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.

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.

tRNA-derived fragments as New Hallmarks of Aging and Age-related Diseases.

tRNA-derived fragments (tRFs), which are non-coding RNAs produced via tRNA cleavage with lengths of 14 to 50 nucleotides, originate from precursor tRNAs or mature tRNAs and exist in a wide range of organisms. tRFs are produced not by random fracture of tRNAs but by specific mechanisms. Considerable evidence shows that tRFs are detectable in model organisms of different ages and are associated with age-related diseases in humans, such as cancer and neurodegenerative diseases. In this literature review, the origin and classification of tRFs and the regulatory mechanisms of tRFs in aging and age-related diseases are summarized. We also describe the available tRF databases and research techniques and lay a foundation for the exploration of tRFs as biomarkers for the diagnosis and treatment of aging and age-related diseases.

Dihydromyricetin promotes longevity and activates the transcription factors FOXO and AOP in Drosophila.

Drugs or compounds have been shown to promote longevity in various approaches. We used Drosophila to explore novel natural compounds can be applied to anti-aging. Here we reported that a flavonoid named Dihydromyricetin can increase stress that tolerance and lipid levels, slow down gut dysfunction and extend Drosophila lifespan. Dihydromyricetin can also lessen pERK and pAKT signaling, consequently activating FOXO and AOP to modulate longevity. Our results suggested that DHM could be used as an effective compound for anti-aging intervention, which could likely be applied to both mammals and humans.

Deubiquitinase USP7 regulates Drosophila aging through ubiquitination and autophagy.

Ubiquitination-mediated protein degradation is the selective degradation of diverse forms of damaged proteins that are tagged with ubiquitin, while deubiquitinating enzymes reverse ubiquitination-mediated protein degradation by removing the ubiquitin chain from the target protein. The interactions of ubiquitinating and deubiquitinating enzymes are required to maintain protein homeostasis. The ubiquitin-specific protease USP7 is a deubiquitinating enzyme that indirectly plays a role in repairing DNA damage and development. However, the mechanism of its participation in aging has not been fully explored. Regarding this issue, we found that USP7 was necessary to maintain the normal lifespan of Drosophila melanogaster, and knockdown of dusp7 shortened the lifespan and reduced the ability of Drosophila to cope with starvation, oxidative stress and heat stress. Furthermore, we showed that the ability of USP7 to regulate aging depends on the autophagy and ubiquitin signaling pathways. Furthermore, 2,5-dimethyl-celecoxib (DMC), a derivative of celecoxib, can partially restore the shortened lifespan and aberrant phenotypes caused by dusp7 knockdown. Our results suggest that USP7 is an important factor involved in the regulation of aging, and related components in this regulatory pathway may become new targets for anti-aging treatments.

Evolutionary analysis of chemokine CXCL16 and its receptor CXCR6 in murine rodents.

The chemokine CXCL16 and its receptor CXCR6 are implicated in various physiological and pathological processes in cooperative and/or stand-alone fashions. Despite the significance of rodent animal models in elucidating the function and clinical relevance of the chemokine and its receptor, the evolutionary characterization of these molecules remains deficient for this taxon to a certain extent. In this study, we implemented a comparison of synonymous and nonsynonymous variation rates in combination with the maximum likelihood (ML) analysis and Tajima's test to evaluate the interspecific and intraspecific evolutions of CXCL16 and CXCR6 in murine rodents. Our results indicate that adaptive selection has frequently contributed to genetic diversity of both CXCL16 and CXCR6 in the murine lineage that is asynchronous with a relative dependence between these genes. This signature is radically different from the lineage-specific and concordant adaptive diversity of the primate homologues of these genes, which was reported in a previous study. The diversity identified in the present study shed further light on molecular strategies against the challenges towards CXCL16 and CXCR6.

The role of Sestrins in the regulation of the aging process.

Sestrins (Sesns) represent a highly conserved family of stress-inducing proteins that are involved in antioxidant and autophagy regulatory functions. They are very important mediators as they can protect the cells under a variety of noxious stimulating conditions. However, the functions of Sesns in aging has not yet been fully understood. Here, we summarize the roles of Sesns in the aging process. A series of studies have shown that Sesns are highly involved in the aging process by regulating the nutritional perception, metabolic homeostasis, immunity, autophagy, lifespan and health span. The details of how Sesns act on them will be described in this review. Due to the conservation of their function during evolution, Sesns may be used as novel targets for aging intervention and also provide new strategies for anti-aging treatment.

