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Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?
Shavonn C Harper1, Andrew Brack1, Scott MacDonnell1
1From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
Insights
Elevating growth differentiation factor 11 (GDF11) in old animals may not rejuvenate muscles or reverse cardiac issues. New research suggests GDF11 may harm skeletal muscle repair and cause adverse effects, potentially worsening aging-related conditions.
Area of Science:
- Cardiovascular Research
- Aging Biology
- Regenerative Medicine
Background:
- The hypothesis that circulating growth differentiation factor 11 (GDF11) decreases with age and its restoration rejuvenates tissues is debated.
- Initial studies suggested GDF11's benefits, but independent validation has been lacking.
Purpose of the Study:
- To critically evaluate the evidence supporting and refuting the role of GDF11 in aging and rejuvenation.
- To assess the impact of restoring GDF11 levels on skeletal muscle repair and cardiac function in aged animals.
Main Methods:
- Review and analysis of existing and new studies on GDF11's effects in aged animal models.
- Examination of data regarding GDF11's impact on skeletal muscle regeneration and cardiac hypertrophy.
Main Results:
- Independent studies failed to validate GDF11's rejuvenating effects on cardiac and skeletal muscle.
- Increased GDF11 or GDF8 levels impaired skeletal muscle repair and did not reverse cardiac pathologies in aged mice.
- High GDF11 levels induced cachexia-like effects, reducing body and heart weight.
Conclusions:
- The evidence does not support GDF11's role in rejuvenating aged skeletal muscle or reversing cardiac pathologies.
- Elevating GDF11 levels in aged individuals may carry risks and potentially cause harm rather than benefit.
Abstract:
This "Controversies in Cardiovascular Research" article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals. One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known. The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.
