GDF11 - Magic or Myth?

Similarly to many other growth factors, GDF11 appears to mainly localize to vesicles.

GDF11, or Growth Differentiation Factor 11, rose to fame as a promising anti-aging molecule in 2013 when repletion in mice was shown to result in an age-related decline and reversal of cardiac hypertrophy (Loffredo, 2013). Subsequent studies further announced abilities to regenerate skeletal muscle and revascularize the brain (Sinha, 2014; Katsimpardi, 2014). In 2022, the biopharmaceutical company Elevian raised $58 million for GDF11 research, prompting a New York Times article titled "Can a 'Magic' Protein Slow the Aging Process?"

GDF11 and its more well-known relative GDF8, or Myostatin, are members of the TGF-β superfamily and share 89% sequence similarity. While GDF8 is restricted to skeletal muscle, negatively regulating muscle fibers, GDF11 is expressed ubiquitously, influencing various tissues during both embryonic development and post-natal stages. Like other TGF-β members, GDF11 operates by binding to activin receptor types I and II, triggering SMAD-mediated signaling and non-canonical pathways like the MAPK and PI3KT/AKT cascade (Nakashima, 1999; Simoni-Nieves, 2019).

Soon after the discovery of GDF11's ability to rejuvenate the cardiac system, enhance neurogenesis and, in contrast to myostatin, skeletal muscle mass, the age-related decrease and rejuvenating effect of GDF11 was either directly contradicted or found irreproducible by a handful of studies (Rando, 2021; Peng, 2022; Rodgers, 2016; Blagosklonny, 2022). The antibodies used in the initial experiments were revealed to cross-react with myostatin, rendering the timely decline of circulating GDF11 unsubstantiated (Rando, 2021; Du, 2017 ). The geronic potential of GDF11 has since been both supported (Ma, 2021; Rodgers, 2015; Demontis, 2014; Wang, 2023) and opposed (Smith, 2015; Kraler, 2023; Mayweather, 2021) with contradictive results partly explained by experimental design, variability of the commercially available GDF11, dose-dependent activity and local vs. hormonal aspects (Driss, 2023; Wolfman, 2003; Cox, 2019). The collective data seems to point to beneficial effects in the heart and brain, but regarding skeletal muscle regeneration, the verdict is still out. So is GDF11 the magical anti-ageing protein that was promised? More data is needed to answer this question, but the story of GDF11 enlightens the complex nature of biology and the importance of antibody and reagent validation. Continued research may fill in the gaps on how to leverage GDF11 as a therapeutic agent, or it may direct efforts elsewhere.