Age-dependent Interaction Research Articles

Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is the most common, adult-onset, progressive motor neurodegenerative disorder that results in death within 3 years of the clinical diagnosis. Due to the clinicopathological heterogeneity, any reliable biomarkers for diagnosis or prognosis of ALS have not been identified till date. Moreover, the only three clinically approved treatments are not uniformly effective in slowing the disease progression. Over the last 15 years, there has been a rapid advancement in research on the complex pathomechanistic landscape of ALS that has opened up new avenues for successful clinical translation of targeted therapeutics. Multiple studies suggest that the age-dependent interaction of risk-associated genes with environmental factors and endogenous modifiers is critical to the multi-step process of ALS pathogenesis. In this review, we provide an updated discussion on the dysregulated cross-talk between intracellular homeostasis processes, the unique molecular networks across selectively vulnerable cell types, and the multisystemic nature of ALS pathomechanisms. Importantly, this work highlights the alteration in epigenetic and epitranscriptomic landscape due to gene-environment interactions, which have been largely overlooked in the context of ALS pathology. Finally, we suggest that precision medicine research in ALS will be largely benefitted from the stratification of patient groups based on the clinical phenotype, onset and progression, genome, exposome, and metabolic identities.

Age-dependent interaction between Life's Essential 8 and chronic kidney disease: A national cross-sectional analysis

ObjectiveChronic kidney disease (CKD), an age-related condition, is closely associated with cardiovascular disease. We aimed to examine the age-dependent interaction between Life's Essential 8 (LE8), the updated measurement of cardiovascular health (CVH), and CKD in the United States. MethodsThe cross-sectional study involved 25,529 participants from National Health and Nutrition Examination Survey in 2007–2018. Multivariate logistic regressions were used to estimate the age-dependent interaction between LE8 and CKD, and restricted cubic spline regressions were used to analyze the dose-response relationships between LE8 and CKD among adults and all age subgroups. ResultsOverall, 2934 (9.3%), 17,278 (66.2%), and 5317 (24.5%) participants had low, moderate, and high CVH, separately. After adjusting for the potential covariates, LE8 was negatively associated with CKD [odds ratio (OR) for per 1 standard deviation (SD) increase and 95%CI, 0.71 (0.67, 0.75)], with a nonlinear dose-response relationship (P for nonlinearity = 0.001). The inversed association was stronger among participants aged 65 and older (0.65 (0.59, 0.71)) compared to youngers [20–39 years, 0.63 (0.59, 0.58), 40–64 years, 0.63 (0.59, 0.58)] (P for interaction = 0.002). ConclusionsCVH, as measured by the LE8 score, was negatively associated with the presence of CKD in non-linear fashions, more pronounced in participants aged 65 and older compared to younger age groups.

Numerical approach to an age-structured Lotka-Volterra model.

We study the impact of an age-dependent interaction in a structured predator-prey model. We present two approaches, the PDE (partial differential equation) and the renewal equation, highlighting the advantages of each one. We develop efficient numerical methods to compute the (un)stability of steady-states and the time-evolution of the interacting populations, in the form of oscillating orbits in the plane of prey birth-rate and predator population size. The asymptotic behavior when species interaction does not depend on age is completely determined through the age-profile and a predator-prey limit system of ODEs (ordinary differential equations). The appearance of a Hopf bifurcation is shown for a biologically meaningful age-dependent interaction, where the system transitions from a stable coexistence equilibrium to a collection of periodic orbits around it, and eventually to a stable limit cycle (isolated periodic orbit). Several explicit analytical solutions are used to test the accuracy of the proposed computational methods.

Protein interaction potential landscapes for yeast replicative aging

We proposed a novel interaction potential landscape approach to map the systems-level profile changes of gene networks during replicative aging in Saccharomyces cerevisiae. This approach enabled us to apply quasi-potentials, the negative logarithm of the probabilities, to calibrate the elevation of the interaction landscapes with young cells as a reference state. Our approach detected opposite landscape changes based on protein abundances from transcript levels, especially for intra-essential gene interactions. We showed that essential proteins play different roles from hub proteins on the age-dependent interaction potential landscapes. We verified that hub proteins tend to avoid other hub proteins, but essential proteins prefer to interact with other essential proteins. Overall, we showed that the interaction potential landscape is promising for inferring network profile change during aging and that the essential hub proteins may play an important role in the uncoupling between protein and transcript levels during replicative aging.

