Редактирование: GDF15 (раздел)

==Publications==

{{medline-entry
|title=Disease-specific plasma levels of mitokines [[FGF21]], [[GDF15]], and Humanin in type II diabetes and Alzheimer's disease in comparison with healthy aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33131010
|abstract=Fibroblast Growth Factor 21 ([[FGF21]]), Growth Differentiation Factor 15 ([[GDF15]]), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that [[GDF15]] is elevated in T2D but not in AD and represents a risk factor for T2D complications, while [[FGF21]] and HN are lower in AD but not in T2D. Moreover, [[FGF21]] reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) [[FGF21]] emerges as a candidate marker of healthy aging.

|keywords=* AD
* Aging
* FGF21
* GDF15
* Humanin
* T2D
|full-text-url=https://sci-hub.do/10.1007/s11357-020-00287-w
}}
{{medline-entry
|title=The Association of Aging Biomarkers, Interstitial Lung Abnormalities, and Mortality.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33080140
|abstract=The association between aging and idiopathic pulmonary fibrosis is established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated. Evaluate associations between aging biomarkers, ILA, and all-cause mortality. In the Framingham Heart Study (FHS), we evaluated associations between plasma biomarkers (interleukin-6 [IL-6], C-reactive protein [[[CRP]]], tumor necrosis factor alpha receptor II [TNFR], growth differentiation factor 15 [[[GDF15]]], cystatin-C, hemoglobin A1C [HGBA1C], insulin, insulin like growth factor [IGF] 1, and IGF binding proteins 1 and 3 [[[IGFBP1]] and 3]), ILA, and mortality. Causal inference analysis was used to determine if biomarkers mediated age. [[GDF15]] results were replicated in COPDGene. In FHS, there was higher odds of ILA per increase in natural log-transformed (ln) [[GDF15]] (OR [95% CI] = 3.4 [1.8-6.4], p=0.0002), TNFR (3.1 [1.6-5.8], p=0.004), IL-6 (1.8 [1.4-2.4], p<0.0001), and [[CRP]] (1.7 [1.3-2.0], p<0.0001). In FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but [[GDF15]] (HR = 2.0 [1.1-3.5], P=0.02), TNFR (1.8 [1.0-3.3], p=0.05), and [[IGFBP1]] (1.3 [1.1-1.7], P=0.01) approached significance. In COPDGene, higher ln([[GDF15]]) was associated with ILA (OR = 8.1 [3.1-21.4], p<0.0001) and mortality (HR = 1.6 [1.1-2.2], p=0.01). Causal inference analysis showed the association of age with ILA was mediated by IL-6 (p<0.0001), TNFR (p=0.002), and likely [[GDF15]] (p=0.008) in FHS, and by [[GDF15]] (p=0.001) in COPDGene. Some aging-related biomarkers are associated with ILA. [[GDF15]], in particular, may explain some of the association between age, ILA, and mortality.

|keywords=* aging
* growth differentiation factor 15
* idiopathic pulmonary fibrosis
* interstitial lung abnormalities
* mortality
|full-text-url=https://sci-hub.do/10.1164/rccm.202007-2993OC
}}
{{medline-entry
|title=Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33031577
|abstract=We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, [[GDF11]], [[GDF15]], [[GHR]], [[NAMPT]], [[PAPPA]], [[PLAU]], [[PTEN]], and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.

|keywords=* age-related disease
* aging
* aging clock
* health span
* life span
* longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681068
}}
{{medline-entry
|title=Mitochondria, immunosenescence and inflammaging: a role for mitokines?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32757036
|abstract=A global reshaping of the immune responses occurs with ageing, indicated as immunosenescence, where mitochondria and mitochondrial metabolism play an important role. However, much less is known about the role of mitochondrial stress response in this reshaping and in particular of the molecules induced by such response, collectively indicated as mitokines. In this review, we summarize the current knowledge on the role of mitokines in modulating immune response and inflammation focusing on [[GDF15]], [[FGF21]] and humanin and their possible involvement in the chronic age-related low-grade inflammation dubbed inflammaging. Although many aspects of their biology are still controversial, available data suggest that these mitokines have an anti-inflammatory role and increase with age. Therefore, we hypothesize that they can be considered part of an adaptive and integrated immune-metabolic mechanism activated by mitochondrial dysfunction that acts within the framework of a larger anti-inflammatory network aimed at controlling both acute inflammation and inflammaging.

