Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age‐related disorders

Fujita, Yasunori; Taniguchi, Yu; Shinkai, Shoji; Tanaka, Masashi; Ito, Masafumi

doi:10.1111/ggi.12724

Cited by 147 publications

(129 citation statements)

References 130 publications

(257 reference statements)

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“…The most significant age‐associated protein was growth differentiation factor 15 (GDF15), a member of the transforming growth factor‐b cytokine superfamily that plays an essential role in regulating the cellular response to stress signals in cardiovascular diseases and is produced by cardiac myocytes in response to ischemia (Dominguez‐Rodriguez, Abreu‐Gonzalez, & Avanzas, 2011). GDF15 levels are high in animal models with mitochondrial dysfunction, patients affected by mitochondrial disease, and in older than in younger persons, possibly as a response to impaired calcium homeostasis and excessive oxidative stress (Davis, Liang, & Sue, 2016; Fujita, Taniguchi, Shinkai, Tanaka, & Ito, 2016). It is an interesting fact that the increase in GDF15 with aging found in this study is consistent with previous data showing that mitochondrial function decline with aging in humans (Choi et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

Plasma proteomic signature of age in healthy humans

Tanaka¹,

Biancotto²,

Moaddel³

et al. 2018

Aging Cell

336

339

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To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22–93 years old, who were disease‐ and treatment‐free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10−5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10−56). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.

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Section: Discussionmentioning

confidence: 99%

Plasma proteomic signature of age in healthy humans

Tanaka¹,

Biancotto²,

Moaddel³

et al. 2018

Aging Cell

336

339

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“…The reduced respiratory capacity we demonstrated in our previous study [5] may render monocytes unable to generate sufficient ATP under aerobic conditions, leading to cellular dysfunction, although currently this is speculative. Because GDF-15 is thought to be a biomarker for mitochondrial dysfunction [30,31] and indeed promotes mitochondrial function in macrophages [32], it is likely that GDF-15 is not causally-related to mitochondrial dysfunction in monocytes, but circulating levels of the protein may serve as a useful proxy measure for myeloid mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Growth differentiation factor-15 is associated with age-related monocyte immunosenescence

Pence

Yarbro

Emmons

2020

Preprint

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Background: Immunosenescence is an age-associated decrease in function of immune cells precipitated by a variety of mechanisms and affecting nearly every immune cell subset. In myeloid cell subsets, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we have described an aging effect on several functions indicating immunosenescence in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide (LPS). We hypothesized that circulating factors altered by the aging process underly these changes. Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta superfamily that has known anti-inflammatory effects in macrophages and has recently been shown to be highly differentially expressed during aging. We used biobanked serum and plasma samples to assay circulating GDF-15 levels in subjects from our previous studies and examined correlations between GDF-15 levels and monocyte mitochondrial function and inflammatory responses. Results: Monocyte interleukin-6 production due to lipopolysaccharide stimulation was negatively correlated to plasma GDF-15 levels. Additionally, serum GDF-15 was positively correlated to circulating CD16+ monocyte proportions and negatively correlated to monocyte mitochondrial respiratory capacity. Conclusions: The results of these analyses suggest that GDF-15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence, and thus may be an attractive candidate for therapeutic intervention to ameliorate this.

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“…Increased circulating GDF15 is associated not only with anorexia but also with several age-related diseases, such as cardiac disease, diabetes and neurodegenerative diseases. 29) The induction of GDF15 may contribute to anorexia, a serious mental problem that leads to an eating disorder observed in many patients with late-stage cancer. Notably, serum GDF15 content correlates with the mortality rate in aging-related diseases in humans.…”

Section: Discussionmentioning

confidence: 99%

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse

Ito

Nakanishi

Yamaji

et al. 2018

Biological & Pharmaceutical Bulletin

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It has been identified that skeletal muscle is an endocrine tissue. Since skeletal muscle aging affects not only to muscle strength and function but to systemic aging and lifespan, myokines secreted from skeletal muscle may be crucial factors for intertissue communication during aging. In the present study, we investigated the expression of myokines associated with skeletal muscle aging in taurine transporter knockout (TauTKO) mice, which exhibit the accelerated skeletal muscle aging. Among transforming growth factor (TGF)-beta family genes, only growth and differentiation factor 15 (GDF15) was markedly higher (>3-fold) in skeletal muscle of old TauTKO mice compared with that of either young TauTKO mice or old wild-type mice. Circulating levels of GDF15 were also elevated in old TauTKO mice. An elevation in circulating GDF15 was also observed in very old (30-month-old) wild-type mice, while skeletal GDF15 levels were normal. The treatment of cultured mouse C2C12 myotubular cells with aging-related factors that mediate cellular stresses, such as oxidative stress (hydrogen peroxide) and endoplasmic reticulum stress (tunicamycin and thapsigargin), leads to an increase in GDF15 secretion. In conclusion, GDF15 is a myokine secreted by agingrelated stress and may control aging phenotype.Key words growth differentiation factor 15 (GDF15); sarcopenia; aging cell; skeletal muscle; myokine Aging-related loss of muscle mass and strength causes physical activities of daily living and decreases the QOL.1) Additionally, it has been demonstrated that skeletal muscle mass and strength are well associated with the mortality rate and aging-related diseases in human.2-4) Moreover, several studies in mammals and fruit flies demonstrated that stress-sensing in skeletal muscle influences systemic aging and lifespan, 4) suggesting that non-autonomous communication between aged skeletal muscle and whole body may play a key role in aging process. Skeletal muscle is an endocrine organ that produce cytokines and growth factors, which is called as myokines. 5)

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Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age‐related disorders

Cited by 147 publications

References 130 publications

Plasma proteomic signature of age in healthy humans

Plasma proteomic signature of age in healthy humans

Growth differentiation factor-15 is associated with age-related monocyte immunosenescence

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse

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