A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.

Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.

General cognitive ability in high school, attained education, occupational complexity, and dementia risk.

INTRODUCTION: We address the extent to which adolescent cognition predicts dementia risk in later life, mediated by educational attainment and occupational complexity. METHODS: Using data from Project Talent Aging Study (PTAS), we fitted two structural equation models to test whether adolescent cognition predicts cognitive impairment (CI) and Ascertain Dementia 8 (AD8) status simultaneously (NCognitive Assessment = 2477) and AD8 alone (NQuestionnaire = 6491) 60 years later, mediated by education and occupational complexity. Co-twin control analysis examined 82 discordant pairs for CI/AD8. RESULTS: Education partially mediated the effect of adolescent cognition on CI in the cognitive assessment aample and AD8 in the questionnaire sample (Ps < 0.001). Within twin pairs, differences in adolescent cognition were small, but intrapair differences in education predicted CI status. DISCUSSION: Adolescent cognition predicted dementia risk 60 years later, partially mediated through education. Educational attainment, but not occupational complexity, contributes to CI risk beyond its role as a mediator of adolescent cognition, further supported by the co-twin analyses. HIGHLIGHTS: Project Talent Aging Study follows enrollees from high school for nearly 60 years. General cognitive ability in high school predicts later-life cognitive impairment. Low education is a risk partially due to its association with cognitive ability.

Nature, Nurture, and the Meaning of Educational Attainment: Differences by Sex and Socioeconomic Status.

Estimated heritability of educational attainment (EA) varies widely, from 23% to 80%, with growing evidence suggesting the degree to which genetic variation contributes to individual differences in EA is highly dependent upon situational factors. We aimed to decompose EA into influences attributable to genetic propensity and to environmental context and their interplay, while considering influences of rearing household economic status (HES) and sex. We use the Project Talent Twin and Sibling Study, drawn from the population-representative cohort of high school students assessed in 1960 and followed through 2014, to ages 68-72. Data from 3552 twins and siblings from 1741 families were analyzed using multilevel regression and multiple group structural equation models. Individuals from less-advantaged backgrounds had lower EA and less variation. Genetic variance accounted for 51% of the total variance, but within women and men, 40% and 58% of the total variance respectively. Men had stable genetic variance on EA across all HES strata, whereas high HES women showed the same level of genetic influence as men, and lower HES women had constrained genetic influence on EA. Unexpectedly, middle HES women showed the largest constraints in genetic influence on EA. Shared family environment appears to make an outsized contribution to greater variability for women in this middle stratum and whether they pursue more EA. Implications are that without considering early life opportunity, genetic studies on education may mischaracterize sex differences because education reflects different degrees of genetic and environmental influences for women and men.

A longitudinal study shows stress proliferation effects from early childhood adversity and recent stress on risk for depressive symptoms among older adults.

Objectives: We evaluated whether the effects of recent stressful life events (SLEs) and early childhood adversities (ECAs) on depressive symptoms are consistent between men and women and across older age, and whether there was evidence for the following: stress sensitization, whereby the psychological impact of SLEs is greater for individuals with ECAs compared with those without; or stress proliferation effect, whereby those with ECAs are more likely to report more SLEs than those without ECAs to effect depressive symptoms.Method: ECAs, SLEs in the past two years, and current depressive symptoms through a modified CES-D were obtained from 11,873 individuals participating in a population representative study of older adults, yielding 82,764 observations. Mixed-effects regression models on depressive symptoms were constructed to control for multiple observations per participant and evaluate within-person effects over time, thereby reducing bias from reverse causation.Results: Results suggest a stress proliferation effect and do not support stress sensitization. ECAs contribute to vulnerability for depressive symptoms, with a dosage effect for each additional ECA. Recent SLEs result in greater depressive symptom risk, with stable effects over age and dosage effects for each additional SLE that were smaller than the effects of ECAs among men, but not women. Belonging to an ethnic minority group, having less education, and less household income at baseline were associated with greater depressive symptom risk.Conclusions: Findings suggest the importance of addressing early childhood adversity and sociodemographic factors, among at-risk older adults to mitigate life-course stress proliferative processes and thereby reduce disparate risk for depression in older age.

The Project Talent Twin and Sibling Study: Zygosity and New Data Collection.

