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Objective: Optimism and purpose in life are associated with improved health outcomes. More information is needed on biological mechanisms, including immunosenescence. We investigated if psychological well-being is associated with healthier immunosenescence-related measures including naïve and terminally differentiated CD4 + and CD8 + T cell percentages, CD4 + :CD8 + , and cytomegalovirus (CMV) IgG response., Methods: Participants were adults over age 50 from the Health and Retirement Study. Optimism was measured using the Life Orientation Test Revised. Purpose in life was assessed using the subscale from the Ryff psychological well-being measure. We examined the cross-sectional associations of optimism and purpose in life with measures of T cell subsets using linear regression and with CMV IgG using ordered logit regression, controlling for potential confounding factors., Results: The final analytic sample ranged from 7250 to 7870. After adjusting for sociodemographic factors, a 1-SD increment in optimism was associated with the percentage of naïve CD4 + T cells increasing by 0.6 (95%CI 0.2%, 1.0%). A 1-SD increment in purpose in life was associated with the percentage of naïve CD4 + T cells increasing by 0.9 (95%CI 0.5%, 1.3%) after adjusting for sociodemographic factors and the association was maintained after further adjustments for health conditions, depression, and health behaviors. For naïve CD8 + T cell percentages, CD4:CD8 ratios, and CMV IgG antibodies, associations were seen only in models that adjusted for age. No significant associations were seen in any models for the terminally differentiated CD4 + and CD8 + T cells., Conclusions: We found associations of optimism and purpose in life with naïve CD4 + T cell percentages., Competing Interests: Declaration of competing interest none., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The cortical epigenetic clock was developed in brain tissue as a biomarker of brain aging. As one way to identify mechanisms underlying aging, we conducted a GWAS of cortical age. We leveraged postmortem cortex tissue and genotyping array data from 694 participants of the Rush Memory and Aging Project and Religious Orders Study (ROSMAP; 11000,000 SNPs), and meta-analysed ROSMAP with 522 participants of Brains for Dementia Research (5,000,000 overlapping SNPs). We confirmed results using eQTL (cortical bulk and single nucleus gene expression), cortical protein levels (ROSMAP), and phenome-wide association studies (clinical/neuropathologic phenotypes, ROSMAP). In the meta-analysis, the strongest association was rs4244620 ( p  = 1.29 × 10 -7 ), which also exhibited FDR-significant cis-eQTL effects for CD46 in bulk and single nucleus (microglia, astrocyte, oligodendrocyte, neuron) cortical gene expression. Additionally, rs4244620 was nominally associated with lower cognition, faster slopes of cognitive decline, and greater Parkinsonian signs (n ~ 1700 ROSMAP with SNP/phenotypic data; all p  ≤ 0.04). In ROSMAP alone, the top SNP was rs4721030 ( p  = 8.64 × 10 -8 ) annotated to TMEM106B and THSD7A . Further, in ROSMAP ( n  = 849), TMEM106B and THSD7A protein levels in cortex were related to many phenotypes, including greater AD pathology and lower cognition (all p  ≤ 0.0007). Overall, we identified converging evidence of CD46 and possibly TMEM106B/THSD7A for potential roles in cortical epigenetic clock age.

Background: Many studies indicate that smaller life space is related to worse cognitive and motor function. It is plausible that cognitive and motor function also predict life space constriction, thus long-term, prospective studies are needed of cognitive and motor function as predictors of life space., Methods: A total of 1246 participants of the Rush Memory and Aging Project, who reported initial maximal life space and at least one follow-up assessment were included in this prospective study, with up to 19 years follow-up. The outcome of interest was the Modified version of the Life Space Questionnaire; which we categorized into large (beyond community), medium (neighborhood/community), and small (home/yard) life space. Participants also had detailed composite measures of global cognition and motor function as predictors and available at the first life space assessment. Life space transitions over one-year periods were modeled using multistate Markov modeling, including confounders and both predictors simultaneously., Results: Better cognitive and motor function were broadly associated with lower odds of life space constriction (Cognitive: Large ➔ medium: OR = 0.91, 95% CI 0.83-1.00; Large ➔ small: OR = 0.85, 95% CI 0.74-0.97; Medium ➔ small: OR = 1.01, 95% CI 0.82-1.22. Motor: large ➔ medium: OR = 0.76, 95% CI 0.69-0.83; large ➔ small: OR = 0.58, 95% CI 0.51-0.67; medium ➔ small: OR = 0.71, 95% CI = 0.57-0.87)., Conclusions: Combined with previous literature that life space predicts function, these results support the notion of complex inter-relations of cognitive function, motor function, and life space., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most species. There is growing evidence that the gut microbiota has a pivotal role in host health and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota are related to healthy aging. Here, we report findings from a small longitudinal study of male C57BL/6 mice maintained on either ad libitum or mild (15%) CR diets from 21 months of age and tracked until natural death. We demonstrate that CR results in a significantly reduced rate of increase in the frailty index (FI), a well-established indicator of aging. We observed significant alterations in diversity, as well as compositional patterns of the mouse gut microbiota during the aging process. Interrogating the FI-related microbial features using machine learning techniques, we show that gut microbial signatures from 21-month-old mice can predict the healthy aging of 30-month-old mice with reasonable accuracy. This study deepens our understanding of the links between CR, gut microbiota, and frailty in the aging process of mice.