|keywords=* Human ageing
* Immunosenescence
* Inflammaging
* Mitochondrial metabolism
* Mitokines
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666292
}}
{{medline-entry
|title=Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32691494
|abstract=Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 ([[GDF15]]) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of [[GDF15]] to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced [[GDF15]] production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of [[GDF15]] as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of [[GDF15]]. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced [[GDF15]] expression in human blood to increased body weight and inflammation. [[GDF15]] deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although [[GDF15]] is not required for Th17 cell differentiation and IL-17 production in Th17 cells, [[GDF15]] contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that [[GDF15]] is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.

|keywords=* T cell
* aging
* inflammation
* mitochondria
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431835
}}
{{medline-entry
|title=Analysis of Epigenetic Age Predictors in Pain-Related Conditions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32582603
|abstract=Chronic pain prevalence is high worldwide and increases at older ages. Signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. A set of DNA methylation (DNAm)-based estimates of age, called "epigenetic clocks," has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. The aim of this study is to assess if different pain-related phenotypes show alterations in DNAm age. In our analysis, we considered three cohorts for which whole-blood DNAm data were available: heat pain sensitivity (HPS), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (FM), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (MOH), 18 episodic migraineurs (EM), and 13 healthy subjects. We used the Horvath's epigenetic age calculator to obtain DNAm-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. We did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. Twins with high HPS had increased CD8  T cell counts (nominal [i]p[/i] = 0.028). HPS thresholds were negatively associated with estimated levels of [[GDF15]] (nominal [i]p[/i] = 0.008). FM patients showed decreased naive CD4  T cell counts compared with controls (nominal [i]p[/i] = 0.015). The severity of FM manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced CD8  T and natural killer cell counts (nominal [i]p[/i] < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal [i]p[/i] = 0.034). No differences in DNAm-based estimates were detected for MOH or EM compared with controls. In summary, our study suggests that HPS, FM, and MOH/EM do not show signs of epigenetic age acceleration in whole blood, while HPS and FM are associated with DNAm-based estimates of immunological parameters, plasma proteins, and telomere length. Future studies should extend these observations in larger cohorts.

|keywords=* DNA methylation
* aging biomarker
* chronic pain
* epigenetic aging
* epigenetic clock
* fibromyalgia
* headache
* pain sensitivity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296181
}}
{{medline-entry
|title=[[GDF15]] Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32477368
|abstract=Growth differentiation factor 15 ([[GDF15]]) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether [[GDF15]] is beneficial or detrimental. The aim of the study was to analyse the levels of circulating [[GDF15]] in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of [[GDF15]] was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of [[GDF15]] increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating [[GDF15]] is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of [[GDF15]] plasma levels, that after the race are similar to that of patients. Moreover, [[GDF15]] plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that [[GDF15]] is associated with decreased muscle performance and increased inflammation.

