Diet and Stress

In this 2019 cross-sectional study, a sample of 105 Arabian male medical students (mean age 21) were taken and examined on their dietary patterns in order to determine its association with stress. These future medics studying at Al-Imam Muhammed Ibn Saud Islamic University completed questionnaires to assess their diet. Freshmen were found to experience higher stress levels than sophomores and juniors, while increased stress related to greater consumption of unhealthy foods compared with lower stress status. The likelihood of these students eating unhealthy foods was positively influenced by the spread of fast-food restaurants. Aljaber et al. (2019) demonstrated the importance of stress-reducing interventions to help the students, leading the researchers to propose a way to decrease academic stress, by converting the longitudinal courses to blocks for example. The development of educational programs aimed at promoting healthy eating habits in medical students was also encouraged following these findings.

This 2019 study analyzed whether healthy and/or unhealthy comfort eating could reduce stress, and whether the time period that the comfort eating took place could lead to greater stress relief. In order to induce stress, the 150 women in this experiment were faced with a socially evaluative stressor. Firstly, the participants underwent the Trier Social Stress Test in the lab before being randomly assigned to one of five conditions. The study adopted a between-subjects design, with food type (healthy or unhealthy) as the first independent variable, eating timing (during stress anticipation or after encountering the stressor) as the second, while the final condition as the control did not receive any food during the experiment. Finch et al. (2019) found that in comparison with the ‘no food’ control, neither the healthy nor unhealthy comfort eating reduced the reactivity of the psychophysiological stress inflicted upon the subjects. In addition, the participants’ reactivity or recovery did not vary by the type of comfort food consumed, suggesting that eating the healthier option of fruits and vegetables will alleviate stress as much as unhealthy foods do, while it improves diet quality and does not have the drawbacks of eating unhealthy foods like gaining extra fat deposits.

Since the impact of diet on stress reactive systems has not been tested long-term, Shively et al. (2020) fed a proportion of 38 adult, socially-housed, female cynomolgus macaques with the western diet and another with the Mediterranean diet, both for 31 months (which is equivalent to 9 human years) in order to analyze the difference in long-term effects on behavioral and physiological responses to acute (brief social separation) and chronic (social subordination) psychosocial stress. Enhanced stress resilience was observed in the macaques fed the Mediterranean diet relative to those fed the western-style foods, indicated by the brisker and more overt heart rate responses to acute stress, the lower sympathetic activity, quicker recovery, and lower cortisol responses to acute psychological stress and adrenocorticotropin (ACTH) challenge. In addition, the Mediterranean diet appeared to delay the age-related increases in sympathetic activity and cortisol responses to stress. These findings imply that implementing a Mediterranean-like dietary pattern could be a cost-effective intervention on psychological stress, and could potentially promote healthy aging.

El Ansari et al. (2014) assessed the relationship between nutritional behavior with stress and depressive symptoms, by sex and university, using a sample of undergraduates (n = 3706) studying in one of England, Wales and Northern Ireland. The self-administered questionnaires included a 12-item food frequency questionnaire, Cohen's Perceived Stress Scale and modified Beck Depression Inventory. Variations in data such as in frequencies of food group consumption, depressive symptoms and perceived stress, arose by university and sex. Unhealthy eating of foods such as sweets, cookies, snacks, fast food, were associated with greater perceived stress in women, while it related to more depressive symptoms in both sexes. On the other hand, healthy foods such as fresh fruits, salads, cooked vegetables had a significantly negative relationship with both perceived stress and depressive symptoms in both sexes. Other associations identified include fish/seafood consumption with depressive symptoms (significantly negative among males only). The likes of lemonade/soft drinks, meat/sausage products, dairy/dairy products, and cereal/cereal products weren’t associated with either perceived stress or depressive symptoms. This study concluded that consumption of healthier foods might accompany interventions aimed at reducing depressive symptoms and stress among students.

