Holistic Rehabilitation: Biological Embedding of Social Adversity and Its Health Implications

Abstract

Human health is affected by lived experiences, both past and present. The environments we encounter throughout our lives, therefore, shape how we respond to new challenges, how we maintain a healthy immune system, and even how we respond to treatment and rehabilitation. Early in life and throughout adulthood, social experiences—such as exposure to various forms of adversity—can alter how cells in our body function, with far-reaching consequences for human health, disease, and treatment. This Perspective highlights studies from an ever-growing body of literature on the social determinants of health, with a focus on exposure to social adversities, such as social isolation, discrimination, or low social status, experienced both early in life and adulthood and how they variably impact health. By focusing on recent observational studies in humans and experimental studies on social nonhuman animals, this article details how social adversity can become biologically embedded in our cells at the molecular level. Given that humans are social animals, it is no surprise that social adversity can negatively impact our health, and experimental animal studies have helped us to uncover some of the causal mechanistic pathways underlying the link between social adversity and health outcomes. These molecular consequences can have far-reaching implications and, when combined with our growing knowledge on the social determinants of health, should inform how we approach treatment and rehabilitation.

Introduction

As humans, we are inherently social organisms, and, as a consequence, our social environment and life experiences can profoundly impact our health and survival.^1,2 These social experiences, particularly those that lead to increased risk of disease and death, termed “social adversity,” are key to a holistic approach to treating individual patients. As researchers and clinicians, we must take into account these “social determinants of health” and understand how they “get under the skin” to impact individual susceptibility to disease and, crucially, responsiveness to treatment and rehabilitation.

From an evolutionary standpoint, it is no surprise that social adversity, most commonly social isolation, discrimination, or low social status, can negatively impact our health. The vast majority of our close nonhuman relatives live in highly social environments.³ Consequently, social relationships and sociality have been strong evolutionary forces across the evolutionary tree; individuals with more and stronger social relationships live healthier, longer lives and produce more offspring.¹ In humans, the all-cause mortality risk attributed to social isolation exceeds the risks of smoking, obesity, and air pollution,^4–6 and differences in socioeconomic status can translate to differences of a decade or more of life expectancy.⁷ We are now only beginning to identify precisely how these environmental factors “get under the skin” to affect our health and mortality risk. In this Perspective, we argue that identifying and understanding these mechanisms, and in particular their molecular routes, is essential to improving all aspects of the health care system and treatment.

This Perspective is also timely and not just due to the recent social distancing measures. Over the past few decades, we have seen rising social isolation, discrimination, and inequality.^8–11 Social adversity is thus a growing priority for public health and policy. In response to these growing health disparities, the UK government appointed a “Minister for Loneliness” in 2018, and the World Health Organization has launched initiatives to focus attention on the social determinants of health.^5,6,12,13 In this Perspective, we detail the molecular and immunological routes through which social adversity can alter health and how this can inform personalized approaches to treatment and rehabilitation. This piece is not meant to be a comprehensive review of the link between social adversity and health and mortality outcomes, which has been the subject of many excellent recent reviews.^1,14,15 Rather, we focus on a brief description of the mechanisms through which adverse experiences can alter physiological and immunological pathways that can impede successful rehabilitation.

Social Adversity as a Chronic Stressor

Strong social relationships and high social status are associated with stability and predictability, thus reducing uncertainty in our day-to-day lives. Individuals in unpredictable social environments, such as those who are socially isolated, face discrimination, and/or are low social status, can be more psychosocially stressed than their socially advantaged counterparts. In fact, there are many situations that, when repeated, can be considered chronic social stressors, including workplace stress, family disputes, chronic care of ill family members, bullying, discrimination, and many others.¹⁶ As singular instances, each of these events would elicit an acute physiological stress response that may not have long-term consequences (depending on the severity of the stressor). But on repeated (or continuous) exposure, as is the case with many of these experiences, the stress response pathway wears down, leading to long-term negative physiological changes and health consequences.¹⁷

Currently, the best supported hypothesis is that this chronic stress of social adversity induces lasting changes to our stress response pathway (the hypothalamic–pituitary–adrenal [HPA] axis), which can have dramatic downstream consequences on immune function and metabolism. In response to an acute stress, we activate the HPA axis, which leads to the rapid secretion of glucocorticoids (GCs) that shunt energy from noncritical functions (like reproduction and immunity) while mobilizing energy to respond to the acute stressor.¹⁸

The HPA-axis is part of a negative feedback loop that ultimately puts a limit on the magnitude and duration of the physiological response (Fig. 1). On release, GCs bind to their primary receptor, the glucocorticoid receptor (GCR), and rapidly alter transcription of many cells in the body,¹⁹ including those that deactivate the HPA-axis and halt further GC secretion. However, when chronically stimulated—as seen in people experiencing chronic social adversity—this negative feedback loop is dampened, GCs are secreted for a longer time period, and their ordinarily short-lived effects are longer-lasting, leading to a state called “glucocorticoid resistance” (Fig. 1). Perhaps because GCs are also potent anti-inflammatories, this GC resistance is causally linked to unchecked, low-grade proinflammation²⁰ that is the etiology of many non-communicable diseases, including heart disease and diabetes.²¹

Figure 1.

