Knowledge Tree
Allostatic load
Also known as: Allostatic load, allostatic load model
synthesized from dimensionsAllostatic load is the cumulative physiological "wear and tear" on the body and brain that results from chronic or inefficient stress responses. Originally coined by Bruce McEwen and Stellar in 1993 and further elaborated by McEwen in 1998, the concept is rooted in the framework of allostasis—the process of achieving stability through change. Unlike homeostasis, which maintains a constant internal state, allostasis involves anticipating environmental demands and adjusting physiological parameters to meet them. Allostatic load represents the price the body pays for these adaptations when they are prolonged, excessive, or poorly regulated allostasis framework.
The accumulation of allostatic load occurs through four primary pathways: frequent activation of stress responses, failure to shut down these responses after a stressor has passed, an inadequate response to stress, or the inability to adapt to repeated stressors four pathways to allostatic load. These processes involve key systems such as the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. When these systems are chronically engaged, they trigger physiological changes—such as elevated cortisol, blood pressure, and inflammatory markers—that build load over time.
There are two primary, albeit distinct, conceptual models of allostatic load. The pathology-focused model views it as tissue damage resulting from prolonged exposure to stress mediators like glucocorticoids definition by McEwen. The energetic model, developed by McEwen and Wingfield, quantifies load as an energetic demand (Eload) that sums basal existence, routine activity, and perturbations from unpredictable events energetic formula. Within this energetic framework, researchers distinguish between two types of "allostatic overload": Type I, where load exceeds available environmental resources, and Type II, where load remains chronically high without necessarily surpassing resources, leading to pathology Type 1 overload Type 2 overload.
Clinically, allostatic load is measured using composite biomarker scores—typically 10 to 18 markers across neuroendocrine, cardiovascular, metabolic, and inflammatory domains biomarker composite score. This composite approach is often considered superior to single-marker measurements for predicting outcomes such as 22% higher all-cause mortality. However, the field lacks standardized measurement protocols and quantitative thresholds for defining "overload," and current research is often limited by cross-sectional study designs lack of standardization.
The significance of allostatic load lies in its role as a unifying mechanism for a wide range of health disparities and chronic conditions. High load is strongly associated with low socioeconomic status, weight stigma, and racial disparities, with higher scores frequently observed in African American and Latino populations per Vadiveloo and Mattei (2017). It is linked to cardiovascular disease, type 2 diabetes, cancer, depression, and cognitive decline unifying mechanism for diseases. Because it accumulates over the lifespan, it can be influenced by childhood adversity, though it may plateau in old age due to survivor effects.
Despite the damage caused by chronic stress, allostatic load is not immutable. Buffering factors, including strong social support, resilience, and healthy lifestyle interventions—such as exercise, improved nutrition, sleep hygiene, and stress-reduction techniques like CBT or Tai Chi—have been shown to mitigate physiological burden CBT reduces parameters Jackson Heart Study on resilience. While debates persist regarding the exact role of glucocorticoids and the relationship between different conceptual models, allostatic load remains a critical construct for understanding how the environment "gets under the skin" to impact long-term health.
Model Perspectives (5)
openrouter/x-ai/grok-4.1-fast definitive 96% confidence
Allostatic load refers to the cumulative physiological wear and tear on the body and brain from chronic or inefficient stress responses, as defined by McEwen in 1998 citing earlier work by Sterling and Eyer (1988), and coined by McEwen and Stellar in 1993. It accumulates via three mechanisms: frequent stress activation, failure to shut down responses post-stressor, and inadequate responses like excessive inflammation, per McEwen's framework. This affects systems like the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, where stress triggers shallow breathing, elevated heart rate, blood pressure, and cortisol, building load over time. Measurement uses a composite of 10-18 biomarkers across neuroendocrine (e.g., cortisol, DHEA-S), cardiovascular (e.g., blood pressure), metabolic, and inflammatory domains, outperforming single markers for predicting outcomes like 22% higher all-cause mortality. High load links to disparities, with low SES, weight stigma doubling risk per Vadiveloo and Mattei (2017), and higher scores in African Americans/Latinos. Allostatic overload, a threshold beyond load, involves multi-system dysregulation, with two types by McEwen and Wingfield, manifesting in sleep issues, hypertension, diabetes. Buffers include social support, resilience from Jackson Heart Study, slow breathing enhancing vagal activity, exercise, CBT, and Tai Chi reducing burden parameters.
openrouter/x-ai/grok-4.1-fast definitive 92% confidence
Allostatic load represents the cumulative physiological burden on the body from chronic stressors, including psychosocial pressure, drug abuse, chronic infections, daily routines, injury, disease, and aging, as defined in multiple sources. cumulative burden from stressors cumulative stress response effect It arises through four specific pathways: repeated novel stressors, failure to adapt, inability to shut off responses, or overactive reactions. four pathways to allostatic load Fava and colleagues propose a staging system with Stage 0 (optimal wellbeing), Stage 1 (elevated strain), Stage 2 (overload with dysregulation), and Stage 3 (clinical disease). Fava staging system Social isolation increases it while community support reduces dysregulation; resilience modifies its link to cardiovascular disease per the Jackson Heart Study. isolation raises allostatic load Jackson Heart Study on resilience It accumulates over the lifespan, starting from childhood adversity, potentially plateauing in old age due to survivor effects, and links to diseases like cardiovascular issues, diabetes, depression, cognitive decline, cancer, and immune dysfunction. lifespan accumulation from adversity unifying mechanism for diseases High load can occur without perceived stress due to habituation or external factors like social dysfunction and air pollution. high load without felt stress air pollution elevates load Measurement involves composite biomarker scores (cortisol, blood pressure, glucose, CRP), but lacks standardization, with varying panels and no quantitative thresholds for overload. biomarker composite score lack of standardization Interventions like cognitive behavioral therapy, Tai Chi Chih, lifestyle changes (sleep, nutrition, exercise), and structural improvements reduce it. CBT reduces parameters lifestyle interventions in older adults
openrouter/x-ai/grok-4.1-fast definitive 92% confidence
Allostatic load, originally defined by Bruce McEwen and Stellar (1993) and elaborated by McEwen (1998), refers to the 'wear and tear' on the body from chronic stress, particularly elevated glucocorticoids, leading to pathologies definition by McEwen. McEwen's quote on price of adaptation. George Koob and Michel Le Moal described it as the cost of adapting to adverse situations Koob and Le Moal's description. It fits within the allostasis framework of 'stability through change,' contrasting homeostasis by anticipating demands allostasis framework. maladaptation concept.
