TY - JOUR Y1 - 2025/02// N2 - Introduction: The understanding of biological pathways related to loneliness and social isolation remains incomplete. Cutting-edge population-based proteomics offers opportunities to uncover novel biological pathways linked to social deficits. // Methods: This study employed a proteome-wide and data-driven approach to estimate the cross-sectional associations between objective measures of social connections (i.e., social isolation) and subjective measures (i.e., loneliness) with protein abundance, using the English Longitudinal Study of Ageing. // Results: Greater social isolation was associated with higher levels of 11 proteins (TNFRSF10A, MMP12, TRAIL-R2, SKR3, TNFRSF11A, VSIG2, PRSS8, FGFR2, KIM1, REN, and NEFL) after minimal adjustments; and three proteins were significantly associated after full adjustments (TNFRSF10A, TNFRSF11A, and HAOX1). Findings from two-sample Mendelian randomization indicated that a lower frequency of in-person social contact with friends or family causally increased levels of TNFRSF10A, TRAIL-R2, TNFRSF11A, and KIM1, and decreased the level of NEFL. The study also highlighted several enriched biological pathways, including necrosis and cell death regulation, dimerization of procaspase-8, and inhibition of caspase-8 pathways, which have previously not been linked to social deficits. // Conclusion: These findings could help explain the relationship between social deficits and disease, confirming the importance of continuing to explore novel biological pathways associated with social deficits. ID - discovery10200748 UR - http://dx.doi.org/10.1016/j.bbi.2024.11.024 VL - 124 SP - 85 A1 - Gong, Jessica A1 - Preminger, Zohar A1 - Steptoe, Andrew A1 - Fancourt, Daisy JF - Brain, Behavior, and Immunity PB - Elsevier BV TI - Protein signatures associated with loneliness and social isolation: Plasma proteome analyses in the English Longitudinal Study of Ageing, with causal evidence from Mendelian randomization SN - 0889-1591 AV - public EP - 94 N1 - Copyright © 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). KW - Social isolation; Loneliness; Proteomics; Mendelian randomization; Ageing ER -