Epigenetic clocks are calculated by combining DNA methylation states across select CpG sites to estimate biologic age, and have been noted as the most successful markers of biologic aging to date. Yet, limited research has considered epigenetic clocks calculated in brain tissue. We used DNA methylation states in dorsolateral prefrontal cortex specimens from 721 older participants of the Religious Orders Study and Rush Memory and Aging Project, to calculate DNA methylation age using four established epigenetic clocks: Hannum, Horvath, PhenoAge, GrimAge, and a new Cortical clock. The four established clocks were trained in blood samples (Hannum, PhenoAge, GrimAge) or using 51 human tissue and cell types (Horvath); the recent Cortical clock is the first trained in postmortem cortical tissue. Participants were recruited beginning in 1994 (Religious Orders Study) and 1997 (Memory and Aging Project), and followed annually with questionnaires and clinical evaluations; brain specimens were obtained for 80-90% of participants. Mean age at death was 88.0 (SD 6.7) years. We used linear regression, logistic regression, and linear mixed models, to examine relations of epigenetic clock ages to neuropathologic and clinical aging phenotypes, controlling for chronologic age, sex, education, and depressive symptomatology. Hannum, Horvath, PhenoAge and Cortical clock ages were related to pathologic diagnosis of Alzheimer's disease (AD), as well as to Aβ load (a hallmark pathology of Alzheimer's disease). However, associations were substantially stronger for the Cortical than other clocks; for example, each standard deviation (SD) increase in Hannum, Horvath, and PhenoAge clock age was related to approximately 30% greater likelihood of pathologic AD (all p < 0.05), while each SD increase in Cortical age was related to 90% greater likelihood of pathologic AD (odds ratio = 1.91, 95% confidence interval 1.38, 2.62). Moreover, Cortical age was significantly related to other AD pathology (eg, mean tau tangle density, p = 0.003), and to odds of neocortical Lewy body pathology (for each SD increase in Cortical age, odds ratio = 2.00, 95% confidence 1.27, 3.17), although no clocks were related to cerebrovascular neuropathology. Cortical age was the only epigenetic clock significantly associated with the clinical phenotypes examined, from dementia to cognitive decline (5 specific cognitive systems, and a global cognitive measure averaging 17 tasks) to Parkinsonian signs. Overall, our findings provide evidence of the critical necessity for bespoke clocks of brain aging for advancing research to understand, and eventually prevent, neurodegenerative diseases of aging., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Healthy lifestyles are promising targets for prevention of cognitive aging, yet the optimal time windows for interventions remain unclear. We selected a case-control sample nested within the Nurses' Health Study (starting year 1976, mean age = 51 years), including 14,956 women aged ≥70 years who were free of both stroke and cognitive impairment at enrollment in a cognitive substudy (1995-2001). Cases (n = 1,496) were women with the 10% worst slopes of cognitive decline, and controls (n = 7,478) were those with slopes better than the median. We compared the trajectories of body mass index (weight (kg)/height (m)2), alternate Mediterranean diet (A-MeDi) score, and physical activity between groups, from midlife through 1 year preceding the cognitive substudy. In midlife, cases had higher body mass index than controls (mean difference (MD) = 0.59 units, 95% confidence interval (CI): 0.39, 0.80), lower physical activity (MD = -1.41 metabolic equivalent of task-hours/week, 95% CI: -2.07, -0.71), and worse A-MeDi scores (MD = -0.16 points, 95% CI: -0.26, -0.06). From midlife through later life, compared with controls, cases had consistently lower A-MeDi scores but a deceleration of weight gain and a faster decrease in physical activity. In conclusion, maintaining a healthy lifestyle since midlife may help reduce cognitive decline in aging. At older ages, both deceleration of weight gain and a decrease in physical activity may reflect early signs of cognitive impairment., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: We investigated the relation between self-reported hearing loss and risk of subjective cognitive function (SCF) decline among women., Methods: We conducted a longitudinal study of 20,193 women in the Nurses' Health Study aged ≥66 years who reported their hearing status and had no subjective cognitive concerns in 2012. SCF scores were assessed by a 7-item questionnaire in 2012 and 2014. SCF decline was defined as a new report of at least one cognitive concern during follow-up., Results: Self-reported hearing loss was associated with higher risk of SCF decline. Compared with women with no hearing loss, the multivariable-adjusted odds ratios (95% confidence interval) for incident SCF score ≥1 were 1.35 (1.25, 1.47), 1.39 (1.24, 1.56), and 1.40 (1.21, 1.75) among women with mild, moderate, and severe hearing loss, respectively. Recent progression of hearing loss was associated with even higher risk., Discussion: Self-reported hearing loss was associated with higher risk of incident subjective cognitive function decline in women., (© 2020 the Alzheimer's Association.)

Objective: Mounting evidence suggests that higher optimism is associated with reduced risk of age-related morbidities and premature mortality. However, possible biological mechanisms underlying these associations remain understudied. One hypothesized mechanism is a slower rate of cellular aging, which in turn delays age-related declines in health., Methods: We used data from two large cohort studies to test the hypothesis that higher optimism is associated with longer leukocyte telomere length. With cross-sectional data from the Health and Retirement Study (HRS; n = 6417; mean age = 70 years) and the Women's Health Initiative (WHI; N = 3582; mean age = 63 years), we used linear regression models to examine the association of optimism with relative telomere length (assessed in leukocytes from saliva [HRS] or plasma [WHI]). Models adjusted for sociodemographics, depression, health status, and health behaviors., Results: Considering both optimism and telomere length as continuous variables, we found consistently null associations in both cohorts, regardless of which covariates were included in the models. In models adjusting for demographics, depression, comorbidities, and health behaviors, optimism was not associated with mean relative telomere length (HRS: β = -0.002, 95% confidence interval = -0.014 to 0.011; WHI: β = -0.004, 95% confidence interval = -0.017 to 0.009)., Conclusions: Findings do not support mean telomere length as a mechanism that explains observed relations of optimism with reduced risk of chronic disease in older adults. Future research is needed to evaluate other potential biological markers and pathways.

Most research on exceptional longevity has investigated biomedical factors associated with survival, but recent work suggests nonbiological factors are also important. Thus, we tested whether higher optimism was associated with longer life span and greater likelihood of exceptional longevity. Data are from 2 cohorts, women from the Nurses' Health Study (NHS) and men from the Veterans Affairs Normative Aging Study (NAS), with follow-up of 10 y (2004 to 2014) and 30 y (1986 to 2016), respectively. Optimism was assessed using the Life Orientation Test-Revised in NHS and the Revised Optimism-Pessimism Scale from the Minnesota Multiphasic Personality Inventory-2 in NAS. Exceptional longevity was defined as survival to age 85 or older. Primary analyses used accelerated failure time models to assess differences in life span associated with optimism; models adjusted for demographic confounders and health conditions, and subsequently considered the role of health behaviors. Further analyses used logistic regression to evaluate the likelihood of exceptional longevity. In both sexes, we found a dose-dependent association of higher optimism levels at baseline with increased longevity ( P trend < 0.01). For example, adjusting for demographics and health conditions, women in the highest versus lowest optimism quartile had 14.9% (95% confidence interval, 11.9 to 18.0) longer life span. Findings were similar in men. Participants with highest versus lowest optimism levels had 1.5 (women) and 1.7 (men) greater odds of surviving to age 85; these relationships were maintained after adjusting for health behaviors. Given work indicating optimism is modifiable, these findings suggest optimism may provide a valuable target to test for strategies to promote longevity., Competing Interests: Conflict of interest statement: E.S.K. has worked as a consultant with AARP and United Health Group.

