GDF15 in aging, metabolic disease and cachexia

Growth Differentiation Factor 15(GDF15), also known as macrophage inhibitory cytokine 1(MIC-1), is a divergent member of the TGF-β superfamily first identified in 1997 [1]. Although its role in inflammation, cancer, cardiovascular diseases and obesity has since been recognized [2], a major breakthrough did not come until 2017, when glial cell-derived neurotrophic factor family receptor α-like(GFRAL) was identified as its orphan receptor in the hindbrain [3]. This discovery greatly advanced understanding of its physiological effects on appetite regulation, cancer cachexia, energy homeostasis and age-related conditions.

Indeed, GDF15 has emerged as one of the most up-regulated proteins during aging, and has been proposed as the key player in human aging [4]. As a stress-response protein that can be induced by mitochondrial dysfunction, inflammation, and cellular stress, elevated GDF15 has been linked to functional decline [5,6], malnutrition [7,8], anorexia [9], cognitive deterioration [[10], [11], [12]], depressive symptoms [13] and psychological vulnerability [5] in older adults. These observations collectively suggest that GDF15 may serve as a systemic biomarker that reflect domains of Intrinsic Capacity(IC) proposed by the World Health Organization [14], particularly locomotion, vitality, cognition and psychology, whereas evidence for sensory domain remains comparatively limited.

Recent review also supports the value of GDF15 as a biomarker and predictor of frailty [15], a highly prevalent syndrome among individuals with chronic kidney disease (CKD). Intriguingly, GDF15 appears to play a context-dependent role in kidney disease. On the one hand, experimental evidence has suggested that GDF15 exerts a potentially protective effects against renal fibrosis [16]; on the other hand, clinically elevated GDF15 levels has been significantly associated with CKD progression and adverse renal outcomes [17].The study by Lin et al. [18], published in this issue of The Journal of Nutrition, Health & Aging, reinforces the involvement of GDF15 in CKD and provides further insights by examining its association with cachexia-related phenotypes in CKD. The authors demonstrated that higher GDF15 levels are consistently related to an increased risk of muscle wasting and anemia among 268 non-dialysis patients with stages 3–5 CKD. This is noteworthy, given that monoclonal antibodies targeting GDF15 have already shown benefits in patients with cancer cachexia, including improvements in appetite, body weight and cachexia-related symptoms [19,20]. These findings raise the possibility that GDF15 may represent a shared mechanistic pathway across different cachectic conditions. However, Lin et al.’s [18] findings should be interpreted cautiously as the cross-sectional design precludes causal inference and the study did not fully assess cachexia, lacking direct measures such as weight loss. Yet, the values of this study lie in shifting the discussion from GDF15 as a general prognostic biomarker of CKD to a candidate signal of cachexia-related phenotypes in CKD. In this sense, the study also raises the possibility of considering GDF15 as a potential pharmacological target in the management of CKD-related cachexia. The perspective may also be extended to frailty and IC decline, as weight loss and nutritional deterioration represent shared clinical manifestation among cachexia, frailty and IC. From the perspective of geroscience, improving IC and preventing frailty are central in promoting heathy aging and recent recommendations have emphasized the importance of developing biomarkers for geroscience-oriented clinical trials [21]. Within this framework, GDF15, as a candidate systemic biomarker that is readily measurable and inexpensive, may be worth exploring in future frailty and IC research.

More broadly, GDF15 may be one of the best examples of a biologically double-edged molecule as summarized in Fig. 1. In the context of aging, cancer, CKD, persistent elevation of GDF15 is often viewed as an alarm signal associated with functional decline, frailty and disease progression. In these settings, blockade of GDF15 signaling might potentially be beneficial, as suggested by recent studies in cancer cachexia [19,20]. In contrast, in obesity and type 2 diabetes, pharmacologic agonism of the GDF15 pathway has attracted attention given its potential to reduce food intake, lower body weight, and improve metabolic parameters [22]. Mice studies also suggest its amelioration effects on insulin sensitivity [23]. A related example is metformin, which has been reported to increase circulating GDF15 levels, with part of its effects on appetite regulation and body-weight control potentially mediated through GDF15-GFRAL axis [24]. It would be therefore overly simplistic to regard GDF15 as either a beneficial or a harmful molecule, given its highly context-dependent biology.

Fig. 1.

GDF15 is a stress-induced cytokine upregulated by mitochondrial dysfunction, chronic inflammation, and cellular senescence. GDF15 reduces appetite and weight loss by its central receptor GFRAL and may also signal through unidentified peripheral receptor(s). While GDF15 may exert beneficial effects in metabolic disease and renal protection, persistent elevation is associated with aging-related decline, cachexia, and CKD progression. These context-dependent effects highlight the potential value of GDF15 as a biomarker and therapeutic target in metabolic disease, cancer cachexia, CKD cachexia/wasting, and geroscience-oriented clinical trials.

However, the role of GDF15 in aging and age-associated diseases is likely more complex than initially anticipated [4]. Some studies suggest its pro-inflammation actions [25], whereas others point to anti-inflammatory effects in both humans and mice [26]. The coexistence of such divergent observations indicates that the currently established GDF15-GFRAL axis may not fully explain the broad spectrum of GDF15 physiology, particularly its peripheral associations with inflammation, fibrosis, erythropoiesis, and organ dysfunction. It is therefore increasingly speculated that additional peripheral signaling mechanisms may exist [22,23] and may mediate physiological functions distinct from those of the hindbrain GFRAL pathway, although these mechanisms remain to be identified and validated.

Overall, the work by Lin et al. adds to the growing evidence that GDF15 is not merely a prognostic marker of CKD progression but also a clinically informative signal linking CKD to muscle wasting and anemia. Yet, the evidence remains preliminary, and future longitudinal and interventional studies will be required to determine whether targeting GDF15 can improve cachexia-related outcomes in CKD. Looking forward, two directions deserve particular attention: first, the identification and validation of possible peripheral signaling mechanisms or receptors beyond GFRAL; and second, experimental and clinical evaluation of GDF15-targeted strategies in CKD-associated cachexia or wasting syndromes. Addressing these questions will help clarify how GDF15 links aging, metabolic diseases and cachexia, and whether it can be translated into clinical therapeutic benefits.

Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the authors used AI for language polishing and grammar checking. After using the tool, the authors reviewed and edited the content as needed and takes full responsibility for the content of the published article.

Financial support and sponsorship

This work was performed in the context of the IHU HealthAge, which has benefited from funding by the Agence Nationale de la Recherche under the France 2030 program (reference number: ANR- 23-IAHU-0011).

Declaration of competing interest

There are no conflicts of interest.