GDF-15 is significantly increased under acute complete starvation and positively correlated with triglyceride-rich lipoproteins, a trend more pronounced in patients with Relative Energy Deficiency in Sport, suggesting that it may be used as ‘a marker of energy metabolism’ [33]. In another study, intermittent fasting increases the level of GDF-15 in obese women by 5% compared with caloric restriction, but this change is not directly delivered to food intake, implying alternative pathways associated with energy metabolism regulation other than GFRAL [34]. Obesity represents a global health problem, whose pathogenesis can be attributable to the imbalance between energy metabolism and nutritional intake.

As an appetite-related stress signal, GDF-15 may possess multiple potentials in obesity: animal experiments have confirmed that recombinant GDF-15 can exert anti-obesity effects by inhibiting appetite and reducing body weight [35]. Although GDF-15 has been reported to lower body weight, circulating GDF-15 levels in obese patients are generally elevated [36]. This may reflect a compensatory action in which GDF-15 is accommodated to obesity-related metabolic disorders, such as insulin resistance (IR), and serves as a stress-response cytokine. However, long-term intensive metabolic derangement may dampen this compensation. It is shown that GDF-15 inhibits appetite and reduces food intake by activating the GFRAL signaling pathway in hindbrain neurons, thereby markedly reducing body weight and improving blood glucose in obese models [18, 37]. This pathway provides clearer causal evidence for GDF-15-mediated appetite suppression in animal models. Exogenous GDF-15 treatment can rapidly improve insulin tolerance in obese rats independent of body weight changes. In other words, GDF-15 may restore or even enhance insulin sensitivity in the liver and adipose tissue through mechanisms mediated by the β-adrenergic receptor regardless of GFRAL [26, 38]. Mechanistically, this protective effect involves the regulation of adipose tissue function and macrophage polarization [38]. In weight-loss interventions for rat models, the response of GDF-15 appears to be pleiotropic: bariatric surgery (e.g., sleeve gastrectomy) significantly increases GDF-15 levels in the circulation and gastrointestinal tissues, especially in those with metabolic syndrome (MetS)-like conditions; high expression of GDF-15 after surgery fosters energy balance, partially interpreting the phenomenon of weight loss postoperatively [39]. During exercise interventions, 60 min of moderate-intensity continuous intervention can increase the GDF-15 level among obese individuals alongside appetite suppression, and there is no energy compensation after exercise [40]. In other words, individuals do not compensate for the energy expended during exercise by increasing food intake afterward, thus helping to create a negative energy balance. Accordingly, preclinical studies have argued that GDF-15 analogues can become a potential therapeutic target against the global obesity epidemic [41]. Altogether, a line of evidence indicates that GDF-15 is dynamically regulated by energy status and correlates closely with starvation, obesity, exercise, and weight loss. Its causal role in suppressing appetite and reducing body weight is well established in animal studies via the GDF-15/GFRAL/rearranged during transfection (RET) axis, yet the mechanisms mediating these effects independently of this axis remain largely unknown. Therefore, elevated circulating GDF-15 should be interpreted as an integrated signal of energy deficit, lipid metabolism, inflammation, and tissue stress—not merely as an anorectic marker.

As a key regulator of appetite and metabolic stress, GDF-15 has gained prominence in anorexia nervosa (AN)—a severe mental disorder characterized by significant weight loss, persistent dietary restriction, and disrupted energy balance [42]. Elevated GDF-15 levels are implicated in appetite suppression, weight loss, and early satiety—hallmarks of AN pathology.

