Reviewing GDF11 as a Basis for Regenerative Therapy

I think it fair to say that GDF11 was the first concrete target to emerge from the modern reinvention of parabiosis research, in which the circulatory systems of an old mouse and a young mouse are joined. The old mouse rejuvenates a little, and the young mouse is aged a little, most of which seems to emerge from effects on inflammation and stem cell activity. Researchers thereafter started looking for specific signals carried in the bloodstream that might mediate this effect.

There has been no shortage of debate in this part of the field, such as over whether or not it is possible that beneficial factors from young blood can exist, given the evidence. Or whether the early work on GDF11 holds up at all. Work has continued, however, and matters have progressed to the point at which a well-funded biotech company, Elevian, has been launched. The Elevian researchers claim to have resolved the early conflicting evidence and confusion regarding GDF11, and are now well underway to building a regenerative therapy.

Cardiac hypertrophy is a prominent pathological feature of age-related heart failure. Using the parabiosis model, it has been demonstrated that age-related cardiac hypertrophy can be reversed via exposure to a young circulatory environment. These experiments revealed that age-related cardiac hypertrophy is at least in part mediated by circulating factors, such as GDF11, which is able to reverse the condition.

The reversal of cardiac hypertrophy in old mice exposed to a young circulation cannot be explained by a reduction in blood pressure in the older mice. An extensive proteomics analysis was performed on the serum and plasma of the animals. GDF11 was reduced in the circulation of aged mice and its levels were restored to those in young animals by parabiosis. A significant decrease was also found in both GDF11 gene expression and GDF11 protein levels in the spleens of old mice. These results suggest exciting therapeutic approaches for the management of age-related cardiac hypertrophy by restoring youthful levels of circulating GDF11.

Recently, the goal of a study in old mice was to reexamine the possibility to restore youthful levels of GDF11 by injecting recombinant GDF11 (rGDF11) and thus reversing cardiac hypertrophy and imparting a young phenotype to the old heart. The conclusions were that recombinant GDF11 (rGDF11) had no effect on cardiac structure and cardiac pump function; these results do not support the concept that GDF11 could be an anti-aging compound.

Muscle satellite cells are responsible for the postnatal growth and major regeneration capacity of adult skeletal muscle. Previous studies demonstrated that impaired regeneration in aged muscle can be reversed by parabiosis, which exposes aged tissues to a youthful systemic environment and restores injury-induced satellite cell activation by the up-regulation of Notch signaling. To determine whether supplementation of GDF11 from the young partner might underlie changes in skeletal muscle in the condition of heterochronic parabiosis, aged mice were treated with daily intraperitoneal injections of rGDF11 to increase systemic GDF11 levels.

After 4 weeks, satellite cell frequency, determined by flow cytometry, and function increased in the muscles of rGDF11-treated mice, whereas other myofiber-associated mononuclear cell populations were unaffected. Aged mice treated with rGDF11 also showed increased numbers of satellite cells with intact DNA. These results indicate that GDF11 is able to regulate muscle aging and may be therapeutically suitable for skeletal muscle dysfunction.

Link: https://dx.doi.org/10.3390/ijms19123998

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