The aim of this study was to analyze TL in a sample of 542 individuals with BD and to investigate gene expression levels of 29 age/TL-associated genes in a subgroup of 129 individuals. We first replicated the identification of a subgroup of young individuals, but with already degraded TL in an independent and larger cohort. In addition, we identified a decrease in POT1 gene expression in the “Young Aged” group and showed that POT1 expression level correlated with TL only in this specific subgroup.
TL is the most studied marker of aging in psychiatric diseases including BD [12]. TL is shortened in individuals with BD compared to general population in most previous studies, but without any consensus about the potential clinical determinants [10, 12]. As expected, TL was negatively correlated with age in our sample [8].
First, we confirmed our previous finding of a subgroup of young individuals with an already pronounced telomere shortening [11] in a larger and independent sample of 542 individuals. As previously found, the two clusters of young patients - but with different TL - do not differ for all tested clinical variables. These negative results contrast with previous published ones. Shortened TL has been suggested to be associated with factors such as a high early life trauma score in both general population [32, 33] in individuals with psychiatric disorders including BD [14, 34], but also with a higher number of mood episodes [15]. However, as in our previously published study [11], we did not find an association between TL shortening and these variables in our sample. Another correlation has been suggested between long-term lithium treatment and longer TL [13, 35–37], however the duration of lithium treatment was available for only 13% of the individuals in our database. Therefore we could not test this hypothesis. In addition, the previously observed higher anticonvulsant current use in the cluster of young patients with low TL [11] was not found in this sample. We therefore cannot conclude about the clinical determinants of accelerated cellular aging in the subgroup of young individuals with shortened TL.
Second, we analyzed the expression levels of 29 gene involved in the maintenance of TL or whose expression have been associated to age [18–20, 28, 29]. However, mRNA were available only for a subset of the individuals in the cohort, thus leading to some potential power issues. Nevertheless, expression levels of three genes (CD27, MYC and POT1) were significantly different between the two clusters of young individuals. After adjustments with age, sex, BMI and current smoker status only BMI and POT1 remained significantly associated with the “Young Aged” group. The observed negative association of BMI with TL in the “Young Aged” subgroup is consistent with in a meta-analysis of 87 studies in general population [38].
POT1 (Protection Of Telomeres 1) encodes a protein of the “shelterin complex”. This complex includes six proteins POT1, TRF1, TRF2, TPP1 (ACD), TIN2 and RAP1 and participates in telomere maintenance [39]. POT1 directly interacts with telomeric DNA with the single-stranded G-rich tip where it prevents telomeres from degradation [39]. In addition, its affinity with telomeric DNA is enhanced by TPP1 binding [40] and the POT1-TPP1 complex has an essential role in telomere extension by recruiting telomerase to allow DNA synthesis of telomeres [41]. In this study, we found that POT1 expression was decreased in the “Young Aged” cluster (shorter TL) as compared to the “Young” cluster suggesting that the formation of the POT1-TPP1 complex might be impaired in the “Young Aged” group. We hypothesize that this may result in less protection of the telomeric ends and a less effective recruitment of the telomerase. This is consistent with the increase telomere instability induced by POT1 depletion in mice models [42, 43]. Furthermore, depletion of POT1 has been shown to promote telomere fragility in several human cell lines [44–46] In addition, decreased POT1 expression level has been associated with decreased TL in individuals with severe aplastic anemia [47], which is consistent with the correlation we observed specifically in the “Young Aged” cluster. To our knowledge, this is the first evidence of POT1 decrease of expression in BD or any other psychiatric disorders. Moreover, we found that POT1 expression level correlated with TL only in the “Young Aged” cluster. This suggests that, in this cluster, POT1 expression level has a high impact on TL.
This study has several strengths and limitations. First, a large cohort of 542 individuals with BD was used for TL analyzes with a large spectrum of clinical variables available. However, some variables could not be analyzed due to missing data. This was the case especially for all somatic comorbidities variables due to the limited number of patients in each group and missing data (for example 11 subjects with diabetes versus 509 without diabetes). Indeed, many somatic comorbidities associated with an accelerated aging [48, 49] are also associated with BD. These are therefore important additional factors to analyze, but comorbidities data are often not collected properly and few studies can analyze them. Second, DNA and RNA samples were available in the same cohort, allowing us to analyze both TL and gene expression levels in the same individuals. However, RNA was not available for the whole sample and this may have led to a decrease in the power of gene expression analyses. Here, we cannot exclude some false negative results. The aim of this study was to investigate the association between TL and expression levels of age-related genes with clinical variables in individuals with BD. However, it would have been interesting to compare POT1 mRNA levels in healthy controls samples and individuals with BD. Finally, although we have included telomerase (TERT) in the tested genes, its expression level was too low and could not be analyzed. Furthermore, as blood cells were not available in this sample, telomerase activity could not be analyzed in this study. Therefore, we can’t rule out a role for telomerase (in addition to the decreased POT1 gene expression) in the observed decrease in telomere length in the “Young Aged” group compared to the “Young” group.
In conclusion, this study confirmed the existence of a subgroup of young individuals with BD presenting with shorter TL in a larger and independent sample. None of the available clinical variables in this sample was associated with this prematurely aged phenotype. For the first time, we studied 29 genes whose expression levels are associated with age or TL in a sample of individuals with BD. We showed that a component of the shelterin complex (POT1) is under-expressed in the subgroup of prematurely aged patients compared to the subgroup of similar age. This downregulation is in line with previously described mechanisms of telomere instability. Therefore, our results suggest a newly described cellular mechanism in individuals with BD, that may, at least in part, contribute to telomere shortening. Further studies in independent samples are required to replicate the downregulation of POT1 and provide a better understanding of the mechanisms at stake in cellular aging in individuals with BD.