|keywords=* GDF15
* healthy aging
* inflammation
* physical activity
* sedentarity
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235447
}}
{{medline-entry
|title=Systematic review and analysis of human proteomics aging studies unveils a novel proteomic aging clock and identifies key processes that change with age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32311500
|abstract=The development of clinical interventions that significantly improve human healthspan requires robust markers of biological age as well as thoughtful therapeutic targets. To promote these goals, we performed a systematic review and analysis of human aging and proteomics studies. The systematic review includes 36 different proteomics analyses, each of which identified proteins that significantly changed with age. We discovered 1,128 proteins that had been reported by at least two or more analyses and 32 proteins that had been reported by five or more analyses. Each of these 32 proteins has known connections relevant to aging and age-related disease. [[GDF15]], for example, extends both lifespan and healthspan when overexpressed in mice and is additionally required for the anti-diabetic drug metformin to exert beneficial effects on body weight and energy balance. Bioinformatic enrichment analyses of our 1,128 commonly identified proteins heavily implicated processes relevant to inflammation, the extracellular matrix, and gene regulation. We additionally propose a novel proteomic aging clock comprised of proteins that were reported to change with age in plasma in three or more different studies. Using a large patient cohort comprised of 3,301 subjects (aged 18-76 years), we demonstrate that this clock is able to accurately predict human age.
|mesh-terms=* Aged
* Aging
* Animals
* Biomarkers
* Gene Expression Regulation
* Humans
* Longevity
* Mice
* Proteomics
|keywords=* Aging
* Biomarkers
* Healthspan
* Lifespan
* Longevity
* Proteomics
|full-text-url=https://sci-hub.do/10.1016/j.arr.2020.101070
}}
{{medline-entry
|title=Systemic [[GDF11]] stimulates the secretion of adiponectin and induces a calorie restriction-like phenotype in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31637864
|abstract=Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could be linked has never been investigated. Here, we report that systemic [[GDF11]] triggers a calorie restriction-like phenotype without affecting appetite or [[GDF15]] levels in the blood, restores the insulin/IGF-1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain. These findings suggest that [[GDF11]] has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction. As such, [[GDF11]] could be considered as an important therapeutic candidate for age-related neurodegenerative and metabolic disorders.

|keywords=* GDF11
* adiponectin
* aging
* calorie restriction
* heterochronic parabiosis
* rejuvenation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974718
}}
{{medline-entry
|title=[[GDF15]] is an epithelial-derived biomarker of idiopathic pulmonary fibrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31432710
|abstract=Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 ([i]Gdf15[/i]), as the most significantly upregulated secreted protein. [i]Gdf15[/i] expression is induced in response to telomere dysfunction and bleomycin challenge in mice. [i]Gdf15[/i] mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, [i][[GDF15]][/i] mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of [i][[GDF15]][/i], and circulating concentrations of [[GDF15]] are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that [[GDF15]] is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.
|mesh-terms=* Aged
* Alveolar Epithelial Cells
* Animals
* Bleomycin
* Bronchoalveolar Lavage Fluid
* Case-Control Studies
* Disease Models, Animal
* Female
* Gene Expression Profiling
* Growth Differentiation Factor 15
* Humans
* Idiopathic Pulmonary Fibrosis
* Lung
* Male
* Mice
* Middle Aged
* Respiratory Function Tests
* Severity of Illness Index
* Survival Analysis
* Telomere
* Transcriptome
|keywords=* MIC-1
* NAG-1
* SASP
* aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842909
}}
{{medline-entry
|title=Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor [[GDF15]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31389184
|abstract=The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete [[GDF15]] as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of [[GDF15]] in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor [[GDF15]] in promoting CRC formation.
|mesh-terms=* Aging
* Cells, Cultured
* Cellular Senescence
* Colonic Neoplasms
* Fibroblasts
* Growth Differentiation Factor 15
* HEK293 Cells
* Humans
* Phenotype
* RNA, Messenger
* Tumor Microenvironment
|keywords=* GDF15
* colon organoids
* colorectal cancer
* microenvironment
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826139
}}
{{medline-entry
|title=mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30924297
|abstract=Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age-related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in [[TSC1]] knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased [[GDF15]] is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of [[GDF15]] via phosphorylation of [[STAT3]]. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and [[STAT3]]'s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age-related muscle atrophy, and GDF signaling is a proposed mechanism.
