Telomere length (TL) is considered a biomarker of aging, and short TL in leukocytes is related to age and stress-related health problems. Cumulative lifetime stress exposure has also been associated with shorter TL and age-related health problems, but the mechanisms are not well understood. We tested in 108 individuals whether shorter TL in leukocytes is observed in individuals with the GABRA6 TT genotype, which has been associated with dysregulation of hypothalamic-pituitary-adrenal axis activity (the main biological stress system) compared to the CC genotype. We also investigated if individuals carrying the TT genotype show higher stress-induced and diurnal cortisol secretion and if cortisol explains the interindividual variability in TL. The analysis pipeline of this study was pre-registered, and the results showed that GABRA6 TT carriers had shorter TL in CD8+CD28+ cells (Bonferroni corrected). In contrast to previous studies, no differences between groups in cortisol secretion were observed, and TL and cortisol did not show significant associations. This study shows, for the first time, shorter TL in CD8+CD28+ cells in TT carriers for GABRA6 compared to CC carriers, suggesting accelerated cellular aging. Although this difference could be linked to an increased susceptibility to stress in the TT carriers, this could not be attributed to the direct influence of cortisol, suggesting the involvement of other mechanisms.

Acid sphingomyelinase deficiency (ASMD) is a rare disease caused by mutations in the gene encoding ASM, an enzyme that degrades sphingomyelin (SM). In addition to SM accumulation, neuroinflammation and cognitive impairment are pathological hallmarks of neurovisceral ASMD. Since the glucocorticoid system may influence these features, we have characterized it in ASM knockout (ASMko) mice that mimic this form of the disease. While plasma corticosterone levels are not altered in these mice, brain levels of the α, but not the β, isoform of glucocorticoid receptors (GR) are reduced. The reduction is evident in neurons and is due to the accumulation of SM. As a consequence, the expression of the protein, synapsin I, is low in ASMko neurons, leading to the disorganization of synaptic vesicles and to impaired presynaptic plasticity. Treatment with the glucocorticoid hydrocortisone diminished SM levels, increased synapsin I expression, and improved presynaptic function in neuronal cultures and hippocampal slices of ASMko mice. These findings establish, for the first time, a link between the glucocorticoid system and brain pathology in ASMD, highlighting the GR as a potential therapeutic target for this devastating disease.

SiO2 nanoparticles functionalized with glutamate were investigated for their ability to alleviate oxidative stress caused by prolonged exposure to hydrogen peroxide (H2O2). The study involved ten different groups, each consisting of eight animals, to examine the effects of H2O2 -induced oxidative stress. The results demonstrated that exposure to H2O2 stress oxidative biomarkers were altered accompanied with a loss of spatial learning and memory in rats performing the Morris water maze task. Furthermore, SiO2 nanoparticles functionalized with L-glutamic acid alleviated the H2O2-induced acceleration of necrotic and degenerative cell changes in the hippocampus, subiculum, caudate-putamen, and frontal cortex. Additionally, L-glutamic acid-functionalized SiO2 nanoparticles reduced the redox imbalance and interfered with acetylcholinesterase (AChE) and monoamine oxidase (MAO) activities induced by H2O2.

INTRODUCTION:The main objective of the study will be to evaluate the effects of two widely used standardized mindfulness-based programs [Mindfulness-Based Stress Reduction (MBSR) and Compassion Cultivation Training (CCT)], on epigenetic, neurobiological, psychological, and physiological variables.METHODS:The programs will be offered in an intensive retreat format in a general population sample of healthy volunteer adults. During a 7-day retreat, participants will receive MBSR and CCT in a crossover design where participants complete both programs in random order. After finishing their first 3-day training with one of the two programs, participants will be assigned to the second 3-day training with the second program. The effects of the MBSR and CCT programs, and their combination, will be measured by epigenetic changes (i.e., DNA methylation biomarkers), neurobiological and psychophysiological measures (i.e., EEG resting state, EKG, respiration patterns, and diurnal cortisol slopes), self-report questionnaires belonging to different psychological domains (i.e., mindfulness, compassion, well-being, distress, and general functioning), and stress tasks (i.e., an Arithmetic Stress Test and the retrieval of negative autobiographical memories). These measures will be collected from both groups on the mornings of day 1 (pre-program), day 4 (after finishing the first program and before beginning the second program), and day 7 (post-second program). We will conduct a 3-month and a 12-month follow-up using only the set of self-report measures.DISCUSSION:This study aims to shed light on the neurobiological and psychological mechanisms linked to meditation and compassion in the general population. The protocol was registered at clinicaltrials.gov (Identifier: NCT05516355; August 23, 2022).