Evidence indicates associations between higher optimism and reduced risk of age-related conditions and premature mortality. This suggests optimism is a positive health asset, but research identifying potential biological mechanisms underlying these associations remains limited. One potential pathway is slower cellular aging, which may delay age-related deterioration in health. Data were from the Women's Health Initiative (WHI) (N=3,298) and the Veterans Affairs Normative Aging Study (NAS) (N=514), and included dispositional and explanatory style optimism measures. We evaluated whether higher optimism was associated with metrics suggestive of less cellular aging, as indicated by two DNA methylation algorithms, intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA); these algorithms represent accelerated biologic aging that exceeds chronological age. We used linear regression models to test our hypothesis while considering several covariates (sociodemographics, depressive symptoms, health behaviors). In both cohorts, we found consistently null associations of all measures of optimism with both measures of DNA methylation aging, regardless of covariates considered. For example, in fully-adjusted models, dispositional optimism was not associated with either IEAA (WHI:β=0.02; 95% Confidence Interval [CI]:-0.15-0.20; NAS:β=-0.06; 95% CI:-0.56-0.44) or EEAA (WHI:β=-0.04; 95% CI: -0.26-0.17; NAS:β=-0.17; 95% CI: -0.80-0.46). Higher optimism was not associated with reduced cellular aging as measured in this study.

Introduction: Optimism-the expectation that good things will happen-has emerged as a promising health asset, as it appears to be related to healthier behaviors and reduced disease risk. Growing research finds that higher optimism is associated with lower mortality, yet it is critical to understand whether this prolonged longevity is accompanied by good health. This study tested whether higher optimism was associated with increased likelihood of healthy aging., Methods: Prospective data analyzed in 2018 from the Nurses' Health Study included 33,326 women with no major chronic diseases at baseline. Poisson regression models evaluated if optimism was associated with healthy aging 8 years later, considering potential confounders (sociodemographic variables, depression) and intermediate variables (health behaviors). Optimism was assessed in 2004 by validated self-report using mailed questionnaires and healthy aging was assessed in 2012, defined as (1) remaining free of major chronic diseases; (2) having no subjective memory impairment; (3) having intact physical function; and (4) surviving through follow-up., Results: Overall, 20.5% of women (n=6,823) fulfilled the definition of healthy aging in 2012. After adjusting for sociodemographic factors and depression, the most (top quartile) versus least (bottom quartile) optimistic women had a 23% greater likelihood of healthy aging (95% CI=1.16, 1.30). Associations were similar in white and black participants, although the sample of black women was small (n=354)., Conclusions: Higher optimism was associated with increased likelihood of healthy aging, suggesting that optimism, a potentially modifiable health asset, merits further research for its potential to improve health in aging., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Context: Increasing evidence suggests that circadian and sleep parameters influence cognitive function with aging., Objective: To evaluate observational studies of sleep duration and cognition in older adults., Data Sources: A systematic review of OVID Medline and PsycINFO through September 2015, and review of bibliographies from studies identified., Study Selection: English-language articles reporting observational studies of sleep duration and cognitive function in older populations., Data Extraction: Data extraction by 2 authors using predefined categories of desired information., Results: Thirty-two studies met our inclusion criteria, with nearly two-thirds published in the past 4 years. One-third of studies indicated that extreme sleep durations were associated with worse cognition in older adults. More studies favored an association with long vs. short sleep durations (35 vs. 26% of studies, respectively). Four studies found that greater changes in sleep duration over time were related to lower cognition. Study design and analytic methods were very heterogeneous across studies; therefore, meta-analysis was not undertaken., Limitations: We reviewed English-language manuscripts only, with a qualitative summary of studies identified., Conclusions and Implications of Key Findings: Observational studies of sleep duration and cognitive function in older adults have produced mixed results, with more studies suggesting that long (rather than short) sleep durations are related to worse cognition. Studies more consistently indicate that greater changes in sleep duration are associated with poor cognition. Future studies should be prospectively designed, with objective sleep assessment and longer follow-up periods; intervention studies are also needed to identify strategies for promoting cognitive health with aging., (© 2016 S. Karger AG, Basel.)

Background: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting., Methods: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults., Results: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism., Conclusions: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Dietary flavonoids have been related to lower risks of various chronic diseases, but it is unclear whether flavonoid intake in midlife helps to maintain good health and wellbeing in aging., Objective: We examined the relation of flavonoid intake in midlife with the prevalence of healthy aging., Design: We included 13,818 women from the Nurses' Health Study with dietary data and no major chronic diseases in 1984-1986 when they were aged in their late 50s (median age: 59 y); all women provided information on multiple aspects of aging an average of 15 y later. Intakes of 6 major flavonoid subclasses in midlife were ascertained on the basis of averaged intakes of flavonoid-rich foods from 2 food-frequency questionnaires (1984-1986). We defined healthy compared with usual aging as of age 70 y; healthy aging was based on survival to ≥70 y with maintenance of 4 health domains (no major chronic diseases or major impairments in cognitive or physical function or mental health)., Results: Of women who survived until ≥70 y of age, 1517 women (11.0%) met our criteria for healthy aging. Compared with women in the lowest quintile of intake, women in the highest quintile of intake of several flavonoid subclasses at midlife had greater odds of healthy aging. After multivariable adjustment, ORs were as follows: flavones, 1.32 (95% CI: 1.10, 1.58); flavanone, 1.28 (95% CI: 1.08, 1.53); anthocyanin, 1.25 (95% CI: 1.04, 1.50); and flavonol, 1.18 (95% CI: 0.98, 1.42) (all P-trend ≤ 0.02). Consistently, greater intakes of major sources of these flavonoids (i.e., oranges, berries, onions, and apples) were associated with increased odds of healthy aging. We showed no association with flavan-3-ol monomers (P-trend = 0.80) or polymers (P-trend = 0.63)., Conclusion: Higher intake of flavonoids at midlife, specifically flavones, flavanones, anthocyanins, and flavonols, is associated with greater likelihood of health and wellbeing in individuals surviving to older ages., (© 2014 American Society for Nutrition.)

