YOUNG AT HEART, CELL

Within the context of an increasingly aged population, the healthcare costs associated with aging-related heart failure represent a significant healthcare burden. Diastolic heart failure, characterized by impaired cardiac filling during relaxation, in particular, is a condition lacking specific and effective therapies (; ). Though perhaps controversial, there appears to be an association between an age-related increase in cardiac mass (i.e., cardiac hypertrophy) and the development of diastolic dysfunction (; ). Age-related cardiac hypertrophy has been described in humans and animal models, but the physiological, hormonal, cellular, and molecular causes remain poorly understood. Here, Loffredo et al. demonstrate that exposing an old mouse to the circulation of a young mouse using a powerful technique called parabiosis can reverse many of the biological consequences of age-related cardiac hypertrophy (). The authors go on to establish that this effect appears to be at least partially modulated by a circulating protein called growth and differentiation factor 11 (GDF11).

The traditional technique of parabiosis involves joining the vasculature of two animals such that the two animals effectively share the same circulatory system (). With heterochronic parabiosis, an older animal is exposed to the circulation of a younger animal. Here, Loffredo et al. show that 4 months of heterochronic parabiosis reduces cardiac mass and cardiomyocyte cross-sectional area in old mice and promotes a favorable shift in gene expression, including reduced natriuretic factor expression and increased SERCA-2 calcium ATPase expression. The authors demonstrate that these changes are not due to alterations in blood pressure or any behavioral changes due to the physical constraints of the parabiosis itself. Importantly, the authors also show that these changes in cardiac mass do not appear to be due to alterations in body mass. In fact, while old heterochronic parabiosis animals do experience a dramatic reduction in body mass (∼32%), this loss is not significantly different from that seen in old animals from a sham heterochronic parabiosis experiment (∼25%). Given the importance of body mass in dictating the overall metabolic demand and thus cardiac workload, it is certainly important to consider alterations in body mass in these types of parabiotic experiments.

Having established that exposure to a young circulation effectively remodels the aged heart, Loffredo et al. utilize aptamer-based technology to identify GDF11 as one of the circulating factors that is significantly different between young and old mice. A member of the activin/TGFβ superfamily of growth and differentiation factors, GDF11, binds the activin-type IIB receptor (ActRIIB) and promotes activation of the Smad 2/3 pathway (). Within the TGFβ superfamily, GDF11 is most similar to myostatin (mstn or GDF8), a well-known negative regulator of skeletal muscle mass (). However, though there appears to be some functional redundancy between myostatin and GDF11, the overall biological functions of GDF11 are relatively poorly understood (, ). Though myostatin null mice are viable and display a dramatic increase in skeletal muscle mass combined with reduced adiposity, GDF11 null mice die within 24 hr of birth, with severe skeletal and renal abnormalities (; , ). In fact, analysis of GDF11 null mice reveals alterations in Hox gene expression and indicates a role for GDF11 in patterning positional identity along the anterior/posterior axis ().

Follow-up validation experiments by Loffredo et al. confirmed that GDF11 is widely expressed in mouse tissues, with highest levels of mRNA expression in the spleen. Importantly, the authors demonstrate that splenic GDF11 mRNA expression and protein levels decline with aging in the mouse, as do circulating levels. The authors then show that treatment of neonatal rat cardiomyocytes with recombinant GDF11 (rGDF11) inhibits cellular hypertrophy in the presence of the prohypertrophic stimulus, phenylephrine. Furthermore, treatment of human-induced pluripotent stem-cell-derived cardiomyocytes with rGDF11 activates the TGFβ pathway and suppresses FOXO phosphorylation. With these in vitro data in hand, the authors supplemented old mice with rGDF11 to restore “youthful” levels of the signaling factor. In fact, old mice given rGDF11 for 30 days demonstrate a similar cardiac phenotype as the old mice from the heterochronic parabiotic pair experiments, with reduced cardiac mass, smaller cardiomyocytes, and favorable changes in gene expression. Interestingly, the authors show that daily rGDF11 supplementation does not impact cardiac hypertrophy due to aortic constriction, indicating that the cardiac effects of GDF11 with respect to cardiac hypertrophy appear to be etiology specific.

These findings raise several questions for future research. Considering that the “aged” phenotype often includes reduced skeletal muscle mass, increased adiposity, and reduced insulin sensitivity, it will be interesting to see whether circulating GDF11 impacts these body systems in addition to the heart (Figure 1). Though skeletal-muscle-derived GDF11 does not appear to regulate skeletal muscle fiber size and composition, the effects of systemic circulating GDF11 on skeletal muscle are poorly understood (). Based on the data of Loffredo et al., it is intriguing to speculate that the age-related decline in circulating GDF11 may also impact skeletal muscle mass and function. Likewise, the effects of circulating GDF11 on adiposity and fat metabolism are unknown. However, given that mice lacking myostatin have increased muscle mass and reduced adiposity, it might be predicted that an age-related decline in GDF11 could produce similar (albeit smaller) effects. Similarly, there are conflicting data, suggesting that GDF11 may or may not be involved in the maintenance of pancreatic β-cell function (; ). Together, these data and those of Loffredo et al. indicate that age-related alterations in circulating GDF11 levels may also impact glucose/insulin homeostasis. Overall, these questions suggest that further study of GDF11 and its relative contributions with respect to the system-wide aged phenotype are worthwhile.