Introduction:Prolonged social isolation is a form of passive chronic stress that has consequences on human and animal behavior. The present study was undertaken to elucidate whether the long-term isolation would precipitate age-related changes in anxiety and spatial learning and memory in degus.Methods:We investigated the effects of long-term social isolation on anxiety levels in the light-dark test, and spatial orientation abilities in the Barnes maze. Middle-aged female Octodon degus were allocated to either group-housed (3 animals per cage) or individually-housed for 5 months.Results:Under this experimental condition, there were no significant group differences in the anxiety level tested in the light-dark test and in the motivation to escape from the Barnes maze. There were no significant differences in cortisol levels between individually- and group-housed animals. On the last acquisition training day of spatial learning, individually- housed animals had a significantly higher number of correct responses and a smaller number of reference and working memory errors than the group-housed animals. In addition, isolated animals showed a tendency for reference and working memory impairment on the retention trial, while group-housed degus showed improvement in these parameters.Discussion and conclusion:The present study indicates that prolonged social isolation during adulthood in female degus has a dual effect on spatial orientation. Specifically, it results in a significant improvement in acquisition skills but a slight impairment in memory retention. The obtained cognitive changes were not accompanied by modification in anxiety and cortisol levels.

Research in psychology and social neuroscience distinguishes between dispositional and situational empathy for the cognitive and affective aspects of empathy. Yet, the Pictorial Empathy Test (PET) is one of the few brief tests focusing on situational affective empathy. This paper describes the adaptation of PET in a two-stage process, consisting of instrument translation and exploratory analysis of the construct in a university student sample, followed by confirmatory factor analysis and psychometric validation in a general population sample (Study 1, N = 79 and Study 2, N = 580). Our results indicate that the Spanish PET version constitutes a single factor structure with high internal consistency as well as high construct stability across genders and across in-person and online test administration setups. We report satisfactory convergent, discriminant, and nomological validity of the Spanish PET, as reported for the original version, in addition to when explored across new dimensions, like the Interpersonal Reactivity Index or in relation to age and prosocial tendencies. Based on the above, we discuss delineation of the distinct components of emotional empathy as measured by the instrument. The work presented supports the use of the Spanish PET version as a brief screening toot for state affective (emotional) empathy.

Cognitive decline is one of the most important consequences of aging and pharmacological therapies had been largely unsuccessful. Other strategies include the use of functional foods to reduce the burden of cognitive decline. The MFGM is an important source of polar lipids and glycoproteins that decline in the aging brain. We have developed a milk drink fortified with MFGM (MFGM-M) as a dietary supplement and studied it in a randomized clinical pilot study. Forty-four > 65-year-old healthy or mildly cognitively impaired subjects received MFGM-M or control milk (CM) for 14 weeks, during which they underwent a battery of cognitive tests. Lipidomic analyzes were also performed. The female participants showed improvement in episodic memory, the ability to recall events in our lives. It is conceivable that any intervention should be started before clinical symptoms manifest, as a preventive measure against cognitive decline. Future long-term studies may shed further light on this point.

In this work, we tested the hypothesis that the development of dementia in individuals with type 2 diabetes (T2DM) requires a genetic background of predisposition to neurodegenerative disease. As a proof of concept, we induced T2DM in middle-aged hAPP NL/F mice, a preclinical model of Alzheimer's disease. We show that T2DM produces more severe behavioral, electrophysiological, and structural alterations in these mice compared with wild-type mice. Mechanistically, the deficits are not paralleled by higher levels of toxic forms of Aβ or by neuroinflammation but by a reduction in γ-secretase activity, lower levels of synaptic proteins, and by increased phosphorylation of tau. RNA-seq analysis of the cerebral cortex of hAPP NL/F and wild-type mice suggests that the former could be more susceptible to T2DM because of defects in trans-membrane transport. The results of this work, on the one hand, confirm the importance of the genetic background in the severity of the cognitive disorders in individuals with T2DM and, on the other hand, suggest, among the involved mechanisms, the inhibition of γ-secretase activity.

