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Replenishment of GDF11 Reverses Cardiac Hypertrophy in Aging Animals

By BiotechDaily International staff writers
Posted on 22 May 2013
Image: Senior author Dr. Richard Lee (left) with contributing author Dr. Amy J. Wagers (right) (Photo courtesy of Harvard University).
Image: Senior author Dr. Richard Lee (left) with contributing author Dr. Amy J. Wagers (right) (Photo courtesy of Harvard University).
Experimental data collected by a team of cardiovascular disease researchers identified the decline in levels of the blood-borne protein growth differentiation factor 11 (GDF11) as contributing to deterioration of the heart muscle (cardiac hypertrophy) that occurs with advanced age and showed that restoration of GDF11 could reverse this process.

Investigators at Harvard University (Boston, MA, USA) searched for factors leading to the development of cardiac hypertrophy by using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation.

The circulatory systems of old and young mice were surgically joined. After four weeks of exposure to the circulation of young mice, indicators of cardiac hypertrophy in old mice dramatically regressed. Changes included reduced cardiomyocyte size and molecular remodeling. This reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of the parabiosis procedure, implicating a blood-borne factor.

The investigators used modified aptamer-based proteomics to identify the TGF-beta superfamily member GDF11 as a circulating factor in young mice that declined with age. Aptamers are nucleic acid species that have been engineered through repeated rounds of in vitro selection to bind to various molecular targets such as small molecules, proteins, and nucleic acids. Aptamers are useful in biotechnological and therapeutic applications as they offer molecular recognition properties that rival that of antibodies. In addition to their discriminate recognition, aptamers offer advantages over antibodies as they can be engineered completely in a test tube, are readily produced by chemical synthesis, possess desirable storage properties, and elicit little or no immunogenicity in therapeutic applications.

GDF11 is a member of the bone morphogenetic protein (BMP) family and the TGF-beta (transforming growth factor beta) superfamily. This group of proteins is characterized by a polybasic proteolytic processing site, which is cleaved to produce a mature protein containing seven conserved cysteine residues. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies in animals suggest that this protein is involved in mesodermal formation and neurogenesis during embryonic development.

Results published in the May 9, 2013, online edition of the journal Cell revealed that treatment of old mice that restored GDF11 to youthful levels replicated the effects of parabiosis by reversing age-related hypertrophy, a finding that implies a possible therapeutic use for this protein in geriatric medicine.

"There has been evidence that circulating bloodstream factors exist in mammals that can rejuvenate tissues, but they have not been identified. This study found the first factor like this," said senior study author Dr. Richard Lee, professor of medicine at Harvard University.

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