Biomarkers of aging for the identification and evaluation of longevity interventions.

With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.

Evidence for protein leverage on total energy intake, but not body mass index, in a large cohort of older adults.

BACKGROUND: Protein leverage (PL) is the phenomenon of consuming food until absolute intake of protein approaches a 'target value', such that total energy intake (TEI) varies passively with the ratio of protein: non-protein energy (fat + carbohydrate) in the diet. The PL hypothesis (PLH) suggests that the dilution of protein in energy-dense foods, particularly those rich in carbohydrates and fats, combines with protein leverage to contribute to the global obesity epidemic. Evidence for PL has been reported in younger adults, children and adolescents. This study aimed to test for PL and the protein leverage hypothesis (PLH) in a cohort of older adults. METHODS: We conducted a retrospective analysis of dietary intake in a cohort of 1699 community-dwelling older adults aged 67-84 years from the NuAge cohort. We computed TEI and the energy contribution (EC) from each macronutrient. The strength of leverage of macronutrients was assessed through power functions ( TEI = µ * EC L ). Body mass index (BMI) was calculated, and mixture models were fitted to predict TEI and BMI from macronutrients' ECs. RESULTS: In this cohort of older adults, 53% of individuals had obesity and 1.5% had severe cases. The mean TEI was 7673 kJ and macronutrients' ECs were 50.4%, 33.2% and 16.4%, respectively for carbohydrates, fat, and protein. There was a strong negative association (L = -0.37; p < 0.001) between the protein EC and TEI. Each percent of energy intake from protein reduced TEI by 77 kJ on average, ceteris paribus. However, BMI was unassociated with TEI in this cohort. CONCLUSIONS: Findings indicate clear evidence for PL on TEI, but not on BMI, likely because of aging, body composition, sarcopenia, or protein wasting.

Effect of Extra Virgin Olive Oil on Anthropometric Indices, Inflammatory and Cardiometabolic Markers: a Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: A large body of literature associated extra virgin olive oil (EVOO) consumption with low risk of cardiovascular disease and mortality. However, findings from clinical trials related to EVOO consumption on blood pressure, lipid profile, and anthropometric and inflammation parameters are not univocal. OBJECTIVES: The aim of this systematic review and meta-analysis was to evaluate the effect of EVOO consumption on cardiometabolic risk factors and inflammatory mediators. METHODS: We searched PubMed/MEDLINE, Scopus, and Cochrane up through 31 March, 2023, without any particular language limitations, in order to identify randomized controlled trials (RCTs) that examined the effects of EVOO consumption on cardiometabolic risk factors, inflammatory mediators, and anthropometric indices. Outcomes were summarized as standardized mean difference (SMD) with 95% confidence intervals (CIs) estimated from Hedge's g and random-effects modeling. Heterogeneity was assessed by Cochran Q-statistic and quantified (I2). RESULTS: Thirty-three trials involving 2020 participants were included. EVOO consumption was associated with a significant decrease in insulin (n = 10; SMD: -0.28; 95% CI: -0.51, -0.05; I2 = 48.57%) and homeostasis model assessment of insulin resistance levels (HOMA-IR) (n = 9; SMD: -0.19; 95% CI: -0.35, -0.03; I2 = 00.00%). This meta-analysis indicated no significant effect of consuming EVOO on fasting blood glucose, triglycerides, total cholesterol, low density lipoproteins, very low density lipoproteins, high density lipoproteins, Apolipoprotein (Apo) A-I and B, lipoprotein a, blood pressure, body mass index, waist circumference, waist to hip ratio, C-reactive protein, interleukin-6, interleukin-10, and tumor necrosis factor α levels (P > 0.05). CONCLUSIONS: The present evidence supports a beneficial effect of EVOO consumption on serum insulin levels and HOMA-IR. However, larger well-designed RCTs are still required to evaluate the effect of EVOO on cardiometabolic risk biomarkers. This study was registered in PROSPERO as CRD42023409125.

