity of dFOXO in Drosophila. Together, these results provide molecular evidence that the nutrition in the early life of animals could program the health of their later life and their longevity.

The Expression Pattern of tRNA-Derived Small RNAs in Adult Drosophila and the Function of tRF-Trp-CCA-014-H3C4 Network Analysis.

tRNA-derived small RNAs (tsRNAs) are derived from tRNA and include tRNA halves (tiRNAs) and tRNA fragments (tRFs). tsRNAs have been implicated in a variety of important biological functions, such as cell growth, transcriptional regulation, and apoptosis. Emerging evidence has shown that Ago1-guided and Ago2-guided tsRNAs are expressed at 3 and 30 days in Drosophila and that tRF biogenesis in fruit flies affects tRNA processing and tRNA methylation. However, a wide analysis of tsRNA patterns in different ages of Drosophila have not been reported via the small RNA sequencing method. In the present study, tsRNAs of young (7 days) and old (42 days) Drosophila were sequenced and their expression characteristics were analysed. Then, a specific tRF (named tRF-Trp-CCA-014) was determined and was found to be conserved in fruit flies, mice, and humans. The expression patterns of tRF-Trp-CCA-014 in different tissues and stages of fruit flies and mice, and mouse NIH/3T3 cells were detected. Furthermore, mouse embryonic fibroblast NIH/3T3 cells were used as a model to analyse the function and targets of tRF-Trp-CCA-014. The RNA-seq data of six groups (Mimics, Mimic NC, Inhibitors, Inhibitor NC, Aging (adriamycin), and Control (Normal)) in mouse NIH3T3 cells were analysed. The results showed that the number of tsRNAs at 42 days (417) was more than at 7 days (288); thus, it was enriched with age. tRFs-1 were the most enriched, followed by 5'-tRFs and 3'-tRFs. Twenty-one differentially expressed tsRNAs were identified between 7 days and 42 days. Then, the conserved tRF tRF-Trp-CCA-014 was identified and found to accumulate in aged fruit flies and aged mouse NIH3T3 cells. RNA-seq data showed that most differentially expressed genes were involved in the immune system, cancer: overview, and signal translation. Furthermore, tRF-Trp-CCA-014 was found to bind to the 3'UTR of H3C4 in a dual-luciferase reporter gene assay. tRF-Trp-CCA-014 and H3C4 were detected in the cytoplasm of aged NIH3T3 cells by RNA in situ hybridization. These results suggest that the H3C4 gene is the target of tRF-Trp-CCA-014. This study will advance the current understanding of tRF roles and their implication in Drosophila and mouse studies.

Age-related ceRNA networks in adult Drosophila ageing.

As Drosophila is an extensively used genetic model system, understanding of its regulatory networks has great significance in revealing the genetic mechanisms of ageing and human diseases. Competing endogenous RNA (ceRNA)-mediated regulation is an important mechanism by which circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) regulate ageing and age-related diseases. However, extensive analyses of the multiomics (circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA) characteristics of adult Drosophila during ageing have not been reported. Here, differentially expressed circRNAs and microRNAs (miRNAs) between 7 and 42-day-old flies were screened and identified. Then, the differentially expressed mRNAs, circRNAs, miRNAs, and lncRNAs between the 7- and 42-day old flies were analysed to identify age-related circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA networks in ageing Drosophila. Several key ceRNA networks were identified, such as the dme_circ_0009500/dme_miR-289-5p/CG31064, dme_circ_0009500/dme_miR-289-5p/frizzled, dme_circ_0009500/dme_miR-985-3p/Abl, and XLOC_027736/dme_miR-985-3p/Abl XLOC_189909/dme_miR-985-3p/Abl networks. Furthermore, real-time quantitative PCR (qPCR) was used to verify the expression level of those genes. Those results suggest that the discovery of these ceRNA networks in ageing adult Drosophila provide new information for research on human ageing and age-related diseases.

Complete Mitogenome of Oreolalax Omeimontis Reveals Phylogenetic Status and Novel Gene Arrangement of Archaeobatrachia.

Species of the genus Oreolalax displayed crucial morphological characteristics of vertebrates transitioning from aquatic to terrestrial habitats; thus, they can be regarded as a representative vertebrate genus for this landing phenomenon. But the present phylogenetic status of Oreolalax omeimontis has been controversial with morphological and molecular approaches, and specific gene rearrangements were discovered in all six published Oreolalax mitogenomes, which are rarely observed in Archaeobatrachia. Therefore, this study determined the complete mitogenome of O. omeimontis with the aim of identifying its precise phylogenetic position and novel gene arrangement in Archaeobatrachia. Phylogenetic analysis with Bayesian inference and maximum likelihood indicates O. omeimontis is a sister group to O. lichuanensis, which is consistent with previous phylogenetic analysis based on morphological characteristics, but contrasts with other studies using multiple gene fragments. Moreover, although the duplication of trnM occurred in all seven Oreolalax species, the translocation of trnQ and trnM occurred differently in O. omeimontis to the other six, and this unique rearrangement would happen after the speciation of O. omeimontis. In general, this study sheds new light on the phylogenetic relationships and gene rearrangements of Archaeobatrachia.

