Adverse Childhood Experiences (ACEs) and Adult Inflammation: Anti-Inflammatory & other Effects of Exercise

Original Editor - Andrea Sturm

Top Contributors - Tarina van der Stockt, Simisola Ajeyalemi, Lucinda hampton, Jess Bell and Kim Jackson  

Adverse Childhood Experience

Childhood trauma, including abuse and neglect, is probably the single most important public health challenge in the United States, a challenge that has the potential to be largely resolved by appropriate prevention and intervention. Each year, more than 3 million children are reported to authorities for abuse or neglect in the US; about 1 million of those cases are substantiated. Many thousands more undergo traumatic medical and surgical procedures and are victims of accidents and of community violence. However, most trauma begins at home; the vast majority of people (about 80%) responsible for child maltreatment are children's own parents.

Inquiry into developmental milestones and family medical history is routine in medical and psychiatric examinations. In contrast, social taboos prevent obtaining information about childhood trauma, abuse, neglect, and other exposures to violence. Research has shown that traumatic childhood experiences not only are extremely common but also have a profound impact on many different areas of functioning. For example, children exposed to alcoholic parents or domestic violence rarely have secure childhoods; their symptomatology tends to be pervasive and multifaceted and is likely to include depression, various medical illnesses, and a variety of impulsive and self-destructive behaviors. Approaching each of these problems piecemeal, rather than as expressions of a vast system of internal disorganization, runs the risk of losing sight of the forest in favor of one tree.

In the Adverse Childhood Experiences (ACE) study by Kaiser Permanente and the Centers for Disease Control and Prevention, 17,337 adult health maintenance organization (HMO) members responded to a questionnaire about adverse childhood experiences, including childhood abuse, neglect, and family dysfunction. Eleven percent reported having been emotionally abused as a child, 30.1% reported physical abuse, and 19.9% sexual abuse. In addition, 23.5% reported being exposed to family alcohol abuse, 18.8% were exposed to mental illness, 12.5% witnessed their mothers being battered, and 4.9% reported family drug abuse.

The ACE study showed that adverse childhood experiences are vastly more common than recognized or acknowledged and that they have a powerful relationship to adult health a half-century later. The study confirmed earlier investigations that found a highly significant relationship between adverse childhood experiences and depression, suicide attempts, alcoholism, drug abuse, sexual promiscuity, domestic violence, cigarette smoking, obesity, physical inactivity, and sexually transmitted diseases. In addition, the more adverse childhood experiences reported, the more likely a person was to develop heart disease, cancer, stroke, diabetes, skeletal fractures, and liver disease.

Childhood trauma and Adulthood Inflammation

A meta-analysis finds a significant association between childhood trauma and the inflammatory markers, with effect sizes being greatest for tumour necrosis factor-α (TNF-α) (z=0.20, 95% CI=0.10–0.29), followed by interleukin-6 (IL-6) (z=0.09, 95% CI=0.04–0.15) and then C-reactive protein (CRP) (z=0.08, 95% CI=0.04–0.11). As such, this provides strong evidence that childhood traumatic events significantly impact on the inflammatory immune system, with trajectories reaching into adulthood, thus offering a potential molecular pathway by which early trauma confers vulnerability to developing psychiatric and physical disorders later in life.

The molecular mechanisms that account for these long-term changes in immune function need to be further explored. Putatively, changes in epigenetic regulation of gene expression may be responsible for this increased immune activation; this appears plausible in view of the considerable evidence that childhood trauma induces modifications of hypothalamic-pituitary-adrenal- (HPA) and neuroplasticity-related methylation patterns. In particular, early trauma leads to greater methylation of the glucocorticoid receptor (GR) and greater demethylation of FKBP5. The increased methylation of the GR correlates with reduced GR function as shown by impaired negative feedback of the HPA axis, while FKBP5 is a heat-shock protein that binds and thereby inhibits the cytosolic GR. As the GR itself is a crucial regulator of inflammatory activity, lower expression and function of the GR due to epigenetic suppression may allow for this exacerbated inflammatory activity.

Notably, increased inflammation itself can then maintain and exacerbate the impaired GR function, thus leading to sustained GR resistance into adulthood. Notably, based on differences in effects sizes found in the present analysis, the association between childhood trauma and adulthood inflammation is stronger for inflammatory pathways related to TNF-α and, indeed, the GR is crucial in regulating TNF-α signalling and TNF-induced cytokine production, as well as conveying protection against TNF-related tissue damage.

The paper also found evidence that individual types of trauma exposure impact differentially on the inflammatory markers: most interestingly, physical and sexual abuse is associated with significant increased TNF-α and IL-6, but not CRP. Conversely, CRP seemed to be primarily related to parental absence during early development. Interestingly, rodent models have demonstrated that maternal separation is associated with elevated TNF-α levels in the periphery and cerebrospinal fluid as well as in prefrontal and hippocampal brain regions. These results stress the need for assessing the potential different effects of each type of trauma in future research. Moreover, this finding raises the question as to why different types of childhood trauma are associated with different aspects of inflammatory dysregulation.

While there is currently no clear answer to this question, several variables associated with individual trauma types, including chronicity and context of the stressor, age of exposure, duration of exposure or relationship to the perpetrator, may offer some insight. For example, it has been shown in adolescent women that episodic stress in the context of high chronic stress leads to reduced GR expression, while GR expression is increased in the absence of chronic stress. Moreover, there is evidence that different types of trauma impact differentially on mental health: specific subtypes of anxiety disorders appear to develop depending on whether one is exposed to physical or sexual childhood abuse, and childhood sexual abuse is particularly associated with the development of auditory verbal hallucinations in psychosis. The effect of early trauma on behaviour in adulthood may be further modulated by other developmental insults.