Notably, serum GDF-15 levels are approximately 15% higher in acute AN patients than in healthy controls, and decrease significantly with refeeding and nutritional recovery [43]. This reversible pattern suggests that GDF-15 reflects nutritional state and metabolic stress rather than a fixed trait of AN; this finding simultaneously supports its sensitivity to hunger and malnutrition, positioning it as a potential marker of disease activity. Furthermore, high serum GDF-15 levels correlate with ghrelin, jointly predicting BMI reduction probably due to appetite suppression in AN patients [44]. This interaction may partially interpret persistent appetite suppression, but current evidence is insufficient to determine whether GDF-15 precedes or follows weight loss. A high GDF-15 level (>0.8 ng/mL) is also linked to fibroblast growth factor 21 (FGF21) metabolic changes and mitochondrial dysfunction, suggesting AN patients may be in a prolonged state of energy deficiency and metabolic stress [45]. The elevation of GDF-15 is associated not only with the pathology of AN but also with chronic metabolic stress. Exercise, high insulin levels, and certain metabolic drugs (e.g., metformin) can significantly induce GDF-15 expression in AN patients, mediated by insulin and glucagon’s coordinated regulation [46–48]. This highlights GDF-15’s sensitivity to energy balance and metabolic changes. Accumulating evidence suggests that GDF-15 acts on appetite-control centers in the brainstem, amplifying feelings of disgust and avoidance associated with hunger [49]. These studies reveal that elevated GDF-15 not only reflects nutritional status but may directly contribute to appetite inhibition through central appetite regulation. However, direct causality in AN remains uncertain, as appetite restriction is strongly shaped by psychiatric and behavioral factors. Collectively, the current evidence mainly supports GDF-15 as a dynamic marker of starvation, malnutrition and chronic metabolic stress in AN. Although GDF-15 may contribute to appetite suppression through brainstem and gut-brain pathways, its causal role remains difficult to separate from psychiatric drivers, excessive exercise, hormonal adaptation and low body weight.

Referring to the appetite regulation, GDF-15 has been regarded as ‘an anorectic factor’ and exerts an intrinsic function (Figure 3). The underlying mechanism of anorexia induced by GDF-15 has been broadly corroborated in the existing literature. GDF-15 activates its specific receptor GFRAL, which is primarily localized in neurons of the AP and nucleus of the solitary tract (NTS) within the hindbrain. This interaction induces anorectic action and subsequently triggers the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), AMP-activated protein kinase (AMPK) and PI3K/Protein kinase B (Akt) signaling pathways [6, 8, 18, 50]. This process inhibits hypothalamic orexigenic neuropeptide Y (NPY) neurons and stimulates the activity of anorexigenic proopiomelanocortin (POMC) neurons, and in turn leads to decreased appetite. The GDF-15/GFRAL/RET pathway is regarded as a canonical regulatory pathway for anorexia and resultant weight loss alongside a novel therapeutic target for cachexia [5, 51]. In addition, there are other mechanisms responsible for GDF-15-directed anorexia: GDF-15 activates the hypothalamic-pituitary-adrenal axis (HPA), leading to the secretion of corticotropin-releasing hormone (CRH) and glucocorticoids (GC), thereby leading to the appetite inhibition in patients with cachexia [52]. It is worth noting that GDF-15 can additionally influence the loss of fat and muscle. Tumor-bearing mice with overexpressed GDF-15 exhibited a significant anorexia phenotype, manifested with a continuous decrease in food intake [5]. This feeding inhibition indirectly causes metabolic chain reactions such as decreased fat mass and muscle atrophy (tibialis anterior and gastrocnemius), responsible for an overall weight loss of 28%.

Beyond its role in general appetite and energy homeostasis, GDF-15 has been implicated in a metabolic status characterized by profound weight loss and disordered energy metabolism, that is disease-related cachexia. This includes cancer cachexia and other types such as cardiac cachexia and chronic obstructive pulmonary disease (COPD)-associated cachexia.

Regarding pancreatic cancer and non-small cell lung cancer, elevated serum GDF-15 levels (>3.4 ng/mL, as reported by Suzuki H et al.) are associated with cachexia characterized by continuous weight loss, deterioration of physical condition, and excessive tumor burden [15, 53]. In patients with advanced cardiac failure, high GDF-15 levels (>1.2 ng/mL) may pinpoint a higher incidence of cachexia and predict a higher incidence of adverse events [54]. In this regard, it is plausible to improve cardiac function and delay the progression of cachexia by blocking the GDF-15 pathway in mice with heart failure-associated cachexia [55]. In childhood cancers, GDF-15 upregulation not only predicts the risk of chemotherapy-related nausea, vomiting, anorexia, and weight loss, but also is connected to anthracycline cardiotoxicity and increased mortality [56]. Several clinical studies have verified that GDF-15 in anorexic cancer patients (median: 1.2 ng/mL) is significantly higher than that in non-anorexic cancer patients (median: 0.8 ng/mL) and healthy controls (median: 0.6 ng/mL) [57]. Notably, GDF-15 in patients with cachexia is positively correlated with the magnitude of anorexia, conferring its potential as a biomarker contextually [5, 53, 54, 57]. Besides, cancer cachexia triggers intractable anorexia and weight loss by activating the brainstem GDF-15/GFRAL nausea or vomiting center, and treatment-related nausea or vomiting due to chemotherapy (e.g., platinum drugs) inducible GDF-15 secretion, where all antiemetic drugs cannot effectively prevent and treat this discomfort [58]. Collectively, GDF-15 is involved in cancer cachexia development. Current observational and cross-sectional evidence shows that elevated GDF-15 levels correlate positively with cachexia severity, anorexia, chemotherapy-induced nausea, and poor prognosis, yet mechanistic validation studies are still lacking. The current view favors that GDF-15 acts synergistically with tumor burden, systemic inflammation, and treatment toxicity rather than as an independent cause. GDF-15 should be defined as a sensitive marker and amplifier of disease-related anorexia, not a single etiological agent of cancer cachexia.