Oral and fecal microbiome of confiscated Bengal slow lorises in response to confinement duration.

Slow lorises are small arboreal and nocturnal primates. Due to the illegal trade, a large number of slow lorises were confiscated into wildlife sanctuaries or rescue centers. The re-release has been considered a preferable approach for alleviating the captive pressure, but inappropriate and long-term confinement make it difficult to achieve this goal. In this study, we investigated and compared the fecal and oral microbiome of Bengal slow lorises (Nycticebus bengalensis) under long-term captivity (LC) and short-term captivity (SC) groups based on 16s rRNA high-throughput gene sequencing. The oral microbiome displayed higher Chao1 richness but lower Shannon and Simpson indices than the fecal microbiome. The Bengal slow lorises under long-term captivity had abundant pathogenic genera in both gut and oral microbiomes, such as Desulfovibrio, Actinomyces, Capnocytophaga, Neisseria, and Fusobacterium, while some specific bacterial taxa associated with intestinal balance were more enriched in the SC group. Due to the plant gum scarcity in the diet, both groups had a low abundance of Bifidobacterium. Function profile prediction indicated that the LC group was enriched with genetic information processing and metabolism pathways due to the stable food intake. The increased membrane transport and xenobiotic metabolism and degradation functions in the SC group could be explained by the function of the host microbiome in facilitating adaptation to changing environments and diets. The results demonstrated that the oral microbiome had the potential to be used as a regular surveillance tool. Also, current captive management should be improved to ensure reintroduction success.

Complete Mitogenomes of Polypedates Tree Frogs Unveil Gene Rearrangement and Concerted Evolution within Rhacophoridae.

New developments in sequencing technology and nucleotide analysis have allowed us to make great advances in reconstructing anuran phylogeny. As a clade of representative amphibians that have radiated from aquatic to arboreal habitats, our understanding of the systematic status and molecular biology of rhacophorid tree frogs is still limited. We determined two new mitogenomes for the genus Polypedates (Rhacophoridae): P. impresus and P. mutus. We conducted comparative and phylogenetic analyses using our data and seven other rhacophorid mitogenomes. The mitogenomes of the genera Polypedates, Buergeria, and Zhangixalus were almost identical, except that the ATP8 gene in Polypedates had become a non-coding region; Buergeria maintained the legacy "LTPF" tRNA gene cluster compared to the novel "TLPF" order in the other two genera; and B. buergeri and Z. dennysi had no control region (CR) duplication. The resulting phylogenetic relationship supporting the above gene rearrangement pathway suggested parallel evolution of ATP8 gene loss of function (LoF) in Polypedates and CR duplication with concerted evolution of paralogous CRs in rhacophorids. Finally, conflicting topologies in the phylograms of 185 species reflected the advantages of phylogenetic analyses using multiple loci.

Circular RNAs Involved in the Regulation of the Age-Related Pathways.

Circular RNAs (circRNAs) are a class of covalently circular noncoding RNAs that have been extensively studied in recent years. Aging is a process related to functional decline that is regulated by signal transduction. An increasing number of studies suggest that circRNAs can regulate aging and multiple age-related diseases through their involvement in age-related signaling pathways. CircRNAs perform several biological functions, such as acting as miRNA sponges, directly interacting with proteins, and regulating transcription and translation to proteins or peptides. Herein, we summarize research progress on the biological functions of circRNAs in seven main age-related signaling pathways, namely, the insulin-insulin-like, PI3K-AKT, mTOR, AMPK, FOXO, p53, and NF-κB signaling pathways. In these pathways, circRNAs mainly function as miRNA sponges. In this review, we suggest that circRNAs are widely involved in the regulation of the main age-related pathways and are potential biomarkers for aging and age-related diseases.

VhaAC39-1 regulates gut homeostasis and affects the health span in Drosophila.

Gut homeostasis is a dynamically balanced state to maintain intestinal health. Vacuolar ATPases (V-ATPases) are multi-subunit proton pumps that were driven by ATP hydrolysis. Several subunits of V-ATPases may be involved in the maintenance of intestinal pH and gut homeostasis in Drosophila. However, the specific role of each subunit in this process remains to be elucidated. Here, we knocked down the Drosophila gene VhaAC39-1 encoding the V0d1 subunit of V-ATPases to assess its function in gut homeostasis. Knockdown of VhaAC39-1 resulted in the loss of midgut acidity, the increase of the number of gut microbiota and the impairment of intestinal epithelial integrity in flies. The knockdown of VhaAC39-1 led to the hyperproliferation of intestinal stem cells, increasing the number of enteroendocrine cells, and activated IMD signaling pathway and JAK-STAT signaling pathway, inducing intestinal immune response of Drosophila. In addition, knockdown of VhaAC39-1 caused the disturbance of many physiological indicators such as food intake, triglyceride level and fecundity of flies, which ultimately led to the shortening of the life span of Drosophila. These results shed light on the gut homeostasis mechanisms which would help to identify interventions to promote healthy aging.

