Adversity exposure during sensitive periods predicts accelerated epigenetic aging in children
Introduction
Exposure to childhood adversity, such as abuse or poverty, represents one of the most potent risk factors for a range of negative health outcomes across the lifespan, with estimates linking such exposures to at least a two-fold increase in subsequent risk for mental disorders (Dunn et al., 2012; McLaughlin et al., 2010). Although these associations are well-established, the specific mechanisms through which adversity becomes biologically embedded remain poorly understood.
Accumulating evidence suggests adversity may become biologically embedded through accelerated aging of cells, tissues, and organs (Gassen et al., 2017; Zannas et al., 2015). Accelerated biological aging, in which biological age outpaces chronological age, is known to be a valid indicator of impaired functionality of both the cell and the biological system in which the cell interacts (Teschendorff et al., 2013).
Recently, DNA methylation (DNAm) patterns at specific CpG sites have been proposed as a promising measure of biological aging. These DNAm-based measures are referred to as “epigenetic clocks” due to their remarkably high correlation with chronological age (Hannum et al., 2013; Horvath, 2013). Two independent algorithms developed to generate these DNAm-based age estimates are the Horvath clock (Horvath, 2013) and the Hannum clock (Hannum et al., 2013). Both clocks can be used to capture accelerated epigenetic aging, which represents the discrepancy between the estimate of epigenetic age based on DNAm patterns and an individual’s chronological age (Hannum et al., 2013; Horvath, 2013). In adults, accelerated epigenetic aging as measured by these epigenetic clocks has been correlated with numerous adverse health outcomes (Breitling et al., 2016; Dhingra et al., 2018), including increased mortality risk (Marioni et al., 2016). These epigenetic clocks have been shown to reliably correlate with chronological age in younger populations as well (Horvath et al., 2016; Simpkin et al., 2017); accelerated epigenetic aging in children and adolescents has been associated with both more advanced growth and development and increased youth mental health problems (Suarez et al., 2018a; Sumner et al., 2018).
A handful of recent studies have explored how exposure to adversity influences epigenetic aging in adulthood (Brody et al., 2016; Fiorito et al., 2017; Lawn et al., 2018; Simons et al., 2016; Wolf et al., 2017; Zannas et al., 2015). These studies have shown that individuals who have perceived subjective high levels of stress across their lifetimes (Zannas et al., 2015), including exposure to sexual abuse (Lawn et al., 2018), a parent’s mental illness (Brody et al., 2016; Davis et al., 2017), or chronic financial stress (Simons et al., 2016), have epigenetic ages that outpace their chronological age. One recent meta-analysis quantified this age acceleration, showing that any exposure to childhood trauma was associated with an epigenetic “outpace” of as much as 6 months (when epigenetic age was estimated with Hannum’s, but not with Horvath’s clock) (Wolf et al., 2017).
However, to our knowledge, only two studies––both of which are cross-sectional––have investigated these associations in children. In one study of youth ages 6–13 years, children who were at least one standard deviation epigenetically older than their peers were found to score twice as high on a measure of lifetime violence exposure (Jovanovic et al., 2017). A more recent study of youth ages 8–16 years reported that each childhood experience of threat (e.g., abuse, domestic violence) was associated with approximately one additional month of epigenetic age acceleration (Sumner et al., 2018).
Although evidence from these studies suggests a link between adversity exposure and accelerated aging, most of this work has primarily focused on one or two types of adversity, as opposed to a range of possible exposure types. As noted, previous studies investigating adversity-induced epigenetic aging in children have also all been limited to cross-sectional designs, rather than studies using prospective assessment of adversity exposure. Furthermore, to our knowledge, no studies have examined the importance of the timing of adversity exposure. Given the growing body of support for “sensitive periods” in development, during which time developing organs, tissues, and biological systems may be particularly susceptible to the effects of experience (Bornstein, 1989; Knudsen, 2004; Shonkoff et al., 2009), consideration of the timing of adversity across the life course is warranted. Indeed, a recent study found that the effects of childhood adversity on epigenetic patterns were largely driven by when the adversity occurred, with the period from birth to age 3 emerging as a sensitive period when exposure to adversity was associated with more epigenetic changes (Dunn et al., 2019). Importantly, a standard epigenome-wide association study of lifetime adversity exposure (versus no exposure) failed to detect these associations (Dunn et al., 2019). Findings like these emphasize the need to investigate not only the biological consequences of adverse experiences, but also the possibility of time-dependent effects that may be obscured by simple exposed vs. unexposed models.
In the current study, we aimed to address these limitations and test the central hypothesis that postnatal adversity exposure does have an accelerating effect on epigenetic age in childhood, and that these effects may be strongest and most detectable during sensitive periods in development. Investigating sensitive periods may not only help to reveal otherwise undetectable time-dependent effects, but it may also help to identify “high risk/high reward” periods in development, when adversity exposure can be most potent but health-promoting interventions might be most impactful.
Section snippets
Study overview
We tested three consecutive hypotheses. We first assessed the independent associations between a set of postnatal adversity exposures and accelerated epigenetic age at age 7.5, regardless of the timing of exposure. Second, given the previously described evidence from epigenetic studies that simple classification of individuals as exposed versus unexposed to adversity may dilute observed effects (Dunn et al., 2019), we then tested––for each adversity type––a sensitive period model, which posits
Results
There were 973 children in the analytic sample (50.2% female, 97.2% white). Descriptive statistics on other covariates are presented in Supplemental Table 4.
Discussion
This study tested the hypothesis that adversity exposure during sensitive periods in development is associated with accelerated epigenetic aging in childhood as measured by two epigenetic clocks, and that these associations can be better detected using methods that account for exposure timing, rather than simple comparisons of exposed versus unexposed individuals. To allow for the possibility of other timing effects, we also compared sensitive period models to alternative theoretical life
Conclusions
In conclusion, we found that adversity experiences assessed in very early, early, and middle childhood were differentially associated with accelerated epigenetic aging at age 7.5. These findings suggest that accelerated epigenetic aging may function as one of the mechanisms through which childhood adversity becomes biologically embedded, and that adversity exposures during sensitive periods in childhood may have a particularly strong accelerating effect on epigenetic age. Future research
Authors’ contributions
SM, ECD, TWS, ADACS and EJW designed the study. TWS, MJS, ADACS and CRL produced the data. Statistical analyses were performed by SM, TWS, YZ and AJS. SM, KAD and ECD wrote the manuscript. All authors revised the manuscript critically and approved it for submission.
Declarations of Competing Interest
None.
Acknowledgments
This work was supported by the National Institute of Mental Health of the National Institutes of Health under Award Numbers [K01MH102403 and 1R01MH113930 E.C.D.] and under [R03AG051877 and 3R03AG051877-02S1 E.W.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, or the United States Government. The authors thank Alice Renaud for her assistance in preparing
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These authors contributed equally.