With increasing life expectancy1 older adults are more likely to be confronted with changes in their social network structure2. As a consequence, loneliness is on the rise with about 20 to 40 percent of older adults in Western countries reporting to feel lonely today3. Loneliness is typically defined as a result of perceiving a discrepancy between the desired quantity and quality of people’s social life and one’s actual social relationships4,5. Loneliness can be described as the subjective experience that one’s social network is insufficient in size or unsatisfactory in quality and it has been linked to emotions that need to be regulated to maintain mental and physical well-being6. Interestingly, loneliness seems to be a stronger predictor of physical and mental health outcomes than quantitative objective measures of social integration (e.g., social network size, number of friends, marital status, and frequency of contacts7,8. In particular, having a large social network does not necessarily prevent the feeling of loneliness9.

Lifespan research has long demonstrated that loneliness is associated with key outcomes of aging, including increases in morbidity, overall mortality3,7,10, and poorer mental health9,11,12,13. Even though numerous studies have examined behavioral, physical and structural brain correlates of loneliness in relation to specific mental disorders such as anxiety, depression14,15 astonishingly little is known about the neural structures and processes associated with feelings of loneliness among healthy older adults16,17.

Loneliness in old age

Feelings of social connectedness are a fundamental human concern18 and thus, the subjective experience that one’s social network is sufficient in size or satisfactory in quality is often considered to be a crucial constituent of successful aging2,4. Conceptual models suggest that across adulthood and old age numerous social and health factors profoundly shape perceptions of loneliness19,20. Because these key sources of loneliness are often accumulating in old age4, one could expect that older adults have increasingly fewer opportunities to be socially embedded and integrated, thereby resulting in age-related increases of overall loneliness.

At the same time, it has long been argued that with decreases in remaining lifetime older adults aim to increase their well-being by focusing more on fewer but emotionally meaningful relationships and less on expanding their social networks21. For example, when being confronted with an increasing number of losses in ones’ social network, older adults may focus on the most meaningful and important relationships and therefore maintain their overall sense of social embeddedness. As a consequence, loneliness would be expected to remain relatively stable across adulthood and old age.

Empirical studies on age-related changes in loneliness have so far revealed an inconsistent pattern. A number of studies have reported moderate to strong increases in loneliness with increasing age22,23; see also the meta-analysis24, suggesting that despite older adults’ ability to compensate ageing-related losses, feelings of loneliness emerge as older adults inevitably begin to lose emotionally close relationships23. In contrast, other studies did not find associations between loneliness and age, especially when accounting for well-known correlates of loneliness and age (e.g., income4,25). These discrepant findings may be caused by study differences in the selection of the samples, its characteristics and size, or measurement and also highlight the need for more fine-grained exploration of the antecedents and consequences of loneliness in old age.

Loneliness and brain structure

Cacioppo and Patrick (2008) suggested that an increased sensitivity to social disconnection, difficulties in self-regulating one’s emotions associated with feeling isolated, and that the cognitive representations and expectations about others contribute to loneliness. Thus, individual differences in subjective perception of loneliness may in part reflect differences in brain regions that are functionally involved in processing, expressing, and regulating emotionally and socially relevant information16,26. Indeed, several findings from functional and structural neuroimaging studies have reported links between specific brain structures and loneliness. It can be assumed that age-related increases in loneliness might be linked to age-related structural changes in brain regions that are in turn related to cognitive processing of emotional and social stimuli and their regulation16,26. To shed light onto the current state of research in this field, we reviewed recent studies that aimed to examine neuronal correlates of perceived loneliness. We provide a comprehensive overview of the measures used and reported relevant outcomes of these studies in the Supplementary Information.

For example, in a recent VBM study Kanai and colleagues (2012) showed that individuals reporting higher loneliness showed less gray matter volume of left posterior superior temporal sulcus, a region that has been implicated in processing of social information. Although this study showed that such brain correlates of loneliness may indeed exist, the sample consisted exclusively of younger and middle-aged adults and consequently does not allow to draw conclusions about how these associations evolve in older age. Additionally, the authors did not control for well-known covariates that have been linked to loneliness such as depressive affect, overall physical functioning and personality traits such as openness.

In a different study Sato and colleagues (2016) showed that larger amygdala volume was associated with more perceived social support in a sample of younger adults27. However, the authors focused only on associations between perceived social support and amygdala volume, but did not examine the involvement of other covariates of loneliness as well as other brain regions that may be crucial for social and emotional processing.

In contrast, in an intervention study targeting different exercise conditions in older adults D’Agostino, Kattan, and Canli (2018) found a decrease in perceived loneliness which was not related to structural changes in brain regions.

Such discrepant findings could be due to study differences in sample size (ranging from n = 30 to n = 308), sampling strategies (younger vs. older participants), number and type of covariates, or measurement (UCLA loneliness scale vs. NIH Toolbox; see review table in Supplementary Information).

Furthermore, another area of research on brain plasticity has pointed out that changes in environmental demands can shape brain structure, also in the aging brain28,29,30. In recent years, promising evidence from animal models and intervention studies in humans indicates that e.g. the exposure to enriched environments show beneficial effects on structural and neurochemical measures within brain regions that are important for learning and memory such as the hippocampus28,29,31,32,33. One can assume that brain regions that are sensitive to changes in environmental demands and social as well as cognitive stimulation are also more vulnerable to the negative consequences of prolonged loneliness, social disconnection and environmental deprivation33,34,35,36.

To summarize, conceptual perspectives and empirical evidence have shown that loneliness is associated with specific brain regions and/or networks that are functionally crucial for processing, expressing, and regulating emotionally and socially relevant information16,26. These are e.g. brain regions involved in (i) value encoding, e.g. fronto-parietal and anterior cingulate regions and subcortical regions such as the amygdala; (ii) processing emotional, rewarding and motivational features of stimuli such as the ventral striatum, and brain regions that are (iii) vulnerable to environmental deprivation and which may also provide temporal and spatial social contexts related to memory such as the hippocampus. However, empirical studies have typically examined younger age groups and rarely examined the unique role of loneliness over and above well-known confounds and their interaction with loneliness (see also Supplementary Information A.1). Also, the earlier studies noted have investigated associations between loneliness and brain structure using exploratory analyses such as VBM or only focused on one specific brain region such as the amygdala. In our study, we aim to obtain a broader view on the links and interactions between loneliness, the brain and its covariates by combining exploratory and confirmatory analyses instead. Moreover, relatively little is known about whether and how loneliness and its confounders are associated with the aforementioned brain structures in healthy aging.