Can Childhood Adversity Affect Telomeres of the Next Generation? Possible Mechanisms, Implications, and Next-Generation Research

The potential bidirectional relationship between telomeres and psychopathology just became more complicated, given the transgenerational transmission of each of these. The study by Esteves and colleagues (15), published in this issue of the Journal, leads us into new territory, forcing us to think deeply about both the methods and mechanisms of the telomere mental health relationships. This study examines novel relationships between maternal ACEs and offspring telomere length and whether the combination of these factors predicts infant risk for psychopathology.

The authors first ask whether ACEs in women lead to shorter telomeres in their offspring. Indeed, they found that maternal ACEs uniquely predict the telomere length of the infant. This calls for a serious consideration of the many potential mechanisms that could be involved. How can maternal ACEs affect offspring telomeres? This is a fascinating and important relationship but not a direct pathway by any means. The effects of ACEs on lifelong health within an individual alone are poorly understood and involve alterations in neural networks (including altered threat sensitivity and emotion regulation), how one perceives stressors, attachment schemas, and health behaviors. These changes create a risky neurobiobehavioral profile characterized by higher stress sensitivity throughout life. At the simplest and most parsimonious level, the relationship between ACEs and offspring telomere length might be through a prenatal programming effect of high levels of stress exposure. In this study, however, measures of prenatal stress did not mediate the effect of ACEs, leaving an open question regarding the mechanism.

In addition to the prenatal programming hypothesis, there can be direct telomere-epigenetic transmission. Chromosomes, together with their telomeres, are passed on to offspring through parental gametes. While ACEs and life span stress exposure are associated with shorter blood telomere length, it is not known whether, or to what extent, severe stress exposure also shortens gamete telomeres, or whether these cells are ultimately protected. If they are vulnerable to stress-induced shortening, there could be direct parental transmission of sperm or egg telomere shortness to offspring.

It is also possible that there are “grandmother” effects: a woman’s prenatal stress predicts shorter telomere length in her offspring, and theoretically prenatal stress would affect the baby’s telomeres in the gametes. That shortness can then be transmitted to the next generation (the grandchild) through direct telomere epigenetic-like transmission. We already know that this direct transmission of telomere length can occur with very short telomeres (10) and with long telomeres (affecting both first and second generations) (16). Thus, it is feasible that stress-related moderately shorter gamete telomeres are directly transmitted to future generations of offspring. If so, this has important implications and needs to be tested in intergenerational studies.

Is telomere length a harbinger for future psychopathology? And if so, is it also related to maternal transmission of risk for psychopathology in the offspring? Esteves and colleagues ask these questions, forcing the telomere field to consider a new level of complexity. There are multiple potential causal pathways between maternal preconception and prenatal factors and the child’s risk for psychopathology (e.g., maternal stressor exposure, maternal postnatal behavior and caregiving, and maternal epigenetic factors, including effects on telomere biology). So far, no studies have examined maternal risk on child outcomes using infant telomere attrition as a risk factor for later child well-being. However, Esteves and colleagues use it exactly in this way—as an independent risk factor or moderator for child mental health outcomes. They found that telomere attrition did not directly predict externalizing problems. Rather, in combination with high maternal ACEs, greater telomere attrition predicted an increased risk of child behavioral problems early in life, at 1.5 years old.

What does telomere attrition, in this case, indicate? Marker or mechanism? It is possible that telomere attrition might not be mechanistically linked but rather may reflect a vulnerable phenotype programmed by prenatal and preconception exposures. Taken together, high ACEs plus higher telomere attrition may more strongly indicate greater underlying biological chronic stress processes, such as higher oxidative stress, inflammation, and lower telomerase activity. This model is consistent with life history theory, in which greater early-life adversity accelerates development, leading to early puberty, which may have costs that are associated with earlier aging. If this were true, in this study, the highest risk group (those with ACEs and the fastest telomere attrition) should also have early puberty. No one has applied life history theory to understand telomere shortening in infancy and its consequences, although these relationships have been theorized (17).

If childhood experience indeed leads to shorter telomeres of the next generation, this has critical implications for public health. Telomere length tends to track throughout life, and telomere length at birth or in early childhood is a powerful predictor of adult telomere length, although life span studies are needed (18). However, this does not mean that interventions cannot help stabilize or slow telomere attrition, at least in the short-term, and there is growing support for lifestyle intervention effects in young, midlife, and older adults (19–21). We need more intervention research earlier in life, with multiple measures of telomere biology and other indices of aging.

The next generation of telomere studies will be the most exciting. Several institutes at the National Institutes of Health have recently prioritized funding directed toward enhancing the understanding of the measurement of telomeres, their sensitivity to different types of exposures, and their ability to predict later health outcomes. As part of this initiative, the National Institute on Aging (NIA) and the National Institute of Environmental Health Sciences have funded a Telomere Research Network to help guide the field in identifying gold-standard measurement protocols. Coincidentally, this is led by the senior author of the study by Esteves and colleagues, Stacy S. Drury, M.D., Ph.D., together with other leaders in the telomere field and in related fields such as environmental health.

Better measurement will enhance our ability to test changes in telomere biology over time within individuals, including during intervention studies. Increased funding and interdisciplinary collaboration will lead to more multilevel measures of the exposome (social, chemical, and environmental factors) and individual factors that affect telomeres. Advances in measurement of stress, to a more refined measurement of exposures versus responses, will be important, as advocated by the NIA stress measurement network (see Appendix 1 in the study by Epel and colleagues [22]). In terms of ACEs, it will be important to distinguish between threat and deprivation, which have different effects, including that threat exposures differentially lead to accelerated aging (23). Some of the most important studies will be longitudinal transgenerational cohort studies. This opens up the potential for “freezer studies”: use of stored whole blood or DNA from longitudinal cohort studies to facilitate discoveries. Integration of telomere length with other biomarkers of aging that are meaningful in youth, in studies that include both psychiatric and physical health monitoring, will lead to new discoveries relevant to understanding the rate of biological aging and allostatic load through the life span (24).

Despite the complexity of the findings, and the speculative nature of identifying putative mechanisms, the implications of Esteves and colleagues’ findings are clear. As the authors state, there is an emerging picture of “strong support for the need to integrate a multigenerational life-course perspective into our understanding of the biopsychosocial etiology of mental illness.” We also need widespread screening for stressors across the life course and social context. This is already happening in California, where the surgeon general has initiated universal screening of ACEs in primary care, along with referrals and education such as lifestyle counseling. The effects of this screening will be important to evaluate.

The author thanks Drs. Elizabeth Blackburn, Jay Belsky, Sonja Entringer, Idan Shalev, and Ned Kalin for their editorial comments.