GDF15, an emerging key player in human aging

Highlights

• GDF15 is one of the most up-regulated proteins during aging and a key molecule in the mechanisms of human stress response.

• The role of GDF15 in aging and age-associated diseases is more complex than previously thought and not yet totally clear.

• GDF15 is proposed to be the central core of a bow tie biological model.

• GDF15 may play a role in a dormancy program to mediate tissue tolerance during inflammation and tissue injury.

• GDF15 is associated with both positive and detrimental effects and may be an example of antagonistic pleiotropy.

Abstract

Growth differentiation factor 15 (GDF15) is recently emerging not only as a stress-related mitokine, but also as a key player in the aging process, being one of the most up-regulated protein with age and associated with a variety of age-related diseases (ARDs). Many data indicate that GDF15 has protective roles in several tissues during different stress and aging, thus playing a beneficial role in apparent contrast with the observed association with many ARDs. A possible detrimental role for this protein is then hypothesized to emerge with age. Therefore, GDF15 can be considered as a pleiotropic factor with beneficial activities that can turn detrimental in old age possibly when it is chronically elevated. In this review, we summarize the current knowledge on the biology of GDF15 during aging. We also propose GDF15 as a part of a dormancy program, where it may play a role as a mediator of defense processes aimed to protect from inflammatory damage and other stresses, according to the life history theory.

Introduction

Growth differentiation factor 15 (GDF15), originally described as macrophage inhibitory cytokine-1, is a distant member of the transforming growth factor-β superfamily (Bootcov et al., 1997) and is considered a stress responsive cytokine induced by mitochondrial dysfunction, cellular stress, inflammation or mitochondrial unfolded protein response (UPRmt) pathway, with positive effects on health and lifespan of model organisms. For this reason, it perfectly suits the definition of “mitokine” as provided by Dillin and co-workers (Durieux et al., 2011).

In contrast with this tenet, GDF15 expression is very low in healthy individuals and young subjects (Fujita et al., 2016, Tsai et al., 2018, Conte et al., 2019, Conte et al., 2020a). The levels of GDF15 dramatically increase in chronic or acute illness conditions, in presence of age-related diseases, such as cardiovascular diseases, insulin resistance and type 2 diabetes, neurodegeneration, renal chronic disease and cancer, as well as with aging independently from the health state, thus GDF15 has been proposed as a novel biomarker of biological aging in humans (Lee et al., 2021, Liu et al., 2021). Accordingly, several studies in humans have in fact reported that GDF15 is one of the most up-regulated protein during aging (Fujita et al., 2016; Tsai et al., 2018; Tanaka et al., 2018; Lehallier et al., 2019; Conte et al., 2019, Conte et al., 2020a; Liu et al., 2021). The value of GDF15 as a marker of biological age has been further supported by a recent study reporting that GDF15 is expressed more in subjects with accelerated aging such as Down Syndrome persons, with respect to their siblings of similar age (Conte et al., 2019).

GDF15 is expressed in different types of tissues, such as placenta, skeletal muscle, brain, liver, heart, and it is found at circulating level, however, its pathophysiological role in the aging process is still poorly understood, as several studies suggested opposite functions for this protein. In particular, it is not yet clear whether increased levels of this mitokine in old age have detrimental or beneficial/protective effects on the organisms.

Many studies have proposed an anti-inflammatory role for GDF15. As an example, it has been demonstrated that GDF15 reduces the expression of pro-inflammatory cytokines and prevents the activation of T cells in liver of mice with fibrosis. In addition, GDF15 knockout (KO) induces in mice the production of TNF-α by T cells and the activation of CD4+ and CD8+ T cells, thus aggravating liver injury and fibrosis (Chung et al., 2017). In agreement, Abulizi and co-workers reported that GDF15 KO mice display elevated intensities of inflammatory responses and severe renal and cardiac damage in response to lipopolysaccharide (LPS), while GDF15 transgenic mice are protected from LPS-mediated organ injury (Abulizi et al., 2017). Moreover, an in vitro study on macrophages showed that GDF15 limits the action of TNF-α. These studies are in line with another finding in human prostate, where an inverse correlation between GDF15 levels, quantified by immunohistochemistry image analysis, and CD3+ , CD4+ , CD8+ , CD68+ and INOS+ leukocytes has been demonstrated. Moreover, the expression of IL-8 is downregulated by GDF15 (Lambert et al., 2015). In agreement with these data, a recent study by Moon and colleagues identified a link between age-related induction of GDF15 and the protection of tissues from inflammation, in both humans and mouse models. In particular, these authors demonstrated that aged GDF15 KO mice presented higher levels of inflammatory markers in liver and adipose tissues, as well as impaired glucose homeostasis. Therefore, these data suggest that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation (Moon et al., 2020).

