Natural products improve healthspan in aged mice and rats: a systematic review and meta-analysis

Over the last decades a decrease in mortality has paved the way for late onset pathologies such as cardiovascular, metabolic or neurodegenerative diseases. This evidence has led many researchers to shift their focus from researching ways to extend lifespan to finding ways to increase the number of years spent in good health; “healthspan” is indeed the emerging concept of such quest for ageing without chronic or disabling diseases and dysfunctions. Regular consumption of natural products might improve healthspan, although the mechanisms of action are still poorly understood. Since preclinical studies aimed to assess the efficacy and safety of these compounds are growing, we performed a systematic review and meta-analysis on the effects of natural products on healthspan in mouse and rat models of physiological ageing. Results indicate that natural compounds show robust effects improving stress resistance and cognitive abilities. These promising data call for further studies investigating the underlying mechanisms in more depth

Trehalose administration in C57BL/6N old mice affects healthspan improving motor learning and brain anti-oxidant defences in a sex-dependent fashion: a pilot study

Aim of this study was to characterize the effects of oral trehalose administration (2%w/v) on healthspan in old mice. Trehalose was administered in drinking water for 1 month to male and female C57BL/6N mice aged 25-months. After behavioral phenotyping (grip strength, beam walking and rotarod tests), autophagy (LC3-II/actin) and oxidative stress were tested in the cerebral cortex and gastrocnemius muscle. The latter parameter was indirectly assessed by evaluating carbonyl groups added to proteins as a result of oxidative reactions, in addition to central levels of NRF2 protein, a transcription factor that regulates the expression of antioxidant enzymes. In comparison with sex-matched controls, trehalose-treated males performed better in motor planning and coordination tasks. This behavioral phenotype was associated with an activation of the ubiquitin-proteasome system, autophagy and antioxidant defences in cerebral cortex. Independently from trehalose administration, females were characterized by better motor performance and showed higher levels of ubiquitinated proteins and NRF2 in cerebral cortex, suggesting an up-regulation of basal antioxidant defences. In conclusion, trehalose was effective in counteracting some aspects of age-related decay, with specific effects in male and female subjects

Ion-pairing chromatography and amine derivatization provide complementary approaches for the targeted LC-MS analysis of the polar metabolome.

Liquid chromatography coupled to mass spectrometry is a key metabolomics/metabonomics technology. Reversed-phase liquid chromatography (RPLC) is very widely used as a separation step, but typically has poor retention of highly polar metabolites. Here, we evaluated the combination of two alternative methods for improving retention of polar metabolites based on 6-aminoquinoloyl-N-hydroxysuccinidimyl carbamate derivatization for amine groups, and ion-pairing chromatography (IPC) using tributylamine as an ion-pairing agent to retain acids. We compared both of these methods to RPLC and also to each other, for targeted analysis using a triple-quadrupole mass spectrometer, applied to a library of ca. 500 polar metabolites. IPC and derivatization were complementary in terms of their coverage: combined, they improved the proportion of metabolites with good retention to 91%, compared to just 39% for RPLC alone. The combined method was assessed by analyzing a set of liver extracts from aged male and female mice that had been treated with the polyphenol compound ampelopsin. Not only were a number of significantly changed metabolites detected, but also it could be shown that there was a clear interaction between ampelopsin treatment and sex, in that the direction of metabolite change was opposite for males and females

Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity

Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions

Prenatal psychological or metabolic stress increases the risk for psychiatric disorders: the “funnel effect” model

Adverse stressful experiences in utero can redirect fetal brain development, ultimately leading to increased risk for psychiatric disorders. Obesity during pregnancy can have similar effects as maternal stress, affecting mental health in the offspring. In order to explain how similar outcomes may originate from different prenatal conditions, we propose a “funnel effect” model whereby maternal psychological or metabolic stress triggers the same evolutionarily conserved response pathways, increasing vulnerability for psychopathology. In this context, the placenta, which is the main mother-fetus interface, appears to facilitate such convergence, re-directing “stress” signals to the fetus. Characterizing converging pathways activated by different adverse environmental conditions is fundamental to assess the emergence of risk signatures of major psychiatric disorders, which might enable preventive measures in risk populations, and open up new diagnostics, and potentially therapeutic approaches for disease prevention and health promotion already during pregnancy

Throwing darts in ICU: how close are we in estimating energy requirements?

