Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex

Abstract

Subjective social isolation, loneliness, is associated with poor mental and physical health, but the underlying molecular mechanisms are poorly understood. Here we analyzed loneliness data collected on average 5 years ante-mortem and RNA gene expression at death in postmortem dorsolateral prefrontal cortex (DLPFC) from 181 participants in the Rush Memory and Aging Project (MAP), a longitudinal, prospective cohort study of common chronic conditions of aging. Our analytic protocol controlled for biographical variables (age, sex, education), psychological and health variables (depressive symptoms, interval between assessment and autopsy, slope of cognitive decline, AD pathology, presence of infarcts) and RNA integrity. Our results are based on a pre-ranked Gene Set Enrichment Analysis (GSEA) at FDR-corrected q-values <0.05, using these collections from the Molecular Signatures Database (v6.0 MSigDB): (1) Hallmarks, (2) Canonical, (3) Gene Ontology (GO), (4) Chemical and Genetic Perturbations, (5) Immunologic Signatures, (6) Oncogenic Signatures, and (7) Cancer Modules. We now report on 337 up-regulated and 43 down-regulated gene sets, among which the most significant ones were associated with Alzheimer’s disease, psychiatric illness, immune dysfunction, and cancer. These gene sets constitute attractive targets for future studies into the molecular mechanisms by which loneliness exacerbates a wide range of neurodegenerative, psychiatric, and somatic illnesses.

Religious Orders Study and Rush Memory and Aging Project

“…Further, neuroticism modified the association of vision with cognition [206]. Finally, loneliness was associated with AD risk and cognitive decline, but not with neuropathologies [30]; and we identified numerous genes in the amygdala and the dorsolateral prefrontal cortex related to loneliness [207, 208].…”

Connectome-based individualized prediction of loneliness

“…Loneliness is a negative emotional state induced by subjective perception of social isolation even when among other people (Weiss, 1973; Cacioppo and Cacioppo, 2018). Susceptibility to loneliness is a trait-like phenotype that is moderately heritable, stable across time and varied across individuals (McGuire and Clifford, 2000; Boomsma et al, 2005; Boomsma et al, 2007; Canli et al, 2018). People high on loneliness experience less reward from daily social interactions, exhibit hypersensitivity to negative social information, show impaired social skills and have poor self-regulation (Jones et al, 1982; Hawkley et al, 2007; Bangee et al, 2014; Yildiz, 2016; Cacioppo et al, 2017).…”

Aging, Frailty and Complexity

“…Detailed knowledge of pathophysiology helps to answer this question, but still requires integration of the different parts with the case specific environmental knowledge. On the other hand, knowledge of the global view itself, and the knowledge of complex signaling networks, may also improve the molecular understanding of the interactions at micro levels, as for example was nicely shown for the study on the molecular genetic and cellular effects of loneliness [21,22]. Therefore, this new era of applying complexity science methods can help us make a new jump in understanding frailty, resilience and aging.…”