Intriguingly, the anorexic effect pertinent to GDF-15 has a dual role regarding obesity and cachexia. In obesity, high levels of GDF-15 may potentiate appetite control and weight reduction; in the circumstance of cachexia, GDF-15 may aggravate this detrimental status, accelerate disease progression, and reduce the quality of life and survival time. Its effect on metabolism may be diminished under long-term intensive metabolic stress due to obesity [19]. On the other hand, sustained high levels of GDF-15 lead to uncontrollable energy consumption [15, 59]. Notably, most evidence is derived from rodent models, with marked differences in GFRAL expression and downstream signaling between humans and mice. The dual role of GDF-15 in obesity and cachexia suggests its function is highly context-dependent, yet a clear dose-response relationship has not been established in humans. Therefore, GDF-15 should be recognized as a context-dependent molecule: it may act as an anorexigenic mediator under specific experimental conditions, but in most clinical populations, it more frequently serves as a biomarker of metabolic stress and disease burden.

GDF-15 appears to have multifaceted roles in muscle status that differ between physiological adaptation and pathological stress. Under physiological conditions, GDF-15 regulates exercise stress and skeletal muscle health. Both acute high-intensity exercise and chronic moderate-intensity exercise can upregulate the expression of GDF-15 in humans and mice [12, 60–62]. Its circulation level peaks at 120 min after stopping exercise and decreases toward baseline 48 h after exercise in trained individuals (before exercise: 0.6 ± 0.1 ng/mL; end of exercise: 2.3 ± 0.5 ng/mL; 48 h post-exercise: 0.9 ± 0.2 ng/mL, as reported by Tchou I et al.) [12, 61]. Although animal experiments demonstrate that acute exercise is insufficient to alter circulating GDF-15, a marked increase of GDF-15 in muscle tissue may be protective against exercise stress response [60]. In another study, prolonged endurance exercise increases circulating GDF-15 levels comparable to those under pathological stress in healthy adults; further animal experiments confirmed that this process was accompanied by increased GDF-15 expression in the liver, skeletal muscle, and myocardia [63]. Mechanistically, GDF-15 may inhibit the differentiation of fast muscle fibers and promote the formation of slow muscle oxidative fibers by activating the Akt/mTOR pathway to strengthen muscle endurance [64]. Of note, GDF-15 induction during exercise is sensitive and dependent on exercise intensity and time; that is, short-term (≤1 month) moderate-intensity training is capable of increasing GDF-15 expression, in contrast to short-term high-intensity interval training and long-term (>6 months) regular exercise training, which appear to have only limited effects on GDF-15 [65]. This pattern suggests that GDF-15 may reflect whether exercise load exceeds the current adaptive capacity, rather than simply indicating training benefit itself. Intriguingly, the upregulation of GDF-15 after exercise is more pronounced in individuals with a sedentary lifestyle [62]. In terms of striated muscle repair, GDF-15 strengthens muscle regeneration via multiple mechanisms. Taking myocardial injury as an example, overexpressed GDF-15 after myocardial injury can reduce cell damage by up-regulating the expression of telomerase reverse transcriptase and activating the AMPK signaling pathway [66]. Meanwhile, GDF-15 effectively tackles inflammatory response in the process of satellite cell activation, myoblast proliferation and muscle regeneration, and accelerates muscle fiber remodeling and functional recovery in mice [67].

