02575nas a2200253 4500008004100000022001400041245014800055210006900203260001600272520175400288100002002042700001802062700001602080700002002096700002202116700001602138700002202154700002302176700002002199700002002219700002202239700002402261856003602285 2023 eng d a1758-535X00aCirculating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders.0 aCirculating Growth Differentiation Factors 11 and 8 Their Antago c2023 Aug 253 a

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 follistatin-like (FSTL)-3 by immunoassay, in two 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-βsuperfamily pathways as potential therapeutic targets.

1 aKizer, Jorge, R1 aPatel, Sheena1 aGanz, Peter1 aNewman, Anne, B1 aBhasin, Shalender1 aLee, Se-Jin1 aCawthon, Peggy, M1 aLeBrasseur, Nathan1 aShah, Sanjiv, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aCummings, Steven, R uhttps://chs-nhlbi.org/node/948102580nas a2200229 4500008004100000022001400041245019900055210006900254260001600323520178300339100002002122700001802142700001702160700001602177700002202193700001902215700002302234700002102257700001602278700002002294856003602314 2023 eng d a1758-535X00aEvaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8 and their Binding Proteins Follistatin and Follistatin-like protein-3 with Dementia and Cognition.0 aEvaluation of Associations of Growth Differentiation Factor11 Gr c2023 Jan 203 a

BACKGROUND: Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models.

METHODS: We assessed Growth Differentiation Factor (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in in the Cardiovascular Health Study (N=1506) and the Health ABC study (N=1237). CLL-11 and Beta 2 microglobulin (B2M) 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 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 implicates TGF-B superfamily inhibition in the pathogenesis of dementia.

1 aNewman, Anne, B1 aPatel, Sheena1 aKizer, Jorge1 aLee, Se-Jin1 aBhasin, Shalinder1 aCawthon, Peggy1 aLeBrasseur, Nathan1 aTracy, Russel, P1 aGanz, Peter1 aCummings, Steve uhttps://chs-nhlbi.org/node/9290