Recipient Sex Differences in Kidney Graft Survival Are Influenced by Donor Sex and Recipient Age.

An age-dependent interaction has been described for the effect of donor-recipient sex mismatch on outcomes after kidney transplant in the United States. However, this has not been verified or tested in a different cohort from another country. Data of 25 140 deceased donor kidney transplant recipients (2000-2016) were retro-spectively analyzed at a population-cohort level using the United Kingdom transplant registry. Within sub-groups of donor sex, associations between recipient sex and death-censored graft survival were assessed for the cohort as a whole and within recipient age subgroups. No differences in graft survival were detected between female versus male recipients of male donor kidneys (adjusted hazard ratio: 1.05; P = .227). However, a significant interaction between the age and sex of recipients was identified (P = .007). Female recipients aged 25 to 44 years had significantly shorter graft survival than male recipients (adjusted hazard ratio: 1.27; P = .003), but this effect was reversed in recipients who were 45 years or older (adjusted hazard ratio: 0.94; P = .258), where there was a nonsignificant tendency for longer graft survival in females. No such effect was observed in the subgroup of female donor transplants, with no significant difference between female versus male recipients overall (adjusted hazard ratio: 1.02; P = .638) and no significant interaction with age (P = .470). Graft survival is influenced by the combination of recipient age and sex in recipients of male donor kidneys only. This work demonstrates findings broadly similar to published reports but presents differences in observed effect sizes among certain subgroups. Our research suggests further work is warranted to explore personalized approaches to age- and sex-adapted immunosuppression.

Age-dependent interaction between sex and geographic ultraviolet index in melanoma risk

Ultraviolet (UV) exposure may not affect melanoma development equally in different sexes and ages. Whether and how these factors interact with each other in relation to melanoma risk is unknown. This study attempts to estimate interactions among UV index (UVI), sex, and age in melanoma risk. Melanoma incidence data were collected from 42 cancer registries. Geographic UVI was collected from local satellite stations. Negative binomial regression models were used to estimate the impact of each risk factor and their interactions. Sex, UVI, and age, as well as interactions between any 2 of these factors, were significantly associated with melanoma risk. In younger age groups, female sex is an independent risk factor for melanoma that is not affected by ambient UV exposure. In older age groups, however, female sex interacts with UV exposure as a risk factor, exhibiting a protective effect. The switching age category is 45 to 49, which correlates with dramatic hormonal changes. The interaction between sex and UVI is measured at an ecologic level. The interaction between sex and UVI is age dependent. Female sex is an independent risk factor for early-onset melanoma, but female sex also protects against UV-associated melanoma in older age groups.

Assessment of age-related changes in heritability and IGF-1 gene effect on circulating IGF-1 levels

It is well established that insulin-like growth factor 1 (IGF-1) circulating levels correlate with age and that heritability and influence of IGF-1 gene variation on IGF-1 levels also well-known. However, the influence of age on the genetic factors determining IGF-1 levels is not clear. In this study, we compared heritability estimates between younger (<52 years) and older (>52 years) twins and tested: (a) whether single nucleotide polymorphisms (SNPs) lying within 100 kbp of the IGF-1 gene are also associated with IGF-1 variation and (b) whether associated SNPs show interaction with age on IGF-1 levels. To achieve these aims, we measured plasma levels of IGF-1 and genotyped 18 SNPs with minor allele frequency >0.1 in a large sample, 4,471 UK female twins. Heritability explained 42 % of IGF-1 variation adjusted for age and in unadjusted sample was independent of age. Ten SNPs in four haploblocks showed significant association with IGF-1 levels, with p = 0.01-0.0005. The most distal SNP was located up to 90 kbp from the IGF-1 gene. When their age-dependent effects were examined, one SNP, rs855203, showed significant (p = 0.0009) age-dependent interaction effect on IGF-1 levels variation. This is the first study to test the age × genotype interaction in IGF-1 levels. The genomic region marked by rs855203 may consequently be of significance for further molecular and pharmacogenetic research, in particular in advanced age.

