GDF11 Rejuvenates Neural Stem Cells Via Smad2/3-PI3K-AKT-mTOR and Reverses Aged-Dependent Cognitive Decline

Whether GDF11 is a systemic factor from young animals’circulation that mediates the rejuvenation process in old animals during heterochronic parabiosis has been debated. We carried out transcriptomic analyses of young versus old monkey and human blood samples demonstrating negative correlations between GDF11 expression and old age, which is further confirmed by quantitative RT-PCR of GDF11 mRNA from more than 400 young and old human blood samples. Reduced GDF11 expression is also correlated with age-dependent cognitive decline. Tail vein injection of recombinant mature GDF11 into aged mice led to increased numbers of cerebral blood vessels and cerebral blood flow, enhanced neurogenesis and spatial learning. Objective and systemic transcriptomic analyses of GDF11-treated brains revealed and subsequently confirmed through biological assays, that rGDF11 regulated angiogenesis, neurogenesis, cell cycle, energy metabolism, clearance of senescent cells, as well as increased telomere length and GDF11 gene expression in neural stem cells via the Smad2/3-PI3K-AKT-mTOR pathway.