The generalized unsafety theory of stress (GUTS) states that the stress response is a default response and chronic stressors are caused by generalized unsafety, independent of stressors of their cognitive representation. There three prevalent conditions which are vulnerable to becoming compromised in terms of generalized unsafety and this has considerable health risks:

1. Compromised bodies
   This refers to conditions with reduced bodily capacity (e.g. obesity; older age).
2. Compromised social networks
   This refers to conditions where one is not part of a cohesive social network (e.g. loneliness).
3. Compromised contexts
   This refers to daily contexts which are neutral by themselves which then are seen as unsafe after association with stressors via context conditioning.

Chronic psychological stress responses are the crucial causal factor leading to disease. However, the precise causes of these responses are unclear. The reactivity hypothesis states that multiple intense responses during stressors are important. However, this theory (and other similar ones) neglects the duration of exposure that often outlasts the stressful events themselves.

Perseverative cognition refers to cognitive representation of stressors and this may be important in the perseverance of the stress response. Perseverative cognition causes prolonged physiological responses. Chronic responses, over time, lead to allostatic load (i.e. biological dysregulation).

It is possible that not the perseverative cognition but the generalized perception of unsafety is the crucial explanatory mechanism in the adverse effects of chronic stress.

The stress response is a default response of an organism and the organism automatically falls back on this response when no other information is available. Generalized perception of unsafety (GU) may cause the default response to remain activated because the brain fails to register situations of the modern society as safe. The generalized unsafety theory of stress states that not being able to inhibit the default stress response is not dependent on actual stressors or perseverative cognition. The generalized perception of unsafety is sufficient.

The stress response is mediated by subcortical areas in the brain (e.g. amygdala; limbic system). It is normally under continuous inhibition by the prefrontal cortex (i.e. ventromedial prefrontal cortex). The inhibition is decreased when safety is in doubt and the amygdala activity is enhanced.  The stress response is not triggered but disinhibited. Inhibition of this response may be more cost-efficient than activation of the same response.

The default mode network refers to a network of brain areas which are activated when the brain perceives safety and is not involved in any particular task. This is not the same as the default response, which occurs when there is no information regarding safety available. This means that the default stress response is typically inhibited during the default mode network.

The brain will assess the surroundings to evaluate whether it is safe. However, if the safety of the surroundings cannot be guaranteed, then the stress response remains disinhibited. Safety signals are learned cues that predict the stress free periods. The stress reducing effect of predictability refers to the inhibition of the default response when stressors could be predicted. It is recognizing a safe period between stressful stimuli.

There are individual and state-dependent influences on not recognizing safety that appears to be strongly associated with the activity level of the autonomic nervous system, especially the nervus vagus (i.e. vagus activity). High vagal activity is reflected in high heart rate variability. Low heart rate variability seems to be sufficient for not recognizing safety.

Heartrate variability is associated with vagus nerve activity. The vagus nerve is important in the regulation of several physiological systems (e.g. cardiovascular system; inflammation). Low heartrate variability is associated with inflammation. A low heartrate variability, which indicates vagal withdrawal is linked to prefrontal cortex inhibition of subcortical areas. Low resting heartrate variability is an index of the chronically disinhibited default stress response.

During development, children learn to predict safety signals. During maturation, young humans acquire an increasingly complex fear learning capacity. The direction of learning is from generalized anxiety to specific fear (i.e. humans start with the default stress response but gradually learn to predict threats). It is important that organisms experience stressors and develop some experience with the control of stressors. An organism that never experiences a stressor also never learns to control it and never learns to experience safety.

There is enhanced stress vulnerability in later life as a result of chronic early life stress. There are three major domains that are vulnerable to the development and maintenance of perceived unsafety (GU). The body (1), the social network (2) and the context (3). The context (i.e. modern society) is safe compared to ancestral context. The domains are compromised when they fail to contribute to perceptions of safety. When these domains are compromised, they carry highly prevalent major risk factors for somatic disease. This occurs in all three domains:

1. Compromised bodies
   The state of the body (e.g. obese) could lead to a person not recognizing sufficient safety to inhibit the default stress response. This is also the result of our fitness as this is the physical capability to cope with stressors. Unfit bodies are unable to recognize safety signals with respect to the physical ability to deal with stressors.
2. Compromised social networks
   A lack of a personal social network (e.g. loneliness) could lead to people being unable to recognize social safety signals. The stress response which is the result of loneliness may mediate the effect of loneliness on health.
3. Compromised contexts
   Perceptions of unsafety and a low heartrate variability may occur in situations or environments that are neutral by themselves but have acquired threat value by their association with a stressor through context conditioning.

Stress-related cognition is not necessary for a continued default stress response.