Differential Regulation of GLT-1/EAAT2 Gene Expression by NF-κB and N-myc in Male Mouse Brain During Postnatal Development

The synaptic glutamate level homeostasis is mainly maintained by the astrocytes membrane bound glutamate transporter type-1 (GLT-1/EAAT2). Alterations in its expression during development and aging and the underlying mechanisms are not well studied. Here, we report that NF-κB interaction was highest in both cerebral and cerebellar cortices at day 15 when compared with that at day 0 during development, and it further declined significantly in day 45, and remained unchanged in 20 and 70 weeks mice. On the other hand, N-myc interaction was highest at 0 day which significantly declined at 15-day and interestingly remained unaltered at later ages in both the cortices. This age dependent reciprocal pattern of NF-κB and N-myc interactions with their cognate GLT-1 promoter sequences was further correlated with GLT-1 protein and transcript levels. We found that higher NF-κB interaction with its cognate GLT-1 promoter sequences correlates with up-regulation whereas the higher N-myc interaction correlates with down-regulation of GLT-1 expression during postnatal developmental age up to 15 day, however, such phenomenon was not found in the higher ages from day 45 to 70 weeks. Thus our data suggests a postnatal development- and age dependent differential interaction of transcription factors NF-κB and N-myc to their respective sequences and they act as positive and negative regulator, respectively of GLT-1 gene expression in the brain during early developmental period in both cerebral and cerebellar cortices which might be different in aging of mice.

Inhibition of x-box binding protein 1 reduces tunicamycin-induced apoptosis in aged murine macrophages

Endoplasmic reticulum (ER) stress is induced by the accumulation of unfolded and misfolded proteins in the ER. Although apoptosis induced by ER stress has been implicated in several aging-associated diseases, such as atherosclerosis, it is unclear how aging modifies ER stress response in macrophages. To decipher this relationship, we assessed apoptosis in macrophages isolated from young (1.5-2months) and aged (16-18months) mice and exposed the cells to the ER stress inducer tunicamycin. We found that aged macrophages exhibited more apoptosis than young macrophages, which was accompanied by reduced activation of phosphorylated inositol-requiring enzyme-1 (p-IRE1α), one of the three key ER stress signal transducers. Reduced gene expression of x-box binding protein 1 (XBP1), a downstream effector of IRE1α, enhanced p-IRE1α levels and reduced apoptosis in aged, but not young macrophages treated with tunicamycin. These findings delineate a novel, age-dependent interaction by which macrophages undergo apoptosis upon ER stress, and suggest an important protective role of IRE1α in aging-associated ER stress-induced apoptosis. This novel pathway may not only be important in our understanding of longevity, but may also have important implications for pathogenesis and potential treatment of aging-associated diseases in general.

Abstract 380: Aging Enhances Endoplasmic Reticulum Stress-Induced Apoptosis in Murine Macrophages

Introduction and hypothesis Aging enhances atherosclerosis for unclear reasons. As macrophage apoptosis and endoplasmic reticulum (ER) stress contribute to atherosclerosis, we examined if aging sensitizes these cells to apoptosis during ER stress. Methods and Results Peritoneal macrophages were isolated from young (aged 2-4 months) and aged (aged 16-18 months) mice, exposed to the ER stress inducer tunicamycin (TM) in vitro, and apoptosis was measured by Annexin V staining via fluorescent microscopy. We found that aged macrophages exhibited significantly more apoptosis than young macrophages (see Figure). We next measured key ER stress proteins in macrophages by Western blot to determine the underlying molecular pathways impacted by aging. With aging, we found reduced activation of inositol-requiring enzyme-1 (IRE1α), a key ER stress transducer. We next examined if augmenting activated IRE1α levels in aged macrophages reduced apoptosis during ER stress. We employed siRNA to knock down x-box binding protein 1 (XBP1), a downstream effector of IRE1α, which has been shown to induce feedback activation of IRE1α in hepatocytes. siRNA to XBP1 significantly reduced tunicamycin-induced cell apoptosis in aged macrophages from 26.1±0.408% to 5.48±1.38% (p&lt;0.05) but not in young macrophages. Conclusions Our study has uncovered a novel, age-dependent interaction by which macrophages undergo apoptosis upon ER stress, and suggests that enhancing IRE1α activation will alleviate aging-augmented ER stress and subsequent apoptosis. This novel interaction may have important implications for the pathogenesis of atherosclerosis with aging.