Multidimensional associations between nutrient intake and healthy ageing in humans.

BACKGROUND: Little is known about how normal variation in dietary patterns in humans affects the ageing process. To date, most analyses of the problem have used a unidimensional paradigm, being concerned with the effects of a single nutrient on a single outcome. Perhaps then, our ability to understand the problem has been complicated by the fact that both nutrition and the physiology of ageing are highly complex and multidimensional, involving a high number of functional interactions. Here we apply the multidimensional geometric framework for nutrition to data on biological ageing from 1560 older adults followed over four years to assess on a large-scale how nutrient intake associates with the ageing process. RESULTS: Ageing and age-related loss of homeostasis (physiological dysregulation) were quantified via the integration of blood biomarkers. The effects of diet were modelled using the geometric framework for nutrition, applied to macronutrients and 19 micronutrients/nutrient subclasses. We observed four broad patterns: (1) The optimal level of nutrient intake was dependent on the ageing metric used. Elevated protein intake improved/depressed some ageing parameters, whereas elevated carbohydrate levels improved/depressed others; (2) There were non-linearities where intermediate levels of nutrients performed well for many outcomes (i.e. arguing against a simple more/less is better perspective); (3) There is broad tolerance for nutrient intake patterns that don't deviate too much from norms ('homeostatic plateaus'). (4) Optimal levels of one nutrient often depend on levels of another (e.g. vitamin E and vitamin C). Simpler linear/univariate analytical approaches are insufficient to capture such associations. We present an interactive tool to explore the results in the high-dimensional nutritional space. CONCLUSION: Using multidimensional modelling techniques to test the effects of nutrient intake on physiological dysregulation in an aged population, we identified key patterns of specific nutrients associated with minimal biological ageing. Our approach presents a roadmap for future studies to explore the full complexity of the nutrition-ageing landscape.

Which interventions with youths counter ageism toward older adults? Results from a realist review.

Age-related social biases - ageism - are developed at an early age. Interventions to counter ageism have been identified but little is known about their mechanisms, particularly in children. This study aimed to provide a comprehensive understanding of which interventions in youths are most effective, under which circumstances, how, and with what outcomes. Using 46 keywords in 6 databases, a realist review identified 24 studies published between 2000 and 2022 targeting youths under 18. A content analysis of these studies led to the construction of a Context-Mechanisms-Outcomes explanatory model. Contextual facilitators triggering mechanisms for changing stereotypes, prejudices and discrimination were: 1) enhancing knowledge about aging and older adults by providing nuanced information, 2) improving the quality of intergenerational contacts, 3) increasing opportunities to apply previously acquired knowledge in intergenerational interactions, and 4) promoting reflective thinking about experiences with older adults. However, stereotypes and prejudices appeared to be resistant and changes difficult to generalize. Insufficiently advanced cognitive development in children or viewing healthy and socially engaged older adults as unrepresentative of their age group were obstacles that reduced intervention effectiveness. Future studies should explore how advancing age influences interventions as well as the characteristics of older adults involved.

Vitamin B-12 Intake from Dairy but Not Meat Is Associated with Decreased Risk of Low Vitamin B-12 Status and Deficiency in Older Adults from Quebec, Canada.