|mesh-terms=* Aging
* Animals
* Cells, Cultured
* Humans
* Mechanistic Target of Rapamycin Complex 1
* Mice
* Mice, Knockout
* Mice, Transgenic
* Muscle Fibers, Skeletal
* Oxidative Stress
* Tuberous Sclerosis Complex 1 Protein
|keywords=* aging
* mTORC1
* oxidative stress
* signal transduction
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516169
}}
{{medline-entry
|title=Expression of lipogenic markers is decreased in subcutaneous adipose tissue and adipocytes of older women and is negatively linked to [[GDF15]] expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30912009
|abstract=In aging, the capacity of subcutaneous adipose tissue (SAT) to store lipids decreases and this results in metabolically unfavorable fat redistribution. Triggers of this age-related SAT dysfunction may include cellular senescence or endoplasmic reticulum (ER) stress. Therefore, we compared lipogenic capacity of SAT between young and older women and investigated its relation to senescence and ER stress markers. Samples of SAT and corresponding SAT-derived primary preadipocytes were obtained from two groups of women differing in age (36 vs. 72 years, n = 15 each) but matched for fat mass. mRNA levels of selected genes (lipogenesis: [[ACACA]], [[FASN]], SCD1, [[DGAT2]], ELOVL6; senescence: p16, p21, [[NOX4]], [[GDF15]]; ER stress-[[ATF4]], XBP1s, PERK, [[HSPA5]], GADD34, [[HYOU1]], CHOP, [[EDEM1]], DNAJC3) were assessed by qPCR, protein levels of [[GDF15]] by ELISA, and mitochondrial function by the Seahorse Analyzer. Compared to the young, SAT and in vitro differentiated adipocytes from older women exhibited reduced mRNA expression of lipogenic enzymes. Out of analyzed senescence and ER stress markers, the only gene, whose expression correlated negatively with the expression of lipogenic enzymes in both SAT and adipocytes, was [[GDF15]], a marker of not only senescence but also mitochondrial dysfunction. In line with this, inhibition of mitochondrial ATP synthase in adipocytes strongly upregulated [[GDF15]] while reduced expression of lipogenic enzymes. Moreover, adipocytes from older women had a tendency for diminished mitochondrial capacity. Thus, a reduced lipogenic capacity of adipocytes in aged SAT appears to be linked to mitochondrial dysfunction rather than to ER stress or accumulation of senescent cells.
|mesh-terms=* Adipocytes
* Adult
* Aged
* Aging
* Biomarkers
* Cell Differentiation
* Cellular Senescence
* Endoplasmic Reticulum Stress
* Female
* Growth Differentiation Factor 15
* Humans
* Lipogenesis
* Mitochondria
* Subcutaneous Fat
|keywords=* Aging
* Lipogenesis
* Mitochondrial dysfunction
* Senescence
* Stress of endoplasmic reticulum
* Subcutaneous adipose tissue
|full-text-url=https://sci-hub.do/10.1007/s13105-019-00676-6
}}
{{medline-entry
|title=Growth differentiation factor 15 ([[GDF15]]): A survival protein with therapeutic potential in metabolic diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30790643
|abstract=Growth Differentiation Factor 15 ([[GDF15]]), also known as NSAID activated gene-1 (NAG-1), is associated with a large number of biological processes and diseases, including cancer and obesity. [[GDF15]] is synthesized as pro-[[GDF15]], is dimerized, and is cleaved and secreted into the circulation as a mature dimer [[GDF15]]. Both the intracellular [[GDF15]] and the circulating mature [[GDF15]] are implicated in biological processes, such as energy homeostasis and body weight regulation. Although there have been many studies on [[GDF15]], [[GFRAL]], a member of the glial-derived neurotropic factor receptor α family, has only been recently identified as a receptor for mature [[GDF15]]. In this review, we focused on cancer and energy homeostasis along with obesity and body weight, and the effect of the identification of the [[GDF15]] receptor in these investigations. In addition, the therapeutic potential of [[GDF15]] as a pharmacological agent in obesity and other metabolic diseases was discussed.
