Bad Company: Loneliness Longitudinally Predicts the Symptom Cluster of Pain, Fatigue, and Depression in Older Adults

Victoria D. Powell MD; Navasuja Kumar MBBS, MPH; Andrzej T. Galecki MD, PhD; Mohammed Kabeto MS; Daniel J. Clauw MD; David A. Williams PhD; Afton Hassett PsyD; Maria J. Silveira MD, MA, MPH


J Am Geriatr Soc. 2022;70(8):2225-2234. 

In This Article

Abstract and Introduction


Background: Pain, fatigue, and depression frequently co-occur as a symptom cluster. While commonly occurring in those with cancer and autoimmune disease, the cluster is also found in the absence of systemic illness or inflammation. Loneliness is a common psychosocial stressor associated with the cluster cross-sectionally. We investigated whether loneliness predicted the development of pain, fatigue, depression, and the symptom cluster over time.

Methods: Data from the Health and Retirement Study were used. We included self-respondents ≥50 year-old who had at least two measurements of loneliness and the symptom cluster from 2006–2016 (n = 5974). Time-varying loneliness was used to predict pain, fatigue, depression, and the symptom cluster in the subsequent wave(s) using generalized estimating equations (GEE) and adjusting for sociodemographic covariates, living arrangement, and the presence of the symptom(s) at baseline.

Results: Loneliness increased the odds of subsequently reporting pain (aOR 1.22, 95% CI 1.08, 1.37), fatigue (aOR 1.47, 95% CI 1.32, 1.65), depression (aOR 2.33, 95% CI 2.02, 2.68), as well as the symptom cluster (aOR 2.15, 95% CI 1.74, 2.67). The median time between the baseline and final follow-up measurement was 7.6 years (IQR 4.1, 8.2).

Conclusions: Loneliness strongly predicts the development of pain, fatigue, and depression as well as the cluster of all three symptoms several years later in a large, nonclinical sample of older American adults. Future studies should examine the multiple pathways through which loneliness may produce this cluster, as well as examine whether other psychosocial stressors also increase risk. It is possible that interventions which address loneliness in older adults may prevent or mitigate the cluster of pain, fatigue, and depression.


Pain, fatigue, and depression co-occur more frequently than expected by chance alone,[1] resulting in poor quality of life and impaired functional status.[2] Together, these symptoms form a cluster which may have shared underlying mechanisms.[3] This cluster is best characterized in patients with cancer, where 8%–13% of survivors[4,5] and 10%–76% of those with active cancer[6–8] report the co-existence of pain, fatigue, and depression. The presence of this cluster shows no apparent relationship with a specific malignancy; it has been reported in those with lung,[6,7,9] breast,[5] prostate,[4] and gastrointestinal cancers.[8] These symptoms are quite common in other clinical populations with prevalence estimates of 66% of patients with systemic lupus erythematosus,[10] 16% of patients with multiple sclerosis,[11] and 11% of patients with end-stage renal disease.[8] In the general population, prevalence appears to be somewhat lower, around 5%–6%.[12,13] That the cluster is found in multiple unrelated conditions suggests that its etiology may be distinct from a specific condition but perhaps shared with several. One factor that appears to be associated with the emergence of this symptom cluster is the subjective experience of social isolation even when other people are present, which defines the phenomenon of loneliness.[14] Loneliness is only modestly correlated with objective social isolation, and feeling lonely may predict poor outcomes better than objective social isolation.[15,16]

Loneliness can induce emotional states (e.g., anxiety disrupting sleep) and physiological changes (e.g., alterations in gene expression and immune function) that activate a general stress response and promote behaviors that increase the likelihood of short-term survival.[17] However, when loneliness persists, the same responses that are adaptive in the short-term can cause adverse long-term health consequences.[18] Indeed, loneliness has been associated with many poor outcomes, including a 26% increased risk of premature mortality.[18] Moreover, the negative impact of loneliness may be increasing due to social distancing measures necessary for controlling the coronavirus disease 2019 (COVID-19) pandemic.[19,20]

Several studies have demonstrated strong cross-sectional relationships between loneliness and pain, fatigue, and depression,[12,21] but the directionality of the relationship remains unclear. Longitudinal studies examining the temporal relationship to date have included only a single component of the cluster (i.e., pain)[22,23] or were limited by small sample sizes and examination of select populations.[24] Findings have been mixed, with loneliness preceding pain[25] or the symptom cluster,[24] pain preceding loneliness,[22] and bidirectional relationships[23] all reported. Notably, "pain" is frequently captured broadly as either present or not, with no information on pain's severity and/or functional impact.[13,22,23] These factors are important because they influence decisions to seek treatment.[26] It remains unclear to what extent loneliness predicts development of clinically significant pain along with fatigue and depression.

In this study, we examined the longitudinal relationship between loneliness and the symptom cluster of pain, fatigue, and depression in a large cohort of older Americans, hypothesizing that loneliness would predict the subsequent development of each symptom and the cluster. For the reasons above, we chose to focus only on pain reported as moderate to severe in intensity that interferes with daily activities. Understanding the directionality of the relationship is a critical step in the development and refinement of interventions for those with co-occurring pain, fatigue, and depression. Should loneliness play a causal role in symptom cluster development, interventions aimed at palliating feelings of loneliness might have a role in its treatment or prevention.