By Daniel P. Keating
The central story line for Born Anxious starts with stress methylation — an “epigenetic modification” that occurs early in life, in the womb or during the first year of an infant’s life. Like all epigenetic modifications, this specific one alters how the gene works, but doesn’t change the DNA in any way. There are kinds of biological embedding beyond this specific epigenetic methylation (of the gene NR3C1 that exerts control over the glucocorticoid feedback loop). These other kinds of biological embedding include epigenetic modifications of other key genes in response to social and physical exposures (that is, other genes also listen to the environment in early life), and other mechanisms that have an impact on gene expression.
From this starting point, the consequences follow: it leads to stress dysregulation, keeping the stress response on a high alert status; this in turn leads to a lifetime of problems in development and health, from relationship difficulties, to school and work problems, to stress-related diseases in adulthood, and an elevated risk of early death; and the social distribution of these outcomes shows that inequality is a new predator, increasing both stress-dysregulation and a stress epidemic that shows up in increasing reports that we feel stressed, increasing biological markers of stress that lead to diseases, and more stress-related diseases. Among wealthy societies that are more unequal, and especially show increases in inequality, these consequences show up more than in societies with lower inequality.
So why focus primarily on methylation of this stress gene for the central story line, that leads to such dramatic outcomes? First, it was the focus of the original groundbreaking work by Michael Meaney’s research group at McGill that largely launched the field of social epigenetics, and because the accumulating evidence for its similar operation across multiple species is strong. Second, the site of its action is the HPA-axis, and we know a great deal about how dysregulation of the stress-response system affects health and development across the lifespan. Third, this pattern of outcomes from stress dysregulation tracks closely with what we have learned about the nature of the social gradient in developmental health, supporting the view that it is a key player in how social inequality “gets under the skin.” Fourth, the links from micro to macro show a strong consilience — a jumping together of superficially unrelated findings — that raises our confidence in the main conclusion: a powerful dynamic system connects stress methylation to the effects of stress dysregulation across the lifespan, to the social gradient and social inequality, to how societies differ in the way that they deal with social inequality, and returns full circle to promote or inhibit stress methylation in subsequent generations.
Most people in advanced societies today do not confront predators or similar threats of our ancient ancestors, when having a high alert stress system would have advantages. So what causes the level of stress to trigger stress methylation today? In some situations — war zones or highly dangerous neighborhoods, for example — the stress is similar, namely, threats to survival. And we do see differential methylation in those situations. But we also see evidence of it in individuals who experience economic deprivation and uncertainty, leading to early life adversity in their children.
So it is easy to see how early life adversity from poverty or disadvantage could matter, but why would it affect middle or upper class families and individuals? As societies become highly unequal, such as we are experiencing today, being in the middle or even upper classes is no guarantee of maintaining that position. Significant downturns in employment or financial status, as in the Great Recession beginning in 2008, can make most anyone feel vulnerable. And if not for oneself, worries that we have for our children in a decreasingly mobile society, can generate stress in terms of them “sliding down” the social ladder.
This might imply that everyday stress for anyone might trigger stress methylation throughout the population, so it’s important to ask how much stress does an expectant mom need to experience to trigger this? We don’t have (yet) a dose-response curve — we don’t know exactly how much stress is too much. In part, this is because research is just beginning to look at this in the population as a whole. But also, there is not a direct translation from external circumstances to the experience of stress — the perception of threats plays a major role in how stressed one feels. Everyday hassles and moderate stressors are likely not enough, but sustained levels of worry or stress at a significant level are.
In addition to high stress during pregnancy, leading to cortisol levels in the fetus that can lead to stress methylation, a poor, high-stress nurturing environment in the first year or so can have the same effect. The kind of nurturing issues that can lead to stress methylation range from obvious extremes to those experienced in more typical circumstances. At the extreme, as in the Romanian orphanages through the 1980s, the absence of any contact other than cleaning and feeding leads almost inevitably to that outcome. In more typical circumstances, low levels of sensitive, warm, and responsive contact with the infant are sufficient. This can happen for a number of reasons, but very high levels of stress in the parents are clearly associated with problematic nurturing. Lack of experience in parenting or mental health challenges of the parents can lead to similar outcomes.
The links from inequality to early life adversity to stress dysregulation seem enough to set up a spreading problem of stress with increasing inequality, but what evidence is there for a stress epidemic? There are several convergent lines of evidence. One is through surveys of self-reported stress, or symptoms of stress like feeling agitated, which show increasing reports of this. A repeated survey of a nationally representative population sample has shown steady increases over a number of years, as well as a recent spike coincident with the 2016 election and the 2017 Inauguration from a different survey by the American Psychological Association. A second line of evidence comes from the significant increases in stress-related disorders and diseases, as charted over years by the Center for Disease Control and Prevention (CDC), including metabolic disorders, obesity, sleep deficiencies, and others. Third, recent evidence at a population level shows an increase in physiological stress — such as cholesterol and markers of liver and heart function — from the late 1970s to today. And, the social inequality of that physical “stress load” has also gotten worse.
We see the biological consequences of rising inequality in several ways. One is the direct measure of a physical stress load measure, as just noted. Another is that fraying of the social safety net can lead to insecurity about the basic necessities for a much larger part of the population. As well, even those not directly affected by this kind of insecurity at the moment will experience greater uncertainty about what the future may hold for them and for their children. As more people experience this inequality-generated stress — as the “new predator” — there is more stress around in general, carried from home to work to school, in a circle of contagion.
Looking back over the story that links the epigenetic change of methylation in how our genes function, to the lifelong impact this can have on developmental health through stress dysregulation, to the role played by the new predator of increasing social inequality, we may begin to feel a bit overwhelmed by the seemingly insurmountable challenge this poses. It can seem even more like our inevitable destiny when we recall the other rub to the epigenetics story: this change to the stress gene can be biologically inherited. The amped-up stress system that it leads to may can be caused not only by excess prenatal stress on the mother or by early life stress that the infant experienced. Also, the methylated version might have been passed down from one or several generations back.
With so many possible routes to poorly functioning stress systems, why isn’t everyone dysregulated? There is a real paradox here. We know that the long-term trend across human history is toward less conflict, less overall violence, lowered chances of dying from non-natural causes, and less harsh social environments. This is tough to square with a pandemic of amped-up, dysregulated stress throughout the whole population. And in comparing different countries today, we also find that some have steeper social inequality, to the detriment of their overall health and development. The countries that are more equal enjoy substantially better overall outcomes. Clearly, then, inequality is not destiny.
What we have seen is that although there are no magic bullets, many things can help to break the cycle, which are discussed in some detail in Born Anxious. Understanding how the vicious cycle works is an essential first step, but so is understanding the ways that we can interrupt the cycle: for our children, for our loved ones, for ourselves, for the communities where we live and the places where we work, and even for our societies. Redirecting entrenched systems is not easy, but over time, many small changes add up, helping to put in place a virtuous cycle that benefits all of us — and can lead to enduring gains for society as a whole.
DANIEL P. KEATING is a professor of psychology at the University of Michigan, and received his Ph.D. at Johns Hopkins. Keating has conducted research at leading North American universities; at Berlin’s Max Planck Institute; and with the Canadian Institute for Advanced Research, where he was a fellow for two decades and led the program in human development. He focuses on developmental differences: cognitive, social, emotional, and in physical and mental health. He resides in Ann Arbor, Michigan.
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