AUTHOR=Wang Di-Xian , Zhu Xu-Dong , Ma Xiao-Ru , Wang Li-Bin , Dong Zhao-Jun , Lin Rong-Rong , Cao Yi-Na , Zhao Jing-Wei 

TITLE=Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

JOURNAL=Frontiers in Physiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.726345

DOI=10.3389/fphys.2021.726345

ISSN=1664-042X

ABSTRACT=<p>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 <italic>in vitro</italic> culture model of cellular senescence, we show here that <italic>in vitro</italic> 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 GDF11<sup>KO</sup> 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.</p>