To assess anxiety’s relationship with calorie intake and food cue perception, this 2016 study assessed 55 twins (26 complete, 3 incomplete pairs) on state and trait anxiety using the State-Trait Anxiety Inventory and allowed the subjects to eat freely at a buffet while monitoring food consumption. Before the buffet, the participants were provided with standardized meals, with functional magnetic resonance imaging (fMRI) scans being performed on each individual before and after these meals. The study also involved the twins viewing blocks of fattening and non-fattening food images, and non-food objects during these fMRI scans. The results showed positive associations, in women, between trait anxiety with body mass index (BMI) and with kilocalories consumed at the buffet (p=0.005) and percent kilocalories taken in from fat (p=0.006) when the model was adjusted for BMI. In within-pair models, which control for shared familial and genetic factors, this relationship trait anxiety had with the kilocalories from the buffet remained but not its link with BMI. Women with high trait anxiety were observed not to suppress activation by fattening food cues across brain regions associated with satiety perception after eating a standardized meal (based on the fMRI data). This study has evidence to believe that among women, trait anxiety can potentially predispose excess intake of calories through a change in perception of high-calorie environmental food cues, which could place these women with genetic predispositions toward weight gain at risk of obesity.

This 2013 study assessed whether chronic stress influences activation in reward, motivation and execution brain regions by performing functional magnetic resonance imaging (fMRI) on 30 women while they viewed pictures of high-calorie and low-calorie foods. On separate lab visits, food consumption from a snack food buffet in addition to circulating cortisol levels were examined. The study found exaggerated activity in the regions involving reward, motivation, and habitual decision-making upon viewing pictures of high calorie foods, while significant deactivation in frontal regions (BA10; BA46) linked to strategic planning and emotional control were seen in individuals with higher chronic stress. High chronic stress was related to the strengthening of the connectivity between the amygdala and the putamen based on data from the functional connectivity analysis, while low chronic stress was associated with greater connectivity between amygdala and the anterior cingulate and anterior prefrontal cortex (BA10). Moreover, lower cortisol levels and increased consumption of high calorie foods from the snack food buffet was reported in the high chronic stress group. On the basis of these findings, it appears that persistent stress exposure may influence the brain’s response to foods, increasing the chances for people with poor eating habits to gain weight and possibly becoming obese.

Since high-fat and high-sugar foods have been recently associated with possessing addictive qualities, Yau & Potenza (2013) address stress as a great influence in the development of addiction, which creates further links with increased risk of obesity and other metabolic diseases. Chronic stress alters eating habits and hyperpalatable food consumption, possibly leading to alterations in allostatic load and the triggering of neurobiological adaptations that encourage compulsive behavior. Various factors have been implicated with these changes, including the hypothalamic-pituitary-adrenal (HPA) axis, glucose metabolism, insulin sensitivity, and other appetite-related hormones and hypothalamic neuropeptides. It can be proposed that chronic stress affects the mesolimbic dopaminergic system and other brain regions involved in stress/motivation circuits. It may be multiple pathways synergistically potentiating reward sensitivity, food preference, the desire for hyperpalatable foods, and inducing metabolic changes, while individual susceptibility to obesity and the types of stressors can affect this equation also. To develop effective preventative and treatment strategies for obesity and related metabolic diseases, this review suggests fully elucidating the associations and interactions between stress, neurobiological adaptations, and obesity.

This 2016 article highlights the importance of tackling the problem of obesity and metabolic syndrome from early life, since obesity in infants can influence all body systems up to adulthood. Mocanu et al. (2016) believe in order to prevent obesity it is particularly important to understand the impact of stressors on weight status but the relationship between stress, eating behavior and obesity is not yet fully understood. There is evidence that stress causes disorders in the hypothalamic-pituitary-adrenal (HPA) axis - the system that regulates both stress and feeding responses. Although responses vary depending on type of stressors, chronic stress is associated with inducing HPA stimulation, excess glucocorticoids, insulin resistance, leading to retention of abdominal fat, accumulation of triglycerides, and inhibition of lipid transport.

Since research on interactions between calorie intake, gambling, and impulsive- and addictive-related behaviors is limited, Chamberlain et al. (2017) here investigated the relationship between fat/sugar consumption with gambling behaviors and with other measures of psychopathology and cognition related to addiction. The study discovered a correlation between increased fat and sugar intake with lower education levels and being male, although a significant negative association was revealed after controlling for these variables between sugar and fat intake with gambling and anxiety scores. Additionally, consuming more sugar was strongly related to higher depressive scores, greater alcohol consumption, lower self-esteem, and increased prevalence of one or more mental disorders. While the research team did not find significant relationships between dietary sugar and fat with ADHD symptoms, presence of impulse control disorders, Barratt impulsiveness, nor with cognitive functioning, these overall findings suggest fat/sugar consumption is strongly linked with symptoms of gambling pathology, and not so much with other aspects of impulsivity and behavioral addiction investigated, with alcohol intake being an exception. Education on healthy eating may be crucial in communities heavily influenced by gambling. The mediating mechanisms between calorie intake and gambling symptoms e.g. determining the influences of environmental factors or common dysfunction of brain reward pathways, should be considered in future research.

