Exploring the Causal Relationship and Potential Mediating Mechanisms Between Obesity and Facial Aging: A Two-Sample, Multivariable and Mediation Mendelian Randomization Study

Jiaqi Lian,1,* Zhiyun Zhang,1,* Wenzhuo Yang,2 Lin Pan,1 Xuyang Pan,1 Ying Shao1 1Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Neurosurgery, Cancer Hospital of Sun Yat sen University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying Shao, Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China, Email shao_ying@jlu.edu.cnPurpose: Obesity is well established as a key contributor to multiple age-related diseases; however, its impact on facial aging (FA) remains equivocal. We aimed to elucidate the causal effects of various obesity phenotypes on FA with gender- and age-specific attention, as well as determine the potential mediating mechanisms in these relationships.Patients and Methods: A two-sample, multivariable, and mediation MR analysis was employed. BMI, representing general obesity, and BMI-adjusted WHR, representing central obesity, were derived from the most comprehensive meta-analysis GWAS conducted by the GIANT consortium. Additionally, we utilized sex- and/or age-stratified GWAS summary statistics for both BMI and BMI-adjusted WHR. We performed a two-step MR analysis incorporating 44 potential mediators to elucidate potential mediating pathways underlying this causal relationship. Sensitivity and reverse MR analyses were performed to assess the findings’ robustness rigorously.Results: MR analyses indicated that higher genetically predicted BMI was associated with accelerated FA, though this effect was not observed in women under 50. As for WHR not stratified by sex and age, no association between WHR and FA was found. However, in men over 50, higher genetically predicted WHR was significantly associated with an increased risk of FA. Furthermore, several factors, including myocardial infarction, smoking, and premature menarche, were identified as independent risk factors for FA, independent of high BMI. Myocardial infarction, daily smoking, circulating levels of RAGEs, ischemic stroke, and multiple sclerosis were also found to mediate the causal relationship between BMI and FA partially.Conclusion: Our study reveals distinct and significant variations in the effects of different obesity phenotypes on the acceleration of FA, with these effects exhibiting gender- and age-specific patterns. The findings underscore the critical importance of weight management as a potential intervention for mitigating FA. Furthermore, this research contributes to a deeper understanding of the etiology of FA.Plain Language Summary: Established causal relationship between obesity and accelerated facial aging.Identified gender- and age-specific effects of BMI and WHR on facial aging risk.Uncovered potential mediators like RAGEs and smoking in BMI-FA link. Keywords: obesity, facial aging, body mass index, waist-to-hip ratio, mediation analysis, Mendelian randomization