Background: Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed., Methods: This prospective study included 2,452 adults (mean age: 79.5 years) with available measures of microvascular (brain, retina, kidney) and macrovascular abnormalities (brain, carotid, coronary, peripheral artery) in the Cardiovascular Health Study. The burden of microvascular and macrovascular abnormalities was examined in relation to total, activity-of-daily-living disability-free, and severe disability-free life expectancies in the next 10 years (1999-2009)., Results: At 75 years, individuals with low burden of both abnormalities lived, on average, 8.71 years (95% confidence interval: 8.29, 9.12) of which 7.67 years (7.16, 8.17) were without disability. In comparison, individuals with high burden of both abnormalities had shortest total life expectancy (6.95 years [6.52, 7.37]; p < .001) and disability-free life expectancy (5.60 years [5.10, 6.11]; p < .001). Although total life expectancy was similarly reduced for those with high burden of either type of abnormalities (microvascular: 7.96 years [7.50, 8.42] vs macrovascular: 8.25 years [7.80, 8.70]; p = .10), microvascular abnormalities seemed to have larger impact than macrovascular abnormalities on disability-free life expectancy (6.45 years [5.90, 6.99] vs 6.96 years [6.43, 7.48]; p = .016). These results were consistent for severe disability-free life expectancy and in individuals without clinical cardiovascular disease., Conclusions: Considering both microvascular and macrovascular abnormalities from multiple noninvasive tests may provide additional prognostic information on how older adults spend their remaining life. Optimal clinical use of this information remains to be determined., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain., Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging., Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)-type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals)., Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: -0.054 ± 0.004 and -0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: -0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: -0.01; 95% CI: -0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: -0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment., Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.

Objective: The prediction of successful aging by midlife body mass index (BMI) and waist circumference (WC) was examined., Methods: BMI/WC were assessed in 4869 persons (mean age 51.2, range 42-63 in 1991/1993) and survival and successful aging (alive, no chronic disease at age >60 years, not in the worst age- and sex-standardized quintile of cognitive, physical, respiratory,cardiovascular, and mental health) ascertained over a 16-year follow-up, analyzed using logistic regression adjusted for sociodemographic factors and health behaviors., Results: 507 participants died, 1008 met the criteria for successful aging. Those with BMI ≥ 30 kg/m(2) had lower odds of successful aging (odds ratio or OR) = 0.37; 95% confidence interval or CI: 0.27, 0.50) and survival (OR = 0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5 and 25 kg/m(2) . Those with a large WC (≥102/88 cm in men/women) had lower odds of successful aging (OR = 0.41; 95% CI: 0.31, 0.54) and survival (OR = 0.57; 95% CI: 0.44, 0.73) compared with those with a small waist (<94/80 cm in men/women). Analysis with finer categories showed lower odds of successful aging starting at BMI ≥ 23.5 kg/m(2) and WC 82/68 cm in men/women., Conclusions: Optimal midlife BMI and WC for successful aging might be substantially below the current thresholds used to define obesity., (Copyright © 2013 The Obesity Society.)

Background: Despite widespread use of multivitamin supplements, their effect on cognitive health-a critical issue with aging-remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons., Objective: To evaluate whether long-term multivitamin supplementation affects cognitive health in later life., Design: Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. (ClinicalTrials.gov: NCT00270647) SETTING: The Physicians' Health Study II., Patients: 5947 male physicians aged 65 years or older., Intervention: Daily multivitamin or placebo., Measurements: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease., Results: No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU (95% CI, -0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, -0.005 SU [CI, -0.04 to 0.03 SU])., Limitation: Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin., Conclusion: In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits., Primary Funding Source: National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products.

Background: Maintaining health and well-being in aging populations is critical., Objective: To examine the association between dietary patterns in midlife and prevalence of healthy aging., Design: Cross-sectional observational study., Setting: Nurses' Health Study., Participants: 10 670 women with dietary data and no major chronic diseases between 1984 and 1986, when they were in their late 50s and early 60s (median age, 59 years). Women provided information on health an average of 15 years later., Measurements: Diet quality in midlife was ascertained using the Alternative Healthy Eating Index-2010 (AHEI-2010) and Alternate Mediterranean diet scores, averaged from 2 food-frequency questionnaires (1984 to 1986). "Healthy" aging was defined as survival to 70 years or older with maintenance of 4 health domains: no major chronic diseases or major impairments in cognitive or physical function or mental health., Results: After multivariable adjustment, greater adherence to the AHEI-2010 (upper vs. lower quintiles) in midlife was related to 34% (95% CI, 9% to 66%; P for trend < 0.001) greater odds of healthy versus usual aging. Greater adherence to Alternate Mediterranean diet was related to 46% (CI, 17% to 83%; P for trend = 0.002) greater odds of healthy aging. When the 4 components of healthy aging were analyzed separately, the AHEI-2010 and Alternate Mediterranean diet were significantly associated with greater likelihood of no major limitations in physical function and mental health., Limitations: Residual confounding was possible, although many confounding factors were considered. Bias due to complex patterns of measurement error within diet scores cannot be excluded., Conclusion: Better diet quality at midlife seems to be strongly linked to greater health and well-being in persons surviving to older ages., Primary Funding Source: National Cancer Institute, National Institutes of Health.

Background: Seafood consumption may prevent age-related cognitive decline. However, benefits may vary by nutrient contents in different seafood types. We examined associations between total seafood consumption and cognitive decline and whether these associations differ by seafood types., Methods: We conducted a prospective cohort study of 5,988 women (mean age, 72 years) from the Women's Health Study who self-reported seafood intake at Women's Health Study baseline and also participated in telephone assessments of general cognition, verbal memory, and category fluency administered 5.6 years after Women's Health Study baseline and 2 and 4 years thereafter. Primary outcomes were standardized composite scores of global cognition and verbal memory., Results: After adjusting for potential confounders, different amounts of total seafood consumption were not associated with changes in global cognition (p = .56) or verbal memory (p = .29). Considering seafood types, however, compared with women consuming less than once-weekly tuna or dark-meat finfish, those with once-weekly or higher consumption had significantly better verbal memory (0.079 standard units; p < .01) after 4 years-a difference comparable to that for women 2.1 years apart in age. There was also a statistically nonsignificant suggestion of better global cognition (p = .13) with once-weekly or higher tuna or dark-meat fish consumption. No significant associations were observed for light-meat finfish or shellfish., Conclusions: The relation of seafood to cognition may depend on the types consumed. Total consumption levels of seafood were unrelated to cognitive change. However, consumption of tuna and dark-meat fish once weekly or higher was associated with lower decline in verbal memory for a period of 4 years.