Similarly to inflammation, there are evidences indicating that GDF15 can have also anti-cancer properties, suggesting a tumor suppressor role for this protein. In a recent in vitro study, the overexpression of GDF15 in lung adenocarcinoma A549 cells inhibits the proliferation, migration and invasion of these cells through the activation of TGF-β/Smad signaling pathway (Duan et al., 2019). In agreement, another study indicates that the overexpression of GDF15 significantly suppresses non-small-cell lung cancer cell proliferation and induces apoptosis (Lu et a, 2017). Moreover, GDF15 overexpressing mice are protected from prostate cancer growth, thanks to the activation of CD8+ cytotoxic lymphocytes (Husaini et al., 2020).

In contrast to the above described protective role of GDF15, many other studies indicate that GDF15 can also play a pro-inflammatory role. For example, a study indicates that GDF15 is involved in the development of atherosclerosis by regulating apoptotic cell death and IL-6-dependent inflammatory response (Bonaterra et al., 2012). Another study on LDL-deficient mice has demonstrated that leukocyte-specific KO of GDF15 has beneficial effects against atherosclerosis by reducing macrophage plaque infiltration and decreasing necrotic core formation, suggesting a pro-inflammatory role of GDF15 in atherosclerosis (de Jager et al., 2011). In addition, other studies have identified GDF15 as a candidate biomarker of cellular senescence. In particular, GDF15 has been indicated as a component of the senescence-associated secretory phenotype (SASP) (Guo et al., 2019, Basisty et al., 2020, Di Micco et al., 2021), the pro-inflammatory secretome consisting of numerous cytokines, chemokines, growth factors and proteases released from senescent cells into the tissue microenvironment. Guo et al. have demonstrated that senescent fibroblasts secrete GDF15 as a SASP factor essential to promote cell proliferation, migration and invasion in colon adenoma and colorectal cancer cell lines via the MAPK and PI3K signaling pathways (Guo et al., 2019), suggesting that GDF15 may play an important role in promoting cancer progression. Moreover, several studies have found a strong link between GDF15 and presence of cancer. Circulating levels of GDF15 are in fact significantly higher in patients with different types of cancer compared to healthy controls (Kluger et al., 2011, Wang et al., 2014, Wang et al., 2014, Vocka et al., 2018, O'Neill et al., 2020), thus suggesting that GDF15 can be considered as a marker to identify malignancies and a potential therapeutic target for the treatment of different types of cancer. In agreement, a very recent study demonstrated that circulating levels of GDF15 increase with tumor progression and are very high in patients with hepatocellular carcinoma (Myojin et al., 2021). Moreover, GDF15 KO in hepatic stellate cells suppresses liver tumor formation in mice (Myojin et al., 2021).

In the light of these contrasting findings, the understanding of the biological role of GDF15 appears much more complex than expected, especially in the aging process, where a number of stresses able to induce its expression can occur. Therefore, the analysis of its activities cannot be simple and straight-forward, but rather it has always to consider the biological context in which GDF15 acts. In particular, as it has been established that GDF15 is a stress-response molecule, the levels and nature of stress(es) that accompany GDF15 production should be considered. It is possible that, according to the type and duration of stress, a different role for this protein can be envisaged. In this review we will focus on the role of GDF15 during the aging process and will discuss different aspects of its double-sided nature and propose to consider GDF15 as a representative case of antagonistic pleiotropy. We will also discuss GDF15 in a unifying viewpoint based on the life-history theory, an ecological theory used in the study of aging (Selman et al., 2012, Maklakov and Chapman, 2019) that explains resource allocation during stress response through evolutionary concepts.