Iron Metabolism in Aging and Age-Related Diseases.

Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic and environmental factors. Therefore, it is imperative to investigate the relationship between iron metabolism and aging-related diseases, including neurodegenerative diseases. During aging, the accumulation of nonheme iron destroys the stability of the intracellular environment. The destruction of iron homeostasis can induce cell damage by producing hydroxyl free radicals, leading to mitochondrial dysfunction, brain aging, and even organismal aging. In this review, we have briefly summarized the role of the metabolic process of iron in the body, then discussed recent developments of iron metabolism in aging and age-related neurodegenerative diseases, and finally, explored some iron chelators as treatment strategies for those disorders. Understanding the roles of iron metabolism in aging and neurodegenerative diseases will fill the knowledge gap in the field. This review could provide new insights into the research on iron metabolism and age-related neurodegenerative diseases.

Genetic characterization of nuclear export factor NXT1 and its paralog NXT2 in primates and murine rodents.

Translocation of RNA across the nuclear envelope relies on transport receptors. Receptor nuclear transport factor 2 (NTF2)-like export protein 1 (NXT1 [also called p15 or p15-1]) shuttles between the nucleus and cytoplasm of metazoan cells and contributes to the nuclear export of a diverse spectrum of RNAs. NXT2 (also called p15-2), a paralog of NXT1 in eutherians, also has implications for RNA nuclear export. A comprehensive description is currently lacking as to the genetic signature of these molecules. In this study, we analyzed genetic changes in the NXT1 and NXT2 genes in primates and murine rodents, including the commonly used model organisms Macaca spp., Mus musculus, and Rattus norvegicus. The results show that NXT1 has been subject to functional constraints in both phylogenetic lineages. Conversely, NXT2 exhibits discrepant patterns of genetic changes between these taxa. Murine NXT2 has evolved conservatively; by contrast, adaptive selection has frequently contributed to genetic changes in primate NXT2. The genetic discrepancy of the NXT2 orthologs leads to the suggestion that they had experienced quite different evolutionary fates potentially constituting different functional implementations in these taxa. These findings raise awareness of further study on different organisms to comprehensively understand their functional characteristics.

Flavonoids-Natural Gifts to Promote Health and Longevity.

The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.

Structural characterization of immune receptor family short pentraxins, C-reactive protein and serum amyloid P component, in primates.

The short pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are a family of pattern-recognition molecules that play versatile roles in innate immunity and inflammation. A comprehensive description is currently lacking as to the genetic characteristics of these molecules in primates. In the present study, we analyzed genetic changes of CRP and SAP genes in this phylogenic lineage. The results revealed that adaptive selection has brought about interspecific diversities of both genes. The adaptively selected amino acid changes have occurred in or adjacent to the structural domains involved in ligand- and effector-binding and homologous aggregation. Each gene, however, exhibits a striking lack of genetic variation in both commonly-used non-human primate models Macaca fascicularis and M. mulatta. These findings highlight basic facts on the genetic characteristics of primate short pentraxins and would contribute powerfully to the extrapolation of their functional insights and physiological outcomes from primate models to humans.

Inhibitor GSK690693 extends Drosophila lifespan via reduce AKT signaling pathway.

Aging is a process involving physiological changes that lead to the decline of biological functions of various tissues and organs of the body. Therefore, it is crucial to find anti-aging drugs that can intervene with the changes induced because of aging and slow down the degeneration of the biological functions. Among many signaling pathways linked with aging and aging-related diseases, PI3K-AKT signaling pathway has attracted major attention in aging biology. In this research paper, we have demonstrated that AKT inhibitor GSK690693 can extend lifespan in Drosophila irrespective of start of the treatment from the beginning of life or the mid-life. Effect of GSK690693 for lifespan extension has been primarily related to the improvements in oxidative resistance, intestinal integrity and increased autophagy, but not in physical activity or starvation resistance. Furthermore, GSK690693 treatment reduced the activation of AKT and ERK, consequently activating FOXO, GSK-3ß and apoptosis to modulate longevity of flies. Remarkably, GSK690693 did not induce hyperglycemia after treatment. The results indicate that GSK690693 may become an effective compound for anti-aging intervention.

p62 works as a hub modulation in the ageing process.

p62 (also known as SQSTM1) is widely used as a predictor of autophagic flux, a process that allows the degradation of harmful and unnecessary components through lysosomes to maintain protein homeostasis in cells. p62 is also a stress-induced scaffold protein that resists oxidative stress. The multiple domains in its structure allow it to be connected with a variety of vital signalling pathways, autophagy and the ubiquitin proteasome system (UPS), allowing p62 to play important roles in cell proliferation, apoptosis and survival. Recent studies have shown that p62 is also directly or indirectly involved in the ageing process. In this review, we summarize in detail the process by which p62 regulates ageing from multiple ageing-related signs with the aim of providing new insight for the study of p62 in ageing.