The physiological effect of GDF-15 represents a product of exercise-induced muscle protective response along with a key mediator involved in inhibiting fast muscle differentiation, enhancing mitochondrial function, promoting cell regeneration, and participating in muscle adaptive reconstruction. However, current evidence in humans is mostly observational with limited mechanistic research, leaving its causal role in humans unclear. Given the complex origin and context-dependent function of GDF-15, its exercise-induced elevation is more likely a concomitant phenomenon of adaptive muscle remodeling rather than an active driver.

From a pathological view, GDF-15 is related to the symptoms, severity, and prognosis. GDF-15 may serve as a novel biomarker for sarcopenia and frailty. Accumulating cross-sectional evidence has unraveled that higher GDF-15 (>1.2 ng/mL, as reported by Herpich C et al.) is associated with muscle dysfunction, sarcopenia, frail phenotype, decreased physical function, and poor prognosis [20, 68–71]. A sarcopenia index on the basis of GDF-15 and myostatin also exhibits excellent predictive performance in patients undergoing cardiovascular surgery [69]. Furthermore, GDF-15 is negatively correlated with skeletal muscle index, handgrip strength (HGS), knee extension strength and walking speed, but positively correlated with myostatin. GDF-15 has also been proven to be associated with the deterioration of muscle status. In patients with COPD, serum GDF-15 levels are negatively correlated with various metrics concerning muscle quantity, strength, and function [71]. Accordingly, patients with COPD and concurrent sarcopenia have significantly higher GDF-15 levels than controls. In patients with osteoporosis, the abnormal expression of GDF-15 is closely related to muscle homeostasis and bone metabolism imbalance. Muscular expression of GDF-15 mRNA is in alignment with inducible inflammatory factors (i.e., TNF-α and IL-1β), but negatively correlated with areal bone mineral density and distal radius bone mass, highlighting muscle-derived GDF-15-dictated inflammation to instigate obvious bone loss [72]. In addition, GDF-15 derived from muscle may be more critical than circulating GDF-15 to modulate muscle mass and function, and a paracrine pattern may account for this tissue specificity [72]. This may be because the former reflects the local musculoskeletal microenvironment, whereas the latter more often represents systemic stress. These findings jointly reveal that GDF-15 is a pivotal molecule connecting muscle-bone metabolism, and its abnormality may aggravate the occurrence of muscle atrophy and osteoporosis through synergistic inflammatory response and regional tissue action.

In mitochondrial myopathies, elevated GDF-15 levels are suggestive of muscle damage and mitochondrial dysfunction [73]. GDF-15 neutralizing antibody treatment significantly improves the metabolic phenotype of polymerase γ (POLG) mutant mitochondrial myopathy mice, as evidenced by increased body weight, muscle mass, skeletal muscle maximum strength alongside exercise endurance [21]. Mechanistically, the beneficial effects of GDF-15 neutralization are linked to the reversal of transcriptional dysregulation of genes ascribed to autophagy and proteasome signaling. This treatment also appears to dampen GC signaling by suppressing circulating corticosterone levels in the POLG animals [21]. GDF-15 is also associated with disease severity and prognosis of muscle metabolism-related diseases. In idiopathic inflammatory myopathy and juvenile dermatomyositis, GDF-15 level is significantly increased, and positively correlated with multiple disease activity indices (e.g., Disease Activity Score, skin/muscle score and Children Myositis Assessment Scale) [22]. There exists a distinct pattern between the active and remission stages of the disease, since a discriminative capability of GDF-15 has been addressed. In addition, GDF-15 is positively correlated with muscle injury markers (creatine kinase), immune activation indicators (neopterin), and vascular pathological markers (nailfold capillary abnormalities), implicated in the disease process [22]. These findings support GDF-15 as a comprehensive biochemical indicator for assessing disease activity and monitoring progression. Under pathological conditions, elevated GDF-15 is consistently associated with sarcopenia, muscle dysfunction, inflammatory myopathies, and mitochondrial muscle disease. However, most human evidence remains observational, making it unclear whether GDF-15 is a pathogenic driver or merely a marker of tissue damage. In summary, while GDF-15 is reasonably positioned as a “cross-disease marker of muscle assessment,” it should not be regarded as a definitive pathogenic factor in human muscle disorders.

