Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non-canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non-canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis.

Objective: Previous research suggests that everyday discrimination is associated with worse concomitant performance in several cognitive domains, as well as faster subsequent declines in episodic memory. This study aimed to extend knowledge on the specificity, durability, and mechanisms of associations between everyday discrimination and cognition by using a comprehensive neuropsychological battery and a longitudinal mediation design. Method: Participants included 3,304 older adults in the Health and Retirement Study Harmonized Cognitive Assessment Protocol. Discrimination was assessed using the Everyday Discrimination Scale. Depressive symptoms were assessed with the 8-item Center for Epidemiological Studies Depression Scale. Vascular diseases were quantified as the self-reported presence of hypertension, diabetes, and heart disease. Confirmatory factor analysis was used to estimate episodic memory, executive functioning, processing speed, language, and visuoconstruction across a battery of 13 neuropsychological tests. Structural equation models controlled for sociodemographics and baseline cognition ascertained 2 to 4 years prior. Results: Discrimination was associated with more depressive symptoms and vascular diseases. Depressive symptoms mediated negative effects of discrimination on subsequent functioning across all 5 cognitive domains. Vascular diseases additionally mediated negative effects of discrimination on processing speed. After accounting for mediators, direct negative effects of discrimination remained for executive functioning and visuoconstruction. Conclusions: This national longitudinal study in the United States provides evidence for broad and enduring effects of everyday discrimination on cognitive aging, which appear to be partially mediated by mental and physical health. Future research should examine additional mechanisms as well as moderators of these associations to better understand points of intervention.

Objective: Racial/ethnic disparities in cognitive aging are only partly attributable to socioeconomic indicators. Psychosocial factors, such as discrimination and perceived control, also differ across racial/ ethnic groups, and emerging literature highlights their potential role in contributing to cognitive disparities in addition to socioeconomic status. Method: 1,463 older adults (51% Hispanic, 27% non-Hispanic Black, and 22% non-Hispanic White) in the Washington Heights-Inwood Columbia Aging Project completed cognitive and psychosocial measures, including a comprehensive neuropsychological battery, Everyday and Major Experiences of Lifetime Discrimination scales, and the Perceived Control scale. Mediation models quantified separate indirect effects of Black race and Hispanic ethnicity on global cognitive composite scores through education, income, discrimination, and external perceived control. Results: Educational attainment, income, and perceived control each mediated racial/ethnic disparities in global cognition. Socioeconomic indicators (i.e., lower education and lower income) explained approximately 50% of the Black-White and Hispanic-White disparities in global cognition, and more external perceived control explained an additional 5%-8%. Hispanics reported the lowest levels of discrimination, while non-Hispanic Blacks reported the highest levels. However, neither everyday nor major lifetime discrimination was associated with global cognition. Significant racial/ethnic disparities in global cognition remained after accounting for the included socioeconomic and psychosocial factors. Conclusions: This study suggests that psychosocial factors may explain racial/ethnic disparities in cognitive aging above and beyond socioeconomic indicators. More external perceived control, which could reflect chronic exposure to interpersonal and institutional marginalization, may be a particularly salient psychosocial risk factor for poorer cognitive aging among non-Hispanic Black and Hispanic older adults. Key PointsQuestion: What factors explain racial/ethnic inequalities in cognitive functioning among older adults? Findings: Lower socioeconomic status and lower perceived control each contribute independently to racial/ethnic inequalities in cognitive functioning. Importance: Targeting both economic and psychosocial factors may help to reduce racial/ethnic inequalities in cognitive aging. Next Steps: Future research should disentangle causal pathways to inequality involving socioeconomic and psychosocial factors, which may be interactive and/or bidirectional.

Background Physical activity (PA) in later-life may reduce dementia risk, but little is known regarding long-term cognitive effects of PA that occurred earlier in adulthood or mechanisms underlying associations. PA patterns at different ages may independently contribute to dementia risk, which would implicate multiple critical periods for intervention. The current study tested whether retrospective reports of PA in early- and mid-adulthood were independently associated with later-life longitudinal memory outcomes and whether associations were mediated by late-life cardiometabolic diseases. Methods Participants comprised 5,200 Health and Retirement Study Life History Mail Survey respondents. Latent growth curves estimated independent associations between retrospectively reported PA in early-adulthood (age 18-29) and mid-adulthood (age 40-49) and 16-year episodic memory trajectories. Indirect pathways involving the maintenance of PA from early- to mid-adulthood and the influence of PA on later-life cardiometabolic diseases (hypertension, diabetes, and heart disease) were also estimated. Results PA in early- and mid-adulthood independently predicted higher initial memory level and slower memory decline in later-life, respectively. Early-adulthood PA was indirectly associated with later-life memory level through higher mid-adulthood PA and lower rates of later-life hypertension, as well as with subsequent memory decline through higher mid-adulthood PA. Conclusions The current findings highlight the importance of PA throughout adulthood, such that initiating and/or maintaining exercise in early- or mid-adulthood may be protective for later-life cognitive health, and hypertension appears to represent a key mediator of these effects.

Background and Objectives Social media use has been linked to socioemotional health; however, less is known regarding whether these associations are moderated by age. Additionally, as the use of social media in older adult populations is rapidly increasing, there is a greater need for the investigation of psychometric properties of social media usage scales before determining age differences in the impact of social media on socioemotional health outcomes. Research Design and Methods Using an online adult lifespan sample (n=592), the current cross-sectional study tested the measurement invariance of the general social media usage subscale of the Media and Technology Usage and Attitudes Scale across younger (aged 19-54) versus older (aged 55-81) adults and whether age moderated associations between social media use and socioemotional health (depressive symptoms, self-esteem, envy). Results Confirmatory factor analyses revealed that posting-related and checking-related items were noninvariant across age groups. In multi-group structural equation models accounting for differential item functioning, higher social media use was associated with more depressive symptoms in younger adults, but not in older adults. While higher social media use was associated with higher envy in both age groups, this association was stronger in younger adults. Discussion and Implications Findings suggest younger adults may be more susceptible to the detrimental effects of social media use on socioemotional health. Future directions regarding the measurement of social media use and the salience of social media use across the lifespan are discussed.