Lifecourse Pyschosocial Stressors, Immune Function, Infection, and Cognitive Decline & Dementia

The over five million people in the U.S. living with dementia are at an elevated risk of other negative health outcomes due to a diminished ability to care for themselves, contributing significantly to healthcare costs. There is evidence that traumatic life events (TLE) influence later-life cognitive function and decline through chronic activation of the HPA axis. One likely mechanism through which TLEs impact cognition is immune system alterations. Using data on 7,785 participants aged 65+ from the Health and Retirement Study (HRS) and 1,337 participants aged 60+ from the Sacramento Area Latino Study of Aging (SALSA), we investigated these relationships. In HRS, we estimated the association between TLEs and cognitive trajectories and incident dementia from 2006 to 2016. In SALSA, we estimated the associations between baseline immune biomarkers and cognitive outcomes over 10 years. Linear mixed effects models were used to examine these associations and potential interactions or effect measure modification. Stratified cumulative incidence functions were calculated to investigate risk of dementia. We found that TLEs were associated with a higher level of cognitive function and faster rate of decline but not with dementia incidence. The associations were strongest among those who experienced TLEs in late life and those with the lowest educational attainment. However, the type of TLE determined not only the strength but also the direction of the association. We also found that IL-6, TNF-alpha, and CMV IgG levels were associated with poorer cognitive function in SALSA, and the identified relationships were modified by educational attainment. Additionally, IL-6, TNF-alpha, and HSV-1 interacted with cortisol to alter the relationships with cognitive level and age. We did not find any statistically significant associations between exposures and dementia incidence. These findings suggest that TLEs may impact cognitive function and rate of cognitive decline in late life, timing of these events within the lifecourse is important, and these relationships are modified by educational attainment. Furthermore, elevated immune biomarkers may be indicative of lower cognitive function or accelerating decline in older populations. These relationships were modified by educational attainment, and cortisol may interact with immune cells to alter the associations with cognitive outcomes.Doctor of Philosoph

Does cytomegalovirus infection contribute to socioeconomic disparities in all-cause mortality?

The social patterning of cytomegalovirus (CMV) and its implication in aging suggest that the virus may partially contribute to socioeconomic disparities in mortality. We used Cox regression and inverse odds ratio weighting to quantify the proportion of the association between socioeconomic status (SES) and all-cause mortality that was attributable to mediation by CMV seropositivity. Data were from the National Health and Nutrition Examination Survey (NHANES) III (1988–1994), with mortality follow-up through December 2011. SES was assessed as household income (income-to-poverty ratio ≤1.30; >1.30 to ≤1.85; >1.85 to ≤3.50; >3.50) and education (high school). We found strong associations between low SES and increased mortality: hazard ratio (HR) 1.80; 95% confidence interval (CI): 1.57, 2.06 comparing the lowest versus highest income groups and HR 1.29; 95% CI: 1.13, 1.48 comparing high school education. 65% of individuals were CMV seropositive, accounting for 6–15% of the SES-mortality associations. Age modified the associations between SES, CMV, and mortality, with CMV more strongly associated with mortality in older individuals. Our findings suggest that cytomegalovirus may partially contribute to persistent socioeconomic disparities in mortality, particularly among older individuals

Life Course Process of Alzheimer’s Disease: Sex Difference and Biosocial Mechanisms: Integrated Dataset Creation and Public Code Documentation

The project addresses major gaps in existing research on cognitive aging by 1) characterizing age-related cognitive change over the full life span, 2) assessing social disparities in cognitive aging by sex/gender, race/ethnicity, and socioeconomic status as well as other social stressors, and 3) exploring biological mechanisms by which social factors are linked to cognitive health and dementia risk. The foundation for this project is the construction of longitudinal cohort data that spans the adult life course. We address challenges in previous research using single panel data with an extensive longitudinal life course research design and a novel application of integrative data analysis (IDA) to determine for the first time the trajectory of cognitive aging throughout life in Americans aged 12 and older, and main demographic and socioeconomic differentials therein

An Early and Unequal Decline: Life Course Trajectories of Cognitive Aging in the United States

Objectives: Cognitive aging is a lifelong process with implications for Alzheimer’s disease and dementia. This study aims to fill major gaps in research on the natural history of and social disparities in aging-related cognitive decline over the life span. Methods: We conducted integrative data analysis of four large U.S. population-based longitudinal studies of individuals aged 12 to 105 followed over two decades and modeled age trajectories of cognitive function in multiple domains. Results: We found evidence for the onset of cognitive decline in the 4th decade of life, varying gender differences with age, and persistent disadvantage among non-Hispanic Blacks, Hispanics, and those without college education. We further found improvement in cognitive function across 20th century birth cohorts but widening social inequalities in more recent cohorts. Discussion: These findings advance an understanding of early life origins of dementia risk and invite future research on strategies for promoting cognitive health for all Americans

Nrt1 and Tna1-Independent Export of NAD+ Precursor Vitamins Promotes NAD+ Homeostasis and Allows Engineering of Vitamin Production

NAD+ is both a co-enzyme for hydride transfer enzymes and a substrate of sirtuins and other NAD+ consuming enzymes. NAD+ biosynthesis is required for two different regimens that extend lifespan in yeast. NAD+ is synthesized from tryptophan and the three vitamin precursors of NAD+: nicotinic acid, nicotinamide and nicotinamide riboside. Supplementation of yeast cells with NAD+ precursors increases intracellular NAD+ levels and extends replicative lifespan. Here we show that both nicotinamide riboside and nicotinic acid are not only vitamins but are also exported metabolites. We found that the deletion of the nicotinamide riboside transporter, Nrt1, leads to increased export of nicotinamide riboside. This discovery was exploited to engineer a strain to produce high levels of extracellular nicotinamide riboside, which was recovered in purified form. We further demonstrate that extracellular nicotinamide is readily converted to extracellular nicotinic acid in a manner that requires intracellular nicotinamidase activity. Like nicotinamide riboside, export of nicotinic acid is elevated by the deletion of the nicotinic acid transporter, Tna1. The data indicate that NAD+ metabolism has a critical extracellular element in the yeast system and suggest that cells regulate intracellular NAD+ metabolism by balancing import and export of NAD+ precursor vitamins