BACKGROUND: Vitamin B-12 deficiency can result in irreversible neurologic damages. It is most prevalent among older adults (∼5%-15%), mainly due to impaired absorption. Vitamin B-12 bioavailability varies between food sources, so their importance in preventing deficiency may also vary. OBJECTIVES: Using the NuAge Database and Biobank, we examined the associations between vitamin B-12 intake (total and by specific food groups) and low vitamin B-12 status and deficiency in older adults. METHODS: NuAge-the Quebec Longitudinal Study on Nutrition and Successful Aging-included 1753 adults aged 67-84 y who were followed 4 y. Analytic samples comprised 1230-1463 individuals. Dietary vitamin B-12 intake was assessed annually using three 24-h dietary recalls. Vitamin B-12 status was assessed annually as low serum vitamin B-12 (<221 pmol/L), elevated urinary methylmalonic acid (MMA)/creatinine ratio (>2 µmol/mmol), and a combination of both (deficiency). Vitamin B-12 supplement users were excluded. Multilevel logistic regressions, adjusted for relevant confounders, were used. RESULTS: Across all study years, 21.8%-32.5% of participants had low serum vitamin B-12, 12.5%-17.0% had elevated urine MMA/creatinine, and 10.1%-12.7% had deficiency. Median (IQR) total vitamin B-12 intake was 3.19 µg/d (2.31-4.37). Main sources were "dairy" and "meat, poultry, and organ meats." The ORs (95% CIs) in the fifth quintile compared with the first of total vitamin B-12 intake were as follows: for low serum vitamin B-12, 0.52 (0.37, 0.75; P-trend < 0.0001); for elevated urine MMA/creatinine, 0.63 (0.37, 1.08; P-trend = 0.091); and for vitamin B-12 deficiency, 0.38 (0.18, 0.79; P-trend = 0.006). Similarly, ORs (95% CIs) in the fourth quartile compared with the first of dairy-derived vitamin B-12 intake were 0.46 (0.32, 0.66; P-trend < 0.0001), 0.51 (0.30, 0.87; P-trend = 0.006), and 0.35 (0.17, 0.73; P-trend = 0.003), respectively. No associations were observed with vitamin B-12 from "meat, poultry, and organ meats." CONCLUSIONS: Higher dietary vitamin B-12 intake, especially from dairy, was associated with decreased risk of low vitamin B-12 status and deficiency in older adults. Food groups might contribute differently at reducing risk of deficiency in older populations.

An objective metric of individual health and aging for population surveys.

BACKGROUND: We have previously developed and validated a biomarker-based metric of overall health status using Mahalanobis distance (DM) to measure how far from the norm of a reference population (RP) an individual's biomarker profile is. DM is not particularly sensitive to the choice of biomarkers; however, this makes comparison across studies difficult. Here we aimed to identify and validate a standard, optimized version of DM that would be highly stable across populations, while using fewer and more commonly measured biomarkers. METHODS: Using three datasets (the Baltimore Longitudinal Study of Aging, Invecchiare in Chianti and the National Health and Nutrition Examination Survey), we selected the most stable sets of biomarkers in all three populations, notably when interchanging RPs across populations. We performed regression models, using a fourth dataset (the Women's Health and Aging Study), to compare the new DM sets to other well-known metrics [allostatic load (AL) and self-assessed health (SAH)] in their association with diverse health outcomes: mortality, frailty, cardiovascular disease (CVD), diabetes, and comorbidity number. RESULTS: A nine- (DM9) and a seventeen-biomarker set (DM17) were identified as highly stable regardless of the chosen RP (e.g.: mean correlation among versions generated by interchanging RPs across dataset of r = 0.94 for both DM9 and DM17). In general, DM17 and DM9 were both competitive compared with AL and SAH in predicting aging correlates, with some exceptions for DM9. For example, DM9, DM17, AL, and SAH all predicted mortality to a similar extent (ranges of hazard ratios of 1.15-1.30, 1.21-1.36, 1.17-1.38, and 1.17-1.49, respectively). On the other hand, DM9 predicted CVD less well than DM17 (ranges of odds ratios of 0.97-1.08, 1.07-1.85, respectively). CONCLUSIONS: The metrics we propose here are easy to measure with data that are already available in a wide array of panel, cohort, and clinical studies. The standardized versions here lose a small amount of predictive power compared to more complete versions, but are nonetheless competitive with existing metrics of overall health. DM17 performs slightly better than DM9 and should be preferred in most cases, but DM9 may still be used when a more limited number of biomarkers is available.

