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The study to be presented in the chapter explores one potential behavioral mechanism by which loneliness affects inflammatory and metabolic processes in old age. Specifically, it addresses whether physical activity mediates the loneliness—inflammatory/metabolic dysregulation association. Multivariate linear regressions were applied to data derived from the Health and Retirement Study (HRS). The findings revealed that loneliness was prospectively associated with elevated values of log C-reactive protein (log-CRP) and with amplified levels of Glycated hemoglobin (HbA1c), Cystatin C (CysC), and Body Mass Index (BMI), after controlling for socio-demographics. Second, physical activity mediated the association between loneliness with prospective values of log-CRP and also mediated associations between loneliness and prospective levels of metabolic biomarkers. These findings affirm the contribution (i.e., the mediation), of physical activity to the associations between loneliness and immune and metabolic processes and provide insights concerning the mechanism by which this social—biological connection operates.
Paul Baerwald School of Social Work and Social Welfare, The Hebrew University of Jerusalem, Jerusalem, Israel
Ohad Parag
Israel Gerontological Data Center (IGDC), The Hebrew University of Jerusalem, Jerusalem, Israel
Howard Litwin
Israel Gerontological Data Center (IGDC), The Hebrew University of Jerusalem, Jerusalem, Israel
*Address all correspondence to: sharon.shiovitz@mail.huji.ac.il
1. Introduction
A sense of loneliness is a subjective marker for deficits in one’s social relationships conceptualized as the discrepancy between the self-perceived extent of contact and support desired and the actual level of contact and support received [1]. This disparity leads to a cascade of behavioral, neural, hormonal, cellular, and molecular changes in the short-term [2]. In the longer-term, loneliness has been shown to negatively affect health and diminish longevity, especially among older adults [3, 4].
Because of the advancement of the study of the association that exists between loneliness and health in old age, interest has been fostered in better understanding the possible biological basis of this relationship. This is especially the case in industrialized countries where population aging is dramatically increasing and, correspondingly, the costs of dealing with poor health in old age are escalating [5]. Chronic inflammation is one of the postulated bio-physiological pathways through which loneliness may exacerbate the poor health of many older adults. Findings show, for example, that inflammatory responses that lead to prolonged and systemic immune responses, such as a rise in C-reactive protein (CRP) levels, are correlated with feelings of loneliness [6], while these same inflammatory responses also predict cardiovascular diseases [7] and higher mortality [8].
Another possible explanation for the association between loneliness and health in late life is that metabolic dysregulation serves as a trajectory in which different aspects of social disconnectedness, especially loneliness, are associated with the health condition. Studies underscore that loneliness predicts metabolic dysregulation as indicated by high systolic blood pressure and age-related differences in metabolic functioning [9], on the one hand, and that metabolic processes are linked to one’s health state, on the other hand. An example of the latter case is that levels of Glycated hemoglobin (Hba1c), a glucose concentration measure, serve as criteria for diabetes diagnosis [10]. In addition, Body Mass Index (BMI), a measure to assess obesity, as well as Cystatin C, (CysC), a biomarker of kidney function, both prospectively predict cardiovascular events and all-cause mortality among older adults [11, 12]. Recently, loneliness was found to be associated with a change for the worse in several metabolic bio-markers. Specifically, lonely older adults had 39–71% higher odds of developing prospective risk levels in HbA1c, BMI, and metabolic burden [13].
The mechanism through which loneliness is related to inflammatory and metabolic markers, respectively, is yet to be elucidated. Hawkley and Cacioppo [14] outlined several potential mechanisms by which loneliness affects health including compromising health behaviors. They argued that the lonely individual perceives the social world as threatening and that this perspective weakens his or her self-regulation, thus creating patterns of health-compromising behaviors such as physical inactivity, which cause a deterioration of health [14, 15, 16]. This hypothesis was supported by Segrin & Passalacqua [17] who found that exercise mediated the association of loneliness with self-rated health. More recently another cross-sectional study carried out in Denmark found that physical inactivity mediated the relationship between loneliness and adverse health condition such as cardiovascular disease [18].
