Understanding how juvenile protective factors can influence heart disease in the elderly is of paramount importance. We have recently demonstrated that age-related cardiac hypertrophy can be reversed by exposure to a young circulatory environment, utilizing the experimental model of parabiosis. We identified the TGF-beta family member GDF11 as a circulating hormone, with increased levels of GDF11 in the blood of young mice compared to old mice. As described in this proposal, our findings are also relevant to humans, as low serum levels of GDF11 significantly predict increased mortality over the next 8 years in patients with coronary heart disease. The effect of GDF11 is not limited to the heart, as our newly published studies show that administration of GDF11 to old mice can restore skeletal muscle function. In addition, we have now published that GDF11 can improve angiogenesis in the brains of older mice, suggesting that the loss of GDF11 in older mice is an important factor in multiple tissues. These findings reveal that restoring circulating GDF11 in old mice toward youthful levels can reverse some of the effects of aging, and thus GDF11 may represent a juvenile protective factor. It is very plausible that there is an ongoing delicate balance that must be maintained between some of the TGF-beta signaling molecules and their antagonists. Follistatin like 3 (FSTL3) is a known TGF-beta family antagonist and since it lacks a heparin-binding domain, it is particularly interesting as a potential circulating inhibitor of GDF1. Thus exploration of the dynamic interplay between GDF11 and FSTL3 in the regulation of age-induced phenotypes such as cardiac hypertrophy could reveal important insights into this age-dependent hormonal system. Here we propose that increasing levels of FSTL3 in the circulatory system of young mice, which have higher levels of GDF11, can regulate cardiac hypertrophy (Aim 1). We also propose that increased FSTL3 can inhibit the beneficial effects of exogenous GDF11 (Aim 2). The proposed experiments are highly feasible and have the potential to provide understanding of the balance of GDF11 and FSTL3 in adult mammals that is critical to consideration of GDF11 as a juvenile protective factor.
Our Aims are:
Aim 1 : To test the hypothesis that increased circulating FSTL3 in young mice affects cardiac hypertrophy and gene expression.
Aim 2 : To test the hypothesis that increasing levels of circulating FSTL3 regulates the response to GDF11 in the reversal of cardiac hypertrophy of old mice.

Public Health Relevance

Age-related heart failure is a major cause of death in Americans. This project will address a newly uncovered hormonal system that seems to become dysfunctional in the second half of life, affecting the heart. By studying a protein that can inhibit this hormonal system, this project will provide understanding of how this system can be approached for new therapies for heart disease in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
7R03AG049657-03
Application #
9308278
Study Section
Special Emphasis Panel (ZRG1-CB-C (55)R)
Program Officer
Kohanski, Ronald A
Project Start
2015-04-15
Project End
2017-03-31
Budget Start
2017-01-15
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
$139,204
Indirect Cost
$56,835
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Walker, Ryan G; Czepnik, Magdalena; Goebel, Erich J et al. (2017) Structural basis for potency differences between GDF8 and GDF11. BMC Biol 15:19
Walker, Ryan G; Poggioli, Tommaso; Katsimpardi, Lida et al. (2016) Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation. Circ Res 118:1125-41; discussion 1142
Poggioli, Tommaso; Vujic, Ana; Yang, Peiguo et al. (2016) Circulating Growth Differentiation Factor 11/8 Levels Decline With Age. Circ Res 118:29-37
Uygur, Aysu; Lee, Richard T (2016) Mechanisms of Cardiac Regeneration. Dev Cell 36:362-74