Emerging evidence has delineated multiple pathways underlying GDF-15-mediated muscle atrophy, involving central appetite regulation, endocrine stress, lipid metabolism, and inflammation [5, 17, 51]. The proposed interpretations are depicted as follows: (1) Central activation of the brainstem GDF-15/GFRAL/RET pathway and downstream phosphorylated ERK/Akt/Phospholipase C (PLC) signals, mainly in the AP and NTS, suppresses appetite and indirectly promotes muscle wasting in cachectic mice [5, 51]; (2) GDF-15 influences CRH neurons via brainstem GFRAL neurons and their ascending projections, thereby activating the HPA axis and promoting the release of GC. Elevated GC further upregulates the expression of E3 ubiquitin ligase such as muscle-specific RING finger protein 1 (MuRF-1) and muscle atrophy F-box protein 1 (atrogin-1), drives the decomposition of muscle proteins, reduces the diameter of myotubes, and causes muscle atrophy in mice [74–76]; (3) At the peripheral muscle level, GDF-15 activates atrogin-1/MuRF-1 expression through the TGF-β-activated kinase 1 (TAK-1)/nuclear factor kappa B (NF-κB) pathway, and curtails a range of miRNAs (i.e., miR-1, miR-133a and miR-499) in muscle, resulting in decreased muscle mass and muscle atrophy in mice [74, 75]; (4) The activation of GFRAL-RET pathway suppresses the expression of lipid synthesis-related genes [i.e., ATP citrate lyase (Acly), acetyl-CoA carboxylase (Acc), and fatty acid synthase (Fasn)] in the adipose tissue. GDF-15 triggers lipolysis in the adipose tissue independently of anorexia, leading to a decrease in fat and muscle mass/function in tumor-bearing mice [51]; (5) High GDF-15 inhibits the expression of hepcidin and mediates iron overload by regulating forkhead box protein O3a (FoxO3a) expression through the reactive oxygen species (ROS)/PI3K/Akt axis in humans; iron overload itself has also been reported to independently induce muscle atrophy [77, 78]. Additionally, inflammation may also leverage a complicated impact on GDF-15 and muscle metabolic disorders. Elevated GDF-15 levels are significantly correlated with muscle injury markers (creatine kinase) and proinflammatory cytokines (TNF-α, IL-1β), implying that it may be involved in the muscle degeneration challenged by inflammatory insult [22, 72, 79]. It is worth noting that muscle-derived rather than circulating GDF-15 may be more relevant to local muscle mass and function, and its mechanism may involve the activation of core signaling pathways like NF-κB; meanwhile, chronic low-grade inflammation induces sustained high expression of GDF-15, which in turn promotes muscle atrophy [72, 79]. Until now, the relationship between GDF-15 and inflammation in the context of muscle metabolic disorders is still under intensive investigation [73]. Figure 4 demonstrates a mechanistic framework that distinguishes central indirect mechanisms, like anorexia and HPA-axis activation, from peripheral or systemic mechanisms, such as muscle proteolysis, adipose lipolysis, inflammation, and iron dysregulation.

These findings suggest that the role of GDF-15 in muscle homeostasis appears to be multifactorial, involving protein synthesis/degradation rebalance, innervation regulation, and a potential link with inflammation, metabolism, and redox balance. It should be noted that GFRAL is expressed almost exclusively in the brainstem. Therefore, mechanisms involving the GDF-15/GFRAL/RET axis (e.g., appetite suppression and HPA axis activation) are centrally mediated. Whether GDF-15 acts directly on peripheral skeletal muscle via GFRAL-independent pathways remains an open question, as current evidence is largely derived from correlative human studies or indirect animal models. The role of GDF-15 is neither simply protective nor detrimental; rather, it depends on biological context, concentration, duration, and tissue origin. Transient and moderate elevation may promote muscle adaptation and regeneration, whereas sustained high levels indicate or contribute to wasting conditions. It is plausible to use GDF-15 as a trans-disease marker of muscle status, but its direct pathogenic role and therapeutic potential should be judged on a disease- and intervention-specific basis.

