Ed Moderately Severely Diet 4 Unexposed Moderately SeverelyN Packyears, mean (SD) 1684 1514 696 14.2 (12.9) 15.2 (13.6) 17.3 (14.1) Ethanol, g/day mean (SD) 2360 1949 783 12.8 (13.0) 12.7 (12.7) 12.7 (14.1) mMDS, mean (SD) 3450 2838 1237 4.0 (1.5) 4.1 (1.5) 4.0 (1.5)Crude modelP for trendMultivariable modelP for trendMultivariable model 2P for trendInteraction with ageReference 1.01 (0.08; 1.94) 3.10 (1.92; 4.29)<0.Reference 0.95 (0.03; 1.87) 2.58 (1.41; 3.75)<0.Reference 0.98 (0.10; 1.87) 2.53 (1.39; 3.66)<0.0.Reference -0.15 (-0.93; 0.64) -0.09 (-1.15; 0.96)0.Reference -0.16 (-0.93; 0.62) 0.20 (-0.85; 1.25)0.Reference -0.41 (-1.15; 0.33) -0.32 (-1.32; 0.67)0.0.Reference 0.10 (0.03; 0.17) 0.00 (-0.09; 0.10)0.Reference 0.08 (0.01; 0.16) 0.02 (-0.08; 0.11)0.Reference 0.09 (0.02; 0.17) 0.05 (-0.05; 0.14)0.0.multivariable model 1: adjusted for age at start of the famine (October 1, 1944) and educational level;multivariable model 2: adjusted for age at start of the famine, educational level model, BMI, energy intake, physical activity level, smoking status and intensity, alcohol consumption, and mMDS (covariates are excluded if they are the outcome) includes former and current smokers only only current drinkers that drink >1 g/day modified Mediterranean Diet Score excluding alcohol; mMDS: modified Mediterranean Diet Score.2 3doi:10.1371/journal.pone.0156609.tWe observed a higher prevalence of smoking and physical inactivity in participants that were severely exposed to the Dutch famine. As we are the first to study this association, there are no other studies to compare our results with. We can only speculate about the biological pathways along which famine Mdivi-1 molecular weight Exposure early in life may be associated with lifestyle later in life. Severe undernutrition during important developmental periods might impair brain development, as rapid brain development takes place during pregnancy and in the first years of life [1]. However, environment (brain development is affected by experience), timing of the exposure, the degree of exposure and the possibility of recovery might also influence long-term effects of famine exposure on brain function [1]. Vucetic et al. studied the effect of early life protein restriction (pre- and postnatal) in mice and found behavioral abnormalities that were dopamine-related [32]. Dopamine plays a role in behavioral responses, and a dysfunction of the dopamine system is associated with neurobehavioral disorders, like addiction. This may explain the results found for smoking, but not the fact that heavy alcohol consumption was not related to famine exposure. Apart from a direct effect of the famine, famine-related stress or war-related stress may play a role in the adoption of unhealthy behaviors [3, 12]. Stressful life events have been associated with higher risk of smoking and drinking in adolescents [33]. Several studies relate Roc-A web adverse childhood experiences and stress during childhood to increased chronic disease risk later in life, among others via unhealthy lifestyle behaviors [13?5]. MillerPLOS ONE | DOI:10.1371/journal.pone.0156609 May 31,8 /Famine Exposure and Unhealthy Lifestyle Behavioret al. suggest that impaired self-regulation after exposure to stress during childhood creates a proclivity for unhealthy behaviors [13]. The Prospect-EPIC cohort provided us with the unique opportunity to study the long-term relations of famine exposure with lifestyle behavior later in life. Strengths of our study are the large study po.Ed Moderately Severely Diet 4 Unexposed Moderately SeverelyN Packyears, mean (SD) 1684 1514 696 14.2 (12.9) 15.2 (13.6) 17.3 (14.1) Ethanol, g/day mean (SD) 2360 1949 783 12.8 (13.0) 12.7 (12.7) 12.7 (14.1) mMDS, mean (SD) 3450 2838 1237 4.0 (1.5) 4.1 (1.5) 4.0 (1.5)Crude modelP for trendMultivariable modelP for trendMultivariable model 2P for trendInteraction with ageReference 1.01 (0.08; 1.94) 3.10 (1.92; 4.29)<0.Reference 0.95 (0.03; 1.87) 2.58 (1.41; 3.75)<0.Reference 0.98 (0.10; 1.87) 2.53 (1.39; 3.66)<0.0.Reference -0.15 (-0.93; 0.64) -0.09 (-1.15; 0.96)0.Reference -0.16 (-0.93; 0.62) 0.20 (-0.85; 1.25)0.Reference -0.41 (-1.15; 0.33) -0.32 (-1.32; 0.67)0.0.Reference 0.10 (0.03; 0.17) 0.00 (-0.09; 0.10)0.Reference 0.08 (0.01; 0.16) 0.02 (-0.08; 0.11)0.Reference 0.09 (0.02; 0.17) 0.05 (-0.05; 0.14)0.0.multivariable model 1: adjusted for age at start of the famine (October 1, 1944) and educational level;multivariable model 2: adjusted for age at start of the famine, educational level model, BMI, energy intake, physical activity level, smoking status and intensity, alcohol consumption, and mMDS (covariates are excluded if they are the outcome) includes former and current smokers only only current drinkers that drink >1 g/day modified Mediterranean Diet Score excluding alcohol; mMDS: modified Mediterranean Diet Score.2 3doi:10.1371/journal.pone.0156609.tWe observed a higher prevalence of smoking and physical inactivity in participants that were severely exposed to the Dutch famine. As we are the first to study this association, there are no other studies to compare our results with. We can only speculate about the biological pathways along which famine exposure early in life may be associated with lifestyle later in life. Severe undernutrition during important developmental periods might impair brain development, as rapid brain development takes place during pregnancy and in the first years of life [1]. However, environment (brain development is affected by experience), timing of the exposure, the degree of exposure and the possibility of recovery might also influence long-term effects of famine exposure on brain function [1]. Vucetic et al. studied the effect of early life protein restriction (pre- and postnatal) in mice and found behavioral abnormalities that were dopamine-related [32]. Dopamine plays a role in behavioral responses, and a dysfunction of the dopamine system is associated with neurobehavioral disorders, like addiction. This may explain the results found for smoking, but not the fact that heavy alcohol consumption was not related to famine exposure. Apart from a direct effect of the famine, famine-related stress or war-related stress may play a role in the adoption of unhealthy behaviors [3, 12]. Stressful life events have been associated with higher risk of smoking and drinking in adolescents [33]. Several studies relate adverse childhood experiences and stress during childhood to increased chronic disease risk later in life, among others via unhealthy lifestyle behaviors [13?5]. MillerPLOS ONE | DOI:10.1371/journal.pone.0156609 May 31,8 /Famine Exposure and Unhealthy Lifestyle Behavioret al. suggest that impaired self-regulation after exposure to stress during childhood creates a proclivity for unhealthy behaviors [13]. The Prospect-EPIC cohort provided us with the unique opportunity to study the long-term relations of famine exposure with lifestyle behavior later in life. Strengths of our study are the large study po.