Schematic of glucocorticoid resistance as a result of chronic social adversity. Chronic stress wears down the normal acute stress response of the hypothalamic–pituitary–adrenal (HPA) axis, which has a negative feedback loop to reduce the duration of cortisol secretion. With chronic activation of the HPA-axis, the glucocorticoid receptors become less sensitive to the glucocorticoids (cortisol) leading to a prolonged and “leaky” response that can have negative downstream health outcomes. Figure adapted from “Hypothalamic–Pituitary–Adrenal Axis” by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.

Consequences of Social Adversity

The link between chronic social adversity and poor health and survival outcomes has been documented in many comprehensive reviews (eg,^1,2,22–24). These negative effects are not limited to a specific period of life and can accumulate throughout life in a dose-dependent manner. For instance, experiencing at least 1 adverse childhood experience (eg, separation from family members or physical abuse) is associated with a 1.3- to 1.7-fold increase in the risk of ischemic heart disease, and this risk was almost tripled in people who had experienced at least 7 adverse childhood experiences.²⁵ Even in late life, the effects of the social environment can be equally consequential. Among members of the US Health and Retirement Survey, those who lost their jobs in the past year were more than 2 times more likely to experience a myocardial infarction or stroke.²⁶ Across adults of all ages, those who are more socially isolated experience higher rates of psychiatric disorders,²⁷ cardiovascular disease,²⁸ and mortality.^4,29 Together, these findings provide support for foundational frameworks, such as ecosocial theory,³⁰ that aim to integrate social and biological systems across the life course to understand and explain the biological embedding of social determinants of health.

Many of the physiological and disease outcomes associated with social adversity are also well-known consequences of aging. Thus, exposure to adverse life experiences can recapitulate or even accelerate the aging process.³¹ One salient example of this effect is invoked by the “weathering hypothesis,” which posits that chronic social adversity accelerates aging and leads to the early onset of age-associated diseases and death.³² More specifically, groups exposed to more racial discrimination, like African Americans, can exhibit signatures and diseases associated with chronic stress and accelerated aging.^33–36

Molecular Mechanisms

The similarities between chronic social adversity and aging have helped researchers to uncover some of the mechanisms underlying the effects of adversity on health outcomes. Indeed, we are only beginning to identify how these social experiences can “get under the skin” to persistently alter physiology and, consequently, health. To address these, researchers have looked at molecular “hallmarks of aging”³⁷ that are associated with, and in some studies were shown to be caused by, adverse life experiences. Studies of adversity in humans are, by definition, observational and thus can typically only provide evidence for associations, rather than causal links, between adversity and biological outcomes. We acknowledge that newly developed statistical approaches, such as Mendelian Randomization,³⁸ as well as carefully designed interventions to reduce adversity (eg, Moving to Opportunity³⁹) have allowed for causal inferences to be drawn in a handful of human observational studies of adversity. Experimental studies of non-human animals, on the other hand, allow us to test for causal links. Moreover, by studying animals, we can examine how stressful life experiences can molecularly alter many organs, including those involved in immune function, cardiac function, and the central nervous system. Below, we thus draw on findings from studies in humans and other animals to highlight 2 routes through which adverse social experiences can become biologically embedded in our cells and negatively impact health.

Telomere Attrition and Cellular Senescence

As we get older and our cells replicate, the protective caps on the ends of our chromosomes, called “telomeres,” gradually shorten. This shortening is associated with the natural process of cellular senescence and, eventually, cell death, making telomere length a robust biomarker of aging.⁴⁰ Socially adverse experiences, experienced early in life and in adulthood, are also associated with shortening of telomeres. Some of the first evidence of this connection was found in caregiving mothers of chronically ill children: mothers who reported the highest levels of perceived stress had leukocyte telomeres that were the length of someone 9 to 17 years older than they were.⁴¹ Since this landmark study, other observational human studies have found similar links between chronic social adversity and shorter telomeres in white blood cells. Meta-analyses of these studies suggest telomere attrition is significantly associated with exposure to early-life adversity⁴² and less consistently with chronic stress in adulthood.^43,44 These findings highlight the long-lasting cellular effects of exposure to social adversity, with some of the strongest associations coming from adverse experiences during particularly sensitive periods of early development.

