Role of CD127 on CD28⁺ CD45RA⁺ CD8br Treg Cells in Mediating the Association Between GDF-15 and Sarcopenia

Growth Differentiation Factor 15 (GDF-15) is closely associated with the occurrence and progression of sarcopenia, but the causal relationship between GDF-15 and sarcopenia remains unclear, and it is also uncertain whether immune cells mediate the pathway between GDF-15 and sarcopenia. We employed Mendelian randomization analysis to explore the causal relationship between GDF-15 and sarcopenia, using the inverse variance-weighted (IVW) method as the primary analytical approach, and validated the results through sensitivity analyses. In addition, we explored whether 731 immune cell phenotypes mediate these causal relationships. GDF-15 was negatively correlated with all four traits of sarcopenia, specifically with whole body fat-free mass (odds ratio [OR] = 0.989, 95% confidence interval [CI] = 0.979-0.998, pIVW = 2.149E-02), left arm fat-free mass (OR = 0.988, 95% CI = 0.979-0.998, pIVW = 1.345E-02), right arm fat-free mass (OR = 0.987, 95% CI = 0.979-0.995, pIVW = 1.091E-03), and appendicular lean mass (OR = 0.984, 95% CI = 0.974-0.993, pIVW = 7.658E-04). Mediation analysis indicated that CD127 on CD28⁺ CD45RA⁺ CD8br mediated the causal relationship between GDF-15 and sarcopenia, with a mediation proportion of 21.58% (p = 0.023). In conclusion, our study proposed that CD127 on CD28⁺ CD45RA⁺ CD8br mediates the causal relationship between GDF-15 and sarcopenia, providing potential theoretical support and practical guidance for the innovation of treatment strategies and personalized therapies for sarcopenia.