Objective: Berries are high in flavonoids, especially anthocyanidins, and improve cognition in experimental studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are associated with slower rates of cognitive decline in older women., Methods: Beginning in 1980, a semiquantitative food frequency questionnaire was administered every 4 years to Nurses' Health Study participants. In 1995-2001, we began measuring cognitive function in 16,010 participants, aged ≥70 years; follow-up assessments were conducted twice, at 2-year intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariate-adjusted, mixed linear regression, we estimated mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes., Results: Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend = 0.014 and mean difference = 0.04, 95% confidence interval [CI] = 0.01-0.07, comparing extreme categories of intake; for strawberries: p-trend = 0.022 and mean difference = 0.03, 95% CI = 0.00-0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we found for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends = 0.015 and 0.053, respectively, for the global score)., Interpretation: Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults., (Copyright © 2012 American Neurological Association.)

Objective: A study was undertaken to relate dietary fat types to cognitive change in healthy community-based elders., Methods: Among 6,183 older participants in the Women's Health Study, we related intake of major fatty acids (saturated [SFA], monounsaturated [MUFA], total polyunsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years after dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory, and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariate-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake., Results: Higher SFA intake was associated with worse global cognitive (p for linear trend = 0.008) and verbal memory (p for linear trend = 0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest versus lowest SFA quintiles; the multivariate-adjusted odds ratio (OR) with 95% confidence interval (CI) was 1.64 (1.04-2.58) for global cognition and 1.65 (1.04-2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive (p for linear trend < 0.001) and verbal memory (p for linear trend = 0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31-0.88]) and verbal memory (0.56 [0.34-0.94]). Total fat, PUFA, and trans-fat intakes were not associated with cognitive trajectory., Interpretation: Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, whereas higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging., (Copyright © 2012 American Neurological Association.)

Background: Observational studies have documented inverse associations between moderate alcohol consumption and risk of premature death. It is largely unknown whether moderate alcohol intake is also associated with overall health and well-being among populations who have survived to older age. In this study, we prospectively examined alcohol use assessed at midlife in relation to successful ageing in a cohort of US women., Methods and Findings: Alcohol consumption at midlife was assessed using a validated food frequency questionnaire. Subsequently, successful ageing was defined in 13,894 Nurses' Health Study participants who survived to age 70 or older, and whose health status was continuously updated. "Successful ageing" was considered as being free of 11 major chronic diseases and having no major cognitive impairment, physical impairment, or mental health limitations. Analyses were restricted to the 98.1% of participants who were not heavier drinkers (>45 g/d) at midlife. Of all eligible study participants, 1,491 (10.7%) achieved successful ageing. After multivariable adjustment of potential confounders, light-to-moderate alcohol consumption at midlife was associated with modestly increased odds of successful ageing. The odds ratios (95% confidence interval) were 1.0 (referent) for nondrinkers, 1.11 (0.96-1.29) for ≤ 5.0 g/d, 1.19 (1.01-1.40) for 5.1-15.0 g/d, 1.28 (1.03-1.58) for 15.1-30.0 g/d, and 1.24 (0.87-1.76) for 30.1-45.0 g/d. Meanwhile, independent of total alcohol intake, participants who drank alcohol at regular patterns throughout the week, rather than on a single occasion, had somewhat better odds of successful ageing; for example, the odds ratios (95% confidence interval) were 1.29 (1.01-1.64) and 1.47 (1.14-1.90) for those drinking 3-4 days and 5-7 days per week in comparison with nondrinkers, respectively, whereas the odds ratio was 1.10 (0.94-1.30) for those drinking only 1-2 days per week., Conclusions: These data suggest that regular, moderate consumption of alcohol at midlife may be related to a modest increase in overall health status among women who survive to older ages.

Telomeres are short DNA repeats on the ends of mammalian chromosomes, which can undergo incomplete replication leading to gradual shortening with each cell cycle. Age and oxidative stress are contributors to telomere shortening; thus, telomere length may be a composite measure of biologic aging, and a potential predictor of health status in older adults. We evaluated whether relative telomere length (the proportion of telomere repeat copy number to single gene copy number, using a real-time PCR method) predicts cognitive decline measured ten years later among ∼ 2000 older participants in the Nurses' Health Study (NHS). Mixed linear regression was used to evaluate mean differences in cognitive decline according to telomere length. After adjustment for potential confounders, we found that decreasing telomere length was associated with more cognitive decline, although associations were modest (e.g. for a global score, averaging all six tests in our cognitive battery, mean difference=0.03 standard units per SD increase in telomere length; p=0.04). The magnitude of these estimates was similar to the differences we find in this cohort for women one year apart in age (e.g. the differences that we observe between women who are 73 versus 74 years of age); thus, our results suggest that telomere length is not a particularly powerful marker of impending cognitive decline., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes., Methods: Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60-92 years (mean = 71.3 years), in the Physicians' Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5-4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline., Results: Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was -0.62 (-1.15, -0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03)., Conclusions: Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes., (2010 S. Karger AG, Basel.)

Objective: Insulin degradation pathways may be related to Alzheimer's disease pathology. In preliminary analyses, we considered the relation of combined lower insulin secretion (c-peptide) and higher insulin--possibly a phenotype for impaired insulin degradation--to cognitive decline., Method: Fasting plasma c-peptide and insulin were measured in 1,187 non-diabetic Nurses' Health Study participants (mean age = 64 years). Cognitive testing began 10 years later. Participants completed three repeated assessments (over an average span of 4.4 years) of verbal memory, a strong predictor of Alzheimer disease development. C-peptide and insulin distributions were dichotomized at their medians to create four cross-tabulated categories. Multivariable linear mixed effects models were used to relate c-peptide/insulin categories to cognitive decline., Results: Compared to the lower c-peptide/lower insulin group, women with lower c-peptide/higher insulin had a significantly faster rate of verbal memory decline: the mean difference was -0.05 units/year (95% CI -0.09,-0.01). This mean difference was similar to that which we found for women 5 years apart in age, indicating that having a profile of lower c-peptide/higher insulin appeared cognitively equivalent to aging by five years on tests of verbal memory. For women with higher c-peptide/higher insulin, the estimated mean difference in decline compared to those in the lower c-peptide/lower insulin group was statistically significant, but slightly lower, at -0.04 units/year (95% CI: -0.07,-0.02)., Conclusion: These preliminary analyses of a possible phenotype of impaired insulin degradation provide supportive evidence that deficits in insulin degradation may be related to late-life verbal memory decline., ((c) 2008 John Wiley & Sons, Ltd.)