BackgroundIndirect calorimetry (IC) is the gold standard for determining energy requirement. Due to lack of availability in many institutions, predictive equations are used to estimate energy requirements. The purpose of this study is to determine the accuracy of predictive equations (ie, Harris-Benedict equation (HBE), Mifflin-St Jeor equation (MSJ), and Penn State University equation (PSU)) used to determine energy needs for critically ill, ventilated patients compared with measured resting energy expenditure (mREE).MethodsThe researchers examined data routinely collected as part of clinical care for patients within intensive care units (ICUs). The final sample consisted of 68 patients. All studies were recorded during a single inpatient stay within an ICU.ResultsPatients, on average, had an mREE of 33.9 kcal/kg using IC. The estimated energy requirement when using predictive equations was 24.8 kcal/kg (HBE×1.25), 24.0 kcal/kg (MSJ×1.25), and 26.8 kcal/kg (PSU).DiscussionThis study identified significant differences between mREE and commonly used predictive equations in the ICU.Level of evidenceIII.</jats:sec

High-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats

Prenatal stress (PNS) affects foetal programming and, through an interaction with subsequent challenges, can increase vulnerability to mood and metabolic disorders. We have previously shown that, following PNS, adult male rats are characterized by increased vulnerability to a metabolic stressor experienced at adulthood (8-week-high-fat diet—HFD). In this study, we specifically assessed whether PNS might interact with an adult metabolic challenge to induce an inflammatory phenotype. Changes in the expression levels of inflammatory (Il-1β, Tnf-α, Il-6) and of stress response mediators (Nr3c1, Fkbp5) as well as of mood and metabolic regulators (Bdnf, Ghs-R) were investigated in the hippocampus, prefrontal cortex and hypothalamus, brain regions involved in the pathogenesis of depression and prone to inflammation in response to stress. Overall, PNS reduced the expression of Bdnf and Tnf-α, while HFD administered at adulthood counteracted this effect suggesting that PNS impinges upon the same pathways regulating responses to a metabolic challenge at adulthood. Furthermore, HFD and PNS affected the expression of both Nr3c1 and Fkbp5, two neuroendocrine mediators involved in the response to stress, metabolic challenges and in the modulation of the emotional profile (as shown by the correlation between Fkbp5 and the time spent in the open arms of the elevated plus-maze). Overall, these results indicate that the same metabolic and neuroendocrine effectors engaged by PNS are affected by metabolic challenges at adulthood, providing some mechanistic insight into the well-known comorbidity between mood and metabolic disorders

Prenatal N-acetyl-cysteine administration moderates the long-term negative effects of maternal obesity in adolescent male and female mouse offspring

Obesity during pregnancy may affect offspring developmental trajectories representing a risk factor for mental health. Amongst the mechanisms called into question inflammation, oxidative stress and the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis appear as the most suitable. We investigated the emotional phenotype of male and female offspring of dams exposed to a high-fat diet (HFD, a mouse model of maternal obesity) before and during pregnancy. We also tested the efficacy of N-acetyl-cysteine (NAC – an antioxidant) in preventing the negative effects of HFD. We focused on adolescence, an age of main vulnerability for the onset of psychopathologies. Female C57BL/6N mice were fed HFD for 13 weeks and, after 5 weeks, were also exposed to NAC (1 g/kg b.w.) via drinking water, until delivery. Emotionality was assessed in 35-45-day-old adolescent mice by means of the elevated-plus-maze (EPM) and social interaction tests (SIT). A forced swimming test was used both to evaluate depressive-like behaviour as well as a stressful challenge to measure HPA axis reactivity. NAC was effective in moderating body weight gain in HFD-treated dams. Prenatal HFD reduced exploratory behaviours in the EPM in periadolescent offspring; NAC administration resulting in increased social interactions in the offspring of HFD dams. Analyses of depression-like behaviours, HPA axis functionality and brain transcriptomics are currently ongoing for mechanistic insight. Data from these studies indicate that the long-term effects of maternal obesity may be mediated by changes in oxidative stress and point to NAC as a potential preventive strategy. ERANET-NEURON-JTC 2018 (Mental Disorders) Project ‘‘EMBED”