Adverse Childhood Experiences (ACEs) and Adult Inflammation: Anti-Inflammatory & other Effects of Exercise
Original Editor - Andrea Sturm
Adverse Childhood Experience (ACE)
Childhood trauma includes abuse and neglect, mostly this happens in the child's home with around 80% of maltreatment is by a child's own parents. This is a major public health challenge in the United States and with appropriate intervention and prevention, this challenge can potentially be resolved. Childhood trauma also includes when children are victims in accidents, community violence, or traumatic medical and surgical procedures. It also includes neglect on a physical, emotional, and on an educational level. 
Complex trauma is "the experience of multiple, chronic and prolonged, developmentally adverse traumatic events, most often of an interpersonal nature (eg, sexual or physical abuse, war, community violence) and early-life onset.)" 
Any traumatic childhood experience has a significant impact on a child's life growing up and extends into adulthood. An example of this is the insecurity of children that experience domestic violence or if they have parents that are alcoholics, these children could display multifaced symptoms like depression, various medical conditions/illnesses, and self-destructive of impulsive behaviors. The risk these children face is that each of these problems is approached one by one instead of finding the root cause. A reason for this is that due to social taboos, medical and psychiatric examinations don't usually include information about childhood trauma like violence, abuse and neglect. 
Kaiser Permanente and the Centers for Disease Control and Prevention did an ACE study where 17,337 adults responded to a questionnaire. The questionnaire included questions about adverse childhood experiences that included abuse, neglect, and family dysfunction. 11% of adults reported that they were emotionally abused as a child, 30.1% were physically abused, and 19.9% were sexually abused. Participants also reported that they were exposed to or witnessed the following as children, 23.5% family alcohol abuse, 18.8% mental illness, 12.5% domestic abuse (being done to the mother), and 4.9% family drug abuse. This shows that adverse childhood experiences are very common and that it can even affect adult health 50 years later.  The authors of this study 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 by Baumeister et al. (2016) was done on published articles to investigate whether adversity in early life contributes to "potentially pathogenic pro-inflammatory phenotypes in adult individuals". The authors found a significant association between childhood trauma and inflammatory markers, with the greatest effect sizes being for tumour necrosis factor-α (TNF-α), then interleukin-6 (IL-6), followed by C-reactive protein (CRP). This proves that traumatic childhood experiences have a significant impact on the inflammatory immune system and follows the child into adulthood. The authors describe it as a "molecular pathway by which early trauma confers vulnerability to developing psychiatric and physical disorders later in life".
Further studies are needed to explore the molecular mechanisms involved. The increase in immune activation might be explained by changes in epigenetic regulation of gene expression. There are also evidence that childhood trauma induces the following:
- modifications of hypothalamic-pituitary-adrenal- (HPA) and neuroplasticity-related methylation patterns
- greater demethylation of FKBP5 - it is a heat-shock protein that binds and then inhibits the cytosolic GR
- greater methylation of the glucocorticoid receptor (GR) - GR is a crucial regulator of inflammatory activity and its function is reduced leading to an exacerbated inflammatory activity
- the inflammation then maintains and increases the impaired GR function, leading to GR resistance into adulthood. 
Specific inflammatory profiles are also linked to specific types of trauma:
- physical and sexual abuse leads to increased TNF-α and IL-6 (CRP is not increased)
- absence of parent during early developmental years is related to CRP
Mental health condition can be linked to different types of trauma:
- physical or sexual childhood abuse can lead to specific subtypes of anxiety disorders to develop
- childhood sexual abuse can lead to the development of auditory verbal hallucinations in psychosis
The Anti-Inflammatory Actions of Exercise Training
More and more diseases are recognised as having an inflammatory origin. The following conditions have been linked to or shown to be exacerbated by poorly regulated inflammatory processes: cardiovascular disease, diabetes, osteoporosis, Alzheimer's disease and geriatric cachexia (a syndrome with symptoms of weight loss, reduction in muscle mass, and decreased physical activity). These chronic diseases are mostly linked to older or more sedentary people.
Physical activity decreases inflammation through different mechanisms including the change in cytokine release, the down-regulation of toll-like receptors (they play an important role in immunity), decreasing adipose tissue in the viscera and the increase of vagal tone".
There is also an increase in research that shows the biomarkers linked with chronic inflammation are reduced in people who are, or become physically active. Previously, it was believed that this decrease in inflammation was because of weight loss or change in a person's body mass index (BMI), but recently more studies are showing that exercise has "body fat–independent anti-inflammatory effects" and this effect mostly happen regardless of age or when chronic disease is present. Adults who are physically active or participate in exercises have a significant decrease in low-grade systemic inflammatory markers. 