However, to the best of our knowledge, the role of physical activity as a significant agent in the prospective association between loneliness and inflammatory and metabolic biomarkers has not yet been fully tested within the same study. Studies substantiated the relationship between loneliness and engagement in physical activity, with loneliness found to be associated with transitioning from physically active status to sedentary status [19], on one hand. Studies report a positive association between physical activity and improvement in inflammatory and metabolic regulation, as manifested by a more substantial reduction in CRP levels [20] and by higher HbA1c declines [21], on the other hand.
Consequently, the aim of the current inquiry is to address the dynamics of this assumed relationship systematically. Toward this end, we examine whether physical activity mediates the postulated association between loneliness and two key biological processes among older adults, looking specifically at its effect in relation to both inflammation and metabolic deficits. The focus on older adults in the current study is warranted insofar as research has validated that older people face loneliness more frequently [22]. They are also more prone to immune and metabolic defectiveness than are younger adults [23, 24]. Moreover, social-physiological interconnections have more prominent effects on older age cohorts [9]. The spotlight on the older age strata is also crucial in that previous studies have revealed that loneliness accelerates physiological aging [16].
The data for the analysis were drawn from the Health and Retirement Study (HRS), a nationally representative, a biennial longitudinal survey sponsored by the National Institute on Aging and the Social Security Administration, and run by the Survey Research Center at the University of Michigan’s Institute for Social Research. The HRS gathers a wide range of economic, social, and health data on older adults [25]. The Institutional Review Board of the University of Michigan granted ethical approval [26]. The loneliness data and all of the social-demographic variables for the present inquiry were retrieved from Wave 7 (2006) of the HRS. Information on the frequency of physical activity was taken from Wave 8 (2008). The blood-based inflammatory and metabolic markers, which served as the outcome measures in the current analysis were collected in Wave 9 (2010) of the survey (The HRS collects bio-measures from a portion of the respondents at each Wave, on a rotation basis, and not from the entire sample [27]). The BMI scores, another metabolic outcome, were also taken from the Wave 9 data.
We limited the analytic sample to respondents aged 60 and above who had valid data regarding social-demographic background, loneliness, frequency of physical activity, and at least one inflammatory or metabolic bio-marker from Wave 9. The resultant analytic sample thus numbered some 3,735 respondents. This number varied slightly across the respective multivariate analyses, as has been similarly reported in related studies [28]. Descriptive statistics of the respondents in the current study are reported in Table 1.
Wave 7
Wave 9
Women
58.4%
Age, mean (SD)
71.1 (7.2)
White
84.3%
Married
66.9%
>12 years of education
25.7%
Currently working
14.3%
Depressed
10.7%
Loneliness, mean (SE)
4.3 (0.03)
Moderate physical activity, at least once a week (wave 8)
54.1%
Log-CRP, mg/dL, mean (SE)
0.16 (0.01)
Hba1c, %, mean (SE)
5.87 (0.02)
BMI, kg/m2, mean (SE)
29.77 (0.11)
CysC, mean (SE)
1.22 (0.01)
Table 1.
Demographics, loneliness scores, frequency of physical activity, and bio- markers values of the sample.
2.2 Variables
2.2.1 Predictor
Loneliness was evaluated by the abbreviated 3-item form of the R-UCLA Loneliness Scale, a widely used questionnaire that was developed for use in large-scale surveys and was proven to be valid and reliable [29]. Participants were asked on a 3-point scale, ranging from 1 (hardly ever) to 3 (often), how often they felt a sense of (1) being left out, (2) lack of companionship, and (3) isolation. The three items were summed to create a scale score ranging from 3 to 9, with higher scores representing a greater extent of loneliness. As can be seen in Table 1, the average loneliness score was M = 4.3, with SE = 0.03.
2.2.2 Outcomes—Bio-measures
The bio-measures (except for BMI) were produced through the collection of Dried Blood Spot (DBS) samples, a minimally invasive and highly valid method [30]. Inflammatory processes were marked by values of CRP, subsequently log-transformed due to skewed distributions, as has been done previously [31]. Respondents with CRP levels >10 mg/L were excluded from the current CRP analyses because we were interested in low-grade inflammation, also in accordance with Yang et al. [31]. Metabolic processes were represented by levels of –Hba1c, [10] and Cystatin C (CysC, [32]), as well as by BMI (weight/height2) [33].