Age-dependent interaction between atopy and eosinophils in asthma cases: results from NHANES 2005-2006.

Atopy is an established risk factor for asthma, and an elevated eosinophil level is a hallmark of atopic and non-atopic asthma. Whether atopy and eosinophils act independently or interact to influence asthma has clinical and public health implications. To investigate the relationship between atopy and eosinophils in asthma. Data on current asthma, atopy (IgE positive to ≥ 1 allergen), and blood eosinophil percent (dichotomized at the median) were obtained for persons aged ≥ 6 years from the National Health and Nutrition Examination Survey 2005-2006. Interaction on an additive scale was evaluated by estimating the prevalences of asthma for combinations of atopy (yes or no) and eosinophil percent (high or low) and calculating the excess prevalence due to interaction. For all ages combined, the adjusted prevalences of asthma were 4.6%, 7.6%, 6.9% and 17.2% for persons with neither factor, atopy alone, a high eosinophil percent alone and both factors respectively. The excess prevalence of asthma due to interaction was 7.2%, indicating synergism. The excess prevalence was greatest in children aged 6-17 years (15.3%), and it decreased with each older age category until it was absent in adults aged ≥ 55 years (-0.2%). In children, 94% of asthma cases attributable to the 2 factors were attributable to the interaction, whereas in the oldest adults, no cases were attributable to the interaction. Interaction between atopy and an elevated eosinophil level in asthma cases was very strong in children but absent in the oldest adults, which suggests different mechanistic pathways for these factors by age and supports the notion that asthma is a heterogeneous disease. In addition, the age-dependent interaction between the factors has potential implications for the selection of asthma patients for treatments that would target either IgE or a high eosinophil level.

Age-dependent interaction of apolipoprotein E gene with eastern birthplace in Finland affects severity of coronary atherosclerosis and risk of fatal myocardial infarction—Helsinki Sudden Death Study

Background. Mortality from coronary heart disease (CHD) has been constantly higher in eastern late settlement regions compared to western early settlements in Finland, unrelated to classical risk factors. In line with this, eastern birthplace was an age-dependent predictor of severe coronary atherosclerosis and pre-hospital sudden coronary death among male residents of Helsinki. We investigated a possible interaction of apolipoprotein E (APOE) gene with birthplace on the risk of myocardial infarction (MI) and coronary atherosclerosis.Method. APOE genotypes were analyzed in the Helsinki Sudden Death Study series comprising out-of-hospital deaths among males aged 33–70 years (n = 577), who were born in high (east, n = 273) or low (west, n = 304) CHD mortality area.Results. Eastern-born men ≤ 55 years carried 30% more often (P = 0.017) and older men 40% less often (P = 0.022) the APOE ϵ4 allele compared to western-born men (P = 0.003 for birthplace-by-age interaction). In multivariate analysis, the ϵ4 allele associated with the risk of out-of-hospital MI (odds ratio 2.58; 95% CI 1.20–5.55; P = 0.016) only in eastern-born men and with advanced atherosclerosis in both regions of origin, respectively.Conclusions. Birthplace-bound risk of CHD was age-dependently modified by APOE ϵ4 allele, suggesting genetic differences in CHD susceptibility between early and late settlement regions in Finland and providing one explanation for the eastern high mortality.

The Importance of Age and High Degree, in Protein-Protein Interaction Networks

Here we present an in-depth analysis of the protein age patterns found in the edge and triangle subgraphs of the yeast protein-protein interaction network (PIN). We assess their statistical significance both according to what would be expected by chance given the node frequencies found in the yeast PIN, and also, for the case of triangles, given the age frequencies observed in the currently available pairwise data. We find that pairwise interactions between Old proteins are over-represented even when controlling for high degree, and triangle interactions between Old proteins are over-represented even when controlling for pairwise interaction frequencies. There is evidence for negative selection of interactions between Middle-aged and Old proteins within triangles, despite pairwise Middle-Old interactions being common. Most triangles consist solely of vertices with high degree. Our findings point towards an architecture of the yeast PIN that is highly heterogeneous, having connected clumps which contain a large number of interacting Old proteins along with selective age-dependent interaction patterns. Supplementary Material is available online (www.liebertonline.com/cmb).

