ReviewMismatch or cumulative stress: Toward an integrated hypothesis of programming effects

This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective.

Graphical abstractDownload full-size imageHighlights► We integrate the mismatch hypothesis with the cumulative stress hypothesis. ► Mismatch hypothesis: high disease risk when early and adult environments mismatch. ► Cumulative stress hypothesis: high disease risk with increasing levels of adversity. ► Mismatch hypothesis applies to individuals with high sensitivity to programming. ► Cumulative stress hypothesis applies to individuals with low programming sensitivity.