The Project Talent Twin and Sibling (PTTS) study includes 4481 multiples and their 522 nontwin siblings from 2233 families. The sample was drawn from Project Talent, a U.S. national longitudinal study of 377,000 individuals born 1942-1946, first assessed in 1960 and representative of U.S. students in secondary school (Grades 9-12). In addition to the twins and triplets, the 1960 dataset includes 84,000 siblings from 40,000 other families. This design is both genetically informative and unique in facilitating separation of the 'common' environment into three sources of variation: shared by all siblings within a family, specific to twin-pairs, and associated with school/community-level factors. We term this the GIFTS model for genetics, individual, family, twin, and school sources of variance. In our article published in a previous Twin Research and Human Genetics special issue, we described data collections conducted with the full Project Talent sample during 1960-1974, methods for the recent linking of siblings within families, identification of twins, and the design of a 54-year follow-up of the PTTS sample, when participants were 68-72 years old. In the current article, we summarize participation and data available from this 2014 collection, describe our method for assigning zygosity using survey responses and yearbook photographs, illustrate the GIFTS model applied to 1960 vocabulary scores from more than 80,000 adolescent twins, siblings and schoolmates and summarize the next wave of PTTS data collection being conducted as part of the larger Project Talent Aging Study.

Hepatic WDR23 proteostasis mediates insulin homeostasis by regulating insulin-degrading enzyme capacity.

Maintaining insulin homeostasis is critical for cellular and organismal metabolism. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here, we establish a hepatic regulatory axis for IDE through WDR23-proteostasis. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults, supporting the use of WDR23 as a new molecular determinant of metabolic health in humans.

Cross-National and Cross-Generational Evidence That Educational Attainment May Slow the Pace of Aging in European-Descent Individuals.

OBJECTIVES: Individuals with more education are at lower risk of developing multiple, different age-related diseases than their less-educated peers. A reason for this might be that individuals with more education age slower. There are 2 complications in testing this hypothesis. First, there exists no definitive measure of biological aging. Second, shared genetic factors contribute toward both lower educational attainment and the development of age-related diseases. Here, we tested whether the protective effect of educational attainment was associated with the pace of aging after accounting for genetic factors. METHODS: We examined data from 5 studies together totaling almost 17,000 individuals with European ancestry born in different countries during different historical periods, ranging in age from 16 to 98 years old. To assess the pace of aging, we used DunedinPACE, a DNA methylation algorithm that reflects an individual's rate of aging and predicts age-related decline and Alzheimer's disease and related disorders. To assess genetic factors related to education, we created a polygenic score based on the results of a genome-wide association study of educational attainment. RESULTS: Across the 5 studies, and across the life span, higher educational attainment was associated with a slower pace of aging even after accounting for genetic factors (meta-analysis effect size = -0.20; 95% confidence interval [CI]: -0.30 to -0.10; p = .006). Further, this effect persisted after taking into account tobacco smoking (meta-analysis effect size = -0.13; 95% CI: -0.21 to -0.05; p = .01). DISCUSSION: These results indicate that higher levels of education have positive effects on the pace of aging, and that the benefits can be realized irrespective of individuals' genetics.

High school quality is associated with cognition 58 years later.

We leveraged a unique school-based longitudinal cohort-the Project Talent Aging Study-to examine whether attending higher quality schools is associated with cognitive performance among older adults in the United States (mean age = 74.8). Participants (n = 2,289) completed telephone neurocognitive testing. Six indicators of high school quality, reported by principals at the time of schooling, were predictors of respondents' cognitive function 58 years later. To account for school-clustering, multilevel linear and logistic models were applied. We found that attending schools with a higher number of teachers with graduate training was the clearest predictor of later-life cognition, and school quality mattered especially for language abilities. Importantly, Black respondents (n = 239; 10.5 percentage) were disproportionately exposed to low quality high schools. Therefore, increased investment in schools, especially those that serve Black children, could be a powerful strategy to improve later life cognitive health among older adults in the United States.

Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species.

The influence of genetic variation on the aging process, including the incidence and severity of age-related diseases, is complex. Here, we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a predictive biomarker for age-related changes in muscle health by combining Caenorhabditis elegans genetics and a gene-wide association scanning (GeneWAS) from older human participants of the US Health and Retirement Study (HRS). In a screen for mutations that activate oxidative stress responses, specifically in the muscle of C. elegans, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. Each of these genetic mutations mapped to the ALH-6 polypeptide and led to the age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