|mesh-terms=* Animals
* Body Weight
* Growth Differentiation Factor 15
* Humans
* Metabolic Diseases
* Neoplasms
* Receptors, Cytokine
|keywords=* Aging
* Appetite suppression
* Cancer prevention
* Energy metabolism
* GFRAL receptor complex
* Growth differentiation factor 15
* Non-steroidal anti-inflammatory drug activated gene-1
* Obesity
* Survival
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196666
}}
{{medline-entry
|title=[The role of «Youth and aging proteins» in essential hypertension pathogenesis.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30584875
|abstract=Essential hypertension (EG) is an age-associated disease. Often EG of elderly patients haven't good way of treatment. Thus, the search of new target molecules for EG therapy is an actual goal of gerontology and molecular medicine. It was shown, that during EG concentrations of [[GDF11]] «youth protein» decreased in 3,3 times and [[GDF15]], JAM-A/1, [[CCL11]] «aging proteins» increased in 1,4-2,4 times. EG patients have abnormal microcirculation processes. It was shown as decreasing in 1,3 and 1,7 times of hemodynamic HI1 and H1-H3 indexes. EG patients have negative correlation of [[GDF15]] concentration with arterial pressure. EG patients have no correlation of JAM-A/1 concentration with arterial pressure. Normal is positive correlation with [[GDF15]], JAM-A/1 concentration with arterial pressure. [[GDF15]] blood level during EG have positive correlation with HI1-HI3 and negative correlation with NEUR_HI2 and MAYER_HI3 indexes. It can show on pathogenesis mechanisms of endothelial and smooth muscles function of vessels tissues. We suppose, that the regulation of [[GDF11]], [[GDF15]], JAM-A/1, [[CCL11]] «youth and aging proteins» can be target object of EG therapy.
|mesh-terms=* Aged
* Aging
* Arterial Pressure
* Essential Hypertension
* Growth Differentiation Factor 15
* Hemodynamics
* Humans
* Proteins
|keywords=* CCL11
* GDF11
* GDF15
* JAM-A/1
* aging
* essential hypertension

}}
{{medline-entry
|title=A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30151729
|abstract=Recent advances indicate that biological aging is a potentially modifiable driver of late-life function and chronic disease and have led to the development of geroscience-guided therapeutic trials such as TAME (Targeting Aging with MEtformin). TAME is a proposed randomized clinical trial using metformin to affect molecular aging pathways to slow the incidence of age-related multi-morbidity and functional decline. In trials focusing on clinical end-points (e.g., disease diagnosis or death), biomarkers help show that the intervention is affecting the underlying aging biology before sufficient clinical events have accumulated to test the study hypothesis. Since there is no standard set of biomarkers of aging for clinical trials, an expert panel was convened and comprehensive literature reviews conducted to identify 258 initial candidate biomarkers of aging and age-related disease. Next selection criteria were derived and applied to refine this set emphasizing: (1) measurement reliability and feasibility; (2) relevance to aging; (3) robust and consistent ability to predict all-cause mortality, clinical and functional outcomes; and (4) responsiveness to intervention. Application of these selection criteria to the current literature resulted in a short list of blood-based biomarkers proposed for TAME: IL-6, TNFα-receptor I or II, [[CRP]], [[GDF15]], insulin, [[IGF1]], cystatin C, NT-proBNP, and hemoglobin A1c. The present report provides a conceptual framework for the selection of blood-based biomarkers for use in geroscience-guided clinical trials. This work also revealed the scarcity of well-vetted biomarkers for human studies that reflect underlying biologic aging hallmarks, and the need to leverage proposed trials for future biomarker discovery and validation.