Since high levels of anxiety causes the release of sympathetic hormones that can decrease insulin secretion and even elevate cortisol and glucose levels, as well as possibly modulate the sensitivity of the insulin hormone, this 2019 review explored how stress and anxiety can affect type II diabetes by evaluating 3 research articles. The participants of the first article with non-insulin dependent diabetes were injected with saline or norephedrine, which saw norephedrine administration causing a decrease in glucose disposal and slower insulin secretion rate. The second article provided diabetic (type II) African-American adults with surveys focused on finding out whether stress, anxiety, and depression can influence lifestyle changes such as exercise and healthy dieting. Those subjects with higher stress levels were less likely to comply with their lifestyle regimes. The third article investigated brain activity (using an MRI) in 2 female sample groups (high and low chronic stress) as they viewed pictures of high-caloric foods. The responses in multiple brain structure activities were different between those with high chronic stress and those with low levels of chronic stress. This data could prove helpful for healthcare providers in managing patients with exacerbated type II diabetes resistant to medication and lifestyle changes.

In this chapter, O’Connor & Conner (2011) discuss the impact of stress on health and eating behavior, including the conflicting associations of stress with increased saturated fat consumption and decreased overall calorie intake. Some studies have linked stress with increased intake of snacks in adults and adolescents, although these results do not completely prove the effect on health. Stress is thought to influence health directly (through autonomic, neuroendocrine, and biological processes) and indirectly through behavior changes. Now there is considerable evidence pointing to the importance of stress-induced eating behavior changes in health outcomes. This review not only highlights the current knowledge on the effects of stress on eating behaviors but also identifies the remaining gaps in research which require addressing in the future.

This 2007 review analyzed human and animal literatures to determine how different types of psychological stress affects diet. Adam & Epel (2017) consider a theoretical model of reward-based stress eating, which highlights how cortisol and the reward circuitry are involved in the motivation of consuming high caloric foods and demonstrates potential neuroendocrine mediators in the relationship between stress and eating. The researchers then turn their attention to addiction literature which heavily link the brain reward circuitry with stress-induced food consumption. Since stress and eating palatable foods can induce the release of opioids, opioid secretion was proposed as one of the organism’s defense mechanisms providing protection from the detrimental effects of stress through reduced activity of the HPA axis. Repeated stimulation of these reward pathways and eating highly palatable foods may cause neurobiological adaptations promoting the compulsive nature of overeating, while cortisol may modulate the reward value of foods. Under chronic stress, glucocorticoids may have a role in increasing food intake and accumulation of visceral fat too. While scientists are working on elucidating these mechanisms, the widespread chronic stress may be currently exacerbating this obesity epidemic.

In this review, Gonzalez & Miranda-Massari (2014) explains how higher levels of stress follows unhealthy dietary habits, which results in greater and greater health problems over time as the issues remain unresolved. Prolonged stress can enhance the body’s metabolic needs, leading to increased nutrient use and excretion. This can then result in nutrient deficiency, which is worsened further by stress. In this way, diet and stress can have detrimental consequences on human health.

The aim of this 2020 study was to analyze the eating habits of 378 undergraduate medical students (aged 19-26) and assess their relationship with sociodemographic, socioeconomic, and psychological factors. The students were in their second through to sixth academic year at King Abdulaziz University, Jeddah, Saudi Arabia when they were asked to complete self-administered questionnaires on sociodemographics, eating habits, and psychological aspects of their lives. Eating habit score was discovered to be much lower among students who were smokers, did not exercise regularly, lived alone, lived in rented accommodation, and whose parents had separated. Looking at the multivariate analysis results, many psychological factors such as living alone and stress, were linked with dietary patterns. Alzahrani et al. (2020) determined that socioeconomic and psychological circumstances significantly affected these medical students’ eating patterns, which were mostly poor and unhealthy.