Ageing is inevitable, but what makes one person 'age well' and another decline more quickly remains largely unknown. While many aspects of ageing are clearly linked to genetics, the specific genes involved often remain unidentified. Sarcopenia is an age-related condition affecting the muscles. It involves a gradual loss of muscle mass that becomes faster with age, and is associated with loss of mobility, decreased quality of life, and increased risk of death. Around half of all people aged 80 and over suffer from sarcopenia. Several lifestyle factors, especially poor diet and lack of exercise, are associated with the condition, but genetics is also involved: the condition accelerates more quickly in some people than others, and even fit, physically active individuals can be affected. To study the genetics of conditions like sarcopenia, researchers often use animals like flies or worms, which have short generation times but share genetic similarities with humans. For example, the worm Caenorhabditis elegans has equivalents of several human muscle genes, including the gene alh-6. In worms, alh-6 is important for maintaining energy supply to the muscles, and mutating it not only leads to muscle damage but also to premature ageing. Given this insight, Villa, Stuhr, Yen et al. wanted to determine if variation in the human version of alh-6, ALDH4A1, also contributes to individual differences in muscle ageing and decline in humans. Evaluating variation in this gene required a large amount of genetic data from older adults. These were taken from a continuous study that follows >35,000 older adults. Importantly, the study collects not only information on gene sequences but also measures of muscle health and performance over time for each individual. Analysis of these genetic data revealed specific small variations in the DNA of ALDH4A1, all of which associated with reduced muscle health. Follow-up experiments in worms used genetic engineering techniques to test how variation in the worm alh-6 gene could influence age-related health. The resulting mutant worms developed muscle problems much earlier than their normal counterparts, supporting the role of alh-6/ALDH4A1 in determining muscle health across the lifespan of both worms and humans. These results have identified a key influencer of muscle health during ageing in worms, and emphasize the importance of validating effects of genetic variation among humans during this process. Villa, Stuhr, Yen et al. hope that this study will help researchers find more genetic 'markers' of muscle health, and ultimately allow us to predict an individual's risk of sarcopenia based on their genetic make-up.

A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events.

BACKGROUND: Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the 'next-generation' epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2. RESULTS: Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant). CONCLUSIONS: We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.

The dynamic association between body mass index and cognition from midlife through late-life, and the effect of sex and genetic influences.

Body mass index (BMI) is associated with cognitive abilities, but the nature of the relationship remains largely unexplored. We aimed to investigate the bidirectional relationship from midlife through late-life, while considering sex differences and genetic predisposition to higher BMI. We used data from 23,892 individuals of European ancestry from the Health and Retirement Study, with longitudinal data on BMI and three established cognitive indices: mental status, episodic memory, and their sum, called total cognition. To investigate the dynamic relationship between BMI and cognitive abilities, we applied dual change score models of change from age 50 through 89, with a breakpoint at age 65 or 70. Models were further stratified by sex and genetic predisposition to higher BMI using tertiles of a polygenic score for BMI (PGSBMI). We demonstrated bidirectional effects between BMI and all three cognitive indices, with higher BMI contributing to steeper decline in cognitive abilities in both midlife and late-life, and higher cognitive abilities contributing to less decline in BMI in late-life. The effects of BMI on change in cognitive abilities were more evident in men compared to women, and among those in the lowest tertile of the PGSBMI compared to those in the highest tertile, while the effects of cognition on BMI were similar across groups. In conclusion, these findings highlight a reciprocal relationship between BMI and cognitive abilities, indicating that the negative effects of a higher BMI persist from midlife through late-life, and that weight-loss in late-life may be driven by cognitive decline.

Family and personal protective factors moderate the effects of adversity and negative disposition on smoking among Chinese adolescents.

Tobacco use among Chinese adolescents is increasing at approximately 80,000 new smokers per day. Assessing the causes for initiating tobacco use in China will be important in developing effective interventions and policies to stem rising prevalence rates. This study tested predictors of Resilience Theory in a sample of 602 Chinese adolescents. Results revealed that prior adversity, measured through school and family-related events, was significantly associated with increased smoking in females. Family factors (i.e., family cohesion, family adaptability, parental monitoring) and one personal factor (i.e., academic score) were associated with lower odds for smoking due to prior adversity and negative disposition.

Female vulnerability to the effects of smoking on health outcomes in older people.

Cigarette smoking is among the leading risk factors for mortality and morbidity. While men have a higher smoking prevalence, mechanistic experiments suggest that women are at higher risk for health problems due to smoking. Moreover, the comparison of smoking effects on multiple conditions and mortality for men and women has not yet been done in a population-based group with race/ethnic diversity. We used proportional hazards models and restricted mean survival time to assess differences in smoking effects by sex for multiple health outcomes using data from the U.S. Health and Retirement Study (HRS), a population-representative cohort of individuals aged 50+ (n = 22,708, 1992-2014). Men had experienced more smoking pack-years than women (22.0 vs 15.6 average pack-years). Age of death, onset of lung disorders, heart disease, stroke, and cancer showed dose-dependent effects of smoking for both sexes. Among heavy smokers (>28 pack-years) women had higher risk of earlier age of death (HR = 1.3, 95%CI:1.03-1.65) and stroke (HR = 1.37, 95%CI:1.02-1.83). Risk of cancer and heart disease did not differ by sex for smokers. Women had earlier age of onset for lung disorders (HR = 2.83, 95%CI:1.74-4.6), but men risk due to smoking were higher (Smoking-Sex interaction P<0.02) than women. Passive smoke exposure increased risk of earlier heart disease (HR = 1.33, 95%CI:1.07-1.65) and stroke (HR:1.54, 95%CI:1.07-2.22) for non-smokers, mainly in men. Smoking cessation after 15 years partially attenuated the deleterious smoking effects for all health outcomes. In sum, our results suggest that women are more vulnerable to ever smoking for earlier death and risk of stroke, but less vulnerable for lung disorders. From an epidemiological perspective, sex differences in smoking effects are important considerations that could underlie sex differences in health outcomes. These findings also encourage future mechanistic experiments to resolve potential mechanisms of sex-specific cigarette smoke toxicity.