There have been few experiments aimed at testing if social adversity causes telomere attrition. Young male mice that were exposed to the stress of overcrowding had shorter telomeres than mice not exposed to this stressor, but this was not the case in female mice.⁴⁵ More recent studies of chronic stress in adult male mice identified no significant differences between dominant males and chronically stress-subordinate males despite demonstrably strong effects of social subordination on other aging biomarkers, health, and mortality.⁴⁶ In nonhuman primates, which are much more evolutionarily close to humans than rodents,⁴⁷ there is only 1 study to date demonstrating equivocal evidence for early-life stress leading to shorter telomeres in circulating blood cells in adults.⁴⁸ This lack of a clear causal link between social adversity and telomere attrition suggests that there may be other components of the human environment or experience that mediate this link.

Gene Regulation (Epigenetics, Gene Expression)

Many different socially adverse experiences have been shown to alter the molecular machinery of our cells, with most of this work being conducted in our primary immune cells, leukocytes.⁴⁹ In these cells, exposure to various forms of social adversity, ranging from adverse childhood experiences to social isolation, can alter the expression of hundreds of genes, which has led to a seemingly exponential increase in the study of “social genomics.”⁵⁰ This field has been driven by observational studies in humans focused first on just a few genes and then, with the advent of high-throughput sequencing technologies, across the entire human genome. There are 2 primary molecular metrics that have been used to quantify social environmental effects on our cells.

One is gene expression, which is the molecular readout of the cell and an intermediate phenotype that reflects what RNA the cell is making, which roughly reflects what proteins the cell is producing. In humans, for example, growing up in a low–socioeconomic status household is associated with altered HPA-axis function and increased proinflammatory gene expression in adulthood.⁵¹ Racial discrimination throughout life can have a similarly strong effect on the leukocyte transcriptome: African Americans exhibit higher expression of proinflammatory genes compared with European Americans, and at least 50% of this effect can be attributed to reported experiences of racism in this cohort.⁵² The second molecular readout is DNA methylation, which is one measure of the epigenome⁵³ that regulates which, when, and how much genes are expressed. Because DNA methylation marks tend to be stable, long-term molecular changes, they represent a promising route through which lived experiences can become biologically embedded and exert long-lasting effects.^53–55 Thus, there is a growing body of literature on the link between social adversity and DNA methylation in human immune cells. For instance, early-life adversity, cortisol output, and perceived stress were associated with levels of DNA methylation across the genome, and these changes predicted the ex vivo cellular response to a pathogen.⁵⁶ Epigenetic marks also reflect age-related changes and can be used to estimate “biological age.”⁵⁷ This allows for the quantification of age acceleration, which is the difference between chronological age and biological age.⁵⁷ In 1 study, low socioeconomic status in early life and adulthood was associated with a 1-year age acceleration, but this acceleration was less pronounced in people who experienced improved conditions later in life, suggesting that interventions to improve the social environment may be effective.⁵⁸ These observational studies demonstrate that by taking a life course perspective, we see that lived experiences can leave a biological residue on our cells that can have lasting and important effects on our health and well-being.

These human studies, however, often fall short in identifying what it is about the social environment that causes these changes, which is an essential precursor to developing effective interventions. For instance, many forms of adversity co-occur and can be associated with other systemic issues, such as inadequate access to health care, which itself is associated with health outcomes. To control for these potential confounds, we can turn to experimental animal models. Social adversity in humans has many animal homologs across the animal kingdom (Fig. 2), of which nonhuman primates and rodents are study species of choice. These experimental studies have proven to be particularly fruitful in identifying causal links between social adversity and molecular changes in the periphery and central nervous system. In rodents, early-life separation from the mother causes dramatic epigenetic and transcriptional changes in the brain.^59,60 Moreover, adult mice subjected to chronic social defeat (a form of chronic stress) exhibit increases in proinflammatory gene expression.⁶¹ Some of the strongest evidence for a causal link between social adversity and health-relevant molecular changes come from studies in nonhuman primates. In rhesus macaques, maternal separation early in life induces an inflammatory transcriptional program that may last into adulthood.⁶² In this same species, experimental manipulations of dominance rank, which is homologous to social status in humans, induce strong epigenomic and transcriptomic changes to white blood cells.^63,64 These changes not only impact baseline inflammatory and immune function but also how the immune system responds to future pathogens and infections.⁶⁴ Further, this proinflammatory response is in large part due to epigenomic changes in the 3D structure of DNA—specifically chromatin accessibility—that reflect molecular signatures of GC resistance in white blood cells.⁶⁵ In these experimental systems, we can also test the efficacy of behavioral interventions by improving the social environment of individuals who previously experienced experimentally induced social adversity. The results of this work are somewhat promising: although monkeys that increased in social status exhibited a transcriptional profile that reflected their improved social environment, they still exhibited a number of signatures associated with their past, most socially adverse, conditions.⁶⁶

Figure 2.