Age and Ageing journal 50th anniversary commentary seriesWhy illness is more important than disease in old age.

Clinical reasoning and research in modern geriatrics often prioritises the disease concept. This is understandable as it has brought impressive advances in medicine (e.g. antibiotics, vaccines, successful cancer treatment and many effective surgeries). However, so far the disease framework has not succeeded in getting us to root causes of many age-related chronic diseases (e.g. Alzheimer's disease, diabetes, osteoarthritis). Moreover, in aging and disease constructs alone fail to explain the variability in illness presentations. Therefore, we propose to apply the underused illness concept in a new way by reconsidering the importance of common symptoms in the form of a dynamic network of symptoms as a complementary framework. We show that concepts and methods of complex system thinking now enable to fruitfully monitor and analyse the multiple interactions between symptoms in such in networks, offering new routes for prognosis and treatment. Moreover, close attention to the symptoms that bother older persons may also improve weighing the therapeutic objectives of well-being and survival and aligning treatment targets with the patients' priorities.

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship.

Technological advances promise unprecedented opportunities for whole exome sequencing and proteomic analyses of populations. Currently, data from genome and exome sequencing or proteomic studies are searched against reference genome annotations. This provides the foundation for research and clinical screening for genetic causes of pathologies. However, current genome annotations substantially underestimate the proteomic information encoded within a gene. Numerous studies have now demonstrated the expression and function of alternative (mainly small, sometimes overlapping) ORFs within mature gene transcripts. This has important consequences for the correlation of phenotypes and genotypes. Most alternative ORFs are not yet annotated because of a lack of evidence, and this absence from databases precludes their detection by standard proteomic methods, such as mass spectrometry. Here, we demonstrate how current approaches tend to overlook alternative ORFs, hindering the discovery of new genetic drivers and fundamental research. We discuss available tools and techniques to improve identification of proteins from alternative ORFs and finally suggest a novel annotation system to permit a more complete representation of the transcriptomic and proteomic information contained within a gene. Given the crucial challenge of distinguishing functional ORFs from random ones, the suggested pipeline emphasizes both experimental data and conservation signatures. The addition of alternative ORFs in databases will render identification less serendipitous and advance the pace of research and genomic knowledge. This review highlights the urgent medical and research need to incorporate alternative ORFs in current genome annotations and thus permit their inclusion in hypotheses and models, which relate phenotypes and genotypes.

Evidence from two cohorts for the frailty syndrome as an emergent state of parallel dysregulation in multiple physiological systems.

Frailty is a clinical syndrome often present in older adults and characterized by a heightened vulnerability to stressors. The biological antecedents and etiology of frailty are unclear despite decades of research: frailty is associated with dysregulation in a wide range of physiological systems, but no specific cause has been identified. Here, we test predictions stemming from the hypothesis that there is no specific cause: that frailty is an emergent property arising from the complex systems dynamics of the broad loss of organismal homeostasis. Specifically, we use dysregulation of six physiological systems using the Mahalanobis distance approach in two cohorts of older adults to test the breadth, diffuseness, and nonlinearity of associations between frailty and system-specific dysregulation. We find clear support for the breadth of associations between frailty and physiological dysregulation: positive associations of all systems with frailty in at least some analyses. We find partial support for diffuseness: the number of systems or total amount of dysregulation is more important than the identity of the systems dysregulated, but results only partially replicate across cohorts. We find partial support for nonlinearity: trends are exponential but not always significantly so, and power is limited for groups with very high levels of dysregulation. Overall, results are consistent with-but not definitive proof of-frailty as an emergent property of complex systems dynamics. Substantial work remains to understand how frailty relates to underlying physiological dynamics across systems.

Effects of Sex and Physical Activity Level on Serum Biomarker-Based Physiological Dysregulation: The Impact to Predict Frailty and Mortality in the Quebec NuAge Cohort.