Two main definitions exist: pathology-focused (damage from stress, per Picard et al. 2014, Juster and McEwen 2015) and energetic (total energy costs), with unevaluated congruity evolving definitions. In the energetic model, allostatic load (Eload) sums basal existence (Ee), routine (Ei, varying by life-history like breeding), and perturbation costs (Eo from unpredictable events) energetic formula. Eo perturbations. Perturbation resistance potential (PRP) is resource availability minus baseline load PRP formula. Overload Type 1 hits when load exceeds resources (negative balance, triggering emergency life-history stage or ELHS); Type 2 is chronic high load without it Type 1 overload. Type 2 overload. Glucocorticoids link to energy balance and coping, rising to overload thresholds glucocorticoid role.
Applications span humans (e.g., Bizik et al. 2013 on mental illness, Mauss et al. 2015 workforce review, Mathew et al. 2021 cancer meta-analysis, Juster et al. 2010 biomarkers review) and animals (Seeley et al. 2022 scoping review). cancer association. It predicts comorbidities, mortality (Akinyemiju et al. 2020), CVD (Stabellini et al. 2024). Debates include glucocorticoid correlations (limited per McEwen and Wingfield 2003; Word et al. 2022 rejected in birds) and alternatives like Reactive Scope model (Romero et al. 2009), which complements but differs in thresholds Reactive Scope. Starvation critiques addressed by model tweaks starvation debate.
openrouter/x-ai/grok-4.1-fast definitive 88% confidence
Allostatic load, introduced by McEwen in 1998, refers to the 'wear and tear' on the body from chronic stress, defined as tissue damage from prolonged exposure to stress mediators like glucocorticoids, per McEwen and Wingfield (2003). In their energetics framework, it is quantified as an energetic demand (Eload) summing basal existence (Ee), routine activity (Ei), and perturbations (Eo), per McEwen and Wingfield. They distinguish Type I overload, where load exceeds environmental resources, and Type II, where it stays high without surpassing basal energy, leading to pathology from elevated glucocorticoids. Clinically, it is measured via biomarker scores like blood pressure, cholesterol, and hemoglobin, though limited by single-time points and variability, as noted in clinical studies. It links to Perceived Resource Potential (PRP = Ecr - Eload), correlating with glucocorticoids rather than load directly [fact:6d5ea45a-aa53-4564-a307-aa72ff12f942], and triggers emergency life-history stage (ELHS) in overload [fact:304109b0-87a7-4bd7-857f-be3f839f3afc]. Research by Juster, McEwen (2015), and others applies it to sleep, mental illness, and workforce, but definitions vary without assessed congruity [fact:84588fd0-cffc-4c05-b14b-1fdd9832f923].
openrouter/x-ai/grok-4.1-fast definitive 92% confidence
Allostatic load refers to the cumulative physiological wear and tear on the nervous system and body systems, particularly the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, resulting from chronic stress, overpreparation, or misaligned predictions, as described by TrueSelf Health. According to McEwen (1998), it involves mediator profiles like elevated flattened plateaus, failure to adapt to repeated stressors, or blunted responses linked to burnout. Early warning signs include persistent sleep disturbances, fatigue, mood fluctuations, and elevated blood pressure, per CannElevate. Physical consequences encompass hypertension, cardiovascular disease, type 2 diabetes, and accelerated aging, while psychological effects involve irritability, impaired functioning, and overwhelm. Measurement in clinical practice uses composite biomarker scores from neuroendocrine, cardiovascular, metabolic, and inflammatory markers, as noted by CannElevate. Factors elevating allostatic load include low socioeconomic status, racial disparities (higher in African Americans and Latinos versus Whites), and social dysfunction, though social support buffers it; accumulation progresses over lifespan but may plateau in old age due to survivor effects. Interventions like improved sleep, nutrition, exercise, and stress management reduce it in older adults. Research by McEwen and Wingfield distinguishes overload types, with studies cited in Nature on clinical applications (e.g., Fava et al.) and links to cancer, though limited by cross-sectional designs.
Facts (235)
Sources
Allostasis revisited: A perception, variation, and risk framework frontiersin.org Sep 28, 2022 81 facts
formulaPerturbation resistance potential (PRP) is calculated as Eg – (Ee + Ei), representing the difference between allostatic load and resource availability.
claimMcEwen and Wingfield (2003) established the allostatic load framework, but research assessing the relationship between animal energetics and hallmarks of allostatic load, such as circulating glucocorticoid levels, remains limited.
claimThe congruity between the pathology-focused definitions and the energetic-quantity-focused definitions of allostatic load has not been assessed, despite the assumption that they are equivalent or not in conflict.
claimIn the McEwen and Wingfield (2003) model, Type I allostatic overload occurs when allostatic load exceeds the energetic resources available in the environment.
claimHigh internal fat stores, including fatty acid levels, muscle glycogen, and leptin, indicate a high probability of surviving short-term allostatic overload.
claimAllostatic overload Type 2 occurs when allostatic load is chronically high but the animal is not in a negative energy balance, and in this state, an emergency life-history stage (ELHS) is not triggered.
claimGlucocorticoid concentrations rise from level A (homeostatic level) to level B (reactive scope) as conditions deteriorate, and to level C (allostatic overload) when conditions become extreme, which triggers facultative responses such as the Emergency Life History Stage (ELHS).
claimIn the energetics-based framework for allostatic load, Type II allostatic overload occurs when allostatic load remains high without exceeding basal energy available, resulting in pathology associated with chronically elevated glucocorticoids.
claimCalculating allostatic load requires selecting an appropriate time interval to average energy expenditure, as moment-to-moment fluctuations should not trigger overload.
claimIn the revised allostasis model, allostatic load is defined as an energetic quantity (Eload), but its importance is reduced because it is not always a primary determinant of the Perceived Resource Potential (PRP).
claimPerturbation-related costs (Eo) in the allostatic load framework are inherently unpredictable and include costs associated with injury, disease, unexpected wear-and-tear, habitat loss, habitat degradation, predation risk, and major weather events.
referenceThe Reactive Scope model, introduced by Romero et al. (2009), serves as a complementary framework to the allostatic load model.