Background: Both type 2 diabetes and hyperinsulinemia have been related to diminished cognition. To address independent effects of increasing mid-life insulin secretion on late-life cognition, we prospectively examined the relation of plasma C-peptide levels to cognitive decline in a large sample of older women without diabetes or stroke., Methods: Plasma C-peptide levels were measured in 1187 "young-old" women (mean age=64 years) without diabetes in the Nurses' Health Study. Cognitive decline was assessed approximately 10 years later. Three repeated cognitive batteries were administered over an average of 4.4 years using telephone-based tests of general cognition, verbal memory, category fluency, and attention. Primary outcomes were general cognition (measured by the Telephone interview for Cognitive Status [TICS], as well as a global score averaging all tests) and a verbal memory score averaging four tests of word-list and paragraph recall. Linear mixed effects models were used to compute associations between C-peptide levels and rates of cognitive decline., Results: Higher C-peptide levels were associated with faster decline in global cognition and verbal memory. Compared to those in the lowest C-peptide quartile, multivariable-adjusted mean differences (95% CI) in rates of decline for women in the highest quartile were -0.03 (-0.06,-0.00) units/year for the global score, and -0.05 (-0.09,-0.02) units/year for verbal memory. Each one standard-deviation increase in C-peptide was associated with significantly faster decline on the TICS (p-trend=0.05), global score (p-trend=0.04) and verbal memory (p-trend=0.006)., Conclusions: Higher levels of insulin secretion in those without diabetes may be related to decline in general cognition and verbal memory.

Background: Type 2 diabetes has been associated with an increased risk of dementia. To assess possible independent effects of insulin, we investigated the relation of insulin levels to cognitive decline in nondiabetic women., Methods: Fasting plasma insulin levels were measured in mid-life in 1,416 nondiabetic Nurses' Health Study participants, who also completed cognitive testing that began 10 years later (current age: 70-75 years). Over 4 years, 3 assessments of general cognition, verbal memory, category fluency and attention were administered. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) performance, the global score (average of all tests) and verbal memory (average of verbal recall tests). Linear mixed-effects models were used to calculate the association between insulin and cognitive decline., Results: Higher insulin levels were associated with a faster decline on the TICS and verbal memory. For analysis, batch-specific quartiles of insulin levels were constructed. Compared to the lowest quartile, adjusted differences in the annual rates of decline (with 95% CI values in parentheses) for the second, third and fourth quartiles were: TICS, -0.06 (-0.16, 0.03), -0.14 (-0.24, -0.04), and -0.09 (-0.19, 0.01) points (p trend = 0.04); verbal memory, -0.01 (-0.04, 0.02), -0.05 (-0.08, -0.02), and -0.02 (-0.05, 0.01) units (p trend = 0.02). These associations remained after multivariable adjustment., Conclusions: Our study provides evidence for a potential role of higher fasting insulin levels in cognitive decline, possibly independent of diabetes., ((c) 2008 S. Karger AG, Basel)

Background: Emerging biologic and epidemiologic evidence suggests benefits of insulin-like growth factor-I (IGF-I) in cognitive aging., Objective: To examine the relation of circulating IGF-I to cognition., Methods: We measured plasma IGF-I and IGF-binding protein-3 (IGFBP-3) in 590 women aged 60-68 years. An average 10 years later, we administered telephone-based tests of general cognition (Telephone Interview of Cognitive Status [TICS]), verbal memory, category fluency, and attention. We estimated multivariable-adjusted mean differences in performance across levels of IGF-I/IGFBP-3 molar ratio., Results: On the TICS, each standard deviation (S.D.) increase in molar ratio was significantly associated with better performance: multivariable-adjusted mean difference=0.2 units, 95% confidence interval (0.0,0.4), p=0.05. This effect estimate for each S.D. increase in molar ratio was cognitively equivalent to the mean difference we observed on the TICS between women 1 year apart in age. On a global score combining all tests, there was also a trend of better performance with each S.D. increase in molar ratio (p=0.07). IGF-I levels were not associated with performance in verbal memory., Conclusions: Higher IGF-I levels may be associated with better general cognition.

Context: Emerging biological and epidemiological evidence suggests possible benefits of higher IGF-I levels in cognitive aging., Objective: The objective of the study was to examine the relation of midlife plasma IGF-I levels to late-life cognition., Design, Setting, and Participants: We conducted a secondary analysis from the Physicians' Health Study II, a prospective cohort of U.S. male physicians. Participants provided blood samples from 1982 to 1984 (mean age 57 yr). Using stored samples, we measured free IGF-I in 376 men and total IGF-I and IGF binding protein-3 in 460 men. Starting in 2001, we administered telephone-based tests of general cognition [the Telephone Interview of Cognitive Status (TICS)], verbal memory, and category fluency. We estimated multivariable-adjusted mean differences in cognitive performance across levels of free IGF-I and IGF-I to IGF binding protein-3 molar ratio., Main Outcome Measures: Global score (averaging performance across all individual cognitive tests), the TICS, and a verbal memory score were measured., Results: Each sd increment in free IGF-I was associated with a multivariable-adjusted increase of 0.08 U (P = 0.02) on the global score. This mean difference was equivalent to that observed between men 2 yr apart in age: i.e. each sd increase in free IGF-I appeared cognitively equivalent to staying 2 yr younger. No significant mean differences in TICS scores were observed across free IGF-I levels. For verbal memory, each sd increment in free IGF-I was associated with an adjusted mean difference of 0.08 U (P = 0.03). Results appeared consistent for the molar ratio but were not statistically significant., Conclusion: Higher midlife free IGF-I may be associated with better late-life cognition.

Background: Apparently discrepant findings have been reported by the Women's Health Initiative (WHI) trial compared with observational studies of postmenopausal hormone therapy (HT) and coronary heart disease (CHD)., Methods: We prospectively examined the relation of HT to CHD, according to timing of hormone initiation relative to age and time since menopause. Participants were postmenopausal women in the Nurses' Health Study, with follow-up from 1976 to 2000. Information on hormone use was ascertained in biennial, mailed questionnaires. We used proportional hazards models to calculate multivariable adjusted relative risks (RR) and 95% confidence intervals (CI). We also conducted sensitivity analyses to determine the possible influence of incomplete capture of coronary events occurring shortly after initiation of HT., Results: Women beginning HT near menopause had a significantly reduced risk of CHD (RR = 0.66, 95% CI 0.54-0.80 for estrogen alone; RR = 0.72, 95% CI 0.56-0.92 for estrogen with progestin). In the subgroup of women demographically similar to those in the WHI, we found no significant relation between HT and CHD among women who initiated therapy at least 10 years after menopause (RR = 0.87, 95% CI 0.69-1.10 for estrogen alone; RR = 0.90, 95% CI 0.62-1.29 for estrogen with progestin). Among women who began taking hormones at older ages, we also found no relation between current use of estrogen alone and CHD (for women aged 60+ years, RR = 1.07, 95% CI 0.65-1.78), although there was a suggestion of possible reduced risk for combined HT (RR = 0.65, 95% CI 0.31-1.38). In sensitivity analyses, we found that the incomplete capture of coronary events occurring shortly after initiation of HT could not explain our observation of a reduced risk of coronary disease for current users of HT., Conclusions: These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk.