Roohafza et al. (2013) studied the relationship between food intake and stress levels in an Iranian adult population, using the 9549 participants (aged 18+) of the third phase of Isfahan Healthy Heart Program (IHHP). The subjects were divided into two groups (high- and low- stress) according to their stress levels [assessed by General Health Questionnaire-12 (GHQ-12)]. Those individuals assigned to the low-stress group were significantly younger, had lower LDL cholesterol readings, were less likely to be current smokers, tended to do more physical activities and have higher education levels. The 49- item Food Frequency Questionnaire (FFQ) revealed greater consumptions of unsaturated oils, grains, fruits, vegetables, meat, and dairy products in the low-stress group, while they included less saturated oils in their diets and had lower Global Dietary Index (GDI) scores. After adjustments were made based on sex, age, smoking, and physical activity, stress level was reported to be significant positive associated with GDI (OR=1.24) and saturated oils (OR=1.17), whereas stress levels were inversely related to consumption of unsaturated oils (OR=0.84), fruits and vegetables (OR=0.83), meat (OR=0.88), and dairy products (OR=0.88). This significant positive relation between dietary intake and stress emphasized the need to consider psychological factors in dietary recommendations and also pay close attention to diet when managing highly stressed individuals. The causal relationship between stress and dietary factors should be investigated in the future in prospective longitudinal studies.

For the purpose of expanding our knowledge of the effect of whole food diets on stress, Soltani et al. (2018) conducted this randomized controlled trial documenting the impact of a diet based on the Dietary Guidelines for Americans (DGA) on psychological and physiological stress. Overweight and obese women were randomly assigned to either a diet based on the 2010 DGA or a diet based on a Typical American Diet (TAD) for 8 weeks while their stress load was monitored using the Perceived Stress Scale and allostatic load. The changes in perceived stress and allostatic load were not significantly different between the two diet intervention groups after the 8 weeks, although inverse associations were found between 8-week stress difference and intervention-based improvements in diet quality - indicated by lower sodium and higher vegetable consumption. When these negative associations were statistically accounted for, perceived stress and allostatic load did appear to be higher in the DGA group (p<0.04). These findings suggest that improving on vegetable and sodium components of the diet mediated the impact of the diet intervention on psychological and physiological stress load, providing more reason to consider optimizing vegetables and reducing sodium consumption when aiming to improve mental health.

This 2020 review evaluated the literature on the associations between diet, stress, obesity and psychiatric disorders related to stress since the nature of these relationships is not well understood. Bremner et al. (2020) learnt that diet and obesity can have direct impacts on mood, with certain aspects of diet stimulating inflammation in the process which has led to research on polyunsaturated fatty acids (PUFAs) as treatments for depression. While stress-related mental disorders may induce dietary changes likely to affect weight, stress or predisposition alone may lead to obesity and stress-related mental disorders such as depression and posttraumatic stress disorder (PTSD). There are likely to be bidirectional relationships between these various factors. This review also addresses the increasingly reported connection between the gut and the brain, which relates the gut microbiome with brain function and thus mood and behavior. Since this identifies another way diet can influence mental health and disorders, this relationship is probably mediated by the same areas of the brain and peptides that are involved in both mood and appetite. Elucidating the relationship between diet, stress and mood and behavior could provide crucial implications for the treatment of both stress-related mental disorders and obesity.

This 2020 paper systematically reviewed and conducted meta-analysis on literature to uncover the relationship between psychological stress and diet quality among women of reproductive age (18-49 years old). The 24 studies included in this review were conducted in various countries, and consisted of studies on diet quality (8) and on food intake and consumption frequency (16). The 6 cross-sectional and 2 longitudinal designed studies on diet quality yielded data on 3982 participants, and used various indices to measure diet quality, including Alternate Healthy Eating Index (n = 2), Healthy Eating Index (n = 2), Dietary Approach to Stop Hypertension (DASH) Diet Index (n = 2), Dietary Quality Index- Pregnancy (n = 2), and Dietary Guideline Adherence Index (n = 1). The majority of the studies used Cohen's perceived stress scale and no study measured biological stress response. Sensitivity analysis left only 5 studies (3471 participants) to be included in the meta-analysis, which revealed a significant negative association between stress and diet quality, albeit considerable heterogeneity between studies also. This paper found that stress was significantly related with unhealthy dietary patterns (high in fat, sweets, salt, and fast food and low in fruits, vegetables, fish, and unsaturated fats). Future studies investigating dietary patterns or quality are advised to include indices and factor analysis, as well as measure biological markers of stress and dietary patterns simultaneously.