quoteGeorge Koob and Michel Le Moal described allostatic load as "the cost or the price the body may have to pay for being forced to adapt to an adverse or deleterious physiological or physical situation."
formulaIn the energetics-based framework proposed by Bruce McEwen and John Wingfield (2003), allostatic load is calculated as the function: allostatic load = Ee (basal existence) + Ei (routine activity) + Eo (unpredictable perturbations).
claimPast acute perturbations may not contribute to allostatic load or the Predictive Reactive Scope (PRP), but they can be integrated into an animal's perception of risk and induce changes in feedback mechanisms that mediate future hormonal responses.
claimGlucocorticoids are implicated in processes related to energy balance, which determines responses to energetic demand (allostatic load) and influences subsequent physiology and behavior associated with coping.
claimAllostatic overload triggers an 'emergency life-history stage' (ELHS), which redirects an individual's physiology and behavior toward survival.
claimIn the allostatic load model, 'Eo' represents the cost of responding to 'labile perturbation factors' (LPFs).
claimFollowing exposure to a labile perturbation factor (LPF), once allostatic load returns to normal levels, the mediator control system resets as if the acute event had not occurred.
claimHigh internal fat stores, including fatty acid levels, muscle glycogen, and leptin, indicate a high probability of surviving short-term allostatic overload. This cue is reliable when the perturbation is short-lived, fat is expendable, and a delayed response is likely to succeed, but it may increase error if fat stores are necessary for escape or if the loss of insulation incurs additional costs.
claimResearch assessing the relationship between animal energetics and hallmarks of allostatic load, such as circulating glucocorticoid levels, is limited according to McEwen and Wingfield (2003).
claimWingfield (2004) posits that fat acts as a buffer against allostatic overload by providing an energy source to supplement Eg (energy expenditure).
formulaAllostatic load (Eload) is calculated as the sum of basal existence energy (Ee), routine metabolic rate (Ei), and energetic costs due to perturbation (Eo), expressed as the formula Eload = Ee + Ei + Eo.
referenceThe hypothesis that variation in allostatic load is correlated with mediators such as plasma glucocorticoid levels was tested in birds and tentatively rejected by Word et al. (2022).
formulaAllostatic load is defined as an energetic quantity (Eload) that can be subdivided into three component parts: basal existence costs (Ee), routine costs (Ei), and perturbation-related costs (Eo).
claimThe original model of allostasis predicted that blood glucocorticoid levels should change in correlation with allostatic load.
claimIn the model of physiological stability, level A represents the homeostatic level of glucocorticoids, level B represents the reactive scope for a specific life-history stage, and level C represents the state of allostatic overload.
claimGlucocorticoid levels are predicted to change in parallel with allostatic load.
claimAs allostatic overload (Eo) progresses, the overall allostatic load increases and the perturbation resistance potential (PRP) decreases.
claimThe Potential Resource Pool (PRP) is determined in part by allostatic load.
referenceAllostasis, defined as stability through change, is a theoretical framework that integrates the demands of predictable and unpredictable environments, known as allostatic load, according to an individual's condition.
claimBaseline glucocorticoid levels in blood tend to increase slowly as environmental conditions deteriorate, which increases allostatic load in Strategy 2.
formulaPRP = Ecr - Eload
claimThe cost of surrendering a physical location includes losing fitness-related investments from the normal life-history stage and increasing the risk of damage from Type II/allostatic overload.
claimThe Potential for Resource Procurement (PRP) is determined, in part, by allostatic load.
claimThe Perceived Resource Potential (PRP) describes the gap between allostatic load (Eload) and resource availability (Ecr), and is proposed to correlate with glucocorticoid levels rather than allostatic load itself.
claimBaseline glucocorticoid levels in blood tend to increase slowly as environmental conditions deteriorate, thereby increasing allostatic load.
claimThe cost of activating the Emergency Life History Stage (ELHS) includes surrendering fitness-related investments associated with a normal life-history stage and potentially increasing the risk of damage associated with Type II/allostatic overload.
claimAllostatic load indicates energetic requirements and is a reliable cue when resources are limited (allostatic load is close to Ecr, and Perturbation Resistance Potential is low), but it increases error when resources vastly exceed requirements (allostatic load is much less than Ecr, and Perturbation Resistance Potential is high).
referenceGoymann and Wingfield (2004) argued that allostatic load and social status are linked, emphasizing that the costs of social status are significant.
formulaAllostatic overload Type 1 occurs when an animal is in a negative energy balance, specifically when the sum of all types of allostatic load exceeds resource availability (Eg).
claimRomero and Wingfield (2016) noted that homeostatic overload and allostatic overload are related but not identical concepts.
claimThe congruity between differing definitions of allostatic load has not been assessed, despite the general assumption that they are equivalent or not in conflict.
claimBiomedical literature commonly estimates allostatic load by generating a score based on metrics including blood pressure, human low density lipoprotein (HLDL) cholesterol, and glycosylated hemoglobin.
formulaPerturbation resistance potential (PRP) is a quantity in the framework of allostasis that describes the difference between allostatic load and resource availability, calculated as Eg – (Ee + Ei), and reflects an individual's vulnerability to allostatic overload Type 1.
claimThe framework of allostasis, allostatic load, and overload is defined as stability through change, attempting to combine homeostasis processes in day-to-day physiological and behavioral responses.
claimThe PRP describes the gap between allostatic load and resource availability, and is proposed to correlate with glucocorticoid levels rather than allostatic load itself.
referenceWord et al. (2022) suggest that the absence of a clear correlation between allostatic load and glucocorticoid levels in previous studies may be explained by cases where energetic requirements (Eg) are very high, causing changes in allostatic load to constitute only proportionally minor changes in the Potential Resource Pool (PRP).
claimMcEwen and Wingfield (2010) argued against the relevance of starvation as a defining factor for the allostatic load model, preferring the concept of energetic demand.
claimThe definition of allostatic load developed by Bruce McEwen and Stellar (1993) and elaborated by Bruce McEwen (1998) refers to specific pathologies associated with chronic stress, particularly chronic exposure to elevated glucocorticoid hormones in humans and laboratory animals.
claimIn the energetics-based framework by McEwen and Wingfield (2003), Type I allostatic overload occurs when allostatic load exceeds the energetic resources available in the environment, while Type II allostatic overload occurs when allostatic load remains high without exceeding basal energy available.