The Anti-Inflammatory Actions of Exercise Training

The list of diseases with a known inflammatory etiology is growing. Cardiovascular disease, osteoporosis, diabetes, geriatric cachexia, and Alzheimer’s disease have all been shown to be linked to or exacerbated by aberrantly regulated inflammatory processes. Nevertheless, there is mounting evidence that those who are physically active, or who become physically active, have a reduction in biomarkers associated with chronic inflammation. There was strong early consensus that exercise-induced reductions in inflammation were explained by body mass index or body fatness, but recent studies provide support for the contention that exercise has body fat–independent anti-inflammatory effects. With few exceptions, the anti-inflammatory effects of exercise appear to occur regardless of age or the presence of chronic diseases. 

Cardiovascular disease, diabetes, osteoporosis, and several other chronic diseases are now known to be strongly linked to inflammatory processes. Chronic diseases linked to inflammation are known to occur in greater frequency in older and sedentary individuals, but evidence is emerging that exercise has anti-inflammatory effects. For example, there is a substantial reduction in biomarkers of low-grade systemic inflammation in physically active adults or adults who undertake exercise training.

Chronic low-grade inflammation, “persistent but more subtle than the acute phase response,” is frequently assessed by measurement of circulating C-reactive protein (CRP) and, somewhat less frequently, serum amyloid A. C-reactive protein concentration is higher in those with high body mass index, metabolic syndrome and/or diabetes, below-normal high-density lipoprotein cholesterol, chronic infection, and in cigarette smokers. Therefore, the inflammation/ damage is diffuse in low-grade inflammation and is apparently associated with several organs and tissues such as endothelial cells and adipocytes. There is evidence that CRP may contribute to damage during myocardial infarct and contribute directly to atherogenesis.

Tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are most commonly measured and are known to stimulate CRP release from the liver. TNF-α and IL-6 are also frequently linked to increased incidence of disease, physical frailty or muscle wasting, and early death. The anti-inflammatory cytokine IL-10 and the adipocytokine adiponectin are also being measured with increased frequency. Adiponectin appears to be released in inverse proportion to fat mass and has anti-inflammatory effects such as negating the influence of TNF-α on endothelial cell adhesion, decreasing NF B activation, and slowing macrophage foam-cell development. 

The mechanisms for the apparent systemic and tissue-specific anti-inflammatory effects of exercise training or increased physical activity have not been fully elucidated. There are several intriguing possibilities, such as exercise-induced release of heat shock proteins, shifts in immune cell phenotype, training-induced reductions in visceral adipose tissue, or reduced tissue hypoxia. The potential anti-inflammatory influences of exercise training may provide a low-cost, readily available, and effective treatment for low-grade systemic inflammation and could contribute significantly to the positive effects of exercise training on chronic disease.

Exercise for Mental Health

In this era of exponential growth of the “metabolic syndrome” and obesity, lifestyle modifications could be a cost-effective way to improve health and quality of life. Lifestyle modifications can assume especially great importance in individuals with serious mental illness. Many of these individuals are at a high risk of chronic diseases associated with sedentary behavior and medication side effects, including diabetes, hyperlipidemia, and cardiovascular disease. An essential component of lifestyle modification is exercise. The importance of exercise is not adequately understood or appreciated by patients and mental health professionals alike. Evidence has suggested that exercise may be an often-neglected intervention in mental health care.

Aerobic exercises, including jogging, swimming, cycling, walking, gardening, and dancing, have been proved to reduce anxiety and depression. These improvements in mood are proposed to be caused by exercise-induced increase in blood circulation to the brain and by an influence on the hypothalamic-pituitary-adrenal (HPA) axis and, thus, on the physiologic reactivity to stress. This physiologic influence is probably mediated by the communication of the HPA axis with several regions of the brain, including the limbic system, which controls motivation and mood; the amygdala, which generates fear in response to stress; and the hippocampus, which plays an important part in memory formation as well as in mood and motivation.

Other hypotheses that have been proposed to explain the beneficial effects of physical activity on mental health include distraction, self-efficacy, and social interaction. While structured group programs can be effective for individuals with serious mental illness, lifestyle changes that focus on the accumulation and increase of moderate-intensity activity throughout the day may be the most appropriate for most patients. Interestingly, adherence to physical activity interventions in psychiatric patients appears to be comparable to that in the general population.

Exercise improves mental health by reducing anxiety, depression, and negative mood and by improving self-esteem and cognitive function. Exercise has also been found to alleviate symptoms such as low self-esteem and social withdrawal. Exercise is especially important in patients with schizophrenia since these patients are already vulnerable to obesity and also because of the additional risk of weight gain associated with antipsychotic treatment, especially with the atypical antipsychotics. Patients suffering from schizophrenia who participated in a 3-month physical conditioning program showed improvements in weight control and reported increased fitness levels, exercise tolerance, reduced blood pressure levels, increased perceived energy levels, and increased upper body and hand grip strength levels.

Thirty minutes of exercise of moderate intensity, such as brisk walking for 3 days a week, is sufficient for these health benefits. Moreover, these 30 minutes need not to be continuous; three 10-minute walks are believed to be as equally useful as one 30-minute walk. Health benefits from regular exercise that should be emphasized and reinforced by every mental health professional to their patients include the following:

• Improved sleep
• Increased interest in sex
• Better endurance
• Stress relief
• Improvement in mood
• Increased energy and stamina
• Reduced tiredness that can increase mental alertness
• Weight reduction
• Reduced cholesterol and improved cardiovascular fitness

Mental health service providers can thus provide effective, evidence-based physical activity interventions for individuals suffering from serious mental illness.

Useful Links

The brain changing effects of Exercise by Wendy Suzuki