With the global shift towards aging populations, the prevalence and economic burden of aging-related diseases are escalating. It is imperative to develop prediction biomarkers and intervention targets of aging-related diseases to enhance the overall healthy lifespan of the people. GDF15 stands out as a prominently upregulated protein in aging processes and various age-related diseases. This protein also falls under the category of senescence-associated secretory phenotype (SASP), which is strongly correlated with increased mortality risk. As a member of the TGFβ superfamily, GDF15 is produced by a variety of immune and tissue cells in response to a broad range of stressors. It can act through the GFRAL receptor expressed in the hindbrain to suppress appetite and induce weight loss. Extensive research has revealed GDF-15's immunomodulatory effects on macrophages, mitigating inflammation by discouraging M1-like macrophage polarization while encouraging M2-like polarization. However, the pathophysiological role of GDF15 during the occurrence and development of aging-related diseases remains poorly understood. In our experiments we found that GDF15 precursor (pro-GDF15), instead of mature GDF15, was significantly increased in the plasma of old people and mice. Through mass spectrometry based targeted protein quantification, we examined the distribution of pro-GDF15 and mature GDF15 within SASPs of senescent cells under various induced conditions, as well as in plasma samples across different age groups. To further our understanding, we treated M0 macrophages with purified pro-GDF15 and mature GDF15, unearthing that pro-GDF15 exhibits a more robust anti-inflammatory impact compared to its mature counterpart. Interactome analysis further demonstrated that pro-GDF15 interacts with gap junction proteins, while mature GDF15 plays a more significant role in macrophage glucose and fatty acid metabolism. These discoveries shed new light on the functions and mechanisms of GDF15 at the proteoform level in the aging process, setting the stage for prospective clinical trials exploring GDF15-based anti-aging interventions.