Understanding the relationship between perceived discrimination, allostatic load, and all-cause mortality in US older adults: A mediation analysis.

OBJECTIVE: To understand the relationship between perceived discrimination, allostatic load, and all-cause mortality; and to determine whether allostatic load is a mediator in the relationship between perceived discrimination and all-cause mortality among an older adult US population. METHODS: Data from the Health and Retirement Study (2006-2012) was analyzed. Cox proportional hazard models were used to investigate the relationship between all-cause mortality and perceived discrimination, and all-cause mortality and allostatic load. Linear regression models were used to investigate the relationship between perceived discrimination and allostatic load. A mediation model with perceived discrimination and allostatic loads as independent variables was used to determine the association with all-cause mortality. RESULTS: There were 5062 adults over the age of 50 included in the analysis. The relationship between perceived discrimination and allostatic load was statistically significant (b:0.14, [95%CI 0.10,0.19]; p < 0.001). The relationship between perceived discrimination and all-cause mortality was statistically significant (HR: 1.12, [95%CI 1.03,1.22]; p = 0.01). The relationship between allostatic load and all-cause mortality was statistically significant (HR: 1.11, [95%CI 1.08,1.13]; p < 0.001). The mediation model resulted in a decrease in hazard ratio and loss of statistical significance for perceived discrimination (HR: 1.09, [95%CI 0.98,1.21]; p = 0.13) when allostatic load (HR: 1.17, [95%CI 1.10,1.24]; p < 0.001) was added to the Cox regression model, indicating full mediation. CONCLUSIONS: Allostatic load fully mediates the relationship between perceived discrimination and all-cause mortality. Understanding the role of allostatic load in this relationship provides an additional implication for screening and indications for tighter control of the modifiable components of allostatic load by healthcare providers, especially among individuals who experience discrimination.

Understanding the relationship between perceived discrimination and mortality in United States adults.

OBJECTIVE: To understand the relationship between mortality and three types of perceived discrimination (lifetime, daily, chronic job) using a nationally representative sample of U.S. adults. METHODS: Data from 4562 adults in the Midlife in the United States (MIDUS) between 2004 and 2006 (MIDUS II and MIDUS African American sample) were analyzed. Unadjusted associations between primary independent discrimination variables (lifetime, chronic job, daily) and mortality were analyzed using univariate Cox's proportional hazards regression models. Covariates were added to the models by group: predisposing (sex, age, race/ethnicity, education, marital status); enabling (household income, employment status, insurance status); and need factors (body mass index, diabetes, hypertension, stroke, cancer) to estimate hazard ratios. RESULTS: After adjusting for all covariates, hazard ratios for lifetime discrimination (HR: 1.09, p = 0.034) and daily discrimination (HR: 1.03, p = 0.030) were statistically significant. There was no relationship between mortality and chronic job discrimination (HR:1.03, p = 0.15). CONCLUSIONS: Adults experiencing lifetime and daily discrimination had significantly increased risk of mortality after adjusting for predisposing, enabling, and need factors. The findings highlight the importance of screening patients during clinical encounters for experiences of discrimination and providing appropriate resources to mitigate the negative impact of discriminatory events on mortality. Future research should work to fully understand the mechanism by which discrimination increases risk of mortality. These future findings should be used to develop targets for interventions designed to decrease mortality among adults who have experienced discrimination.

DMSO-mediated curing of several yeast prion variants involves Hsp104 expression and protein solubilization, and is decreased in several autophagy related gene (atg) mutants.

Chaperones and autophagy are components of the protein quality control system that contribute to the management of proteins that are misfolded and aggregated. Here, we use yeast prions, which are self-perpetuating aggregating proteins, as a means to understand how these protein quality control systems influence aggregate loss. Chaperones, such as Hsp104, fragment prion aggregates to generate more prion seeds for propagation. While much is known about the role of chaperones, little is known about how other quality control systems contribute to prion propagation. We show that the aprotic solvent dimethyl sulfoxide (DMSO) cures a range of [PSI+] prion variants, which are related to several misfolded aggregated conformations of the Sup35 protein. Our studies show that DMSO-mediated curing is quicker and more efficient than guanidine hydrochloride, a prion curing agent that inactivates the Hsp104 chaperone. Instead, DMSO appears to induce Hsp104 expression. Using the yTRAP system, a recently developed transcriptional reporting system for tracking protein solubility, we found that DMSO also rapidly induces the accumulation of soluble Sup35 protein, suggesting a potential link between Hsp104 expression and disassembly of Sup35 from the prion aggregate. However, DMSO-mediated curing appears to also be associated with other quality control systems. While the induction of autophagy alone does not lead to curing, we found that DMSO-mediated curing is dramatically impaired in autophagy related (atg) gene mutants, suggesting that other factors influence this DMSO mechanism of curing. Our data suggest that DMSO-mediated curing is not simply dependent upon Hsp104 overexpression alone, but may further depend upon other aspects of proteostasis.

De novo [PSI +] prion formation involves multiple pathways to form infectious oligomers.

Prion and other neurodegenerative diseases are associated with misfolded protein assemblies called amyloid. Research has begun to uncover common mechanisms underlying transmission of amyloids, yet how amyloids form in vivo is still unclear. Here, we take advantage of the yeast prion, [PSI +], to uncover the early steps of amyloid formation in vivo. [PSI +] is the prion form of the Sup35 protein. While [PSI +] formation is quite rare, the prion can be greatly induced by overexpression of the prion domain of the Sup35 protein. This de novo induction of [PSI +] shows the appearance of fluorescent cytoplasmic rings when the prion domain is fused with GFP. Our current work shows that de novo induction is more complex than previously thought. Using 4D live cell imaging, we observed that fluorescent structures are formed by four different pathways to yield [PSI +] cells. Biochemical analysis of de novo induced cultures indicates that newly formed SDS resistant oligomers change in size over time and lysates made from de novo induced cultures are able to convert [psi -] cells to [PSI +] cells. Taken together, our findings suggest that newly formed prion oligomers are infectious.