Allostasis

Biological concept

Allostasis (/ˌɑːloʊˈsteɪsɪs/) is a physiological mechanism of regulation in which the human body anticipates and adjusts its energy use according to environmental demands. First proposed by Peter Sterling and Joseph Eyer in 1988, the concept of allostasis shifts the focus away from the body maintaining a rigid internal set point, as in homeostasis, to the brain's ability and role to interpret environmental stress and coordinate changes in the body using neurotransmitters, hormones, and other signaling mechanisms. Allostasis is believed to be not only involved in the body's stress response and adaptation to chronic stress; it may also have a role in the regulation of the immune system as well as in the development of chronic diseases such as hypertension and diabetes.

The concept of organisms' ability to stabilize internal bodily mechanisms independently of environmental variations was first popularized by French physiologist Claude Bernard in 1849, coined the constancy of the milieu intérieur (internal environment). He sought to replace the ancient Greek notion of vitalism that proposed the governing of the body through non physical means with a physiological understanding of the mechanisms of the body through feedback and regulation. Harvard physiologist Walter Cannon took Bernard's theory of the milieu intérieur and expanded it to incorporate an evolutionary framework of energy efficiency and preservation. Cannon coined this concept homeostasis in 1926, demonstrating that the organism's body is a self governing system of regulation with certain steady state conditions for optimal functioning. By the late 20th century, neurobiologist Peter Sterling and epidemiologist Joseph Eyer noticed generational patterns of chronic stress and its effects on various human physiological mechanisms that could not be easily explained by homeostasis. They developed the concept of 'allostasis' [from the Greek ἄλλος (állos, "other," "different") + στάσις (stasis, "standing still") to mean "remaining stable by being variable"] to incorporate the body's ability to adjust steady state conditions based on the perception and interpretation of environmental stressors.

In the 1970s, Sterling and Eyer were studying the 20th century morbidity and mortality rates of age specific cohorts in the United States and noticed a correlation between mortality rates of age specific cohorts and the saturation of the labor market at the time the age specific cohorts were entering the labor force. They discovered that the cohorts who entered the labor market during the Great Depression and the resulting economic boom in the 1940s had a lower increased mortality rate due to less job competition and insecurity compared to the cohorts prior to the 1930s and since the 1950s. They also noted a correlation of major stressful events, such as bereavement, divorce, unemployment, and migration, to a higher mortality rate. Despite a preconceived notion that a reduced mortality rate in a younger cohort would experience more chronic diseases later in age, Sterling and Eyer found contradictory evidence that younger cohorts with higher mortality rates actually experienced more chronic health problems such as cardiovascular disease later in life, following the trend of consistently increased morbidity and mortality rates throughout their generation. To explain these epidemiological phenomena, Sterling and Eyer suggested social and systemic stress in the setting of advancing capitalism and industrialization to be the main driver of increased morbidity and mortality rates in age specific cohorts. These studies became the foundation of conceptualizing allostasis a decade later. Sterling and Eyer proposed the concept of allostasis in 1988 to better explain the process of physiological changes in the individual level that are shaped by large scale epidemiological patterns. Animal studies have also shown non homeostatic patterns in times of arousal (or stress). The body elevates blood pressure during stress and returns to normal when the stressor is removed; yet, when the stress becomes chronic, the blood pressure may not return to normal and instead stay elevated.

Allostasis depends on the brain's ability to coordinate all of the organs' functions by innervating organ cells to perform a certain function as well as synthesizing and releasing signaling mechanisms, such as hormones and neurotransmitters. In response to stress, the brain directly innervates the thyroid and pancreas for energy regulation, sends signals to the cardiovascular system to increase cardiac output, stimulates the adrenal glands to release cortisol and aldosterone, and releases hormones from the pituitary gland such as ACTH to regulate urine output through the renin angiotensin aldosterone system. The brain is able to overcome negative feedback in these localized systems and continuously evaluate the body's internal set points. By doing so, the body can regulate its resources and energy storage efficiently. Another key component of allostasis is the brain's perception and subsequent adaptation to chronic stress. Sterling and Eyer theorized that the brain can anticipate stressors to prepare the body to respond adequately to environmental demands through classical conditioning. If the brain persistently interprets or even anticipates stress, then it may cause epigenetic changes to permanently adapt to a chronic state of arousal that results in physiological changes such as thickened blood vessels to support the increased cardiac output and down regulation of stress hormone receptors.

The brain normally coordinates an immune response against a foreign threat that involves the synthesis, differentiation, and migration of immune cells, release of cytokines and interleukins, elevating the internal temperature set point, and redirecting metabolic needs to support this effort. Allostatic (predictive) regulation allows the brain to prioritize needs, for example, by sending more oxygen and nutrients to organs that need it most. For this example, during peak exercise muscle requires an 18 fold increase in oxygenated blood, but the heart can increase its capacity only 3.5 fold. Therefore, the brain temporarily borrows blood from the digestive system and kidney rerouting it to muscle. It later repays the debt when muscle's increased need subsides. Without the ability to prioritize trade offs between organ systems, the heart and lungs would need to be far larger while much of this costly extra capacity would go unused. Every system evolves to operate over a particular range. For example, cone photoreceptors evolved to sense daylight over a 10,000 fold range of intensities, whereas rod photoreceptors evolved a different design to sense moonlight and starlight down to detection of single photons. To function optimally across their wide operating ranges, all systems adapt their sensitivities. A rod photoreceptor adapts to bright moonlight and requires minutes to increase its sensitivity to starlight. From a metaphorical perspective this can be interpreted as a machine running continuously as the machine is overworked; it becomes less efficient over time because more stress is placed on it. Similarly, the process of allostasis becomes less efficient at managing the body's resources when the body endures increased levels of unhealthy stress due to wear and tear on the body and the brain. An increase in allostatic load can impair and reduce neuroplasticity as stress causes the brain to age quicker. This is because with more stress, more synaptic connections are lost in the prefrontal cortex which is responsible for body regulation.

