Protein ADM Mediates Loneliness’ Association With CVD, Stroke, Mortality

Chun Shen, PhD

Credit: Clare Hall, Cambridge

A new study reveals the proteins of GFRA1, ADM, FABP4, TNFRSF10A, and ASGR1 mediate the association between loneliness and the increased risk of heart disease, stroke, and type 2 diabetes.¹

Loneliness can lead to many more consequences than dampening one’s mood. According to the Cleveland Clinic, it can lead to hypertension, cold and flu, cardiovascular disease, stroke, type 2 diabetes, dementia, anxiety, depression, suicide and self-harm, and premature death.²

Research has shown social isolation and loneliness are linked to morbidity and mortality, comparable to smoking and obesity.¹ Investigators sought to examine the underlying mechanisms of loneliness’ link to morbidity and mortality, studying proteins from blood samples.

“We know that social isolation and loneliness are linked to poorer health, but we’ve never understood why,” said lead investigator Chun Shen, PhD, from the department of clinical neurosciences at the University of Cambridge and the Institute of Science and Technology for Brain-Inspired Intelligence at Fudan University, in a statement.³ “Our work has highlighted a number of proteins that appear to play a key role in this relationship, with levels of some proteins in particular increasing as a direct consequence of loneliness.”

Shen and colleagues leveraged 42,062 participants (mean age: 56 years; 52.3% female) across 2,920 plasma proteins in the UK Biobank for a proteome-wide association study and protein co-expression network analysis.¹ During a median follow-up of 13.7 years, 2695 participants developed CVD, 892 developed all-cause dementia, 1703 developed type 2 diabetes, 1521 developed depression, 983 developed strokes, and 4255 died.

In models adjusted by age, sex, site, technical factors, and first 20 genetic principal components, investigators found 776 proteins were significantly associated with social isolation and 519 proteins were associated with loneliness (P < .05). After adjusting for ethnicity, education level, household income, smoking, alcohol consumption, and BMI, 175 proteins were linked to social isolation and 26 proteins were linked to loneliness.

The protein growth differentiation factor 15 (GDF15) demonstrated the strongest association with social isolation (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.17 – 1.27; P = 1.2 ⨯10^-19. Moreover, proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein in the regulation of cholesterol metabolism, had the strongest association with loneliness (OR, 1.15; 95% CI, 1.10 – 1.20 P=4.2⨯10^-11.

Four proteins were discovered to be protective factors against social isolation, with a significant one being C-X-C motif chemokine ligand-14 (CXCL14), an immune and inflammatory modulator (OR, 0.84; 95% CI, 0.81 - 0.88; P =2.4⨯10^-17.

A colocalization analysis showed that ADM and asialoglycoprotein receptor 1 (ASGR1) demonstrated colocalization for loneliness. GDNF family receptor alpha 1 (GFRA1) demonstrated medium support for colocalization between loneliness and pQTL signals.

An analysis adjusted for demographic, socioeconomic, and lifestyle confounders, and the first 20 genetic PCs showed 90.2% of the 179 unique proteins were linked to mortality and > 50% were linked to type 2 diabetes, CVD, and stroke—and only 6.6% were linked to dementia (P < .05).

GDF15 was the top protein linked to an increased risk of all diseases and mortality, excluding type 2 diabetes. The protein M8 demonstrated the strongest relationship with type 2 diabetes (hazard ratio [HR], 2.14; 95% CI, 2.02 – 2.27; P = 1.6 ⨯10^-146. The protein ADM was the only one to have an association with dementia.

When investigators estimated the percentage of excess risk mediated by each MR-identified protein, investigators saw loneliness was not linked to the incidence of type 2 diabetes. ADM was discovered to be the primary mediator linking loneliness to CVD (8.3%), dementia (4.4%), stroke (7.8%), and mortality (16.3%).

“Interesting, ADM was the only protein that significantly mediated the relationship between loneliness and all four diseases,” investigators wrote.

References

1. ^{Shen C, Zhang R, Yu J, Sahakian BJ, Cheng W, Feng J. Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality. Nat Hum Behav. 2025 Jan 3. doi: 10.1038/s41562-024-02078-1. Epub ahead of print. PMID: 39753750.}
2. ^{How Loneliness Can Impact Your Health. Cleveland Clinic. September 30, 2024. https://health.clevelandclinic.org/what-happens-in-your-body-when-youre-lonely. Accessed January 6, 2025.}
3. ^{Loneliness linked to higher risk of heart disease and stroke and susceptibility to infection. EurekAlert! January 3, 2025. https://www.eurekalert.org/news-releases/1068928. Accessed January 6, 2025.}