Associations Between Longitudinal Loneliness, DNA Methylation Age Acceleration, and Cognitive Functioning

Abstract

Objectives: Loneliness may influence aging biomarkers related to cognitive functioning, for example, through accelerated DNA methylation (DNAm) aging.

Methods: In the present study, we tested whether six common DNAm age acceleration measures mediated the effects of baseline loneliness and five different longitudinal loneliness trajectories on general cognitive ability, immediate memory recall, delayed memory recall, and processing speed in 1,814 older adults in the Health and Retirement Study.

Results: We found that baseline loneliness and individuals who belong to the highest loneliness trajectories had poorer general cognitive ability and memory scores. Only DNAm age acceleration measures that index physiological comorbidities, unhealthy lifestyle factors (e.g., smoking), and mortality risk-mediated effects of baseline loneliness on general cognitive ability and memory functioning but not processing speed. These same DNAm measures mediated effects of the moderate-but-declining loneliness trajectory on cognitive functioning. Additionally, immediate and delayed memory scores were mediated by GrimAge Accel in the lowest and two highest loneliness trajectory groups. Total and mediated effects of loneliness on cognitive functioning outcomes were mainly accounted for by demographic, social, psychological, and physiological covariates, most notably self-rated health, depressive symptomatology, objective social isolation, and body mass index.

Discussion: Current findings suggest that DNAm biomarkers of aging, particularly GrimAge Accel, have promise for explaining the prospective association between loneliness and cognitive functioning outcomes.

Keywords: Cognition; DNA methylation; Epigenetic age; Loneliness; Longitudinal.

Figure 1.

Multicategorical Mediation Model. Loneliness trajectory groups 1, 2, … , j refer to the different loneliness trajectory classes found in the Growth Mixture Models. DNAm AgeAccel₂₀₁₆ refers to Horvath Age Acceleration, Hannum Age Acceleration, Horvath (skin) Age Acceleration, DNAm PhenoAge Acceleration, GrimAge Acceleration, and Dunedin PoAm38 Acceleration. CF₂₀₁₆ refers to TICSm, immediate memory recall, delayed memory recall, and processing speed. Covariates include cohort, sex, race/ethnicity, APOE ε4 status, social isolation, current smoking status, depressive symptomatology, self-rated health, and BMI. The parameters a₁, a₂, … , a_j−1, refer to the effect of each loneliness trajectory group on DNAm AgeAccel for j–1 groups (the largest latent class group was selected as the reference group). The parameter b refers to the direct effect of DNAm AgeAccel measure on the cognitive functioning outcome. The parameters c’₁, c’₂, … , c’_j−1, refer to the adjusted direct effect of each loneliness trajectory group for j–1 groups on the cognitive outcome.