The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases

Macroautophagy is a degradation/recycling system ubiquitous in eukariotic cells, which generates nutrients during fasting under the control of amino acids and hormones, and contributes to the turnover and rejuvenation of cellular components (long-lived proteins, cytomembranes and organelles). Tight coupling between these two functions may be the weak point in cell housekeeping. Ageing denotes a post-maturational deterioration of tissues and organs with the passage of time, due to the progressive accumulation of the misfunctioning cell components because of oxidative damage and an age-dependent decline of turnover rate and housekeeping. Caloric restriction (CR) and lower insulin levels may slow down many age-dependent processes and extend lifespan. Recent evidence is reviewed showing that autophagy is involved in ageing and in the anti-ageing action of anti-ageing calorie restriction: function of autophagy declines during adulthood and is almost negligible at older age; CR prevents the age-dependent decline of autophagic proteolysis and improves the sensitivity of liver cells to stimulation of lysosomal degradation; protection of autophagic proteolysis from the age-related decline co-varies with the duration and level of anti-ageing food restriction like the effects of CR extending lifespan; the pharmacological stimulation of macroautophagy has anti-ageing effects. Besides the involvement in ageing, macroautophagy may have an essential role in the pathogenesis of many age-associated diseases. Higher protein turnover may not fully account for the anti-ageing effects of macroautophagy, and effects of macroautophagy on housekeeping of the cell organelles, antioxidant machinery of cell membranes and transmembrane cell signaling should also be considered.     

A Very Low Geno2pheno False Positive Rate Is Associated with Poor Viro-Immunological Response in Drug-Na?ve Patients Starting a First-Line HAART

Background

We previously found that a very low geno2pheno false positive rate (FPR ≤2%) defines a viral population associated with low CD4 cell count and the highest amount of X4-quasispecies. In this study, we aimed at evaluating whether FPR ≤2% might impact on the viro-immunological response in HIV-1 infected patients starting a first-line HAART.

Methods

The analysis was performed on 305 HIV-1 B subtype infected drug-naïve patients who started their first-line HAART. Baseline FPR (%) values were stratified according to the following ranges: ≤2; 2–5; 5–10; 10–20; 20–60; >60. The impact of genotypically-inferred tropism on the time to achieve immunological reconstitution (a CD4 cell count gain from HAART initiation ≥150 cells/mm³) and on the time to achieve virological success (the first HIV-RNA measurement <50 copies/mL from HAART initiation) was evaluated by survival analyses.

Results

Overall, at therapy start, 27% of patients had FPR ≤10 (6%, FPR ≤2; 7%, FPR 2–5; 14%, FPR 5–10). By 12 months of therapy the rate of immunological reconstitution was overall 75.5%, and it was significantly lower for FPR ≤2 (54.1%) in comparison to other FPR ranks (78.8%, FPR 2–5; 77.5%, FPR 5–10; 71.7%, FPR 10–20; 81.8%, FPR 20–60; 75.1%, FPR >60; p = 0.008). The overall proportion of patients achieving virological success was 95.5% by 12 months of therapy. Multivariable Cox analyses showed that patients having pre-HAART FPR ≤2% had a significant lower relative adjusted hazard [95% C.I.] both to achieve immunological reconstitution (0.37 [0.20–0.71], p = 0.003) and to achieve virological success (0.50 [0.26–0.94], p = 0.031) than those with pre-HAART FPR >60%.

Conclusions

Beyond the genotypically-inferred tropism determination, FPR ≤2% predicts both a poor immunological reconstitution and a lower virological response in drug-naïve patients who started their first-line therapy. This parameter could be useful to identify patients potentially with less chance of achieving adequate immunological reconstitution and virological undetectability.     

Political rationale,aims, and outcomes of health-related high-level meetings and special sessions at the UN General Assembly: A policy research observational study

BackgroundRecognising the substantial political weight of the United Nations General Assembly (UNGA), a UN General Assembly special session (UNGASS) and high-level meetings (HLMs) have been pursued and held for 5 health-related topics thus far. They have focused on human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS, 2001), non-communicable diseases (NCDs, 2011), antimicrobial resistance (AMR, 2016), tuberculosis (TB, 2018), and universal health coverage (UHC, 2019). This observational study presents a comprehensive analysis of the political and policy background that prompted the events, as well as an assessment of aims, approaches, and ultimate outcomes.Methods and findingsWe investigated relevant agencies’ official documents, performed a literature search, and accessed international institutions’ websites for the period 1990–2020. Knowledgeable diplomatic staff and experts provided additional information. Outcomes were evaluated from a United Nations perspective based on national and international commitments, and funding trends. Eliciting an effective governmental response through UNGASSs/HLMs is a challenge. However, increased international commitment was evident after the HIV/AIDS (2001), NCDs (2011), and AMR (2016) meetings. The more recent TB (2018) and UHC (2019) HLMs have received general endorsements internationally, although concrete commitments are not yet documented. Although attribution can only be hypothesized, financial investments for HIV/AIDS following the UNGASS were remarkable, whereas following HLMs for NCDs, AMR, and TB, the financial investments remained insufficient to face the burden of these threats. Thus far, the HIV/AIDS UNGASS was the only one followed by a level of commitment that has likely contributed to the reversal of the previous burden trend. Limitations of this study include its global perspective and aerial view that cannot discern the effects at the country level. Additionally, possible peculiarities that modified the response to the meetings were not looked at in detail. Finally, we assessed a small sample of events; thus, the list of strategic characteristics for success is not exhaustive.ConclusionsOverall, UNGASSs and HLMs have the potential to lay better foundations and boldly address key health challenges. However, to succeed, they need to (i) be backed by large consensus; (ii) engage UN authorities and high-level bodies; (iii) emphasise implications for international security and the world economy; (iv) be supported by the civil society, activists, and champions; and (v) produce a political declaration containing specific, measurable, achievable, relevant, and time-bound (SMART) targets. Therefore, to ensure impact on health challenges, in addition to working with the World Health Assembly and health ministries, engaging the higher political level represented by the UNGA and heads of state and government is critical.

