Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.

Background: The Adverse Childhood Experiences (ACE) Pyramid has been widely used for more than two decades to illustrate pathways linking childhood adversity to health outcomes across the lifespan. Since its development, substantial advances in the science of toxic stress have expanded understanding of the biological mechanisms through which adversity influences lifelong health. Objective: To describe the development and scientific rationale for a revised ACE Pyramid that reflects contemporary evidence on toxic stress, the biological pathways linking childhood adversity to health, and opportunities for prevention and healing. Methods: An interdisciplinary revision process was conducted in collaboration with subject matter experts from government, academia, healthcare, professional associations, and community-based organizations. Iterative review and refinement were used to align the framework with current scientific evidence and practice. Results: A revised ACE Pyramid was developed that preserves the familiar structure of the existing framework while incorporating advances in the science of toxic stress, prevention, and healing. Compared with the ACE Pyramid featured on the CDC website during development of the revised framework, the revised framework more explicitly emphasizes prolonged or excessive activation of the stress response as a central mechanistic pathway linking childhood adversity to lifelong health, expands the biological layer to encompass multiple interacting biological systems beyond neurodevelopment alone, and integrates prevention and healing opportunities throughout the framework. Conclusions: The revised ACE Pyramid synthesizes more than two decades of advances in the science of toxic stress into an accessible conceptual framework. It explains how childhood adversity becomes biologically embedded to shape lifelong health while emphasizing that prevention is possible and healing can occur throughout the life course. By providing a shared framework for understanding toxic stress biology, it can guide trauma-informed clinical care, public health action, research, and policy and help advance health equity and improve outcomes for children and families.

Objective: Adverse childhood experiences (ACEs), positive childhood experiences (PCEs) and adult protective and risk factors have each been associated with health outcomes but have rarely been examined together. We examined associations among ACEs, PCEs, adult protective and risk factors, and adult mental, behavioural, and physical health outcomes, including whether adult factors were independently associated with health after accounting for childhood experiences. Design: Cross-sectional observational study. Setting: California, USA. Participants: Data were analysed from 24 453 adults categorised into 5 age categories (18–25, 26–39, 40–54, 55–64 and ≥65 years) participating in the 2021 California Health Interview Survey, a statewide representative survey. Analysis: Outcomes included multiple mental, behavioural and physical health indicators, including composite measures of any physical condition and any mental/behavioural health condition. Weighted logistic regression models examined associations and interactions among ACEs, PCEs, adult protective and risk factors, and health outcomes, adjusting for age, gender and race/ethnicity. Additional models examined adult factors independent of ACEs and PCEs. Results: Greater ACE exposure was associated with higher odds of most poor health outcomes, whereas higher PCE exposure was generally associated with lower odds across mental, behavioural and physical health outcomes. Compared with individuals with high ACE exposure and low PCE exposure, progressively less ACE exposure was associated with progressively lower odds of any mental/behavioural health condition (moderate ACEs OR=0.59, 95% CI 0.50 to 0.70; no ACEs OR=0.30, 95% CI 0.24 to 0.37) and any physical condition (moderate ACEs OR=0.75, 95% CI 0.64 to 0.88; no ACEs OR=0.58, 95% CI 0.45 to 0.75). Adult protective and risk factors remained independently associated with health outcomes after accounting for ACEs and PCEs. Higher cumulative protective factor exposure was associated with lower odds of any mental/behavioural health condition (OR=0.49, 95% CI 0.42 to 0.57) and any physical condition (OR=0.63, 95% CI 0.53 to 0.74). Conclusions: Adult protective and risk factors were associated with health outcomes independent of ACEs and PCEs, extending prior ACE and PCE research beyond childhood experiences. Findings highlight the importance of healthcare and public health approaches that address both childhood and adult adversity and strengthen protective resources and supportive environments.

Background: The Adverse Childhood Experiences (ACE) Pyramid has been widely used for more than two decades to illustrate pathways linking childhood adversity to health outcomes across the lifespan. Since its development, substantial advances in the science of toxic stress have expanded understanding of the biological mechanisms through which adversity influences lifelong health. Objective: To describe the development and scientific rationale for a revised ACE Pyramid that reflects contemporary evidence on toxic stress, the biological pathways linking childhood adversity to health, and opportunities for prevention and healing. Methods: A multidisciplinary revision process was conducted in collaboration with subject matter experts from government, academia, healthcare, professional associations, and community-based organizations. Iterative review and refinement were used to align the framework with current scientific evidence and practice. Results: A revised ACE Pyramid was developed that preserves the familiar structure of the existing framework while incorporating advances in the science of toxic stress, prevention, and healing. Compared with the ACE Pyramid featured on the CDC website during development of the revised framework, the revised framework more explicitly emphasizes prolonged or excessive activation of the stress response as a central mechanistic pathway linking childhood adversity to lifelong health, expands the biological layer to encompass multiple interacting biological systems beyond neurodevelopment alone, and integrates prevention and healing opportunities throughout the framework. Conclusions: The revised ACE Pyramid synthesizes more than two decades of advances in the science of toxic stress into an accessible conceptual framework. It explains how childhood adversity becomes biologically embedded to shape lifelong health while emphasizing that prevention is possible and healing can occur throughout the life course. By providing a shared framework for understanding toxic stress biology, it may help inform trauma-informed clinical care, public health action, research, and policy aimed at advancing health equity and improve outcomes for children and families.