Integrin-associated protein (CD47) is a putative mediator for soluble fibrinogen interaction with human red blood cells membrane

Fibrinogen is a multifunctional plasma protein that plays a crucial role in several biological processes. Elevated fibrinogen induces erythrocyte hyperaggregation, suggesting an interaction between this protein and red blood cells (RBCs). Several studies support the concept that fibrinogen interacts with RBC membrane and this binding, due to specific and non-specific mechanisms, may be a trigger to RBC hyperaggregation in inflammation. The main goals of our work were to prove that human RBCs are able to specifically bind soluble fibrinogen, and identify membrane molecular targets that could be involved in this process. RBCs were first isolated from blood of healthy individuals and then separated in different age fractions by discontinuous Percoll gradients. After isolation RBC samples were incubated with human soluble fibrinogen and/or with a blocking antibody against CD47 followed by fluorescence confocal microscopy, flow cytometry acquisitions and zeta potential measurements. Our data show that soluble fibrinogen interacts with the human RBC membrane in an age-dependent manner, with younger RBCs interacting more with soluble fibrinogen than the older cells. Importantly, this interaction is abrogated in the presence of a specific antibody against CD47. Our results support a specific and age-dependent interaction of soluble fibrinogen with human RBC membrane; additionally we present CD47 as a putative mediator in this process. This interaction may contribute to RBC hyperaggregation in inflammation.

Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases

Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD.

How Does Your Cortex Grow?

Understanding human cortical maturation is a central goal for developmental neuroscience. Significant advances toward this goal have come from two recent strands of in vivo structural magnetic resonance imaging research: (1) longitudinal study designs have revealed that factors such as sex, cognitive ability, and disease are often better related to variations in the tempo of anatomical change than to variations in anatomy at any one time point; (2) largely cross-sectional applications of new surface-based morphometry (SBM) methods have shown how the traditional focus on cortical volume (CV) can obscure information about the two evolutionarily and genetically distinct determinants of CV: cortical thickness (CT) and surface area (SA). Here, by combining these two strategies for the first time and applying SBM in >1250 longitudinally acquired brain scans from 647 healthy individuals aged 3-30 years, we deconstruct cortical development to reveal that distinct trajectories of anatomical change are hidden within, and give rise to, a curvilinear pattern of CV maturation. Developmental changes in CV emerge through the sexually dimorphic and age-dependent interaction of changes in CT and SA. Moreover, SA change itself actually reflects complex interactions between brain size-related changes in exposed cortical convex hull area, and changes in the degree of cortical gyrification, which again vary by age and sex. Knowing of these developmental dissociations, and further specifying their timing and sex-biases, provides potent new research targets for basic and clinical neuroscience.

AIB1 shows variation in interaction with ERβTAD and expression as a function of age in mouse brain

Estrogen mediates its multiple functions in the brain through the recruitment of a number of interacting proteins. In this paper, we report the identification of 160kD interacting nuclear protein of estrogen receptor (ER)β-transactivation domain (TAD) as amplified in breast cancer 1(AIB1) by pull down assay, immunoblotting, far-western analysis and immunoprecipitation. Further we show the age dependent interaction and expression of AIB1 in the brain of young (6weeks), adult (25weeks) and old (70weeks) AKR strain mice of both sexes. The immunoprecipitation data revealed higher interaction of AIB1 in young than adult and old male mice. In contrast, the interaction was low in young, increased in adult but decreased in old female. However, immunoblotting showed age related increase in the expression of AIB1 in both male and female mice. Further, the level of interaction of AIB1 with ERβTAD in young and old male was significantly higher than female of same age, whereas the expression of AIB1 in adult and old female was significantly higher than male of same age. These data suggest that such age dependent variation in the interaction of AIB1 with ERβTAD and its expression may be helpful to regulate estrogen-mediated gene functions during aging and neurodegenerative diseases.