2.2.3 Mediator
Respondents were asked about the frequency of moderate physical activity that they carry out in their daily life (“How often do you take part in sports or activities that are moderately energetic such as gardening, cleaning the car, walking at a moderate pace”). Vigorous physical activity (“How often do you take part in sports or activities that are vigorous, such as running or jogging, swimming, cycling, aerobics or gym workout, tennis, or digging with a spade or shove”) was also explored for sensitivity analysis. Responses for both types of activities (moderate/vigorous) ranged in the current analysis from 1 (“hardly ever or never”) to 5 (“every day”).
2.2.4 Covariates
Variables that have been shown in other analyses to be relevant to the association that exists between social network relationships and levels of inflammatory and metabolic bio-measures among middle-aged and older adults served as covariates in the current inquiry [6, 31, 34]. Specifically, the regressions were adjusted by gender (men, women), age (60–96), ethnic affiliation (White, Black, or Hispanic), marital status (married, not married), the extent of formal education (up to and including a high-school diploma/GED, more than a high-school diploma/GED), employment status (working/not working) and depression (Yes/ No). Covariates were gathered in Wave 7, aside from depression, which was measured at Wave 8, due to low response rate on this question at Wave 7. The reference categories were men, white, not married, up to and including a high-school diploma/GED, currently not working and not depressed.
2.3 Data analysis
Multiple multivariate linear procedures were employed. The main effect of loneliness on the four bio-markers was analyzed separately for each of the biomarkers: log CRP, Hba1c, BMI, and CysC, after adjusting for the sundry controls (gender, age, ethnic pertaining, education, marital status, employment status, and depression status). The Ns for the respective analyses were: log-CRP (n = 3127), Hba1c (n = 3402), BMI (n = 3538), CysC (n = 3362). The STATA software program 15.0 was used in this stage of the study.
In the second phase of the analysis, physical activity was added to the regressions as a mediator. However, this potential mediation effect was explored only when the main effect of loneliness was significant in phase 1. The second phase was carried out using the PROCESS macro in the SPSS statistical program. The SPSS analytic software was preferred here because it computes the direct and indirect effects in multiple mediator models, by calculating the product of coefficients [35]. Finally, the significance of the mediation was tested by means of bootstrapping, a nonparametric technique that does not require a-priori assumptions about the data distribution [36]. This method empirically estimates the sampling distribution by repeatedly resampling the data. When the confidence interval of 95 percent, which is based upon 1000 bootstrap samples, excludes zero, the mediation effect is significant [37].
The Prediction model results showed that being lonely at Wave 7 was associated with having higher log-CRP levels (β = 0.06, p < 0.01), higher Hba1c levels (β = 0.05, p < 0.01), higher BMI scores (β = 0.06, p < 0.01) and higher CysC values (β = 0.05, p < 0.01) at Wave 9, after adjusting for gender, age, ethnic pertaining, education, marital status, employment status and depression status.
3.2 Phase 2: mediation effect
The Prediction models inFigures 1–4, depict the associations of loneliness with prospective levels of log-CRP, Hba1c, BMI, and CysC with physical activity as a potential mediator. We elaborate here on the association between loneliness with prospective levels of log-CRP (Figure 1) since all other associations present a similar pattern of results. As demonstrated in Figure 1, higher levels of loneliness were significantly associated with increased prospective values of log-CRP (path c). However, the beta coefficient for the effect of loneliness on the frequency of physical activity (path a) and the beta coefficient for the effect of frequency of physical activity on levels of log-CRP (path b), were both significant. Also, the direct effect of loneliness in the presence of the mediator (path c’) was weaker than the total effect of loneliness (path c). This highlights a feasible indirect effect of loneliness through the frequency of physical activity [38]. In other words, greater loneliness decreased the frequency of subsequent physical exercise (β = −0.14) and this reduction in physical activity elevated the prospective levels of log-CRP (β = −0.11). When the mediator was used, the direct effect between loneliness and Log-CRP levels was still significant but weaker, which suggests partial mediation.
Figure 1.
The mediation effect of physical activity upon the association of loneliness with prospective log-CRP levels. Adjusted by all variables in the Prediction model. Based upon 1000 bootstrap samples.
Figure 2.
The mediation effect of physical activity upon the association of loneliness with prospective Hba1c levels. Adjusted by all variables in the Prediction model. Based upon 1000 bootstrap samples.