formulaResource availability (Eg) represents a limit to the energy an animal can expend without entering a negative energy balance and must be measured in the same units as allostatic load.
claimFat reserves act as a buffer against allostatic overload by providing an energy source to supplement energy expenditure, according to Wingfield (2004).
referenceThe allostatic load framework was originally presented by McEwen and Wingfield in 2003.
claimRoutine costs (Ei) in the allostatic load framework vary seasonally based on life-history stages such as breeding, migration, and molting.
claimThe emergency life-history stage (ELHS) is a physiological state triggered by allostatic overload that redirects physiology and behavior toward individual survival, often interrupting normal life history stages.
claimBoth the allostatic load framework and the Reactive Scope model incorporate the concept of a threshold, though they apply the concept differently.
claimThe allostatic load model does not specifically predict cumulative consequences for recurrent acute events, such as escaping a predator, because the mediator control system resets once allostatic load returns to normal levels.
quoteBruce McEwen described allostatic load as "the price of adaptation that promotes pathophysiology."
claimKorte et al. (2005) define the Darwinian concept of stress as involving the benefits of allostasis and the costs of allostatic load, including trade-offs in health and disease.
referenceThe Reactive Scope model serves as an alternative to the allostatic load model and was first detailed in a 2009 paper by Romero et al.
claimType I allostatic overload is distinct from negative energy balance, as animals can routinely burn fat reserves (e.g., during the night) without entering allostatic overload, as noted by Hatchwell et al. (2009).
formulaBruce McEwen and John Wingfield developed an energetics-based framework for allostatic load in 2003, where allostatic load is a function of Ee (basal existence), Ei (routine activity), and Eo (unpredictable perturbations).
claimIn the allostatic load model, it is necessary to select an appropriate time interval to average energy expenditure because large, moment-to-moment fluctuations in energetic quantities should not trigger physiological overload.
claimStrategy 1 for endocrine response involves glucocorticoids gradually elevating in direct inverse correlation with the difference between allostatic load and resource availability (PRP) when PRP is low, reaching the ELHS activation threshold only when PRP equals zero.
claimMcEwen and Wingfield (2010) argued that the suppression of glucocorticoids during Phase II starvation challenges the relevance of starvation as a defining factor for allostatic load.
claimMcEwen (1998) introduced the concepts of allostasis and allostatic load in the context of stress, adaptation, and disease.
claimThe definition of allostatic load has evolved into a spectrum, ranging from a focus on specific pathologies or damage (as defined by Picard et al., 2014 and Juster and McEwen, 2015) to a focus on an all-inclusive energetic quantity (as defined by Lattin and Romero, 2014 and Monaghan and Spencer, 2014).
claimRoutine glucocorticoid fluctuations, such as those occurring with time of day, season, or life-history stage, are distinct from the abnormally high levels associated with allostatic overload (Eo).
claimAllostatic load is defined as an energetic quantity (Eload).
formulaIn the model of allostatic load, perturbation resistance potential (PRP) is quantified as the difference between available resources and all energetic costs of allostatic load, including daily routines, life history stages (such as breeding, migration, and molt), and the impact of environmental perturbations.
claimThe most useful time interval for averaging energy expenditure to reflect allostatic load varies by species, sex, and season, based on the duration an animal can tolerate negative energy balance as part of its daily or seasonal routine.
referenceWeather cues affect food availability and access and may serve as an anticipatory cue for allostatic load; they are most reliable when weather influences food availability and internal energy stores are low, but increase error when food remains available or the weather event is short enough to be survived with internal energy stores.
claimIf the energy consumption rate (Ecr) replaces the energy gain rate (Eg) in the allostatic load model, allostatic overload does not occur until Phase III starvation, which satisfies the requirement that overload occurs concurrently with elevated glucocorticoid levels.
claimPast events, once passed, may not contribute to the energetic quantities of allostatic load or to the Predictive Reactive Profile (PRP), but they may be integrated into an animal’s perception of risk relative to the PRP and induce changes in feedback mechanisms that mediate hormonal responses to future energetic challenges.
claimAllostatic overload Type 2 occurs when an animal's allostatic load is chronically high, but the animal is not in a state of negative energy balance.
claimJuster and McEwen (2015) propose new directions for allostatic load research in the context of sleep and chronic stress.
claimThe article 'Allostasis revisited: A perception, variation, and risk framework' identifies allostasis, allostatic load, perturbation resistance potential, glucocorticoid, and environment as key concepts.
claimWhen environmental conditions become extreme, glucocorticoid levels increase rapidly to level C as a result of allostatic overload, which triggers facultative responses such as the Emergency Life History Stage (ELHS).
claimRomero et al. (2009) cited the suppression of glucocorticoids during Phase II starvation as an argument against the applicability of the allostatic load model.
claimReplacing Eg with Ecr in the allostatic load model delays the occurrence of allostatic overload until Phase III starvation, which satisfies the requirement that overload occurs concurrently with elevated glucocorticoid levels.
Understanding Allostasis: Stability Through Change - Cannelevate cannelevate.com.au Jan 2, 2026 64 facts
claimAllostatic load accumulation is not random but is influenced by social determinants of health, creating disparities in health outcomes.
claimAllostatic load serves as a unifying mechanism that explains why chronic stress is linked to elevated risks for cardiovascular disease, diabetes, depression, and cognitive decline.
claimEarly warning signs of high allostatic load include persistent sleep disturbances, unexplained fatigue, mood fluctuations, difficulty concentrating, feelings of being overwhelmed, changes in appetite, unexplained abdominal weight gain, frequent minor infections, and elevated blood pressure.
claimResearch indicates that African Americans and Latinos have significantly higher allostatic load scores compared to White Australians and Americans.
referenceThe staging system for allostatic load proposed by Fava and colleagues defines four stages of physiological progression: Stage 0 (euthymia/functional allostasis with optimal wellbeing), Stage 1 (allostatic load/elevated strain while still functioning), Stage 2 (allostatic overload/significant dysregulation with impaired functioning), and Stage 3 (clinical disorder or disease/pathophysiology becomes evident).
measurementIn stroke survivors, an allostatic load of 3 or higher predicted 4.9 times greater cardiovascular mortality compared to those with loads of 1 or below.
claimPsychological manifestations of allostatic overload include sleep disturbances, irritability, mood changes, impaired social and occupational functioning, and feelings of being overwhelmed by daily demands.