As a pleiotropic molecule, GDF-15 plays a crucial role in the development and progression of aging and age-related diseases. GDF-15 is markedly expressed in senescent cells, connected to actual age, the formation of epigenetic aging markers (e.g., DNAm GrimAge, DNAm PhenoAge, Hannum, and Zhang clocks), the decrease in telomerase activity, and the production of a senescence-associated secretory phenotype [116, 117]. Its mechanism of action involves multiple biological processes based on distinct biological backgrounds and actual ages [118]. Studies have unraveled that GDF-15 participates in heterogeneous biological pathways including but not limited to energy homeostasis, stress response and inflammatory regulation [116, 119, 120]. Previously, GDF-15 was identified as one predominant marker pertinent to aging and frailty-related genes and proteins, pinpointing its significance in accelerating the aging process. More recently, many studies have addressed that GDF-15 abnormality can reflect the nutritional status and physical function among older people. Circulating GDF-15 levels are not only positively correlated with actual age [23], but also with biological age-related markers [117], malnutrition [32, 121] and physical decline indicators [69, 119, 122]. Aforesaid evidence has jointly regarded GDF-15 as an important molecular node of cell senescence, body senescence and clinical phenotypes. Its multifactorial roles cover the regulation of aging at the cellular level and maintain organ function, therefore providing potential monitoring targets and therapeutic windows against aging-related malnutrition.

As a core biomarker of aging, the serum level of GDF-15 parallels increased age, especially in subjects over 60 years [23]. Older people are often associated with varying magnitudes of anorexia, characterized by decreased appetite and reduced food intake, as well as an increased risk of malnutrition [123]. In the acutely hospitalized older population, elevated GDF-15 levels are linked to deterioration of nutritional status assessed by Mini Nutritional Assessment-Short form (MNA-SF), loss of appetite assessed by the simplified nutritional appetite questionnaire, and decreased physical function in terms of various assessment (i.e., HGS, 30-s chair stand test, and gait speed), independent of age, gender, C-reactive protein levels, metformin or immunosuppressive therapy [121]. The baseline GDF-15 predicts the patients' later loss of appetite and progressive weight loss [124]. In patients undergoing hemodialysis, GDF-15 embraces moderately predictive utility for malnutrition screening [125]. Additionally, GDF-15 may be a potential regulator of malnutrition in older people, and its mechanisms of action and clinical relevance are age- and gender-dependent. On one hand, the fasting GDF-15 level and its dynamic changes are negatively correlated with appetite in older people rather than young women [126], partially interpreting the phenotype of ‘aging anorexia’, known as age-related loss of appetite responsible for insufficient intake of protein and micronutrients alongside increased malnutrition risk [123]. Elevated serum GDF-15 concentration implicates the deterioration of nutritional status in older women, manifested as a decrease in MNA-SF score, and this association persists even after excluding patients with cardiovascular disease or diabetes [32]. On the other hand, there is also a gender disparity pertaining to the connection between GDF-15 and physical function parameters such as HGS and knee extension [68]. This gender disparity may be due to differences in hormone levels or in metabolic stress responses [127]. GDF-15 as a predictor of physical functional decline in older people is being continuously validated. A cross-sectional study enrolling healthy people ≥60 years implicates that high GDF-15 levels are significantly associated with physical defects such as lung dysfunction and HGS decrement, especially in men [117]. Longitudinal studies show that GDF-15 can predict the onset of frailty in older patients hospitalized due to cardiovascular disease, with an increased likelihood of around 4 times [122]. Meanwhile, it is independently associated with numerous body dysfunction indicators, including low HGS, low gait speed, long timed-up-and-go time and scores of lower extremity function [69], further validated in another pre-frail older population [128]. Dynamic observation demonstrates that GDF-15 may be one of the molecules mediating the link between physical activity and later body weight changes in older people [119]. Taken together, GDF-15 may serve as an important surrogate to early identify frailty risk in older people. These findings collectively indicate that GDF-15 is not only a sensitive biomarker of age-related functional decline, but also a key molecule in the pathogenesis of malnutrition and physical decline.

As a multifaceted biomarker, GDF-15 has shown clinical significance in the evaluation of aging, physical function, and nutritional status. Its measurement is more readily available to implement than the epigenetic clock for promptly estimating age-related functional decline and malnutrition [117]. Nevertheless, the predictive efficacy of GDF-15 in older populations still requires further in-depth clinical research for conclusive verification. Other research topics should focus on elucidating the molecular mechanism of gender differences, in particular, the biological basis of women’s sensitivity to GDF-15 administration [32, 117].