Figure 3.
The mediation effect of physical activity upon the association of loneliness with prospective BMI levels. Adjusted by all variables in the prediction model. Based upon 1000 bootstrap samples.
Figure 4.
The mediation effect of physical activity upon the association of loneliness with prospective CysC levels. Adjusted by all variables in the prediction model. Based upon 1000 bootstrap samples.
To test whether the mediation effect was significant we applied a bootstrap method. As may be seen in Figure 1, the association between loneliness with prospective levels of log-CRP was partially mediated because path c’ was still significant. The confidence interval of 95 percent, which was based upon 1000 bootstrap samples, was between 0.01 and 0.02, thus indicating mediation [37]. As already mentioned, similar results emerged in all the other relevant associations that were found to be significant in the first phase (i.e, between loneliness and the prospective concentrations of metabolic biomarkers (Figures 2–4).
Dividing the (standardized) indirect effect by the (standardized) total effect [39] showed that the indirect path of physical activity accounted for 25 percent of the association of loneliness with prospective values of log-CRP, 14 percent of the association with Hba1c, 32 percent of the association with BMI, and 36 percent of the association with CysC (not shown in the Figures). Sensitivity analysis of engagement in more vigorous physical activity showed very similar results (not shown).
This study examined whether physical activity mediates the effect of loneliness on inflammatory and metabolic processes among older Americans. We found, in the first phase of the study, that loneliness was, indeed, associated with increased levels of inflammation, measured 4 years later, as reflected by heightened values of (log) CRP [6]. Similarly, loneliness was associated with subsequent low metabolic regulation, also measured 4 years later, as manifested by elevated concentrations in all three of the metabolic measures that were examined: BMI, Hba1c, and CysC. These measures encompass several different aspects of metabolic processes, such as glucose concentration, kidney function, and CVD profiling, thus emphasizing the effect of loneliness on metabolic process as a whole [10, 33].
As noted, the primary focus of the current study was to consider whether physical activity mediates the loneliness—biomarker associations that emerged in the initial phase of the analysis. The findings show that the association of loneliness with the inflammatory marker log-CRP was partially mediated by the physical activity indirect pathway, which accounted for a quarter of the total effect. In addition, all of the significant associations between loneliness and prospective metabolic bio-markers were either partially or entirely mediated by physical activity. Of particular note is that this indirect effect was not at all minor, as it accounted for a substantial portion of the associations between loneliness and prospective BMI and CysC levels, with about a third of these associations being attributed to it. To the best of our knowledge, these findings are the first to affirm the contribution (i.e., the mediation), of physical activity to the associations between loneliness and immune and metabolic processes and to provide insights concerning the mechanism by which this social—biological connection operates.
The results of this study have important implications insofar as they suggest the deleterious effects of loneliness upon inflammatory and metabolic processes in later life, which have been reported in prior studies [6, 7, 9], can be mediated by physical activity. Our analyses showed that this might indeed occur due to engagement in any level of physical activity, whether moderate or vigorous. This implies that even moderate physical activity serves as a mechanism by which loneliness affects health in old age.
One potential limitation should be taken into account when interpreting the results of our analysis. We do not control whether the loneliness scores that were taken as the baseline indicator in the current analysis (Wave 7 of the HRS) represent transient or chronic loneliness. These two types of loneliness are conceptually different. Whereas transient loneliness may motivate individuals to reconnect with other individuals, loneliness that is accrued over time increases withdrawal [15]. This is a minor shortcoming; however, insofar as most older people have stable loneliness ratings over time [40].
In conclusion, this study identifies an important psycho-physiological mechanism that may be present among older adults. It documents that physical activity mediates the effect of loneliness on inflammatory and metabolic processes in a representative national sample of older Americans. Reduced engagement in physical activities in later life explains to some degree the deleterious health effects of loneliness.
The HRS (Health and Retirement Study) is sponsored by the National Institute on Aging (grant number NIA U01AG009740) and is conducted by the University of Michigan.
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Written By
Sharon Shiovitz-Ezra, Ohad Parag and Howard Litwin
Submitted: 22 March 2022Reviewed: 13 April 2022Published: 30 June 2022
Open access peer-reviewed chapter