Geometry of a Weight-Bearing and Non-Weight-Bearing Bone in the Legs of Young, Old, and Very Old Men

Bone geometry is an important determinant of bone strength and is influenced by muscle pull and weight-bearing. Muscle mass and exposure to weight-bearing decrease with age and thus the purpose of the study was to compare bone geometry of the weight-bearing (tibia) and non-weight-bearing (fibula) bones of the leg in different age groups. Magnetic resonance images of the right leg were acquired in 13 young (26 yr), 13 old (66 yr), and 13 very old men (83 yr). Cortical, medullary and total cross-sectional areas (CSA) of the bones were measured at approximately one-third and two-thirds the length of the leg. Muscle CSA of the anterior, lateral and posterior compartments was measured at the proximal site. Cortical CSA was approximately 14 to 22% smaller in the elderly in the tibia but similar across age in the fibula. Medullary CSA was larger with age (approximately 5 to 65%) in both bones but approximately 15 to 440% greater in the tibia than fibula. Total CSA was similar across age in both bones. Muscle mass was similar between young and old but approximately 25% less in the very old and as a consequence, the magnitude of differences in bone geometry at proximal and distal sites varied in the two elderly groups. These findings indicate that there is a complex age-dependent interaction between muscle pull and weight-bearing. The greater age-related differences in bone geometry in the tibia suggest the weight-bearing role of the tibia makes it more susceptible than the fibula to the reduced activity typically associated with aging.

THE EFFECTS OF GENOTYPE, AGE, AND SOCIAL ENVIRONMENT ON MALE ORNAMENTATION, MATING BEHAVIOR, AND ATTRACTIVENESS

The traits thought to advertise genetic quality are often highly susceptible to environmental variation and prone to change with age. These factors may either undermine or reinforce the potential for advertisement traits to signal quality depending on the magnitude of age-dependent expression, environmental variation, and genotype-age and genotype-environment interaction. Measurements of the magnitude of these effects are thus a necessary step toward assessing the implications of age dependence and environmental variability for the evolution of signals of quality. We conducted a longitudinal study of male guppies (Poecilia reticulata) from 22 full-sibling families. Each fish was assigned at maturity to one of three treatments in order to manipulate his allocation of resources to reproduction: a control in which the male was kept alone, a courtship-only treatment in which he could see and court a female across a clear partition, and a mating treatment in which he interacted freely with a female. We measured each male's size, ornamental color patterns, courtship, attractiveness to females, and mating success at three ages. Size was influenced by treatment and age-treatment interactions, indicating that courtship and mating may impose costs on growth. Tail size and color patterns were influenced by age but not by treatment, suggesting fixed age-dependent trajectories in these advertisement traits. By contrast, display rate and attempted sneak copulation rate differed among treatments but not among ages, suggesting greater plasticity of these behavioral traits. As a result of the different patterns of variation in ornamentation and behavior, male attractiveness and mating success responded to male age, treatment, and the interaction between age and treatment. Neither age nor treatment obscured the presence of genetic variation, and the genetic relationship between male ornamentation and attractiveness remained the same among treatments. Our findings suggest that neither age-dependent variation nor environmentally induced variation in reproductive effort is likely to undermine the reliability of male signaling.

Cigarette Smoking and Adult Coeliac Disease

Background: While coeliac disease is clearly induced by dietary gluten ingestion in genetically susceptible individuals, other environmental factors may influence the onset of disease. Two studies have suggested that cigarette smoking has a protective role, but a third has not. Methods: We examined the relationship between cigarette smoking and coeliac disease in individuals with coeliac disease diagnosed in adulthood from two large population-based disease registers and age and sex-matched controls from local general practitioner lists. Participants were mailed a three-page lifestyle and general health questionnaire. Smoking habits of coeliacs were compared with controls and with habits reported in the Health Survey for England 1995. Results: An inverse association between current smoking and adult coeliac disease was identified (odds ratio: 0.77 (95% CI 0.56-1.06)) and remained when comparing ever smoked versus never smoked (odds ratio: 0.83 (0.68-1.00)). When the smoking habits of the coeliacs were compared with the national figures, the number of coeliacs who currently smoked was 40% lower than expected (smoking ratio 0.60, 0.46-0.78). This inverse association was accounted for by the behaviour of the 35-54-year age group (odds ratio for ever smoked 0.67 (0.51-0.89)). There was no association with having ever smoked in the younger age group (odds ratio: 1.44 (0.75-2.78)) or the older group (odds ratio: 0.92 (0.67-1.26)). Conclusions: There was an inverse association between adult coeliac disease and cigarette smoking which was accounted for by middle-aged coeliacs having never smoked. These results are consistent with an age-dependent interaction between cigarette smoking and the other environmental factors implicated in coeliac disease, including gluten.