Relationship Between Social Isolation, Loneliness, and Systemic Inflammation: A Scoping Review of Biological Signatures and Clinical Outcomes

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Background: Social isolation and loneliness are established social determinants of health, associated with 25–30% higher mortality risk, yet their relationship with systemic inflammation and broader biological and clinical outcomes has not been comprehensively synthesized across life stages. Methods: PubMed/MEDLINE, Scopus, and ScienceDirect were searched (2015–2025), supplemented by citation searching and a targeted supplementary search, for human studies linking social isolation, loneliness, or social connectedness to inflammatory biomarkers or biological/clinical outcomes. PRISMA-ScR guidance was followed; findings were synthesized narratively across five thematic axes as an evidence map. Results: Of 3351 records identified, 73 studies were included. Isolation was most often associated with CRP and fibrinogen, and loneliness with IL-6. Isolation predicted sarcopenia, venous thromboembolism, pancreatic cancer, and cardiovascular disease, with inflammatory or metabolic markers mediating a modest (≈5–19%) share. Proteomic (n = 42,062) and epigenetic analyses linked loneliness to inflammatory, antiviral, and complement-pathway proteins and to accelerated epigenetic ageing; Mendelian randomization supported causal involvement of several proteins. Social connectedness and relationship quality tracked with lower IL-6 and better functional indices. Evidence was strongest in midlife and older cohorts. Conclusions: Social disconnection shows biologically plausible but heterogeneous associations with inflammatory and molecular signatures; harmonized measurement and prospective, hypothesis-free omics designs are needed to clarify causality and inform targeted screening.