DNA methylation is not involved in dietary restriction induced lifespan extension in adult Drosophila.

Dietary restriction (DR) is widely regarded as a viable intervention to extend lifespan and healthspan in diverse organisms. The precise molecular regulatory mechanisms are largely unknown. Epigenetic modifications are not stable upon DR and also keep changing with age. Here, we employed whole genome bisulfite sequencing to determine the DNA methylation changes upon DR in adult Drosophila. Our results indicate that although a low level of DNA methylation exists in the adult Drosophila genome, there is no significant difference in DNA methylation levels upon DR when compared to unrestricted flies. This suggests that other epigenetic components such as histone modifications might be altered by DR.

2,5-Dimethyl-Celecoxib Extends Drosophila Life Span via a Mechanism That Requires Insulin and Target of Rapamycin Signaling.

The search for antiaging drugs is a key component of gerontology research. A few drugs with positive effects on life span in model organisms have been found. Here, we report that 2,5-dimethyl-celecoxib, a derivative of the anti-inflammatory drug celecoxib, can extend Drosophila life span and delay aging by a mechanism involving insulin signaling and target of rapamycin signaling. Importantly, its positive effects were apparent when the treatment window was restricted to the beginning of life or the later half. 2,5-Dimethyl-celecoxib-induced longevity was also associated with improvements in physical activity, intestinal integrity, and increased autophagy. In addition, 2,5-dimethyl-celecoxib exhibited protective effects against several kinds of stress such as starvation and heat. The generally positive effects of 2,5-dimethyl-celecoxib on both health and life span, combined with its mode of action via evolutionarily conserved signaling pathways, indicate that it has the potential to become an effective antiaging drug.

LncRNA mediated regulation of aging pathways in Drosophila melanogaster during dietary restriction.

Dietary restriction (DR) extends lifespan in many species which is a well-known phenomenon. Long non-coding RNAs (lncRNAs) play an important role in regulation of cell senescence and important age-related signaling pathways. Here, we profiled the lncRNA and mRNA transcriptome of fruit flies at 7 day and 42 day during DR and fully-fed conditions, respectively. In general, 102 differentially expressed lncRNAs and 1406 differentially expressed coding genes were identified. Most informatively we found a large number of differentially expressed lncRNAs and their targets enriched in GO and KEGG analysis. We discovered some new aging related signaling pathways during DR, such as hippo signaling pathway-fly, phototransduction-fly and protein processing in endoplasmic reticulum etc. Novel lncRNAs XLOC_092363 and XLOC_166557 are found to be located in 10 kb upstream sequences of hairy and ems promoters, respectively. Furthermore, tissue specificity of some novel lncRNAs had been analyzed at 7 day of DR in fly head, gut and fat body. Also the silencing of lncRNA XLOC_076307 resulted in altered expression level of its targets including Gadd45 (involved in FoxO signaling pathway). Together, the results implicated many lncRNAs closely associated with dietary restriction, which could provide a resource for lncRNA in aging and age-related disease field.

Rapamycin preserves gut homeostasis during Drosophila aging.

Gut homeostasis plays an important role in maintaining the overall body health during aging. Rapamycin, a specific inhibitor of mTOR, exerts prolongevity effects in evolutionarily diverse species. However, its impact on the intestinal homeostasis remains poorly understood. Here, we demonstrate that rapamycin can slow down the proliferation rate of intestinal stem cells (ISCs) in the aging guts and induce autophagy in the intestinal epithelium in Drosophila. Rapamycin can also significantly affect the FOXO associated genes in intestine and up-regulate the negative regulators of IMD/Rel pathway, consequently delaying the microbial expansion in the aging guts. Collectively, these findings reveal that rapamycin can delay the intestinal aging by inhibiting mTOR and thus keeping stem cell proliferation in check. These results will further explain the mechanism of healthspan and lifespan extension by rapamycin in Drosophila.