We prospectively examined fruit and vegetable intake in relation to cognitive function and decline among aging women. Participants were followed from in 1976 with biennial questionnaires, and food frequency questionnaires were administered in 1984, 1986, and every 4 years thereafter. From 1995 to 2001, we administered, by telephone, six cognitive tests measuring general cognition, verbal memory, category fluency, and working memory. We repeated assessments two years later for 13,388 women (>90% follow-up). We averaged dietary intakes from 1984 through the first cognitive assessment, and used linear regression to obtain multivariable-adjusted mean differences in performance and decline in performance across intake levels. Fruits were not associated with cognition or cognitive decline. However, total vegetable intake was significantly associated with less decline. Specifically, on a global score combining all tests, women in the highest quintile of cruciferous vegetables declined slower (by 0.04 unit; 95% confidence interval, 0.003, 0.07; p trend = 0.1) compared with the lowest quintile. Women consuming the most green leafy vegetables also experienced slower decline than women consuming the least amount (by 0.05 unit; 95% confidence interval, 0.02, 0.09; p trend < 0.001). These mean differences were equivalent to those observed for women about 1 to 2 years apart in age.

The apolipoprotein E (APOE) e4 allele increases risk of Alzheimer disease and cardiovascular diseases. We examined APOE genotypes alone or combined with cardiovascular conditions in relation to cognitive function in 4227 Nurses' Health Study participants, 70-80 years old. From 1995 to 2001, and again 2 years later, participants received telephone cognitive assessments of general cognition, category fluency, verbal memory and working memory. In biennial questionnaires since 1976, participants have provided extensive health information including cardiovascular conditions. Compared with women with the e3/3 genotype, e4 carriers performed worse at baseline across all tests (mean global composite score was lower by 0.10 points (95% confidence interval=-0.15, -0.05)) and declined more (mean change in global score was -0.07 points (95% CI=-0.12, -0.03)), with a strong allele dose-response trend (P-trend=0.0003). Among participants 75+ years, e2 carriers performed best. Women with an e4 allele and cardiovascular conditions such as transient ischemic attack or untreated hypertension had the worst cognition. Thus, APOE genotypes strongly influenced cognitive function and decline; prevention of cardiovascular disease may limit these effects.

Background: A randomized trial of postmenopausal women over age 65 reported increased risks of cognitive decline with 4 years of combined estrogen and progestin treatment. However, questions remain, including the effect of longer duration or of hormone therapy initiated at younger ages., Methods: The Nurses' Health Study is a prospective cohort begun in 1976, comprising 121,700 female nurses who report health information via biennial mailed questionnaires. This substudy includes 13,807 participants age 70 to 81 who completed two telephone cognitive assessments, 2 years apart, between 1995 and 2003. General cognition, verbal memory, category fluency, and attention were tested. Multiple linear regression was used to estimate adjusted mean declines and logistic regression to estimate adjusted risks of substantial decline in cognition (> or =2 SD of baseline performance) across hormone groups. APOE genotype was available in a subset of 3,667 participants., Results: Overall, little difference was found in mean cognitive decline between current hormone users and never users. However, for long-term users of estrogen alone or combined with progestin, increased risk of substantial decline was observed on most cognitive tests (relative risk [RR] = 1.25 to 1.72). Decline was particularly high among women initiating hormones at older ages compared with never users: for example, on our test of general cognition, RR of substantial decline was 1.74 (95% CI 1.08, 2.81) and mean difference in decline was -0.43 (95% CI -0.73, -0.12). No significant interactions between hormone use and APOE epsilon4 allele were observed., Conclusion: Postmenopausal hormone therapy provides no appreciable cognitive benefits in older women.

Background: Oxidative damage is critical in the etiology of cataract. Therefore, associations between cataract and other health endpoints may suggest the shared etiologic role of oxidative stress., Methods: To assess any role of oxidative stress in cognitive function and early cognitive decline, we investigated the relation between cognition and cataract extraction in 16,197 community-dwelling women age 70-79 years from the Nurses' Health Study. Six cognitive tests were administered by telephone from 1995 to 2000; second interviews are ongoing and have been completed for 12,995 women. In total, 3,597 women reported cataract extraction prior to their baseline cognitive assessment. We used logistic regression to calculate multivariate-adjusted relative risks of a low score and of substantial decline, comparing those with and without cataract extraction., Results: Using a global score that combines the results of the cognitive tests, there was no relation between cataract and either low score (RR = 0.99; 95% CI = 0.87-1.13) or substantial decline from baseline to second interview (RR = 1.08; CI = 0.93-1.25)., Conclusion: Cataract extraction does not appear to be related to cognitive function in these women.

Objective: To examine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use and cognitive decline in young-old women., Methods: The authors prospectively studied 16,128 Nurses' Health Study participants, aged 70 to 81 years at baseline, who provided information on NSAID use and potential confounders in biennial questionnaires from 1976 through 1998. From 1995 through 2001, we administered, by telephone, six tests of cognitive function, including the Telephone Interview of Cognitive Status (TICS). Second interviews were begun 2 years later and completed on 13,255 women to date. The authors used multiple logistic regression to estimate relative risks (RR) of low baseline scores (defined as the bottom 10%) and substantial decline (worst 10%)., Results: Compared to never users, the RR was 0.75 (95% CI 0.59, 0.96) for a low baseline TICS score with current aspirin use of 15+ years duration, and 0.79 (95% CI 0.62, 1.02) for current use of NSAID (primarily ibuprofen) lasting 8+ years. Results for aspirin users were weaker on other tests, but long-term ibuprofen users had a RR of 0.75 (95% CI 0.56, 1.00) for a low baseline global score (combination of all six tests). The RR for substantial global cognitive decline was 0.93 (95% CI 0.68, 1.26) with long-term aspirin use, and 0.77 (95% CI 0.57, 1.05) with long-term ibuprofen use., Conclusions: In these young-old women, current, long-term NSAID users, especially of nonaspirin agents, showed reduced odds of low cognitive function and possibly lower rates of substantial cognitive decline over 2 years. Continued follow-up will help determine if associations differ at older ages.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

