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

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.

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“…Interestingly, the negative correlation between telomerase and GDF11 is inconsistent with known data. Wang et al found that GDF11 deficiency (in vitro) is associated with telomere shortening and reduced telomerase expression [45]. Similar results are described in the study by Chen et al, who also found that GDF11 enhanced telomerase activity [46].…”

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“…Similarly, c -MYC promotes hTERT deregulation, resulting in the reduction of telomere length, telomerase activity and cell proliferation [ 82 ]. Additionally, TERT can act as a transcription co-factor that regulates expression of several genes [ 77 ], which are summarized in Supplementary Table S1 [ 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 ,…”

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“…In the study by Chen et al , mice with ischemia-reperfusion injury overexpressing GDF11 in the myocardium had higher telomerase activity (Chen et al 2021 ). Wang et al showed that the loss of GDF11 significantly downregulated telomerase activity (Wang et al 2021 ). Zhao et al documented the positive effect of telomerase on GDF11 rejuvenation function in patients after myocardial infarction (Zhao et al 2019 ).…”