claimResearch suggests that allostatic load accumulation may plateau in old age, potentially due to survivor effects.
claimSocial support has a negative association with allostatic load, meaning strong social relationships buffer against the effects of stress.
claimBruce McEwen and Eliot Stellar coined the term "allostatic load" in 1993 to describe the physiological burden of ongoing adaptation and the strain produced by systems under challenge.
claimCumulative measures of allostatic load are superior to individual biomarkers in predicting health outcomes because they capture the interconnected nature of physiological dysregulation.
claimMetabolic markers used to measure allostatic load include waist-hip ratio, body mass index, glucose levels, glycated haemoglobin levels, triglycerides, and high-density lipoprotein cholesterol.
claimFactors such as social dysfunction or environmental exposures can elevate an individual's allostatic load even if the individual does not subjectively perceive high stress.
claimTai Chi Chih specifically reduces allostatic burden in individuals with insomnia.
claimAfrican Americans and Latinos demonstrate significantly higher allostatic load scores compared to White Australians and Americans.
claimAllostatic load serves as the unifying mechanism explaining why individuals experiencing chronic stress face elevated risks for cardiovascular disease, diabetes, depression, and cognitive decline.
claimCognitive behavioural therapy demonstrates reductions in allostatic load parameters.
claimCognitive behavioural therapy demonstrates reductions in allostatic load parameters.
claimAllostatic overload is a critical threshold state where dysregulation occurs across multiple systems when adaptive capacity reaches its limits, representing the transition from adaptive stress responses to pathological consequences.
claimAustralian healthcare is increasingly recognizing the clinical relevance of allostatic load as of 2026, enabling precision approaches to health assessment and early intervention.
procedureHealthcare professionals measure allostatic load in clinical practice by assessing a composite score of biomarkers, including neuroendocrine markers (e.g., cortisol), cardiovascular markers (e.g., blood pressure, heart rate variability), metabolic markers (e.g., glucose, lipid profile), and inflammatory markers (e.g., C-reactive protein).
claimTai Chi Chih specifically reduces allostatic burden in individuals with insomnia.
claimNeuroendocrine markers used to measure allostatic load include cortisol, dehydroepiandrosterone sulphate (DHEA-S), corticotropin-releasing hormone (CRH), epinephrine, and norepinephrine.
claimStructural and systemic interventions, such as improving socioeconomic conditions, reducing health inequalities, enhancing neighbourhood safety, improving healthcare access, implementing workplace stress reduction programmes, and strengthening community support networks, are necessary to address Type 2 allostatic overload.
claimInterventions such as improved sleep, nutrition, physical activity, and stress management can reduce allostatic load in older adults, leading to meaningful improvements in health outcomes.
claimInflammatory markers used to measure allostatic load include C-reactive protein, interleukin-6, fibrinogen, and tumour necrosis factor-alpha.
claimLow socioeconomic status is strongly associated with higher allostatic load.
referenceMcEwen and Wingfield identified two distinct types of allostatic overload, each with unique characteristics and implications.
claimPhysical activity increases endorphin production, improves brain function, and shifts attention to present-moment experience, which affects allostatic load parameters.
measurementIn stroke survivors, an allostatic load of 3 or higher predicts 4.9 times greater cardiovascular mortality compared to those with loads of 1 or below.
claimChildhood adversity can establish the foundation for higher allostatic load later in life.
claimStrong social relationships and community support buffer against stress effects and reduce physiological dysregulation, while social isolation and loneliness increase allostatic load.
procedureHealthcare professionals measure allostatic load in clinical practice by assessing a composite score derived from biomarkers including neuroendocrine markers (e.g., cortisol), cardiovascular markers (e.g., blood pressure, heart rate variability), metabolic markers (e.g., glucose, lipid profile), and inflammatory markers (e.g., C-reactive protein).
claimResearch from the Jackson Heart Study demonstrates that resilience modifies the relationship between allostatic load and cardiovascular disease.
claimIndividuals can experience high allostatic load without feeling stressed because they may habituate to chronic stress or experience physiological dysregulation without conscious awareness.
claimResearch suggests that the accumulation of allostatic load may plateau in old age, potentially due to survivor effects.
claimAdolescence is a period characterized by both vulnerability to allostatic load and opportunities for intervention.
claimAllostatic load accumulates progressively across the human lifespan.
referenceMcEwen and Wingfield identified two distinct types of allostatic overload: Type 1, which occurs when energy demand exceeds available energy supply, and Type 2, which occurs with sufficient or excess energy consumption accompanied by social conflict or dysfunction.
procedureMeasuring allostatic load involves a composite approach assessing 10-18 biomarkers across neuroendocrine, cardiovascular, metabolic, and inflammatory systems.
claimAllostatic load accumulates through three primary mechanisms: frequent stress responses creating cumulative burden, failed shut-down of stress responses after stressors end, and inadequate physiological responses such as excessive inflammatory reactions or blunted cortisol release.
claimInterventions such as improved sleep, nutrition, physical activity, and stress management can reduce allostatic load in older adults, leading to meaningful improvements in health outcomes.
measurementA single-point increase in allostatic load corresponds to an 8-21% increase in cardiovascular mortality risk, depending on the disease type.
claimThe disparity in hypertension rates between African Americans and West Africans suggests that genetics alone do not account for differences in allostatic load.
claimIndividuals can experience high allostatic load without subjectively feeling stressed, as they may habituate to chronic stress or experience physiological dysregulation without conscious awareness.
claimAllostatic load accumulates through three primary mechanisms: frequent stress responses (determined by magnitude and frequency), failed shut-down of stress responses after stressors end, and inadequate physiological responses (such as excessive inflammation or blunted cortisol release).
measurementHigh allostatic load is associated with a 22% increased all-cause mortality risk and a 31% increased cardiovascular mortality risk, according to a meta-analysis of 17 studies.
measurementA meta-analysis of 17 studies found that high allostatic load is associated with a 22% increased risk of all-cause mortality and a 31% increased risk of cardiovascular mortality.
claimResearch from the Jackson Heart Study demonstrates that resilience modifies the relationship between allostatic load and cardiovascular disease.
claimResilience is defined as the ability to maintain wellbeing despite threats and serves as a critical protective factor against allostatic load.
claimSocial isolation and loneliness increase allostatic load, while community support reduces physiological dysregulation.
