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BACKGROUND: Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. METHODS: Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). RESULTS: GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. CONCLUSIONS: GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength.

BACKGROUND: Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models. METHODS: We assessed growth differentiation factors (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in the Cardiovascular Health Study (CHS; N = 1 506) and the Health, Aging and Body Composition (Health ABC) Study (N = 1 237). CLL-11 and beta-2 microglobulin (β2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only), and incident dementia using correlations, linear regression, and Cox proportional hazards models. RESULTS: In CHS, levels of GDF-11, GDF-8, and follistatin were not correlated cross-sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy, or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities, and atrophy on MRI, as well as with incident dementia with an adjusted hazard ratio (HR) of 1.72 (95% CI = 1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95% CI = 1.07, 2.10) per doubling of GDF-8. CONCLUSIONS: Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicate TGFβ superfamily inhibition in the pathogenesis of dementia.

Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.

Titanium dioxide nanoparticles (TiO2NPs) are used in products that are applied to the human body, such as cosmetics and food, but their biocompatibility remains controversial. Pycnogenol (PYC), a natural extract of pine bark, exerts anti-inflammatory and antioxidant effects. In this study, we investigated whether PYC effectively alleviates pulmonary toxicity induced by airway exposure to TiO2NPs, and the beneficial effects of PYC were explained through the analysis of changes to the mechanism of cytotoxicity. TiO2NPs induced pulmonary inflammation and mucus production, increased the levels of malondialdehyde, and upregulated thioredoxin-interacting protein (TXNIP) and cleaved-caspase 3 (Cas3) in the lungs of mice. However, PYC treatment reduced the levels of all toxicity markers of TiO2NPs and restored glutathione levels. These antioxidant and anti-inflammatory effects of PYC were also demonstrated in TiO2NP-exposed human airway epithelial cells by increasing the mRNA levels of antioxidant enzymes and decreasing the expression of TXNIP, cleaved-Cas3, and inflammatory mediators. Taken together, our results showed that PYC attenuated TiO2NP-induced lung injury via TXNIP downregulation. Therefore, our results suggest the potential of PYC as an effective anti-inflammatory and antioxidant agent against TiO2NP-induced pulmonary toxicity. [ABSTRACT FROM AUTHOR]

Background:Follistatin (Fst) promotes brown adipocyte characteristics in adipose tissues. Methods:Abdominal fat volume (CT scan), glucose clearance (GTT test), and metabolomics analysis (mass spectrometry) of adipose tissues from Fst transgenic (Fst-Tg) and wild type (WT) control mice were analyzed. Oxygen consumption (Seahorse Analyzer) and lipidomics (gas chromatography) was analyzed in 3T3-L1 cells. Results:Fst-Tg mice show significant decrease in abdominal fat content, increased glucose clearance, improved plasma lipid profiles and significant changes in several conventional metabolites compared to the WT mice. Furthermore, overexpression of Fst in 3T3-L1 cells resulted in up regulation of key brown/beige markers and changes in lipidomics profiles. Conclusion:Fst modulates key factors involved in promoting metabolic syndrome and could be used for therapeutic intervention.

The regulation of membrane potential and the contractility of vascular smooth muscle cells (VSMCs) by voltage‐dependent K+ (Kv) potassium channels are well‐established. In this study, native VSMCs from rabbit coronary arteries were used to investigate the inhibitory effect of sertindole, an atypical antipsychotic agent, on Kv channels. Sertindole induced dose‐dependent inhibition of Kv channels, with an IC50 of 3.13 ± 0.72 μM. Although sertindole did not cause a change in the steady‐state activation curve, it did lead to a negative shift in the steady‐state inactivation curve. The application of 1‐ or 2‐Hz train pulses failed to alter the sertindole‐induced inhibition of Kv channels, suggesting use‐independent effects of the drug. The inhibitory response to sertindole was significantly diminished by pretreatment with a Kv1.5 inhibitor but not by Kv2.1 and Kv7 subtype inhibitors. These findings demonstrate the sertindole dose‐dependent and use‐independent inhibition of vascular Kv channels (mainly the Kv1.5 subtype) through a mechanism that involves altering steady‐state inactivation curves. Therefore, the use of sertindole as an antipsychotic drug may have adverse effects on the cardiovascular system. Native VSMCs from rabbit coronary arteries were used to investigate the inhibitory effect of sertindole, an atypical antipsychotic agent, on Kv channels. Our findings demonstrate the sertindole dose‐dependent and use‐independent inhibition of vascular Kv channels (mainly the Kv1.5 subtype) through a mechanism that involves altering steady‐state inactivation curves. [ABSTRACT FROM AUTHOR]

Objective We sought to determine whether the levels of complement and other inflammatory and angiogenic mediators in cervicovaginal fluid (CVF) are independently associated with intra-amniotic infection and/or inflammation (IAI) and imminent spontaneous preterm birth (SPTB, £48 hours of sampling) in women with preterm premature rupture of membranes (PPROM). Study Design This was a retrospective study consisting of 85 singleton pregnant women with PPROM at 20 0/7 to 33 6/7 weeks. Amniotic fluid (AF) obtained via amniocentesis was cultured and assayed for interleukin-6. CVF samples collected at the time of amniocentesis were assayed for complement C3a, C4a, and C5a, HSP70 (heat shock protein 70), M-CSF (macrophage colony-stimulating factor), M-CSF-R (macrophage colony-stimulating factor-receptor), S100 A8, S100 A9, thrombospondin-2, VEGF (vascular endothelial growth factor-receptor), and VEGFR-1 (vascular endothelial growth factor-receptor 1) by enzyme-linked immunosorbent assay. Results Multivariate logistic regression analyses revealed that elevated CVF concentrations of complement C3a, 4a, and 5a were significantly associated with an increased risk of IAI and imminent SPTB, whereas those of M-CSF were associated with IAI, but not imminent SPTB (p = 0.063), after adjustment for baseline covariates (e.g., gestational age at sampling). However, univariate, and multivariate analyses showed that the CVF concentrations of angiogenic (thrombospondin-2, VEGF, and VEGFR-1) and inflammatory (HSP70, M-CSF-R, S100 A8, and S100 A9) proteins were not associated with either IAI or imminent SPTB. Conclusion In women with PPROM, elevated CVF concentrations of complement C3a, C4a, and C5a are independently related to an increased risk of IAI and imminent SPTB. These findings suggest that complement activation in CVF is significantly involved in mechanisms underlying preterm birth and in the host response to IAI in the context of PPROM. Key Points Elevated CVF levels of C3a, 4a and 5a are associated with IAI and SPTB. CVF C3a, 4a and 5a have better predictability for SPTB, compared to AF WBC. Elevated CVF levels of M-CSF were associated with IAI, but not SPTB. [ABSTRACT FROM AUTHOR]

Background Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. Methods We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography–tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults. Results In 2 599 participants (age 75.2 ± 4.3) followed for 10.8 ± 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function. Conclusions Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-β superfamily pathways as potential therapeutic targets. [ABSTRACT FROM AUTHOR]