IP6K3 and IPMK variations in LOAD and longevity: evidence for a multifaceted signaling network at the crossroad between neurodegeneration and survival

Several studies reported that genetic variants predisposing to neurodegeneration were at higher frequencies in centenarians than in younger controls, suggesting they might favor also longevity. IP6K3 and IPMK regulate many crucial biological functions by mediating synthesis of inositol poly- and pyrophosphates and by acting non-enzymatically via protein–protein interactions. Our previous studies suggested they affect Late Onset Alzheimer Disease (LOAD) and longevity, respectively. Here, in the same sample groups, we investigated whether variants of IP6K3 also affect longevity, and variants of IPMK also influence LOAD susceptibility. We found that: i) a SNP of IP6K3 previously associated with increased risk of LOAD increased the chance to become long-lived, ii) SNPs of IPMK, previously associated with decreased longevity, were protective factors for LOAD, as previously observed for UCP4. SNP-SNP interaction analysis, including our previous data, highlighted phenotype-specific interactions between sets of alleles. Moreover, linkage disequilibrium and eQTL data associated to analyzed variants suggested mitochondria as crossroad of interconnected pathways crucial for susceptibility to neurodegeneration and/or longevity. Overall, data support the view that in these traits interactions may be more important than single polymorphisms. This phenomenon may contribute to the non-additive heritability of neurodegeneration and longevity and be part of the missing heritability of these traits

LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells

The cardiovascular disease (CVD) frequently developed during metabolic syndrome and type-2 diabetes mellitus is associated with increased levels of aggregation-prone small LDL particles. Aggregated LDL (aggLDL) internalization is mediated by low-density lipoprotein receptor-related protein-1 (LRP1) promoting intracellular cholesteryl ester (CE) accumulation. Additionally, LRP1 plays a key function in the regulation of insulin receptor (IR) and glucose transporter type 4 (GLUT4) activities. Nevertheless, the link between LRP1, CE accumulation, and insulin response has not been previously studied in cardiomyocytes. We aimed to identify mechanisms through which aggLDL, by its interaction with LRP1, produce CE accumulation and affects the insulin-induced intracellular signaling and GLUT4 trafficking in HL-1 cells. We demonstrated that LRP1 mediates the endocytosis of aggLDL and promotes CE accumulation in these cells. Moreover, aggLDL reduced the molecular association between IR and LRP1 and impaired insulin-induced intracellular signaling activation. Finally, aggLDL affected GLUT4 translocation to the plasma membrane and the 2-NBDG uptake in insulin-stimulated cells. We conclude that LRP1 is a key regulator of the insulin response, which can be altered by CE accumulation through LRP1-mediated aggLDL endocytosis

Inositol Polyphosphate Multikinase (IPMK), a Gene Coding for a Potential Moonlighting Protein, Contributes to Human Female Longevity

Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) is a potential moonlighting protein performing multiple unrelated functions. Initially identified as a key enzyme for inositol phosphates synthesis, small messengers regulating many aspects of cell physiology, IPMK is now implicated in a number of metabolic pathways affecting the aging process. IPMK regulates basic transcription, telomere homeostasis, nutrient-sensing, metabolism and oxidative stress. Here, we tested the hypothesis that the genetic variability of IPMK may affect human longevity. Single-SNP (single nuclear polymorphism), haplotype-based association tests as well as survival analysis pointed to the relevance of six out of fourteen genotyped SNPs for female longevity. In particular, haplotype analysis refined the association highlighting two SNPs, rs2790234 and rs6481383, as major contributing variants for longevity in women. Our work, the first to investigate the association between variants of IPMK and longevity, supports IPMK as a novel gender-specific genetic determinant of human longevity, playing a role in the complex network of genetic factors involved in human survival

The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong anti-proliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G1/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both the eukaryotic initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with two main pro-proliferative signaling pathways, i.e. the AKT and the MEK/extracellular signal-regulated kinase (ERK) pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong anti-tumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET

Does long-term warming affect C and N allocation in a Mediterranean shrubland ecosystem? Evidence from a¹³C and¹⁵N labeling field study

© 2017 In the Mediterranean basin the effects of climate warming on ecosystem functioning will strongly depend on the warming intensity directly but also on its effects on evapotranspiration and nutrient cycling. Climate manipulation experiments under field conditions are a source of unique empirical evidence regarding climate-related modifications of biotic processes. A field night-time warming experiment, simulating the predicted near-future increase in ambient temperatures (+0.3 up to 1 °C), was established in a Mediterranean shrub community located in Porto Conte (Italy) in 2001. After 11 years of continuous treatment, we labeled the dominant shrub Cistus monspeliensis with 13 CO 2 and studied the dynamics of the label allocation between aboveground and belowground pools and fluxes in warmed and ambient plots within 2 weeks of the chasing period. The interactions between C and N metabolism were assessed by parallel labeling of soil with K 15 NO 3. Most of the assimilated 13 C was respired by Cistus shoots (28–51%) within two weeks. Cistus under warming respired more 13 C label and tended to allocate less 13 C to leaves, branches and roots. The higher C and N content in microbial biomass in warming plots, combined with the higher N content in plant tissues and soil, evidenced a greater N mobilization in soil and a better nutrient status of the plants as compared to the ambient treatment. Acceleration of N cycling is probably responsible for higher respiratory C losses, but combined with the reduction in the number of frost days, should also positively affect plant photosynthetic performance. We conclude that, although Cistus plants are already growing in conditions close to their thermal optimum, long-term warming will positively affect the performance of this species, mainly by reducing the nutrient constraints. This positive effect will highly depend on the frequency and amount of rain events and their interactions with soil N content

A cross-section analysis of FT3 age-related changes in a group of old and oldest-old subjects, including centenarians’ relatives, shows that a down-regulated thyroid function has a familial component and is related to longevity

Background: several studies suggest that a decreased thyroid activity might be favourable in oldest-old subjects and that subclinical thyroid hyperfunction may be detrimental

Risks, benefits, and knowledge gaps of non-native tree species in Europe

Changing ecosystem conditions and diverse socio-economical events have contributed to an ingrained presence of non-native tree species (NNTs) in the natural and cultural European landscapes. Recent research endeavors have focused on different aspects of NNTs such as legislation, benefits, and risks for forestry, emphasizing that large knowledge gaps remain. As an attempt to fulfill part of these gaps, within the PEN-CAFoRR COST Action (CA19128) network, we established an open-access questionnaire that allows both academic experts and practitioners to provide information regarding NNTs from 20 European countries. Then, we integrated the data originating from the questionnaire, related to the country-based assessment of both peer-reviewed and grey literature, with information from available datasets (EUFORGEN and EU-Forest), which gave the main structure to the study and led to a mixed approach review. Finally, our study provided important insights into the current state of knowledge regarding NNTs. In particular, we highlighted NNTs that have shown to be less commonly addressed in research, raising caution about those characterized by an invasive behavior and used for specific purposes (e.g., wood production, soil recultivation, afforestation, and reforestation). NNTs were especially explored in the context of resilient and adaptive forest management. Moreover, we emphasized the assisted and natural northward migration of NNTs as another underscored pressing issue, which needs to be addressed by joint efforts, especially in the context of the hybridization potential. This study represents an additional effort toward the knowledge enhancement of the NNTs situation in Europe, aiming for a continuously active common source deriving from interprofessional collaboration. Copyright © 2022 Dimitrova, Csilléry, Klisz, Lévesque, Heinrichs, Cailleret, Andivia, Madsen, Böhenius, Cvjetkovic, De Cuyper, de Dato, Ferus, Heinze, Ivetić, Köbölkuti, Lazarević, Lazdina, Maaten, Makovskis, Milovanović, Monteiro, Nonić, Place, Puchalka and Montagnoli