This 2019 review presents findings from human studies to explain the bidirectional relationships between stress, diet, and the gut bacteria, and their effect on immune function and health. Stress and depression can modulate the composition of gut microbiota, which can lead to changes in eating behaviors e.g. promoting intake of highly palatable foods, and alter mood due to the release of metabolites, toxins and neurohormones. It has been proposed that probiotics supplementation may attenuate the increased stress responsiveness and heightened depression risk induced by the gut bacteria.

Herhaus et al. (2020) decided to examine both cortisol reactivity and stress-induced eating in a sample with obesity because cortisol reactivity under stress can be used to predict stress-induced eating behaviors that influence body mass index (BMI),. The aim of the study was to analyze the impact of high and low cortisol reactivity on the participants’ food intake levels. Through the use of the Trier Social Stress Test (TSST), the 36 obese adults and the 36 healthy weight controls (matched for age and gender) were divided into two sub-groups: high cortisol reactors (HCR) and low cortisol reactors (LCR). The group of obese high cortisol reactors significantly greater amounts than the low cortisol reactors. This same subgroup was found to demonstrate less emotional coping strategy of cognitive reappraisal (the subjective interpretation to stimuli in the environment). In the healthy weight controls, however, there were no marked differences between high and low cortisol reactors. In conclusion, stress-related eating in people with obesity is predicted by the degree of their cortisol reactivity to stress. But the same did not apply for healthy weight individuals. It was also suggested that not practicing cognitive reappraisal in emotion regulation may be a sign of susceptibility to stress-induced eating among obese high cortisol reactors.

Pasquali (2012) writes that obesity is believed to develop as a result of people’s inability to adapt to chronic environmental stress exposure that is mediated by a dysregulation of related neuroendocrine axes. One axis that plays a major role in this context is the hypothalamic-pituitary-adrenal axis. But the author reports that a person’s sex also affects their ability to adapt to chronic stress. This is highlighted as stress-related chronic diseases develop following certain pathophysiological events. The regulatory impacts of sex hormones are thought to play a role in this development. The stress experienced may alter feeding as well, with variation according to sex again. Carrying out experimental studies on humans and animals can increase the understanding of the specific phenotypes of obesity that are connected to the chronic exposure to stress. Doing so can potentially sprout novel ideas and treatments for obesity.

Although the hippocampus becomes damaged by exposure to severe and prolonged stress, Rahman et al. (2016) comment that research is lacking on how the hippocampal structure changes after repeatedly experiencing stress, and what sort of behaviors are affected by these alterations. Analyses of behaviors appeared to show that spatial memory becomes impaired over the 10 days of stress. But the consequences are not fully apparent until the stress is removed. Among these same animals, the stressed displayed significantly lower hippocampal volumes as early as the third day, compared with those unstressed. The largest early reductions in hippocampal volumes were seen in the animals behaving the worst at the end of chronic stress. These results link smaller hippocampal volume with stress-induced memory impairments. In addition, hippocampal volumes may be used to identify those at early risk of developing cognitive dysfunction observed in stress-related psychiatric disorders.

This 2015 article summarizes what was said in the "Stress, Palatable Food and Reward" conference, a symposium in which four presentations were given by neuroscientists who mainly work with complex relationships among stress, food intake and emotion. Firstly, Dr Ulrich-Lai showcased her work on discovering the mechanisms by which the rewarding properties of sweet palatable foods help relieve stress. Dr Fulton also presented her rodent model study demonstrating the stimulating effects of long-term dietary lipid consumption, including its withdrawal, on stress-related outcomes. Dr Wilson then talked about his group’s research on how social hierarchy-related stress affects food intake and diet choice in female macaques, while the last speaker Dr Petrovich discussed her research program focused on defining the circuitry (shared between the cerebral cortex, amygdala, and hypothalamus) responsible for diminishing the urge to eat during emotional threat in rats. The complexity of the physiological and behavioral factors connecting stress, food intake and emotional state were apparent.

