Abstract
Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.
Highlights
Growth differentiation factor 11 (GDF11, known as bone morphogenetic protein 11, BMP11) is a member of transforming growth factor-beta (TGF-β) family
We show that in vitro deletion of growth differentiation factor 11 (GDF11) in cells caused the shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT), telomeric RNA component (TERC), and reduction of telomerase activity, whereas both the recombinant and overexpressed GDF11 restored the transcription of TERT in GDF11 Knockout (GDF11KO) cells to the wildtype level
It has been recently reported that both the level of GDF11 in the blood and the leukocyte telomere lengths (LTLs) are inversely correlated to the age, and the LTLs are associated with the GDF11 expression level in patients who suffered coronary artery diseases (Opstad et al, 2019), implying that GDF11 is associated with telomere length but no causal evidence has been provided
Summary
Growth differentiation factor 11 (GDF11, known as bone morphogenetic protein 11, BMP11) is a member of transforming growth factor-beta (TGF-β) family. The expression of GDF11 in proliferative cells suggests its possible important functions in the proliferative cells (Rochette et al, 2015, 2018). As a potential rejuvenating factor, GDF11 has sparkled unusual interest on its possible role in rejuvenating various organs. Previous studies concerning proliferative organs such as heart, muscle, and the vasculature in the nervous system have created controversial results on whether GDF11 can reverse cellular senescence or not, partly due to its underlying mechanisms have not been clearly established (Loffredo et al, 2013; Katsimpardi et al, 2014; Sinha et al, 2014; Ma et al, 2021)
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