Paolo Rodi and colleagues analyze the political and policy response to UN General Assembly and high-level meetings focused on HIV/AIDS, non-communicable diseases, antimicrobial resistance, tuberculosis and universal health coverage.     

Association of SOD2, GPX1, CAT, and TNF Genetic Polymorphisms with Oxidative Stress, Neurochemistry, Psychopathology, and Extrapyramidal Symptoms in Schizophrenia

There is a growing body of evidence confirming the involvement of oxidative stress and inflammation in pathogenesis of schizophrenia. Inter-individual variation in antioxidant capacity caused by different genetic profile could potentially influence patient’s susceptibility to oxidative damage. In this study we evaluated the polymorphisms of manganese superoxide dismutase SOD2Val16Ala, glutathione peroxidase GPX1Pro200Leu, catalase CAT-262C>T and CATc.66+78C>T, and tumour necrosis factor-alpha TNF-308G>A by assessing their association with biomarkers of oxidative stress, neurochemistry, psychopathology of schizophrenia and extrapyramidal symptoms in Caucasian schizophrenia patients treated with haloperidol depot. TNF-308G>A was associated with the increased risk of parkinsonism. No major role of polymorphism of SOD2Val16Ala, CAT-262C>T nor GPX1Pro200Leu in psychopathology of schizophrenia or extrapyramidal symptoms was observed. SOD2Val16Ala polymorphism was associated with dopamine plasma concentration and blood concentration ratio between reduced and oxidised form of glutathione, while GPX1Pro200Leu was related with concentration of reduced glutathione. CATc.66+78C>T was associated with noradrenaline plasma concentration and PANSS negative score. PANSS positive and general scores, were associated with the increased risk of tardive dyskinesia. PANSS positive, negative, and general scores, and GAF score were all associated with the increased risk of akathisia.     

Sex related differences in platelet TxA2 generation

Platelet lipid composition, c arachidonic acid (AA) metabolism by platelets (stimulated with thrombin), serum thromboxane (Tx)B2 production and plasma lipid composition were investigated in 53 healthy females (18-45 years) and 65 males (19-45 years) with similar dietary habits. In males, serum TxB2 production and cholesterol platelet membrane levels were found significantly higher (p less than 0.001 and p less than 0.05) than in females. No differences were observed between the two groups in the AA conversion through cyclo-oxygenase and lipoxygenase pathways or in the platelet phospholipid fatty acid composition. These findings indicate that in males the platelet proaggregatory capacity is greater than in females and the higher platelet TxB2 production does not depend on a larger AA availability or on enzyme activation for its conversion. The increased TxB2 production may be, at least in part, induced by functional differences such as a different membrane cholesterol content inducing, in its turn, an increased microviscosity and/or higher number of platelet receptors for thrombin.     

Spatial distribution and diet of the Neotropical otter<Emphasis Type="Italic">Lontra longicaudis</Emphasis> in the Ibera Lake (northern Argentina)

The seasonal spatial distribution and diet of the Neotropical otterLontra longicaudis (Olfers, 1818) were studied on Ibera Lake within the Esteros del Ibera, an important wetland of NE Argentina (Ramsar site no. 1162). Twelve lake perimeter sites were regularly checked for otter tracks and signs. The amount of signs was compared to environmental parameters to test their influence on otter presence and movements. A positive correlation was found between the amount of signs and the physical structure of the littoral areas, as well as vegetation structure. Lakeside otter presence decreased during the summer sampling throughout all sites. In order to determine otter diet, 205 spraints were examined. Otters fed mainly on fish (mostly Cichlidae), but also on crustaceans and molluscs. Other fish consumed were Characidae, Synbranchidae, Loricariidae and Erythrinidae. Seasonal variation was observed in diet composition: in summer, diet crustaceans and vertebrates other than fish increased. A higher percentage of benthic fish species was also observed in summer, while pelagic and benthopelagic species increased in winter. Such dietary changes may be explained by the different habitat use of otters in different seasons, from the lake coast (winter) towards more internal marshy areas of the wetland (summer).     

Tumor microenvironment: Bone marrow-mesenchymal stem cells as key players

Tumor progression is a multistep phenomenon in which tumor-associated stromal cells perform an intricate cross-talk with tumor cells, supplying appropriate signals that may promote tumor aggressiveness. Among several cell types that constitute the tumor stroma, the discovery that bone marrow-derived mesenchymal stem cells (BM-MSC) have a strong tropism for tumors has achieved notoriety in recent years. Not only are the BM-MSC recruited, but they can also engraft at tumor sites and transdifferentiate into cells such as activated fibroblasts, perivascular cells and macrophages, which will perform a key role in tumor progression. Whether the BM-MSC and their derived cells promote or suppress the tumor progression is a controversial issue. Recently, it has been proposed that proinflammatory stimuli can be decisive in driving BM-MSC polarization into cells with either tumor-supportive or tumor-repressive phenotypes (MSC1/MSC2). These considerations are extremely important both to an understanding of tumor biology and to the putative use of BM-MSC as “magic bullets” against tumors. In this review, we discuss the role of BM-MSC in many steps in tumor progression, focusing on the factors that attract BM-MSC to tumors, BM-MSC differentiation ability, the role of BM-MSC in tumor support or inhibition, the immunomodulation promoted by BM-MSC and metastatic niche formation by these cells.