|mesh-terms=* Aging
* Biomarkers
* Biomedical Research
* Humans
* Hypoglycemic Agents
* Metformin
* Randomized Controlled Trials as Topic
* Reproducibility of Results
|keywords=* Aging
* Biomarkers
* Epidemiology
* Inflammation
* Metformin
* Mortality
* Randomized controlled trial
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294728
}}
{{medline-entry
|title=Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30071357
|abstract=Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) [[CXCL10]] (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), [[CX3CL1]] (C-X3-C motif chemokine ligand 1), (2) [[GDF15]] (growth differentiation factor 15), [[FNDC5]] (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) [[PLAU]] (plasminogen activator, urokinase), [[AGT]] (angiotensinogen), (5) [[BDNF]] (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), [[FGF23]] (fibroblast growth factor 23), [[FGF21]], leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), [[AHCY]] (adenosylhomocysteinase) and [[KRT18]] (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) [[APP]] (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) [[S100B]] (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), [[TGM2]] (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), [[HMGB1]] (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.
|mesh-terms=* Aged
* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Apoptosis
* Biomarkers
* Fibronectins
* Frailty
* Genetic Association Studies
* Growth Differentiation Factor 15
* Humans
* Insulin-Like Growth Factor I
* Interleukin-1 Receptor-Like 1 Protein
* Membrane Glycoproteins
* MicroRNAs
* Signal Transduction
|keywords=* Age-related diseases
* Biomarker panel
* Frailty
* Hallmark of aging pathways
|full-text-url=https://sci-hub.do/10.1016/j.arr.2018.07.004
}}
{{medline-entry
|title=Plasma proteomic signature of age in healthy humans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29992704
|abstract=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  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  ). 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.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Female
* Health
* Humans
* Male
* Middle Aged
* Molecular Sequence Annotation
* Proteomics
* Reproducibility of Results
* Young Adult
|keywords=* aging
* aptamers
* healthy aging
* humans
* plasma
* proteomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156492
}}
{{medline-entry
|title=Human Aging and Longevity Are Characterized by High Levels of Mitokines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29955888
|abstract=Mitochondrial stress elicits the production of stress response molecules indicated as mitokines, including fibroblast growth factor 21 ([[FGF21]]), growth differentiation factor 15 ([[GDF15]]), and humanin (HN). Many diseases are characterized by progressive mitochondrial dysfunction with alterations of mitokine secretion. It is still controversial whether healthy aging and extreme longevity are accompanied by an altered production of mitokines. We analyzed [[FGF21]], HN, and [[GDF15]] plasma levels in 693 subjects aged from 21 to 113 years, and the association of these mitokines with parameters of health status. [[FGF21]], HN, and [[GDF15]] resulted increased in old age, with the highest levels found in centenarians. These molecules are associated with worsened parameters (such as handgrip strength, insulin sensitivity, triglycerides), particularly in 70-year-old persons, and their levels are inversely correlated with survival in the oldest subjects. Considering the positive biological effect of these molecules, our results can be interpreted in the framework of the hormetic paradigm as an attempt of the cells/tissues to cope with a stress that can have beneficial or detrimental effects depending on its intensity. Finally, persons with Down Syndrome (characterized by accelerated aging) have higher levels of [[GDF15]] and HN with respect to their siblings, suggesting that these molecules, especially [[GDF15]], could be considered markers of biological age.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Down Syndrome
* Female
* Fibroblast Growth Factors
* Growth Differentiation Factor 15
* Humans
* Intracellular Signaling Peptides and Proteins
* Longevity
* Male
* Middle Aged
* Mitochondria
* Surveys and Questionnaires
* Unfolded Protein Response
|keywords=* Centenarians
* FGF21
* GDF15
* Humanin
* Mortality
|full-text-url=https://sci-hub.do/10.1093/gerona/gly153
}}
{{medline-entry
|title=Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29491220
|abstract=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 aging-related stress and may control aging phenotype.