Three Dimensional Structure of the MqsR:MqsA Complex: A Novel TA Pair Comprised of a Toxin Homologous to RelE and an Antitoxin with Unique Properties

One mechanism by which bacteria survive environmental stress is through the formation of bacterial persisters, a sub-population of genetically identical quiescent cells that exhibit multidrug tolerance and are highly enriched in bacterial toxins. Recently, the Escherichia coli gene mqsR (b3022) was identified as the gene most highly upregulated in persisters. Here, we report multiple individual and complex three-dimensional structures of MqsR and its antitoxin MqsA (B3021), which reveal that MqsR:MqsA form a novel toxin:antitoxin (TA) pair. MqsR adopts an α/β fold that is homologous with the RelE/YoeB family of bacterial ribonuclease toxins. MqsA is an elongated dimer that neutralizes MqsR toxicity. As expected for a TA pair, MqsA binds its own promoter. Unexpectedly, it also binds the promoters of genes important for E. coli physiology (e.g., mcbR, spy). Unlike canonical antitoxins, MqsA is also structured throughout its entire sequence, binds zinc and coordinates DNA via its C- and not N-terminal domain. These studies reveal that TA systems, especially the antitoxins, are significantly more diverse than previously recognized and provide new insights into the role of toxins in maintaining the persister state

Socioeconomic and race/ethnic differences in immunosenescence: evidence from the Health and Retirement Study

Background The COVID-19 pandemic has highlighted the urgent need to understand variation in immunosenescence at the population-level. Thus far, population patterns of immunosenescence have not well described. Methods We characterized measures of immunosenescence from the 2016 Venous Blood Study from the nationally representative U.S Health and Retirement Study (HRS) of individuals ages 50 years and older. Results Median values of the CD8+:CD4+, EMRA:Naïve CD4+ and EMRA:Naïve CD8+ ratios were higher among older participants and were lower in those with additional educational attainment. Generally, minoritized race and ethnic groups had immune markers suggestive of a more aged immune profile: Hispanics had a CD8+:CD4+ median value of 0.37 (95 % CI: 0.35, 0.39) compared to 0.30 in non-Hispanic Whites (95 % CI: 0.29, 0.31). Non-Hispanic Blacks had the highest median value of the EMRA:Naïve CD4+ ratio (0.08; 95 % CI: 0.07, 0.09) compared to non-Hispanic Whites (0.03; 95 % CI: 0.028, 0.033). In regression analyses, race/ethnicity and education were associated with large differences in the immune ratio measures after adjustment for age and sex. Conclusions Lower educational attainment and minoritized racial ethnic status were associated with higher levels of immunosenescence. This population variation may have important implications for both risk of age-related disease and vulnerability to emerging pathogens (e.g., SARS-CoV-2)

Life course socioeconomic disadvantage and the aging immune system: findings from the health and retirement study

Objectives Previous research has documented a consistent association between current socioeconomic status (SES) and cytomegalovirus (CMV). Early life is likely a critical period for CMV exposure and immune development, but less is known about early-life socioeconomic factors and CMV, particularly in older age populations. Using data from the Health and Retirement Study, we investigated the association between life course socioeconomic disadvantage and immune response to CMV among older adults. Methods Using ordered logit models, we estimated associations between several measures of socioeconomic disadvantage and the odds of being in a higher CMV Immunoglobulin G (IgG) response category in a sample of 8,168 respondents aged older than 50 years. Results We found a significant association between educational attainment and CMV IgG response. Those with less than a high school education had 2.00 (95% confidence interval [CI]: 1.67–2.40) times the odds of being in a higher CMV category compared to those with a college degree or greater. In addition, we also observed a significant association with parental education and CMV response. Individuals with parents having 8 years or less of schooling had 2.32 (95% CI: 2.00–2.70) times the odds of higher CMV response compared to those whose parents had greater than high school education. Discussion CMV IgG levels in older adults are associated with both early-life and adult SES. Life course socioeconomic disadvantage may contribute to disparities in immunological aging

Association between immune response to cytomegalovirus and cognition in the Health and Retirement Study

Chronic infections and the subsequent immune response have recently been shown to be risk factors for cognitive decline and Alzheimer disease and related dementias (ADRD). While some studies have shown an association between cytomegalovirus (CMV), a chronic and highly prevalent infection, and cognition and/or ADRD, these studies have been limited by nonrepresentative and small samples. Using 2016 data on 5,617 adults aged 65 years or more from the Health and Retirement Study, we investigated the cross-sectional associations of both CMV serostatus and immunoglobulin G (IgG) antibody response with cognitive function using linear regression models adjusting for age, sex, race/ethnicity, and educational attainment. We further investigated potential effect-measure modification by educational attainment. Overall, both CMV seropositivity and higher IgG antibody response were associated with lower cognitive function, though the relationship was not statistically significant in adjusted models. Among participants with less than a high school diploma, CMV seropositivity and being in the first tertile of IgG response, relative to seronegative persons, were associated with lower scores on the Telephone Interview for Cognitive Status (-0.56 points (95% confidence interval: -1.63, 0.52) and -0.89 points (95% confidence interval: -2.07, 0.29), respectively), and the relationship was attenuated among those with higher education. Our results suggest that CMV may be a risk factor for cognitive impairment, particularly among persons with fewer educational resources