claimPhysical consequences of allostatic overload include hypertension, cardiovascular disease, type 2 diabetes, metabolic dysfunction, chronic inflammation, autoimmune disorders, weakened immune function, and accelerated cellular aging.
claimAllostatic overload manifests physically through hypertension, cardiovascular disease, type 2 diabetes, metabolic dysfunction, chronic inflammation, autoimmune disorders, weakened immune function, and accelerated cellular aging.
claimAllostatic overload manifests psychologically through sleep disturbances, irritability, mood changes, impaired social and occupational functioning, and feelings of being overwhelmed.
claimAllostatic load accumulation is influenced by social determinants of health rather than occurring randomly across populations.
referenceThe staging system for allostatic load proposed by Fava and colleagues defines four stages: Stage 0 (euthymia, functional allostasis with optimal wellbeing), Stage 1 (allostatic load, elevated strain while still functioning), Stage 2 (allostatic overload, significant dysregulation with impaired functioning), and Stage 3 (clinical disorder or disease, where pathophysiology becomes evident).
claimEarly warning signs of high allostatic load include persistent sleep disturbances, unexplained fatigue, mood fluctuations, difficulty concentrating, feelings of being overwhelmed, changes in appetite, unexplained weight gain (particularly around the abdomen), frequent minor infections, and elevated blood pressure.
claimAllostatic overload is a critical threshold state where dysregulation occurs across multiple systems when adaptive capacity reaches its limits.
claimResilience is defined as the ability to maintain wellbeing despite threats and serves as a critical protective factor against allostatic load.
claimCardiovascular markers used to measure allostatic load include systolic and diastolic blood pressure, pulse rate, and heart rate variability.
measurementEvery single-point increase in allostatic load corresponds to an 8-21% increase in cardiovascular mortality risk, depending on the disease type.
claimLow socioeconomic status is strongly associated with higher allostatic load across numerous studies.
claimAllostatic load accumulates progressively across the human lifespan, with childhood adversity potentially setting the stage for higher load in later life.
claimFactors such as social dysfunction or environmental exposures can elevate an individual's allostatic load even in the absence of perceived high stress.
Integrating allostasis and emerging technologies to study complex ... nature.com Nov 5, 2025 41 facts
referenceMathew, A. et al. (2021) conducted a systematic review and mini meta-analysis on allostatic load in cancer patients, published in Biological Research for Nursing.
referenceLucente, M. & Guidi, J. published 'Allostatic load in children and adolescents: A systematic review' in the journal Psychother. Psychosom. in 2023.
claimDysregulation from allostatic load contributes to DNA damage, immune suppression, and chronic inflammation, which are hallmarks of tumor initiation, progression, and metastasis.
referenceThe paper cites several studies on allostatic load, including Fava et al. (2019) on clinical characterization of allostatic overload, Lucente & Guidi (2023) on allostatic load in children and adolescents, Fava et al. (2023) on allostatic load in clinical practice, McLoughlin et al. (2020) on allostatic load scoring algorithms, Beese et al. (2022) on allostatic load measurement, and Osei et al. (2024) on allostatic load and metabolic syndrome.
referenceAkinyemiju, T. et al. (2020) studied the association of allostatic load with all-cause and cancer mortality, stratified by race and body mass index, using the REGARDS cohort, published in Cancers.
referenceMattei, J. et al. (2010) found that allostatic load is associated with chronic conditions in the Boston Puerto Rican Health Study, published in Social Science & Medicine.
claimBizik et al. (2013) propose allostatic load as a tool for monitoring physiological dysregulations and comorbidities in patients with severe mental illnesses.
referenceServiant-Fine et al. authored a paper titled "Allostatic load: historical origins, promises and costs of a recent biosocial approach," which examines the history and implications of the allostatic load concept.
claimCurrent research on allostasis in the context of cancer is limited by the prevalence of cross-sectional studies, which hinders causal inference and the ability to determine the long-term effects of allostatic load on cancer outcomes.
claimThe measurement of allostatic load lacks standardization because biomarker panels vary significantly between studies, which limits reproducibility and cross-contextual comparisons.
referenceFava, G. A., Guidi, J., Semprini, F., Tomba, E., and Sonino, N. published 'Clinical assessment of allostatic load and clinimetric criteria' in the journal Psychotherapy and Psychosomatics in 2010.
referenceJuster, R.-P. et al. (2013) examined the relationship between sexual orientation, disclosure, psychiatric symptoms, diurnal cortisol, and allostatic load in Biopsychosocial Medicine.
perspectiveAllostatic load and overload are key factors in modulating stress-related immune dysfunction.
referenceOsei, F., Wippert, P.-M. & Block, A. published 'Allostatic load and metabolic syndrome in depressed patients: A cross-sectional analysis' in the journal Depress Anxiety in 2024.
claimCross-study comparisons of allostatic load are complicated by inconsistent metrics and methodologies, as some studies focus solely on physiological markers while others incorporate clinimetric tools to assess psychosocial stress.
claimSustained stress responses across neuroendocrine, immune, and metabolic systems drive allostatic load, which can lead to allostatic overload and multisystem dysfunction when prolonged.
referenceFava, G. A. et al. published 'Clinical characterization of allostatic overload' in the journal Psychoneuroendocrinology in 2019.
claimDepressive symptoms are associated with allostatic load among community-dwelling older adults, according to a 2014 study published in Physiology & Behavior.
claimAllostatic load, characterized by metabolic and inflammatory dysregulation such as elevated blood glucose, CRP, or altered lipid levels, promotes a tumor-permissive environment.
claimAllostatic overload occurs when the physiological burden of allostasis exceeds the body's adaptive capacity, leading to systemic dysregulation and increased disease risk.
claimA systematic review of methods for measuring allostatic load in the workforce was published in Industrial Health in 2015.
claimAllostatic load serves as a tool for monitoring physiological dysregulations and comorbidities in patients with severe mental illnesses, as detailed in a 2013 Harvard Review of Psychiatry article.
claimThe association between elevated allostatic load and cancer history was not observed in racial groups other than black women, indicating that the impact of allostatic load may differ by race.
referenceStabellini, N. et al. (2024) investigated the relationship between allostatic load/chronic stress and cardiovascular outcomes in patients diagnosed with breast, lung, or colorectal cancer, published in the Journal of the American Heart Association.