|mesh-terms=* Aging
* Animals
* Cells, Cultured
* Enzyme-Linked Immunosorbent Assay
* Growth Differentiation Factor 15
* Male
* Membrane Glycoproteins
* Membrane Transport Proteins
* Mice
* Mice, Knockout
* Muscle, Skeletal
* Myoblasts
* Oxidative Stress
* Real-Time Polymerase Chain Reaction
* Sarcopenia
* Transforming Growth Factor beta
|keywords=* aging cell
* growth differentiation factor 15 (GDF15)
* myokine
* sarcopenia
* skeletal muscle
|full-text-url=https://sci-hub.do/10.1248/bpb.b17-00969
}}
{{medline-entry
|title=Cigarette Smoke Induces Human Airway Epithelial Senescence via Growth Differentiation Factor 15 Production.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27093475
|abstract=Cigarette smoke ([[CS]])-induced airway epithelial senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), although the underlying mechanisms remain largely unknown. Growth differentiation factor (GDF) 15 is increased in airway epithelium of smokers with COPD and [[CS]]-exposed human airway epithelial cells, but its role in [[CS]]-induced airway epithelial senescence is unclear. In this study, we first analyzed expression of [[GDF15]] and cellular senescence markers in airway epithelial cells of current smokers and nonsmokers. Second, we determined the role of [[GDF15]] in [[CS]]-induced airway epithelial senescence by using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 genome editing approach. Finally, we examined whether exogenous [[GDF15]] protein promoted airway epithelial senescence through the activin receptor-like kinase 1/Smad1 pathway. [[GDF15]] up-regulation was found in parallel with increased cellular senescence markers, p21, p16, and high-mobility group box 1 in airway epithelial cells of current smokers compared with nonsmokers. Moreover, [[CS]] extract induced cellular senescence in cultured human airway epithelial cells, represented by induced senescence-associated β-galactosidase activity, inhibited cell proliferation, increased p21 expression, and increased release of high-mobility group box 1 and IL-6. Disruption of [[GDF15]] significantly inhibited [[CS]] extract-induced airway epithelial senescence. Lastly, [[GDF15]] protein bound to the activin receptor-like kinase 1 receptor and promoted airway epithelial senescence via activation of the Smad1 pathway. Our findings highlight an important contribution of [[GDF15]] in promoting airway epithelial senescence upon [[CS]] exposure. Senescent airway epithelial cells that chronically accumulate in [[CS]]-exposed lungs could contribute substantially to chronic airway inflammation in COPD development and progression.
|mesh-terms=* Activin Receptors, Type II
* Aged
* CRISPR-Cas Systems
* Cellular Senescence
* Epithelial Cells
* Gene Knockdown Techniques
* Growth Differentiation Factor 15
* Humans
* Lung
* Middle Aged
* Phosphorylation
* Protein Binding
* Signal Transduction
* Smad1 Protein
* Smoking
|keywords=* airway epithelial cells
* cellular senescence
* cigarette smoke
* growth differentiation factor 15
|full-text-url=https://sci-hub.do/10.1165/rcmb.2015-0143OC
}}
{{medline-entry
|title=Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27018280
|abstract=We and other have recently shown that growth differentiation factor 15 ([[GDF15]]) is a useful diagnostic marker for mitochondrial diseases, which are inherited disorders caused by mitochondrial or nuclear genomic mutations that lead to impaired energy production. As the primary cause of mitochondrial diseases is mitochondrial dysfunction, the blood level of [[GDF15]] might reflect mitochondrial function in patients, and thus could be a marker for mitochondrial dysfunction. [[GDF15]] has been implicated in aging and various age-related disorders, such as cardiovascular diseases and diabetes, the blood level of which is reportedly elevated in older adults as well as in patients. Although [[GDF15]] might be induced as a result of various cellular stresses and dysfunctions, it would also be possible that the blood [[GDF15]] level reflects at least in part mitochondrial dysfunction in aging and age-related disorders. In the present review, we summarized the current literature regarding [[GDF15]] in aging and age-related disorders from the perspective of biomarkers, with a particular focus on mitochondrial dysfunction.