IntroductionLoneliness is a distressful feeling that can affect mental and physical health, particularly among older adults. Cortisol, the primary hormone of the Hypothalamic-Pituitary-Adrenal axis (HPA-axis), may act as a biological transducer through which loneliness affects health. While most previous studies have evaluated the association between loneliness, as a unidimensional construct, and diurnal cortisol pattern, no research has examined this relationship discriminating between social and emotional loneliness in older adults. As sex differences in the negative mental health outcomes of loneliness have been reported, we also investigated whether diurnal cortisol indices and loneliness associations occur in a sex-specific manner.MethodsWe analyzed the diurnal cortisol- pattern in 142 community-dwelling, non-depressed, Caucasian older adults (55,6% female) aged 60-90. Social and emotional (family and romantic) loneliness scores were assessed using the Spanish version of the Social and Emotional Loneliness Scale for Adults (SELSA). Five salivary cortisol samples were used to capture key features of the diurnal cortisol pattern, including: awakening and bedtime cortisol levels, awakening response (CAR), post-awakening cortisol output (post-awakening cortisol [i.e., the area under the curve with reference to the ground: AUCG]), total diurnal cortisol release (AUCG), and diurnal cortisol slope (DCS).ResultsAfter controlling for sociodemographic variables, the hierarchical linear multiple regression analyses revealed that in male older adults, higher scores on social and family loneliness were associated with elevated awakening cortisol levels, total diurnal cortisol output, and a steeper diurnal cortisol slope (DCS). However, these associations were not observed in female older adults. In addition, feelings of romantic loneliness were positively associated with bedtime cortisol levels and AUCG in older males. Multilevel growth curve modeling showed that experiencing more social and emotional loneliness predicted higher diurnal cortisol output throughout the day in older male adults.DiscussionThe presence of sex differences in the relationship between cortisol indices and loneliness among older adults holds particular significance for diagnostic and screening procedures. Combining loneliness scales as screening tools with diurnal cortisol measures has the potential to be an effective and cost-efficient approach in identifying higher-risk individuals at early stages.

The accumulation of relatively higher dose of zinc oxide nanoparticles in brain was reported to produce neurotoxicity. Indeed, nanoparticles have a high ability to penetrate biological membranes and be uptaken by cells, which may cause cell disorders and physiological dysfunctions. The aim of the current study was to evaluate, whether oral administration of saffron extract, in rats, can protect from neurotoxicity and behavioural disturbances induced by chronic administration of ZnO-NPs. Daily oral administration of ZnO-NPs was performed for 21 consecutive days to induce oxidative stress-like situation. Then after the saffron extract was concomitantly administrated in several rat groups to overcome the nanotoxicological effect induced by ZnO-NPs. In the frontal cortex, the hippocampus and the cerebellum, ZnO-NPs induced a H2 O2 -oxydative stress-like effect reflected in reduced enzymatic activities of catalase, superoxide dismutase and glutathione S-transferase, and decreased acetylcholinesterase activity. In addition, increased levels of proinflammatory interleukins IL-6 and IL-1-⍺ occurred in the hippocampus, reveal the existence of brain inflammation. The concomitant administration of saffron extract to animals exposed to ZnO-NPs prevented the enhanced anxiety-related to the behaviour in the elevated plus-maze test, the open field test and preserved spatial learning abilities in the Morris water maze. Moreover, animals exposed to ZnO-NPs and saffron showed abnormal activity of several antioxidant enzymes as well as acetylcholinesterase activity, an effect that may underly the preserved anxiety-like behaviour and spatial learning abilities observed in these animals. Saffron extract has a potential beneficial therapeutic effect: antioxidant, anti-inflammatory and neuroprotective agent.

Tachykinin receptor 3 (TACR3) is a member of the tachykinin receptor family and falls within the rhodopsin subfamily. As a G protein-coupled receptor, it responds to neurokinin B (NKB), its high-affinity ligand. Dysfunctional TACR3 has been associated with pubertal failure and anxiety, yet the mechanisms underlying this remain unclear. Hence, we have investigated the relationship between TACR3 expression, anxiety, sex hormones, and synaptic plasticity in a rat model, which indicated that severe anxiety is linked to dampened TACR3 expression in the ventral hippocampus. TACR3 expression in female rats fluctuates during the estrous cycle, reflecting sensitivity to sex hormones. Indeed, in males, sexual development is associated with a substantial increase in hippocampal TACR3 expression, coinciding with elevated serum testosterone and a significant reduction in anxiety. TACR3 is predominantly expressed in the cell membrane, including the presynaptic compartment, and its modulation significantly influences synaptic activity. Inhibition of TACR3 activity provokes hyperactivation of CaMKII and enhanced AMPA receptor phosphorylation, associated with an increase in spine density. Using a multielectrode array, stronger cross-correlation of firing was evident among neurons following TACR3 inhibition, indicating enhanced connectivity. Deficient TACR3 activity in rats led to lower serum testosterone levels, as well as increased spine density and impaired long-term potentiation (LTP) in the dentate gyrus. Remarkably, aberrant expression of functional TACR3 in spines results in spine shrinkage and pruning, while expression of defective TACR3 increases spine density, size, and the magnitude of cross-correlation. The firing pattern in response to LTP induction was inadequate in neurons expressing defective TACR3, which could be rectified by treatment with testosterone. In conclusion, our study provides valuable insights into the intricate interplay between TACR3, sex hormones, anxiety, and synaptic plasticity. These findings highlight potential targets for therapeutic interventions to alleviate anxiety in individuals with TACR3 dysfunction and the implications of TACR3 in anxiety-related neural changes provide an avenue for future research in the field.