Social adversity in human and nonhuman animals. Social adversity can take many forms and has far-reaching impacts on adult health and well-being. These links have been identified across many social species with homologous behaviors and social relationships. In early life, adversity to the pregnant individual can affect the fetus. Similarly, low levels of parental care or high levels of neglect across rodents, monkeys, and humans affect the cells late into life. In adulthood, chronic adversity from job instability, discrimination, social subordination, and other adverse exposures can contemporaneously alter molecular functioning in the immune and central nervous system. The studies in nonhuman animals provide direct causal evidence for links between adversity and health outcomes, which can provide the foundation for testing and implementing effective interventions and treatments. Figure created with BioRender.com.

The observational human and experimental animals studies together suggest important, long-lasting, and causal effects of social adversity on our cellular machinery. This biological embedding of our lived experiences is therefore a promising mechanistic explanation for the negative health outcomes associated with chronic social adversity.

Implications for Rehabilitation and Outlook

From a primary care standpoint, it is clear that not all patients are the same, even if they present with the same symptoms. The treatment and care for a 60-year-old with acute onset of mechanical hip pain is different from that of a 16-year-old patient with the same presentation. We use their current social and living situation in planning treatment, treatment setting, and discharge. So why do we not also take into account past experience and exposures when treating patients? In the examples of the different aged patients with the same diagnosis, past exposure may not necessarily alter the treatment for the impairments we find for this orthopedic problem. When considering treatment planning for 2 patients of the same age with chronic hip pain, considering past exposure and experiences may provide insight into not only treatment choices, but also prognosis. Our current physiological state reflects our life experiences, including social adversity, which as detailed above clearly makes us vulnerable to disease and death.

Thus, because rehabilitation is primarily a behavioral process, we should take a holistic and thoughtful approach to treating each patient. When developing a plan of treatment, we should think about the person first and then the condition. Biological embedding has great relevance for rehabilitation practice and research. In rehabilitation, we always consider past medical history, age, exposures (eg, smoking), and other effectors of healing. We also consider the environment, but in both cases we focus on current conditions (medical, social, and environmental). We do not commonly consider the cumulative effects of psychological stressors (eg, socioeconomic disparities) or childhood deprivation (eg, malnutrition) on biological processes. The concept biological embedding thus has important implications for rehabilitation throughout the lifespan. For example, rehabilitation research has demonstrated that strengthening exercise can induce key molecular changes that impact health and physiology.⁶⁷

Further, although it is clear that social adversity negatively impacts health and survival, it is equally important to look at the other side of the coin to understand how to help. Social adversity is always measured relative to individuals who have not or are not experiencing social adversity, sometimes called “social advantage.” One of the strongest forms of social advantage is the presence of a supportive social network. Indeed, individuals with better social support in their communities and homes are more likely to adhere to medical treatment⁴⁸ and have lower cancer mortality rates after diagnosis.⁶⁸ Thus, although a poor social environment can negatively impact health and rehabilitation, helping to provide and build a more supportive and predictable social environment can be even more impactful.⁶⁹ Physical therapists play key roles in discharge planning for patients in acute care settings and always take into consideration home environment and support systems when determining the setting to which a patient will be discharged (eg, inpatient rehabilitation center, home with home physical therapy, or home with outpatient physical therapy). Physical therapists in home and outpatient physical therapy can work with patients and families to build certainty and caring.

We are long past the nature versus nurture debate. It is clear that the environment drastically outweighs almost all genetic effects when it comes to complex traits and diseases. Thus, training of professionals in the physical therapy world should include at least a primer on the dramatic effects of adverse social experiences on physiology. By demonstrating and teaching that there are, in fact, molecular marks reflecting our lived experiences, we will be able to critically think about how that impacts our treatment decisions and metrics for successful rehabilitation.

Author Contributions

Concept/idea/research design: N. Snyder-Mackler

Writing: N. Snyder-Mackler, L. Snyder-Mackler

Consultation (including review of manuscript before submitting): N. Snyder-Mackler, L. Snyder-Mackler

Acknowledgments

N. Snyder-Mackler would like to thank L. Snyder-Mackler for saddling him with the burden of 2 last names—and, more importantly, for providing a supportive and stimulating environment where he could follow his curiosities and pursue his passion for a better understanding of human and animal behavior and health.

Funding

N. Snyder-Mackler was supported by a grant from the National Institutes of Health (NIH R01-AG060931 and R00-AG051764).

Role of the Funding Source

The funder played no role in the writing of this Perspective.

Disclosures

The authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported no conflicts of interest.