BACKGROUND: Age-related changes in biological processes such as physiological dysregulation (the progressive loss of homeostatic capacity) vary considerably among older adults and may influence health profiles in late life. These differences could be related, at least in part, to the impact of intrinsic and extrinsic factors such as sex and physical activity level (PAL). OBJECTIVES: The objectives of this study were (1) to assess the magnitude and rate of changes in physiologi-cal dysregulation in men and women according to PAL and (2) to determine whether/how sex and PAL mediate the apparent influence of physiological dysregulation on health outcomes (frailty and mortality). METHODS: We used data on 1,754 community-dwelling older adults (age = 74.4 ± 4.2 years; women = 52.4%) of the Quebec NuAge cohort study. Physiological dysregulation was calculated based on Mahalanobis distance of 31 biomarkers regrouped into 5 systems: oxygen transport, liver/kidney function, leukopoiesis, micronutrients, and lipids. RESULTS: As expected, mean physiological dysregulation significantly increased with age while PAL decreased. For the same age and PAL, men showed higher levels of physiological dysregulation globally in 3 systems: oxygen transport, liver/kidney function, and leukopoiesis. Men also showed faster global physiological dysregulation in the liver/kidney and leukopoiesis systems. Overall, high PAL was associated with lower level and slower rate of change of physiological dysregulation. Finally, while mortality and frailty risk significantly increased with physiological dysregulation, there was no evidence for differences in these effects between sexes and PAL. CONCLUSION: Our results showed that both sex and PAL have a significant effect on physiological dysregulation levels and rates of change. Also, although a higher PAL was associated with lower level and slower rate of change of physiological dysregulation, there was no evidence that PAL attenuates the effect of physiological dysregulation on subsequent declines in health at the end of life. Substantial work remains to understand how modifiable behaviors impact the relationship between physiological dysregulation, frailty, and mortality in men and women.

Milk composition in a wild mammal: a physiological signature of phenological changes.

Understanding how spring phenology influences early life can provide important insights into drivers of future development and survival. We combined unique, long-term data from a bighorn sheep population and satellite-derived phenology indices to quantify the relative importance of maternal and environmental influences on milk composition and lamb overwinter survival. Based on 216 milk samples from 34 females monitored over 6 years, we found that longer snow-free and vegetation growing seasons increased milk fatty acid, iron and lactose concentrations. Structural equation modelling revealed no causality between milk energy content, lamb weaning mass and lamb overwinter survival. Our results suggest that spring conditions can affect milk energy content, but we did not detect any effect on lamb overwinter survival either directly or indirectly through lamb weaning mass. The effect of green-up date on milk composition and energy content suggests that herbivores living in seasonal environments, such as the bighorn sheep, might rely on a strategy intermediate between 'capital' and 'income' breeding when energy demands are high.

Causes and short-term consequences of variation in milk composition in wild sheep.

Ecologists seek to understand the fitness consequences of variation in physiological markers, under the hypothesis that physiological state is linked to variability in individual condition and life history. Thus, ecologists are often interested in estimating correlations between entire suites of correlated traits, or biomarkers, but sample size limitations often do not allow us to do this properly when large numbers of traits or biomarkers are considered. Latent variables are a powerful tool to overcome this complexity. Recent statistical advances have enabled a new class of multivariate models-multivariate hierarchical modelling (MHM) with latent variables-which allow to statistically estimate unstructured covariances/correlations among traits with reduced constraints on the number of degrees of freedom to account in the model. It is thus possible to highlight correlated structures in potentially very large numbers of traits. Here, we apply MHM to evaluate the relative importance of individual differences and environmental effects on milk composition and identify the drivers of this variation. We ask whether variation in bighorn sheep milk affects offspring fitness. We evaluate whether mothers show repeatable individual differences in the concentrations of 11 markers of milk composition, and we investigate the relative importance of annual variability, maternal identity and morphological traits in structuring milk composition. We then use variance estimates to investigate how a subset of repeatable milk markers influence lamb summer survival. Repeatability of milk markers ranged from 0.05 to 0.64 after accounting for year-to-year variations. Milk composition was weakly but significantly associated with maternal mass in June and September, summer mass gain and winter mass loss. Variation explained by year-to-year fluctuations ranged from 0.07 to 0.91 suggesting a strong influence of environmental variability on milk composition. Milk composition did not affect lamb survival to weaning. Using joint models in ecological, physiological or behavioural contexts has the major advantage of decomposing a (co)variance/correlation matrix while being estimated with fewer parameters than in a "traditional" mixed-effects model. The joint models presented here complement a growing list of tools to analyse correlations at different hierarchical levels separately and may thus represent a partial solution to the conundrum of physiological complexity.

Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing?

The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such "geroprotective" therapies in humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972-1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.

Aging across the tree of life: The importance of a comparative perspective for the use of animal models in aging.

Use of model organisms in aging research is problematic because our ability to extrapolate across the tree of life is not clear. On one hand, there are conserved pathways that regulate lifespan in organisms including yeast, nematodes, fruit flies, and mice. On the other, many intermediate taxa across the tree of life appear not to age at all, and there is substantial variation in aging mechanisms and patterns, sometimes even between closely related species. There are good evolutionary and mechanistic reasons to expect this complexity, but it means that model organisms must be used with caution and that results must always be interpreted through a broader comparative framework. Additionally, it is essential to include research on non-traditional and unusual species, and to integrate mechanistic and demographic research. There will be no simple answers regarding the biology of aging, and research approaches should reflect this. This article is part of a Special Issue entitled: Animal models of aging - edited by Houtkooper Riekelt.

Physiological predictors of reproductive performance in the European Starling (Sturnus vulgaris).

BACKGROUND: It is widely assumed that variation in fitness components has a physiological basis that might underlie selection on trade-offs, but the mechanisms driving decreased survival and future fecundity remain elusive. Here, we assessed whether physiological variables are related to workload ability or immediate fitness consequences and if they mediate future survival or reproductive success. We used data on 13 physiological variables measured in 93 female European starlings (Sturnus vulgaris) at two breeding stages (incubation, chick-rearing), for first-and second-broods over two years (152 observations). RESULTS: There was little co-variation among the physiological variables, either in incubating or chick-rearing birds, but some systematic physiological differences between the two stages. Chick-rearing birds had lower hematocrit and plasma creatine kinase but higher hemoglobin, triglyceride and uric acid levels. Only plasma corticosterone was repeatable between incubation and chick-rearing. We assessed relationships between incubation or chick-rearing physiology and measures of workload, current productivity, future fecundity or survival in a univariate manner, and found very few significant relationships. Thus, we next explored the utility of multivariate analysis (principal components analysis, Mahalanobis distance) to account for potentially complex physiological integration, but still found no clear associations. CONCLUSIONS: This implies either that a) birds maintained physiological variables within a homeostatic range that did not affect their performance, b) there are relatively few links between physiology and performance, or, more likely, c) that the complexity of these relationships exceeds our ability to measure it. Variability in ecological context may complicate the relationship between physiology and behavior. We thus urge caution regarding the over-interpretation of isolated significant findings, based on single traits in single years, in the literature.

Complex systems dynamics in aging: new evidence, continuing questions.

There have long been suggestions that aging is tightly linked to the complex dynamics of the physiological systems that maintain homeostasis, and in particular to dysregulation of regulatory networks of molecules. This review synthesizes recent work that is starting to provide evidence for the importance of such complex systems dynamics in aging. There is now clear evidence that physiological dysregulation--the gradual breakdown in the capacity of complex regulatory networks to maintain homeostasis--is an emergent property of these regulatory networks, and that it plays an important role in aging. It can be measured simply using small numbers of biomarkers. Additionally, there are indications of the importance during aging of emergent physiological processes, functional processes that cannot be easily understood through clear metabolic pathways, but can nonetheless be precisely quantified and studied. The overall role of such complex systems dynamics in aging remains an important open question, and to understand it future studies will need to distinguish and integrate related aspects of aging research, including multi-factorial theories of aging, systems biology, bioinformatics, network approaches, robustness, and loss of complexity.