|mesh-terms=* Aging
* Biomarkers
* Cardiovascular Diseases
* Growth Differentiation Factor 15
* Humans
* Mitochondria
|keywords=* age-related disorders
* aging
* biomarker
* growth differentiation factor 15
* mitochondrial dysfunction
|full-text-url=https://sci-hub.do/10.1111/ggi.12724
}}
{{medline-entry
|title=[[GDF15]] contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26909594
|abstract=Growth differentiation factor 15 ([[GDF15]]) is an emerging biomarker of cardiovascular risk and disease. Microarray analyses revealed that [[GDF15]] levels were increased during cellular senescence induced by ionizing radiation (IR) in human aortic endothelial cells (HAECs). However, the role of [[GDF15]] in HAEC cellular senescence remains unclear. This study demonstrated that downregulation of [[GDF15]] in HAECs partially prevented cellular senescence triggered by IR, which was confirmed by recovery of cell proliferation and reverse senescence-associated β-galactosidase (SA-β-gal) staining. Conversely, upregulation of [[GDF15]]-induced cellular senescence in HAECs, confirmed by G0/G1 cell cycle arrest, decreased during cell proliferation and increased SA-β-gal staining. [[GDF15]]-induced cellular senescence was observed in p16-knockdown cells but not in p53-knockdown cells. [[GDF15]] expression in endothelial cells also generated reactive oxygen species (ROS), which led to activation of extracellular signal-regulated kinases (ERKs) and induction of senescence by oxidative stress. These results suggested that [[GDF15]] might play an important role in cellular senescence through a ROS-mediated p16 pathway and contribute to the pathogenesis of atherosclerosis via pro-senescent activity. 
|mesh-terms=* Aorta
* Atherosclerosis
* Cell Line
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Endothelial Cells
* Extracellular Signal-Regulated MAP Kinases
* G1 Phase Cell Cycle Checkpoints
* Growth Differentiation Factor 15
* Humans
* Oxidative Stress
* RNA Interference
* RNA, Small Interfering
* Radiation, Ionizing
* Reactive Oxygen Species
* Tumor Suppressor Protein p53
* beta-Galactosidase
|keywords=* Gerotarget
* cellular senescence
* endothelilal cells
* ionizing radiation
* oxidative stress
* p16
* p53
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891072
}}
{{medline-entry
|title=hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25239873
|abstract=Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) or [[GDF15]] is a divergent member of the transforming growth factor beta (TGF-β) superfamily and mice expressing hNAG-1/h[[GDF15]] have been shown to be resistant to HFD-induced obesity and inflammation. This study investigated if hNAG-1 increases lifespan in mice and its potential mechanisms. Here we report that female hNAG-1 mice had significantly increased both mean and median life spans in two transgenic lines, with a larger difference in life spans in mice on a HFD than on low fat diet. hNAG-1 mice displayed significantly reduced body and adipose tissue weight, lowered serum IGF-1, insulin and glucose levels, improved insulin sensitivity, and increased oxygen utilization, oxidative metabolism and energy expenditure. Gene expression analysis revealed significant differences in conserved gene pathways that are important regulators of longevity, including IGF-1, p70S6K, and PI3K/Akt signaling cascades. Phosphorylation of major components of IGF-1/mTOR signaling pathway was significantly lower in hNAG-1mice. Collectively, hNAG-1 is an important regulator of mammalian longevity and may act as a survival factor. Our study suggests that hNAG-1 has potential therapeutic uses in obesity-related diseases where life span is frequently shorter. 
|mesh-terms=* Animals
* Body Weight
* Energy Metabolism
* Female
* Growth Differentiation Factor 15
* Insulin
* Insulin Resistance
* Insulin-Like Growth Factor I
* Longevity
* Mice
* Phosphorylation
* Signal Transduction
* TOR Serine-Threonine Kinases

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169862
}}