Pannicke et al. (2021) discuss the negative effects of wealthier food environments, which appear to encourage the consumption of energy-dense and low-nutrient foods and make it tough for people to maintain a healthy diet and weight. The diet-related targets set by individuals also may be affected by stress, affects, and intense food cravings. This study explored the interlinks between these variables by recording participants’ momentary states and retrospective eating episodes four times a day for 14 days. The 84 subjects (aged between 18 and 38) were mostly recruited from universities. Goal-congruent eating was not specifically predicted by any of the momentary measures of stress (experience of stress or stress coping), momentary affects or craving. But temporal effects showed that participants with higher anticipated stress coping ate a diet more consistent with their goals. It seemed that the more confident individuals were in coping with their upcoming obstacles, the more likely they were to follow their ideal diet plan. So, while most eating behavior interventions look mostly at hunger, craving, negative and positive affect, stress coping is often overlooked although it represents a novel target intervention with plenty of potential.

While physical activity and healthy eating appear to offer protection against stress and negative affect, Schultchen et al. (2019) point out a few studies that have demonstrated a reduction in these behaviors in the face of stress and negative affect. This present study therefore inspected the relationship between these behaviors in daily life using ecological momentary assessment (EMA). For 7 days, 51 university students responded to six daily prompts on items such as stress, emotional experience, physical activity duration, and healthy eating. The results indicated that higher stress, negative affect, and lower positive affect were all linked with lower subsequent physical activity. Inversely, higher physical activity levels were associated with less subsequent stress and negative affect, and more positive affect. There was no such interlink between stress and affect with healthy eating. This study concludes that carrying out physical activity was correlated to improved mood and less stress/negative affect over the next few hours.

The objective of this 2021 study was to investigate the relationship between fruit and vegetable intake and perceived stress in adults aged ≥25 years using the participants of the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. The secondary aim was to find associations between carotenoid levels in the blood, biomarkers of fruit and vegetable intake, and perceived stress. The food frequency questionnaires used to assess dietary intake were administered in 1999-2000 to 8689 individuals. It was found that subjects with the highest intake levels of fruits and vegetables had 10% lower Perceived Stress Questionnaire index values than individuals who ate the least number of fruits and vegetables. Similar interactions were observed when analyzing fruits and vegetables separately. Moreover, subgroup analyses revealed the link between higher fruit and vegetable consumption and lower perceived stress in middle-aged adults (45 to 65 years), which was not replicated in the younger (<45 years) and older participant subgroups (≥65 years). Higher fruit and vegetable intake was also significantly correlated with lower perceived stress in men and women (studied separately). Radavelli-Bagatini et al. also identified an inverse interaction between carotenoid concentration in the blood and perceived stress before (although this did not hold after adjustments were made to the analysis model). To summarize, increased consumption of fruits and vegetables was related to lower perceived stress in Australian adults, particularly in the middle-aged subgroup.

Begdache & Patrissy (2021) discuss how the relationship between the modifiable risk factors of mental distress (diet, dietary practices, and exercise) may be so intricate that individual factors also influence mental health differently when combined with a pattern. In addition, gender and maturity level contribute towards a person’s psychological health. This study therefore split the participants by age and gender and analyzed the combined and individual relationships between food groups, dietary practices and exercise to better understand their links with mental distress. Adults of 30 years and over were asked to complete the food-mood questionnaire that was distributed around several social media platforms. The results suggested that mental health was more strongly associated with dietary factors in women than in men. Furthermore, mental distress and exercise frequency were related to various lifestyle and dietary patterns, supporting the concept that modifying lifestyle and dietary factors can enhance mental wellbeing.

This 2019 review describes the interaction between stress and dietary patterns at a molecular level and connects these factors to brain health and mental fitness. According to Morera et al., people in general prefer to eat high caloric and hyperpalatable foods under chronic stress conditions. The consequences of this interplay between psychosocial stress and dietary patterns can be detrimental. For example, it can influence the hippocampus of the brain to produce a greater neuroinflammatory response, resulting in memory deficits. The composition of the microbes living in the human gut can also be modified by stressful environments, which can ultimately influence behavior and brain health. Furthermore, these biological processes can predispose an individual to develop diseases such as diabetes, obesity, cardiovascular disease, and metabolic syndrome. The findings of this review could assist the development of novel therapeutic targets for chronic diseases.