McEwen and endocrinologist John C. Wingfield proposed two types of allostatic overload which result in different responses:

Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in activation of the emergency life history stage. This serves to direct the animal away from normal life history stages into a survival mode that decreases allostatic load and regains positive energy balance. The normal life cycle can be resumed when the perturbation passes. Type 2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction. The latter is the case in human society and certain situations affecting animals in captivity. In all cases, secretion of glucocorticoids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters, and inflammatory cytokines wax and wane with allostatic load. If allostatic load is chronically high, then pathologies develop. Type 2 allostatic overload does not trigger an escape response, and can only be counteracted through learning and changes in the social structure. Whereas both types of allostasis are associated with increased release of cortisol and catecholamines, they differentially affect thyroid homeostasis: Concentrations of the thyroid hormone triiodothyronine are decreased in type 1 allostasis, but elevated in type 2 allostasis. This may result from type 2 allostatic load increasing the set point of pituitary thyroid feedback control.

Sung Lee introduced the paradigm of allostatic orchestration (PAO), extending the principle of allostasis by stating, “The PAO originates from an evolutionary perspective and recognizes that biological set points change in anticipation of changing environments.” emphasizing that an integrated view of health includes environmental context. Allostasis encourages increased attention to new solutions at the level of society, as well as the individual and immediate community. A brain was needed instead because its large size is much more capable of efficient management. However, in rare cases animal species do not rely on brains nor a similar allostatic process. The sea squirt is one example because once the larvae have fully grown they “absorb their brain.” The sea squirt's allostatic process would not be as complex as a human's for example since both species have ecological niches that are of different complexities (i. e. ”All animals have brains that are adapted to their environmental niches and life cycles”).

Allostasis proposes a broader hypothesis than homeostasis: The key goal of physiological regulation is not rigid constancy; rather, it is flexible variation that anticipates the organism's needs and promptly meets them. Rather than simply responding to the environment, allostasis utilizes predictive regulation, which has a more complex goal in evolution of adaptation by changing based on what it anticipates, rather than by staying the same or "in balance" in response to environmental changes, as homeostasis suggests. This places homeostasis as a function within allostasis; however, some argue it is a larger paradigm altogether. Allostasis redefines health and disease beyond the stable measures from lab tests or blood pressure, for example; and expands it to define health as the flexibility of these values. Blood pressure is one of Sterling's prime examples of a health measure that is best when it can fluctuate in anticipation of the brain body's expected demands, so it can match this demand. The alternative, or a less healthy state on the health disease continuum, would be for blood pressure to remain the same, or "stable," and not meet the new demand. Wingfield states:The concept of allostasis, maintaining stability through change, is a fundamental process through which organisms actively adjust to both predictable and unpredictable events Allostatic load refers to the cumulative cost to the body of allostasis, with allostatic overload being a state in which serious pathophysiology can occur Using the balance between energy input and expenditure as the basis for applying the concept of allostasis, two types of allostatic overload have been proposed. Sterling (2004) proposed several interrelated points that constitute the allostasis model:

Organisms are designed to be efficient. Efficiency requires a brain to predict what will be needed and avoid costly errors. The brain further enhances efficiency by prioritizing needs and enforcing trade offs. All systems, including the brain, organ systems, and single cells are designed for a particular operating range. (Example, cone photoreceptors adapt for daylight, and rod photoreceptors adapt for moonlight and starlight). A system's parameters vary according to predicted demand and adapt their sensitivities. While a wide range denotes a flexible and healthy system, when their evolved operating ranges are chronically exceeded, systems at all levels break down.

Allostasis occurs at the cellular and systems levels. When humans are chronically stressed, the brain chronically raises blood pressure; then arterial muscles predict higher pressure and respond with hypertrophy (like skeletal muscles when we lift weights). Gradually the whole cardiovascular system adapts to life at an elevated pressure level. This is known as chronic hypertension, which elevates mortality from cardiovascular disease and stroke. Similarly, a chronically high carbohydrate diet requires chronically high blood glucose and leads to chronically high levels of insulin that increase in anticipation of the need to manage the high level of carbohydrates. Cells that express insulin receptors, predicting high insulin, adapt by reducing their sensitivity (like photoreceptors in bright light). This leads to type 2 diabetes and elevated mortality from many causes. Although physicians term this response insulin resistance, it can be better understood as consequent to predictive regulation. Allostasis is essential in order to maintain internal viability amid changing conditions.