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Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.

ABSTRACT: Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-? superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum.Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administration on the murine heart.We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses, and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2-month-old) and old (22-month-old) mice in a dose-dependent manner after only 9 days.Our study confirms an age-dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies.

SUBMITTER: Poggioli T

PROVIDER: S-EPMC4748736 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.

Poggioli Tommaso T Vujic Ana A Yang Peiguo P Macias-Trevino Claudio C Uygur Aysu A Loffredo Francesco S FS Pancoast James R JR Cho Miook M Goldstein Jill J Tandias Rachel M RM Gonzalez Emilia E Walker Ryan G RG Thompson Thomas B TB Wagers Amy J AJ Fong Yick W YW Lee Richard T RT

Circulation research 20151021 1

<h4>Rationale</h4>Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum.<h4>Objective</h4>Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administratio ...[more]

PMID: 26489925

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Project description:BACKGROUND:Circulating FGF21 levels are commonly elevated in disease states. There is limited information regarding concentrations of circulating FGF21 in the absence of disease, as well as age-related differences in body composition that may contribute to FGF21 regulation across groups. OBJECTIVE:The objectives of this study were to assess FGF21 levels across age groups (childhood to elder adulthood), and investigate whether body composition indices are associated with age-related differences in circulating FGF21. MATERIALS AND METHODS:We cross-sectionally analyzed serum concentrations of FGF21 in 184 healthy subjects aged 5-80y (45% male). Multiple linear regression was performed to assess the independent association of categorical age (children: 5-12y, young adults: 20-29y, adults: 30-50y, older adults: 55-64y, elder adults: 65-80y) with FGF21 concentration taking into account DXA-measured body composition indices [bone mineral density (BMD) and percent lean, trunk, and fat mass]. We also stratified analysis by tertile of FGF21. RESULTS:Incremental increases in FGF21 levels were observed across age groups (youngest to highest). Age group was positively associated with FGF21 level independent of body composition indices (age group variable: β=0.25, 0.24, 0.24, 0.23, all P<0.0001, controlling for percent lean, BMD, percent fat, and percent trunk fat, respectively). By FGF21 tertile, age group was associated with FGF21 in the lowest tertile only (β=13.1, 0.19, 0.18, all P≤0.01, accounting for percent lean, fat and trunk fat, respectively), but not when accounting for BMD. CONCLUSIONS:Our findings in a healthy population display an age-related increase in serum FGF21, highlighting a potential age effect in response to metabolic demand over the lifecourse. FGF21 levels increase with age independently of body composition. At lower levels of FGF21, BMD, but not other body composition parameters, attenuates the association between FGF21 level and age, suggesting the metabolic demand of the skeleton may provide a link between FGF21 and energy metabolism.

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Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.

Publications

Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.

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