NF-κB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation.

Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in aged adults is associated with neurodegeneration, yet the molecular underpinnings of age-related sensitivity to alcohol are not well described. Studies utilizing rodent models of neurodegenerative disease reveal heightened activation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Nod like receptor 3 (NLRP3) mediate microglia activation and associated neuronal injury. Our group, and others, have implicated hippocampal-resident microglia as key producers of inflammatory mediators, yet the link between inflammation and neurodegeneration has not been established in models of binge ethanol exposure and advanced age. Here, we report binge ethanol increased the proportion of NLRP3+ microglia in the hippocampus of aged (18-20 months) female C57BL/6N mice compared to young (3-4 months). In primary microglia, ethanol-induced expression of reactivity markers and NLRP3 inflammasome activation were more pronounced in microglia from aged mice compared to young. Making use of an NLRP3-specific inhibitor (OLT1177) and a novel brain-penetrant Nanoligomer that inhibits NF-κB and NLRP3 translation (SB_NI_112), we find ethanol-induced microglial reactivity can be attenuated by OLT1177 and SB_NI_112 in microglia from aged mice. In a model of intermittent binge ethanol exposure, SB_NI_112 prevented ethanol-mediated microglia reactivity, IL-1ß production, and tau hyperphosphorylation in the hippocampus of aged mice. These data suggest early indicators of neurodegeneration occurring with advanced age and binge ethanol exposure are NF-κB- and NLRP3-dependent. Further investigation is warranted to explore the use of targeted immunosuppression via Nanoligomers to attenuate neuroinflammation after alcohol consumption in the aged.

Whole body vibration ameliorates anxiety-like behavior and memory functions in 30 months old senescent male rats.

Whole body vibration (WBV) is a form of passive exercise that offers an alternative physical training to aged individuals with limitations in their physical and mental capabilities. The aim of the present study was to explore the therapeutic potential of five weeks of WBV on anxiety-like behaviors as well as learning and memory abilities in senescent thirty months old rats. Animals were exposed to 5 min vibration twice per day, five times per week during the five consecutive weeks. Pseudo WBV treated animals served as controls. After five weeks of WBV treatment, animals were tested for anxiety-like behavior by the open field test and for spatial and object memory functions by the novel and spatial object recognition tests, respectively. As a result, anxiety-like and exploratory behaviors were significantly improved in the WBV treated group compared to the pseudo WBV group. Furthermore, WBV treatment increased discrimination performance in both spatial and object memory function testing. These results indicate that WBV treatment in thirty months old rats seems to have comparable beneficial effects on age-related emotional and cognitive performance as what has been reported in younger age groups.

HOMA-IR is positively correlated with biological age and advanced aging in the US adult population.

BACKGROUND: Insulin resistance (IR) had been reported to be associated with age; however, few studies have explored the association between IR and biological age (BA). The HOMA-IR value is a useful indicator of the extent of IR. This cross-sectional study is to explore the relationship between HOMA-IR and BA/advanced aging in the US population. METHODS: This study is a cross-sectional analysis of National Health and Nutrition Examination Survey (NHANES) data. The survey comprised 12,266 people from the NHANES, and their full HOMA-IR data as well as BA data were extracted. Four multiple linear regressions were performed to analyze the association between HOMA-IR and BA, and four multiple logistic regression models were performed to analyze the association between HOMA-IR and advanced aging. In addition, trend tests and stratified analysis were performed and smoothed fitted curves were plotted to test the robustness of the results. RESULTS: HOMA-IR was positively correlated with BA [ß: 0.51 (0.39, 0.63)], and it was the same to advanced aging [OR: 1.05 (1.02, 1.07)], and both showed a monotonically increasing trend. The trend tests showed that the results were stable (all P for trend < 0.0001). The smoothed fitted curves showed that there were non-linear relationships between HOMA-IR and BA/advanced aging. And the stratified analysis indicated that the relationship between HOMA-IR and BA/advanced aging remained robust in all subgroups. CONCLUSION: The study suggested that HOMA-IR is positively correlated with BA and advanced aging in the US adult population, with a monotonic upward trend. This is a new finding to reveal the relationship between HOMA-IR and age from new standpoint of BA rather than chronological age (CA). And it may contribute to a better understanding of human health aging and may aid future research in this field.

Advanced Brain-Age in Psychotic Psychopathology: Evidence for Transdiagnostic Neurodevelopmental Origins.

Schizophrenia is characterized by abnormal brain structure such as global reductions in gray matter volume. Machine learning models trained to estimate the age of brains from structural neuroimaging data consistently show advanced brain-age to be associated with schizophrenia. Yet, it is unclear whether advanced brain-age is specific to schizophrenia compared to other psychotic disorders, and whether evidence that brain structure is "older" than chronological age actually reflects neurodevelopmental rather than atrophic processes. It is also unknown whether advanced brain-age is associated with genetic liability for psychosis carried by biological relatives of people with schizophrenia. We used the Brain-Age Regression Analysis and Computation Utility Software (BARACUS) prediction model and calculated the residualized brain-age gap of 332 adults (163 individuals with psychotic disorders: 105 schizophrenia, 17 schizoaffective disorder, 41 bipolar I disorder with psychotic features; 103 first-degree biological relatives; 66 controls). The model estimated advanced brain-ages for people with psychosis in comparison to controls and relatives, with no differences among psychotic disorders or between relatives and controls. Specifically, the model revealed an enlarged brain-age gap for schizophrenia and bipolar disorder with psychotic features. Advanced brain-age was associated with lower cognitive and general functioning in the full sample. Among relatives, cognitive performance and schizotypal symptoms were related to brain-age gap, suggesting that advanced brain-age is associated with the subtle expressions associated with psychosis. Exploratory longitudinal analyses suggested that brain aging was not accelerated in individuals with a psychotic disorder. In sum, we found that people with psychotic disorders, irrespective of specific diagnosis or illness severity, show indications of non-progressive, advanced brain-age. These findings support a transdiagnostic, neurodevelopmental formulation of structural brain abnormalities in psychotic psychopathology.

Advanced aging effects on implicit motor imagery and its links to motor performance: An investigation via mental rotation of letters, hands, and feet.

This study focuses on changes in implicit motor imagery during advanced aging and these changes' co-occurrences with physical motor deficits. We administered a mental rotation (MR) task with letters, hands, and feet to 28 young adults (20-27 years) and to 71 older adults (60-87 years), and assessed motor skills (gait mobility and hand dexterity) and neuropsychological performance. Compared to young adults, older adults showed lower MR performance for all stimuli and stronger biomechanical constraint effects on both hand and foot rotation. Moreover, the foot biomechanical constraint effect continued to increase during late adulthood, and declines in hand and foot motor imagery emerged at earlier old ages than declines in visual imagery. These results first demonstrated distinct aging trajectories of hand motor imagery, foot motor imagery, and visual imagery. Exploratory partial correlation analysis for older adults showed positive associations of low-level perceptual-motor skills (Trail Making Test-A performance) with hand and foot MR performance and positive associations of mobility (Timed Up and Go test performance) with foot and letter MR performance. These associations exhibited somewhat different patterns from those of young adults and raised the possibility that age-related declines in motor (and visual) imagery co-occur with declines in motor functioning.