Prevalence and co-occurrence of addictive behaviors among former alternative high school youth.

BACKGROUND AND AIMS: Recent work has studied multiple addictions using a matrix measure, which taps multiple addictions through single responses for each type. METHODS: The present study investigated use of a matrix measure approach among former alternative high school youth (average age = 19.8 years) at risk for addictions. Lifetime and last 30-day prevalence of one or more of 11 addictions reviewed in other work (Sussman, Lisha & Griffiths, 2011) was the primary focus (i.e., cigarettes, alcohol, other/hard drugs, eating, gambling, Internet, shopping, love, sex, exercise, and work). Also, the co-occurrence of two or more of these 11 addictive behaviors was investigated. Finally, the latent class structure of these addictions, and their associations with other measures, was examined. RESULTS: We found that ever and last 30-day prevalence of one or more of these addictions was 79.2% and 61.5%, respectively. Ever and last 30-day co-occurrence of two or more of these addictions was 61.5% and 37.7%, respectively. Latent Class Analysis suggested two groups: a generally Non-addicted Group (67.2% of the sample) and a "Work Hard, Play Hard"-addicted Group that was particularly invested in addiction to love, sex, exercise, the Internet, and work. Supplementary analyses suggested that the single-response type self-reports may be measuring the addictions they intend to measure. DISCUSSION AND CONCLUSIONS: We suggest implications of these results for future studies and the development of prevention and treatment programs, though much more validation research is needed on the use of this type of measure.

Immediate and six-month effects of Project EX Russia: a smoking cessation intervention pilot program.

This study evaluates the performance of the Project EX tobacco use cessation program in Russian summer recreational camps. An eight-session clinic-based tobacco use cessation program for adolescents was tested during the summer of 2011 in an experimental pilot trial that involved different youth that rotated through camps. Conditions were nested within camps. Two rotations of unique subject groups of smokers (program and standard care control) through each of five camps provided the means of controlling for campsite by condition. Assignment of condition by rotation was random (by a flip of a coin), achieving reasonable baseline comparability (total n=164 smokers at baseline, 76 program group, 88 standard care control group). Evaluation involved an immediate pretest and posttest and a six-month telephone follow-up. At immediate posttest, Project EX was moderately well-received, significantly reduced future smoking expectation (46% reduction in EX program condition versus 8% in control, p<.0001), decreased intention to not quit smoking (-5.2% in EX versus +1.4% in control, p<.05), and increased motivation to quit smoking (0.72 versus -0.04, p<.0001). At the six-month follow-up, program subjects reported a higher intent-to-treat quit rate during the last 30days (7.5% versus 0.1%, p<.05). For the subjects who remained monthly smokers at the six-month follow-up, Project EX reduced subjects' level of nicotine dependence (-0.53 versus +0.15, p<.001). The results were quite promising for this program, which included motivation enhancement, coping skill, and alternative medicine material. However, further research on teen tobacco use cessation programming in Russia with larger sample sizes, involving other locations of the country, and with stronger research designs is needed.

Smoking prevalence among monks in Thailand.

Previous studies among Buddhist monks in Thailand have reported smoking rates to be as high as 55%. Because 95% of Thais are Buddhist, monks are highly influential in establishing normative behavioral patterns. As the first population-based study on smoking among Buddhist monks in Thailand, this study aims to determine the smoking prevalence in six regions of the country, and to examine smoking knowledge, risk perceptions, behaviors, and associated demographics among full-fledged and novice monks (n = 6,213). Results demonstrated that the overall prevalence for current smoking monks is 24.4% (95% confidence interval [24.453, 24.464]), with regional differences ranging from 14.6% (North) to 40.5% (East). Findings suggest that integrating prevention and cessation programming into religious courses may be one avenue for reaching many incoming monks. Further, involving monks in tobacco control education and setting a nonsmoking standard among them is vital to the success of reducing smoking rates among the general population in Thailand.