claimClinical studies have traditionally assessed allostatic load using biomarker-based indices derived from single time-point measurements.
referenceThe source cites several key works on stress neurobiology and allostasis, including Godoy et al. (2018) on stress neurobiology, Cannon (1929) on physiological homeostasis, Azmi et al. (2021) on cortisol and circadian rhythm, Sterling and Eyer (1988) on allostasis and arousal pathology, McEwen and Wingfield (2003) on allostasis in biology, Chodkiewicz (2023) on addiction memory and allostasis, George et al. (2012) and Koob and Le Moal (2001) on allostasis and addiction, Savransky et al. (2018) on allostatic load in schizophrenia, and Honkalampi et al. (2021) on allostatic load in depression.
referenceBellingrath, S., Weigl, T. & Kudielka, B. M. (2009) found that chronic work stress and exhaustion are associated with higher allostatic load in female school teachers, as published in the journal Stress.
claimLong COVID is a condition that imposes a sustained allostatic load, reflecting a state of reduced physiological resilience caused by prolonged immune and inflammatory stress.
claimAllostatic load is defined as the cumulative physiological burden imposed on the body by chronic stressors, including persistent psychosocial pressure, drug abuse, and chronic infections.
claimOmics technologies are utilized for the identification of novel biomarkers, the elucidation of regulatory pathways associated with resilience and vulnerability, and the investigation of allostatic load.
claimPrevious studies on allostatic load have largely focused on specific cancer types such as breast and prostate cancers, which limits broader insights across other cancer types.
claimMulti-omics approaches enable system-level mapping of allostatic burden across diverse molecular layers, revealing sustained immune activation and metabolic disruption in conditions such as Long COVID.
claimChronic diseases, including cancer, impose an allostatic load on the immune system.
referenceParente, V., Hale, L. & Palermo, T. (2013) analyzed the association between breast cancer and allostatic load by race using data from the National Health and Nutrition Examination Survey (1999–2008), published in Psycho-Oncology.
claimStress acts as a key driver of allostatic load within the immune system and can modulate various immune components.
referenceSeeley, Proudfoot, and Edes (2022) conducted a scoping review on the application of allostasis and allostatic load in animal species, published in PLoS ONE.
claimIntermediate allostatic states provide a mechanistic window into the progressive accumulation of allostatic load that precedes the manifestation of fully developed pathological conditions.
claimMauss et al. (2015) conducted a systematic review on measuring allostatic load in the workforce.
claimClinical studies assessing allostatic load typically rely on biomarker-based indices derived from single time-point measurements, which are limited by factors such as lifestyle variability, environmental influences, cross-sectional study design, and individual genetic differences.
referenceJuster, R. P., McEwen, B. S. & Lupien, S. J. (2010) reviewed allostatic load biomarkers of chronic stress and their impact on health and cognition in Neuroscience & Biobehavioral Reviews.
claimRecent research has expanded the focus of allostasis beyond neuropsychological conditions to include the role of allostatic load and overload in the development of immune-mediated diseases and cancer.
Homeostasis vs Allostasis — The Urban Health Council urbanhealthcouncil.com 18 facts
claimExposure to high air pollution is an artificial result of human activity that results in unadapted baseline parameters and disease, distinguishing it from natural adaptive allostatic load (AL).
referenceThe paper titled 'Air Pollution, Stress, and Allostatic Load: Linking Systemic and Central Nervous System Impacts' was published in the Journal of Alzheimer's Disease in 2019, spanning pages 597–614.
claimAllostatic overload (AOL) is more chronic and intense than allostatic load (AL) and represents a transition from normal wear-and-tear to significant health disruptions, such as the onset of diabetes or obesity.
perspectiveThe lack of standardized definitions for allostatic load (AL) and allostatic overload (AOL) leads many studies to incorrectly identify genetic makeup as the leading cause for complex diseases like depression, rather than dysregulation from chronic stress exposure.
referenceBruce S. McEwen published the paper 'Allostasis and allostatic load: implications for neuropsychopharmacology' in the journal Neuropsychopharmacology in 2000, spanning pages 108–124.
claimThe physical repercussions of allostatic load (AL) manifest as a general sense of being 'stressed out', which results in symptoms such as fatigue, anger, and frustration.
referenceGuidi, J., Lucente, M., Sonino, N. & Fava, G. A. published 'Allostatic Load and Its Impact on Health: A Systematic Review' in Psychother. Psychosom. in 2020.
procedureAllostatic load (AL) is reached through four specific types of responses: (1) repeated novel stressors causing spikes in mediator levels, (2) failure to adapt to the same stressor, (3) failure to turn off the stress response, or (4) overactive responses.
claimAir pollution and stress are linked to allostatic load and have systemic and central nervous system impacts, according to a 2019 study published in the Journal of Alzheimer's Disease.
claimNo threshold has been proposed for when the body enters the phase of allostatic overload (AOL), likely because the circumstances triggering AOL vary significantly between individuals.
claimThere are no formal quantitative definitions for allostatic load (AL) or allostatic overload (AOL) in biomedical literature.
claimAllostatic overload (AOL) marks the onset of disease where a return to homeostasis is impossible and a new, unhealthy baseline for the body is created by shifting optimal homeostasis parameters like blood pressure.
claimThe engagement of allostatic load (AL) in individuals adapting to harsh environments, such as moving to the North Pole, is a natural phenomenon of adaptation and evolution that changes baseline parameters.
claimAllostatic overload (AOL) is an extreme state for the body resulting from a prolonged dysregulated condition of allostasis.
claimAllostatic load (AL) is a cumulative effect on the stress response caused by changes in mediators and physiological parameter levels resulting from daily routines, injury, disease, and aging.
claimThe new baseline created under allostatic overload (AOL) does not equate to homeostasis; it is an unhealthy, dysregulated baseline caused by persistent exposure to stress.
referenceUllmann, E. et al. published 'From Allostatic Load to Allostatic State-An Endogenous Sympathetic Strategy to Deal With Chronic Anxiety and Stress?' in Front. Behav. Neurosci. in 2019.
claimThere is a lack of agreement regarding which variables should be measured to determine allostatic load (AL) and allostatic overload (AOL), specifically whether to measure only mediators like cortisol or also contributing variables like age, gender, diet, habitat, and health behaviors.
