Overproduction of IL-6, a proinflammatory cytokine, is associated with a spectrum of age-related conditions including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline.
To describe the pattern of change in IL-6 over 6 years among older adults undergoing a chronic stressor, this longitudinal community study assessed the relationship between chronic stress and IL-6 production in 119 men and women who were caregiving for a spouse with dementia and 106 noncaregivers, with a mean age at study entry of 70.58 (SD = 8.03) for the full sample.
On entry into this portion of the longitudinal study, 28 of the caregivers' spouses had already died, and an additional 50 of the 119 spouses died during the 6 years of this study.
Levels of IL-6 and health behaviors associated with IL-6 were measured across 6 years.
Caregivers' average rate of increase in IL-6 was about four times as large as that of noncaregivers.
Moreover, the mean annual changes in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse.
There were no systematic group differences in chronic health problems, medications, or health-relevant behaviors that might have accounted for caregivers' steeper IL-6 slope.
These data provide evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely aging the immune response.
A growing body of evidence has implicated caregiving as a risk factor for health.
Compared with noncaregivers, men and women who provide care to a spouse with a stroke or dementia report more infectious illness episodes, they have poorer immune responses to influenza virus and pneumococcal pneumonia vaccines, their wounds heal more slowly, they are at greater risk for developing mild hypertension, and they may be at greater risk for coronary heart disease.
Moreover, a prospective longitudinal study found that the relative risk for all-cause mortality among strained caregivers was 63% higher than noncaregiving controls.
Recent medical literature has highlighted a spectrum of age-associated diseases whose onset and course may be influenced by pro-inflammatory cytokines, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, Alzheimer's disease, periodontal disease, and frailty and functional decline.
The link to cardiovascular disease, the leading cause of death, has attracted the greatest attention; the association with IL-6 is related in part to the central role that this cytokine plays in promoting the production of C-reactive protein (CRP), an important risk factor for myocardial infarction.
For example, high concentrations of CRP predicted the risk of future cardiovascular disease in apparently healthy men.
CRP and IL-6 have other important health consequences in addition to their role in cardiovascular disease.
Elevated levels of CRP and IL-6 predicted the development of type 2 diabetes in a 4-year follow-up period in healthy women after adjustments for key risk factors; among women in the highest vs. lowest quartiles, the relative risk for developing diabetes was 7.5 for IL-6 and 15.7 for CRP.
In another study, elevated serum IL-6 levels predicted future disability in older adults, a finding that may reflect the effects of the cytokine on muscle atrophy, and/or the pathophysiologic role played by the cytokine in particular diseases.
Proinflammatory cytokines, including IL-6, may slow muscle repair after injury and accelerate muscle wasting; indeed, IL-6 and CRP also play a pathogenic role in a range of diseases associated with disability among the elderly (osteoporosis, arthritis, and congestive heart failure, among others).
Production of IL-6 and other proinflammatory cytokines can be directly stimulated by depression and other negative emotions and stressful experiences.
Indeed, both physical and psychological stressors can provoke transient increases in proinflammatory cytokines.
Additionally, negative emotions contribute to greater risk for infection, prolonged infection, and delayed wound healing, all processes that can fuel sustained proinflammatory cytokine production.
Thus, stressors can directly affect the cells of the immune system and modulate the secretion of proinflammatory cytokines.
Accordingly, we argue that distress-related immune dysregulation may be one central mechanism behind a large and diverse set of health risks associated with caregiving and other chronic stressors.
IL-6 is associated with a variety of age-related illnesses.
Accordingly, the finding that caregivers' average rate of increase in IL-6 was about four times as large as that of control participants has notable implications for morbidity and mortality.
Indeed, these data provide important evidence of a key mechanism through which chronic stressors may have potent health consequences for older adults, accelerating risk of a host of age-related diseases.
The mean rate of increase in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse.
The absence of any notable improvement after cessation of caregiving may be related to both biological and psychological mechanisms.
Stress and depression can permanently alter the responsiveness of the immune system.
For example, prior stressor exposure appears to prime proinflammatory cytokine responses, such that subsequent exposure to a bacterial endotoxin, lipopolysaccharide, resulted in a larger or more rapid induction of proinflammatory cytokines in stressed rats compared with nonstressed controls.
The evidence that prior stress produces exaggerated proinflammatory cytokine responses to infection is important in light of data that caregivers report more infectious illness episodes, and they have poorer immune responses to influenza virus and pneumococcal pneumonia vaccines than noncaregivers.
Thus, stressed caregivers are likely to be at greater risk for infection, and their inflammatory responses to these challenges could be exaggerated and prolonged through this mechanism as well.
Although there are biological mechanisms that may lead to persistent IL-6 changes even after the cessation of caregiving, it is also important to highlight psychological processes that may also have physical repercussions.
In other longitudinal data collected from experiment participants before and after the death of the impaired spouse, scientists examined changes in the same individuals over the period they were caregiving and then after the death of their spouse; they have found that former caregivers' scores on measures of depression and loneliness did not "rebound" to levels comparable to noncaregivers and, in fact, remained similar to those of current caregivers up to 3 years after caregiving had ceased.
These findings stand in contrast to evidence from longitudinal studies of spousal bereavement in the general (noncaregiver) population that have shown that depression returns to baseline within 1-2 years postloss; thus, the changes in caregivers are not simply an artifact of bereavement.
Other longitudinal studies have found that caregivers show some improvement in psychological functioning after bereavement, albeit without returning to normative levels.
Indeed, the loss of social supports and consequent increased loneliness are well-documented correlates of dementia caregiving; after providing care for 3-10 years, many former caregivers may not emerge from the experience with the same social support system that they had before the spouse's dementia.
Social isolation has clear ties to morbidity and mortality, and thus may serve as an additional conduit for perpetuation of caregiving- related stresses.
In one large population-based study of the elderly drawn from a random, stratified sample, caregivers reported less stress during caregiving on average.
Although there are key differences between the two cohorts in the way caregivers were defined as such, it is noteworthy that all-cause mortality among their randomly selected caregivers who described themselves as strained was 63% greater than that of noncaregiving controls.
IL-6 findings provide one viable mechanism that could explain caregivers' substantial differences in mortality across a range of illnesses.
More broadly, scientific data have implications well beyond caregiving; they suggest that if other chronic stressors similarly provoke persistent distress in older adults, then they may also accelerate age-related increases in IL-6.
Indeed, scientists have found preliminary evidence of ethnicity differences, with African Americans having higher IL-6 than non-African Americans.
Such changes may be one factor in the well-documented racial and ethnic disparities in health and deserve further investigation.
Other researchers have demonstrated that higher plasma IL-6 levels are associated with adverse health habits: values are higher in smokers than nonsmokers, in individuals who report less physical activity, in those whose sleep is impaired, and in those with a higher BMI (Body Mass Index), all behaviors that are adversely affected by stress.
Although the linkage between caregiving and IL-6 was still significant in accounting for these health behaviors, chronic stressors are also likely to affect IL-6 and thus health through these pathways as well.
IL-6 is associated with a spectrum of age-associated diseases whose onset and course may be influenced by proinflammatory cytokines.
The finding that caregivers' average rate of increase in IL-6 was about four times as large as that of noncaregivers suggests that a chronic stressor is capable of substantially augmenting normal age-related increases, effectively prematurely aging the immune response.
These data provide important evidence of a key mechanism through which chronic stressors may have potent health consequences for older adults, accelerating risk of a host of age-related diseases.