Chronic low-grade inflammation is described as a chronic inflammation that is more subtle than in the acute phase. Chronic low-grade inflammation is most often tested by measuring the circulating C-reactive protein (CRP). CRP is higher in individuals with a high BMI, if they smoke cigarettes, or if they have they have some or all of the following: metabolic syndrome and/or diabetes, lower than normal high-density lipoprotein cholesterol or chronic infection. Low-grade inflammation leads to damage or inflammation in the body that is more diffuse "is apparently associated with several organs and tissues such as endothelial cells and adipocytes". CRP has also been linked atherogenesis and some evidence exists that it contributes to the damage when a person has a myocardial infarct. 
Tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) stimulate CRP release from the liver and they both are often linked to an "increased incidence of disease, physical frailty or muscle wasting, and early death". TNF-α and IL-6 are frequently measured as well as IL-10 (anti-inflammatory cytokine) and the adipocytokine adiponectin. Adiponectin is inversely released to fat mass and it has an anti-inflammatory action whereby it negates the influence of TNF-α.
From research, it seems like exercise might induce the release of "heat shock proteins, shifts in immune cell phenotype, training-induced reductions in visceral adipose tissue, or reduced tissue hypoxia". Exercise is seen as a cost-effective, easily available and effective management strategy for low-grade systemic inflammation and positively influences chronic disease. 
Also, it has been noted that exercise changes the composition of the gut microbiome, which then, in turn, affects inflammation and that exercise/physical activity is a "natural strong anti-inflammatory strategy to improve brain function". The vagus nerve connects the brain to the abdomen and regulates metabolic homeostasis and physical activity increases vagal tone which changes the inflammatory reflex which in turn decreases systemic inflammation.  Individuals with higher levels of inflammation usually have more stress, depression and anxiety, and thus when thus exercise will decrease inflammation and improve mental health by improving the "gut-brain axis".
It must be noted that very high intensity exercise can have a negative effect when the anti-inflammatory state may increase the risk for upper respiratory tract infections by decreasing the effectiveness of the immune system. 
Exercise for Mental Health
Lifestyle modification especially exercise is seen as a cost-effective management strategy for improved health and quality of life and is an important factor in for people with serious mental disease.  Exercise is easily forgotten in the treatment of these individuals and poorly understood by patients and health-care practitioners. Individuals with serious mental disease have a greater risk to develop chronic conditions (like diabetes, hyperlipidemia, CVD) due to a sedentary lifestyle and side effects from medication. 
Any type of aerobic exercise (jogging, swimming, gardening etc) decreases anxiety and depression due to an increase in blood flow to the brain and on the physiological reactivity to stress by influencing the hypothalamic-pituitary-adrenal (HPA) axis. It is also important to consider the psychological effects of exercise including distraction from negative thoughts, improvement in self-esteem through self-efficacy, and social interaction.   Structured group exercises can be effective but lifestyle changes to include moderate-intensity exercise or activity on a daily basis is more important.  Individuals with mental health disorders adhere to their exercise interventions the same as 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".
A 3-month study that focussed on a conditioning program for individuals with schizophrenia found that the participants improved in weight control, fitness levels, perceived energy levels, exercise tolerance, upper body strength and a reduction in blood pressure. 
Exercise guidelines for the above benefits: 30 minutes, 3x a week of moderate-intensity (like a brisk walk). The 30 minutes could be divided into 10-minute sessions and does not have to be continuous. 
Mental health service providers can provide effective, evidence-based physical activity interventions for individuals with serious mental illness.
In the article Exercise for Mental Health, the authors note health care providers should emphasize and reinforce the following health benefits from regular exercise: 
- 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
- Improved cardiovascular fitness
- Van der Kolk, B. A. Developmental Trauma Disorder: Toward a rational diagnosis for children with complex trauma histories. Psychiatric Annals. 2005; 35(5), 401-408.
- D Baumeister, R Akhtar, S Ciufolini, C M Pariante, V Mondelli, Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α, Mol Psychiatry. 2016 May; 21(5): 642–649.
- Flynn MG, McFarlin BK, Markofski MM. State of the art reviews: The anti-inflammatory actions of exercise training. American Journal of Lifestyle Medicine. 2007 May;1(3):220-35.
- Gingrich A, Volkert D, Kiesswetter E, Thomanek M, Bach S, Sieber CC, Zopf Y. Prevalence and overlap of sarcopenia, frailty, cachexia and malnutrition in older medical inpatients. BMC geriatrics. 2019 Dec;19(1):120.
- Mikkelsen K, Stojanovska L, Polenakovic M, Bosevski M, Apostolopoulos V. Exercise and mental health. Maturitas. 2017 Dec 1;106:48-56.
- Mee-inta O, Zhao ZW, Kuo YM. Physical exercise inhibits inflammation and microglial activation. Cells. 2019 Jul;8(7):691.
- Sharma, A., Madaan, V., & Petty, F. D. Exercise for mental health. Primary care companion to the Journal of clinical psychiatry. 2006; 8(2), 106.