Impact of lithium and valproic acid on telomere length in patient-derived lymphoblastoid cell lines

Background

Individuals with bipolar disorder (BD) have a 15-year reduction in life expectancy compared to the general population, which is associated with early cellular ageing. Telomeres are non-coding DNA sequences located at the ends of chromosomes that shorten with each cell division and are biomarkers of cellular ageing. Individuals with BD have shorter telomere length (TL) compared to the general population[1]. Several clinical studies have reported a potential protective effect of lithium (Li) on TL [2], however, these findings remain controversial [1]. The effects of Li on TL in cells derived from individuals with BD compared to healthy controls (HC) have been poorly studied. The two studies available have reported contradictory findings regarding the impact of Li 1 mM on TL in lymphoblastoid cell lines (LCLs) derived from individuals with BD and HC [3][4]. The impact of other mood stabilizers such as valproic acid (VPA) on TL has not been examined.

Aims

The aim of this study is to measure the effects of Li and VPA on TL between LCLs derived from patients with BD and HC.

Methods

Patient-derived (n=12) and HC-derived (n=6) LCLs were cultured for 7 and 14 days with 1 mM lithium or 0.35 mM VPA and PBS as a control. The T/S ratio was calculated using the delta-delta Cq method [5] and statistical analysis was performed using two way ANOVA in R, with FDR corrections.

Results

No significant changes were identified between TL of BD-derived LCLs exposed to Li, VPA or PBS compared to control-derived LCLs after 7 days of exposure. However, on day 14 TL was significantly different between groups (p_adj = 0.0001). Post-hoc analysis revealed a reduction of TL in BD-derived LCLs exposed to Li (D14, BD-Li vs CTRL-Li, Δ T/S = -2.72 ± 1.00, p_adj = 0.035) and VPA (D14, BD-VPA vs CTRL-VPA, Δ T/S = -3.18 ± 1.00, p_adj = 0.019) compared to control-derived LCLs.

Conclusions

In patient-derived LCLs, neither Li nor VPA had a significant impact on TL after 7 days of exposure, which is consistent with previous findings in the literature. However, a negative impact on TL was detected for Li and VPA after 14 days of exposure in BD-derived cells compared to control-derived cells. These results are the first to analyze the impact of mood stabilizers for more than 7 days in LCLs. Telomeres are maintained by a meticulous homeostasis system that protects and regulates them. Of which the telomerase holoenzyme elongates critically short telomeres and the shelterin complex protects them from external aggressors such as reactive oxygen species. To determine whether telomere shortening results from insufficient telomerase activity or a lack of protection against external damage, additional analyses are performed. These in-depth analyses of markers of TL homeostasis will provide a better understanding of the underlying molecular mechanisms in LCLs derived from individuals with BD and control subjects.

References

1. Sánchez-González JL,et al. Pharmacological interventions and telomere length in patients with schizophrenia and bipolar disorder: A systematic review and meta-analysis. J Psychiatr Res. 2025 Jun
2. Salarda EM, et al. Mini-review: The anti-aging effects of lithium. Neurosci Lett. 2021 Aug
3. Fries GR, et al. The anti-aging effects of lithium in lymphoblastoid cell lines from patients with bipolar disorder and controls. J Psychiatr Res. 2020 Sep
4. Squassina A,et al. Analysis on in vitro effect of lithium on telomere length in lymphoblastoid cell lines from bipolar disorder patients with different clinical response to long-term lithium treatment. Hum Genomics. 2022 Oct 17
5. Lin J, et al. Telomere length measurement by qPCR – Summary of critical factors and recommendations for assay design. Psychoneuroendocrinology. 2019 Jan;