BackgroundResearch has suggested optimism is associated with healthy aging and exceptional longevity, but most studies were conducted among non-Hispanic White populations. We examined associations of optimism to longevity across racial and ethnic groups and assessed healthy lifestyle as a possible mediating pathway.MethodsParticipants from the Women's Health Initiative (N = 159,255) completed a validated measure of optimism and provided other demographic and health data at baseline. We evaluated associations of optimism with increments in lifespan using accelerated failure time models, and with likelihood of exceptional longevity (survival to age ≥90) using Poisson regression models. Causal mediation analysis explored whether lifestyle-related factors mediated optimism-lifespan associations.ResultsAfter covariate adjustment, the highest versus lowest optimism quartile was associated with 5.4% (95% confidence interval [CI] = 4.5, 6.4%) longer lifespan. Within racial and ethnic subgroups, these estimates were 5.1% (95%CI = 4.0, 6.1%) in non-Hispanic White, 7.6% (95%CI = 3.6, 11.7%) in Black, 5.4% (95%CI = -0.1, 11.2%) in Hispanic/Latina, and 1.5% (95% CI = -5.0, 8.5) in Asian women. A high proportion (53%) of the women achieved exceptional longevity. Participants in the highest versus lowest optimism quartile had greater likelihood of achieving exceptional longevity (e.g., full sample risk ratio = 1.1, 95%CI = 1.1, 1.1). Lifestyle mediated 24% of the optimism-lifespan association in the full sample, 25% in non-Hispanic White, 10% in Black, 24% in Hispanic/Latina, and 43% in Asian women.ConclusionsHigher optimism was associated with longer lifespan and a greater likelihood of achieving exceptional longevity overall and across racial and ethnic groups. The contribution of lifestyle to these associations was modest. Optimism may promote health and longevity in diverse racial and ethnic groups. Future research should investigate these associations in less long-lived populations.

OBJECTIVES: Growing evidence supports optimism as a health asset, yet how optimism influences well-being and health remains uncertain. We evaluated 1 potential pathway-the association of optimism with daily stress processes-and tested 2 hypotheses. The stressor exposure hypothesis posits that optimism would preserve emotional well-being by limiting exposure to daily stressors. The buffering hypothesis posits that higher optimism would be associated with lower emotional reactivity to daily stressors and more effective emotional recovery from them. METHODS: Participants were 233 men from the Veterans Affairs Normative Aging Study who completed the Minnesota Multiphasic Personality Inventory-2 Revised Optimism-Pessimism scale in 1986/1991 and participated in up to three 8-day daily diary bursts in 2002-2010 (age at first burst: M = 76.7, SD = 6.5). Daily stressor occurrence, positive affect (PA), and negative affect (NA) were assessed nightly. We evaluated the hypotheses using multilevel structural equation models. RESULTS: Optimism was unrelated to emotional reactivity to or recovery from daily stressors. Higher optimism was associated with higher average daily PA (B = 2.31, 95% Bayesian credible interval [BCI]: 1.24, 3.38) but not NA, independent of stressor exposure. Lower stressor exposure mediated the association of higher optimism with lower daily NA (indirect effect: B = -0.27, 95% BCI: -0.50, -0.09), supporting the stressor exposure hypothesis. DISCUSSION: Findings from a sample of older men suggest that optimism may be associated with more favorable emotional well-being in later life through differences in stressor exposure rather than emotional stress response. Optimism may preserve emotional well-being among older adults by engaging emotion regulation strategies that occur relatively early in the emotion-generative process.

Cognitive function at middle age is of particular public health interest, as it strongly predicts later dementia. Children who have experienced abuse subsequently have worse cognitive function than those who have not. However, it remains unclear whether the association of abuse with cognitive function persists into middle age. In 2014-2016, 14,151 women ages 49-69 years who had previously responded to a childhood abuse questionnaire completed a cognitive battery. In models adjusted for childhood socioeconomic status and head trauma, combined physical, emotional, and sexual abuse was associated with lower scores on both Learning/Working Memory (severe abuse, lower scores similar to that observed in women 4.8 years older in our data) and Psychomotor Speed/Attention (severe abuse, lower scores similar to that observed in women to 2.9 years older in our data). Adjustment for adulthood socioeconomic status and health factors (e.g., smoking, hypertension) slightly attenuated associations. In exploratory analyses further adjusted for psychological distress, associations were attenuated. Women exposed versus unexposed to childhood abuse had poorer cognitive function at mid-life. Associations were particularly strong for learning and working memory and were not accounted for by adulthood health factors. Childhood abuse should be investigated as a potential risk factor for cognitive decline and dementia in old age.

Background & aimsGallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.MethodsWe pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.ResultsDuring 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.ConclusionWe observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.Lay summaryOur findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

IntroductionWe examined the association between endogenous sex hormones and both objective and subjective measures of cognitive function.MethodsWe followed 3044 women up to 23 years in a prospective cohort study. We measured plasma levels of estrone, estrone sulfate, estradiol, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) in 1989-1990, conducted neuropsychologic testing in 1999-2008, and inquired about subjective cognition in 2012.ResultsOverall, we observed little relation between plasma levels of hormones and either neuropsychologic test performance or subjective cognition. However, after adjustment for age and education, we observed a borderline significant association of higher levels of plasma estrone with higher scores for both overall cognition (P trend = .10) and verbal memory (P trend = .08).DiscussionThere were no clear associations of endogenous hormone levels at midlife and cognition in later life, although a suggested finding of higher levels of plasma estrone associated with better cognitive function merits further research.

Worldwide, over 35 million people suffer from Alzheimer's disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.

Alzheimer's disease is the public health crisis of the 21st century. There is a clear need for a widely available, inexpensive and reliable method to diagnosis Alzheimer's disease in the earliest stages, track disease progression, and accelerate clinical development of new therapeutics. One avenue of research being explored is blood based biomarkers. In April 2012, the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened top scientists from around the world to discuss the state of blood based biomarker development. This manuscript summarizes the meeting and the resultant discussion, including potential next steps to move this area of research forward.

Background: Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. Methods: Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. Results: Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. Conclusion: Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms. [ABSTRACT FROM AUTHOR]