A Copernican Approach to Brain Advancement: The Paradigm of ... frontiersin.org Apr 25, 2019 9 facts
claimThe 'allostatic state' is a term labeled by Koob and Le Moal (2001) to describe a midway point in the process of stress, occurring when stress has been chronic but has not yet reached the level of full-blown allostatic load.
referenceAccording to McEwen (1998), allostatic load is associated with various mediator profiles, including elevation toward a flattened plateau, failure to adapt to repeated stressors, or a blunted response linked to psychological burnout.
claimAllostatic load is defined as the condition where acutely valuable stress mediators cross a threshold due to stress chronicity, leading to tissue damage.
claimPharmacological strategies that attempt to clamp set points for neurotransmission, even when intended to target allostatic load, likely suffer from the same complications and limitations as traditional homeostatic therapeutics, according to Sterling (2004).
claimResearchers who utilize concepts related to allostasis or allostatic load may still default to homeostatic thinking in their understanding of physiological stability.
claimThe concept of allostasis is often used to describe the phenomenon where biological set points are temporarily altered due to acute environmental stress, and it is also used to refer to the concept of allostatic load.
referenceSeeman, T., Epel, E., Gruenewald, T., Karlamangla, A., and McEwen, B. S. (2010) examined the relationship between socio-economic status and peripheral biology, specifically focusing on the concept of cumulative allostatic load.
referenceMcEwen and Wingfield (2003) define allostatic load as tissue damage resulting from chronic exposure to allostatic mediators.
referenceUnder the Predictive Adaptive Organization (PAO) framework, allostatic load is classified as one example of an impaired allostatic state, also referred to as allostatic impairment.
Homeostasis vs. Allostasis: Why Your Body Needs More Than Stability trueself.health Jan 5, 2026 9 facts
claimAllostatic load manifests as wear and tear on the nervous system and body systems, including the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting from chronic stress, overpreparation, or misaligned predictions.
claimWhen the sympathetic nervous system (the 'fight-or-flight' system) is activated by stress, respiration rate increases, breathing becomes shallow and rapid, heart rate increases, blood pressure spikes, and cortisol levels rise, which contributes to allostatic load over time.
claimAllostatic load is the cumulative physiological wear and tear on the nervous system and body systems, such as the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting from chronic stress, overpreparation, or misaligned physiological predictions.
claimAllostatic load is the cumulative physiological cost incurred by the body when predictive systems are prolonged or inaccurate, such as when an individual is constantly bracing for stress.
claimAllostatic load is the cumulative physiological wear and tear on the nervous system and body systems, such as the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, resulting from chronic stress, overpreparation, or misaligned predictions.
claimActivation of the sympathetic nervous system during stress increases respiration rate, causes shallow breathing, raises heart rate and blood pressure, and increases cortisol levels, which contributes to allostatic load over time.
claimActivation of the sympathetic nervous system (the "fight-or-flight" system) increases respiration rate, leading to shallow breathing, increased heart rate, spiked blood pressure, and cortisol release, which contributes to allostatic load over time.
claimSlow, deep breathing at a rate of approximately 5-6 breaths per minute enhances parasympathetic activity through vagal pathways, which reduces sympathetic arousal, lowers cortisol, improves heart rate variability, and mitigates allostatic load.
claimSlow, deep breathing, particularly at a rate of approximately 5-6 breaths per minute, enhances parasympathetic activity (the 'rest-and-digest' system) through vagal pathways, which reduces sympathetic arousal, lowers stress hormones like cortisol, improves heart rate variability, and mitigates allostatic load.
Psychosocial Pathways - CDC cdc.gov Sep 1, 2023 3 facts
referenceVadiveloo and Mattei (2017) investigated the relationship between perceived weight discrimination and the 10-year risk of allostatic load among U.S. adults.
measurementWeight-related stigma and perceived discrimination are associated with a two-fold risk of high allostatic load.
measurementA study found that weight-related stigma and perceived discrimination were associated with a two-fold risk of high allostatic load.
Biopsychosocial disequilibrium - Rehabilitation Matters rehabilitationmatters.com Nov 14, 2025 3 facts
referenceJenny Guidi and colleagues conducted a systematic review titled 'Allostatic Load and Its Impact on Health: A Systematic Review' regarding the concept of allostatic load in relation to human health.
claimAllostatic load is a concept indicative of maladaptation by control mechanisms, where bodily changes resulting from present or anticipated situations become harmful if sustained for too long.
referenceKathryn Seeley and colleagues conducted a scoping review titled 'The application of allostasis and allostatic load in animal species' regarding the application of allostasis and allostatic load in animal species.
Self-awareness, self-regulation, and self-transcendence (S-ART) frontiersin.org 2 facts
referenceMcEwen, B. S. (1998) published 'Stress, adaptation, and disease. Allostasis and allostatic load' in Annals of the New York Academy of Sciences, volume 840, pages 33–44, discussing the concepts of allostasis and allostatic load in relation to stress and disease.
claimAllostatic load is defined as the cumulative wear and tear on the body and brain resulting from an overactive or inefficiently managed stress response (citing McEwen, 1998; Sterling and Eyer, 1988).
Explaining biological differences between men and women by ... link.springer.com Mar 23, 2023 1 fact
referenceMcEwen BS and Seeman TE (1999) elaborated on and tested the concepts of allostasis and allostatic load, describing the protective and damaging effects of mediators of stress.
Physiology, Homeostasis - StatPearls - NCBI Bookshelf ncbi.nlm.nih.gov May 1, 2023 1 fact
referenceLogan JG and Barksdale DJ authored 'Allostasis and allostatic load: expanding the discourse on stress and cardiovascular disease' in J Clin Nurs in April 2008.
Psychobiological Response to Acute and Chronic Stress psychologywriting.com 1 fact
claimAllostatic load is defined as the wear and tear of the body due to chronic stress responses resulting from repeated and long-term exposure to stress.
Associations Between Sleep Duration and Cognitive Function ... humanfactors.jmir.org 1 fact
referenceMcEwen and Karatsoreos (2022) examined the impact of sleep deprivation and circadian disruption on stress, allostasis, and allostatic load.
Homeostatic systems, biocybernetics, and autonomic neuroscience pubmed.ncbi.nlm.nih.gov 1 fact
claimThe consequences of models with versus without homeostats remain the same regarding allostatic load and the eventual transition from stabilizing negative feedback loops to destabilizing, pathogenic positive feedback loops.