Maternal levels of endocrine disruptors, polybrominated diphenyl ethers, in early pregnancy are not associated with lower birth weight in the Canadian birth cohort GESTE.

BACKGROUND: Polybrominated diphenyl ethers are known endocrine disrupting environmental contaminants used as flame retardants. Their levels have increased in humans over the last ten years, raising concerns about their consequences on human health. Some animal studies suggest that PBDEs can affect fetal growth; however, the results of human studies are contradictory. This study evaluates the association between the most common PBDEs in maternal blood measured in early pregnancy and birth weight. METHODS: BDE-47, BDE-99, BDE-100 and BDE-153 levels were measured in 349 women during their first prenatal care visit at the University Hospital Center of Sherbrooke (Quebec, Canada). Birth weight and relevant medical information were collected from medical records. In contrast with previous studies, we examined the full range of clinical risk factors known to affect fetal growth as potential confounders, as well as other environmental pollutants that are likely to interact with fetal growth (polychlorinated biphenyls (PCBs), mercury, lead, cadmium and manganese). RESULTS: There was no statistically significant relationship between PBDE levels in early pregnancy and birth weight in both unadjusted and multivariate regression models. CONCLUSIONS: Our results suggest that PBDEs in early pregnancy have little or no direct impact on birth weight, at least at the levels of exposure in our population.

Environmental Factors Associated With Social Participation of Older Adults Living in Metropolitan, Urban, and Rural Areas: The NuAge Study.

OBJECTIVES: We compared the social participation of older adults living in metropolitan, urban, and rural areas, and identified associated environmental factors. METHODS: From 2004 to 2006, we conducted a cross-sectional study using an age-, gender-, and area-stratified random sample of 1198 adults (aged 67-82 years). We collected data via interviewer-administered questionnaires and derived from Canadian censuses. RESULTS: Social participation did not differ across living areas (P = .09), but after controlling for potential confounding variables, we identified associated area-specific environmental variables. In metropolitan areas, higher social participation was associated with greater proximity to neighborhood resources, having a driver's license, transit use, and better quality social network (R(2) = 0.18). In urban areas, higher social participation was associated with greater proximity to neighborhood resources and having a driver's license (R(2) = 0.11). Finally, in rural areas, higher social participation was associated with greater accessibility to key resources, having a driver's license, children living in the neighborhood, and more years lived in the current dwelling (R(2) = 0.18). CONCLUSIONS: To enhance social participation of older adults, public health interventions need to address different environmental factors according to living areas.

Effects of categorization method, regression type, and variable distribution on the inflation of Type-I error rate when categorizing a confounding variable.

The loss of signal associated with categorizing a continuous variable is well known, and previous studies have demonstrated that this can lead to an inflation of Type-I error when the categorized variable is a confounder in a regression analysis estimating the effect of an exposure on an outcome. However, it is not known how the Type-I error may vary under different circumstances, including logistic versus linear regression, different distributions of the confounder, and different categorization methods. Here, we analytically quantified the effect of categorization and then performed a series of 9600 Monte Carlo simulations to estimate the Type-I error inflation associated with categorization of a confounder under different regression scenarios. We show that Type-I error is unacceptably high (>10% in most scenarios and often 100%). The only exception was when the variable categorized was a continuous mixture proxy for a genuinely dichotomous latent variable, where both the continuous proxy and the categorized variable are error-ridden proxies for the dichotomous latent variable. As expected, error inflation was also higher with larger sample size, fewer categories, and stronger associations between the confounder and the exposure or outcome. We provide online tools that can help researchers estimate the potential error inflation and understand how serious a problem this is.