Aging is associated with a decline in cognitive abilities, mainly in memory and executive functioning. A similar but premature deterioration in cognitive capacities is the hallmark of mild cognitive impairment, Alzeimer's disease and dementia. The biochemical mechanisms that cause these neurodegenerative disorders are poorly understood. However, some evidence suggests that insufficient dietary intakes of some phospholipids could impact on brain function and increase the risk of future cognitive impairment and dementia. We evaluated the cognitive and biochemical effects of supplementation with a milk fat globule membrane (MFGM) concentrate in aged rats. We observed that, compared to control animals, MFGM supplemented rats showed enhanced spatial working memory, but both groups exhibited similar reference spatial learning and emotional memory abilities. No significant differences between BDNF levels in the hippocampus and frontal cortex of treated rats as compared to controls were found. The nootropic effects observed were accompanied by significant changes in the lipid composition of synaptic membranes. MFGM supplementation increased the levels of EPA and DHA acids as well as the plasmalogens content in the synaptosomes isolated from the hippocampus (Synapt-HP) and the frontal cortex (Synapt-FC). In addition enhanced levels of phosphatidyl serine (PS), particularly PS(18:1/18:1), and phosphatidyl inositol (PI) molecular species were observed in Synapt-HP and Synapt-FC of treated animals.Lipidomic analysis also revealed greater concentration of phosphatidyl ethanolamine (PE) molecular species containing very long-chain fatty acids and PE plasmenyls in Synapt-HP as well as an increase of the SM content in Synapt-FC from the MFGM group. Although further studies are needed to confirm the underlying mechanism (individual or synergistic), these results suggest that MFGM supplementation could be employed as a dietary implement to restore the proper cerebral concentration of some bioactive lipids and prevent or slow the progression of age-related cognitive impairment.

Abstract Exposure to certain environmental factors and xenobiotic agents can lead to an excess of reactive oxygen species and free radical formation that can damage neuronal cells and affect cognitive function. Silica nanoparticles, as probes for genes or proteins, are already used in nanomedicine as a nanocarrier for several drugs. In the present study, SiO2 NPs were functionalized with glutamate to fight the oxidative-induced stress following chronic exposure to hydrogen peroxide (H2O2). This study aims to investigate whether Glutamate-functionalized Silica Nanoparticles can prevent the neurobehavioral and functional modifications displayed by adult male rats exposed to hydrogen peroxide (H2O2). We observed that subchronic exposure (21 days)to H2O2 induced an anxious state and a decrease in locomotor activity in the animals compared to controls. It the Morris water maze task, rats exposed to H2O2 showed impaired spatial learning and memory abilities. In addition, we observed that compared to controls, H2O2 exposed animals showed an imbalance in the redox status and disturbances of the enzyme’s activities-acetylcholinesterase (AChE) and Monoamine Oxidase (MAO) that were prevented by concomitant SiO2 NPs administration. Furthermore, H2O2 treatment enhanced the occurrence of necrotic and degenerative cell changes in several brain areas (hippocampus, subiculum, caudate-putamen and frontal cortex), that were ameliorated by SiO2 NPs treatment. In summary, the supplementation of L-glutamic acid-functionalized silica Nanoparticles corrected enzymatic activities, reduced behavioral disturbances and diminished histological alterations induced by H2O2. Our results suggest that SiO2 NPs are useful to prevent or ameliorate behavioral impairment, as well as antioxidant enzymatic disturbances and neural damage induced by oxidative stress in the hippocampus and frontal cortex.

Aim The Memory Failures of Everyday (MFE) is a widely used instrument for assessing memory failure. The aim of the study was to analyze the MFE items using the Rasch model in a sample of cognitively older adults in Spain. Methods A cross-sectional validation study in a sample of 214 healthy people aged >= 60 years who used centers for older people in Madrid (Spain). The MFE for the assessment of memory complaints was used. The following properties of the Rasch model were assessed: data fit, reliability, unidimensionality, local dependence and lack of differential item functioning by gender, age and marital status. Results The MFE showed a good fit to the Rasch model (chi(2)(140) = 160.2; P = 0.116) and high reliability (person separation index = 0.808). The questionnaire was unidimensional (6.54% t-test; IC binomial = 0.036-0.095). The items showed lack of local dependence between them and differential item functioning. The MFE scores were transformed into linear interval scores with a median of 44.31 and an observed range of 17.9-89.2 (theoretical range: 0-100). Conclusions The MFE is a unidimensional, reliable instrument to assess memory complaints in cognitively healthy older adults in Spain, with usefulness in clinical research and practice. The construct validity of the MFE linear score could not be fully confirmed and this deserves further investigation. Geriatr Gerontol Int center dot center dot; center dot center dot: center dot center dot-center dot center dot Geriatr Gerontol Int 2022; center dot center dot: center dot center dot-center dot center dot.