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Observational Study
. 2024 Dec;46(6):5981-5994.
doi: 10.1007/s11357-024-01142-y. Epub 2024 Mar 28.

The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality

Julian Mutz  1 , Win Lee Edwin Wong  2   3   4 , Timothy R Powell  5 , Allan H Young  4   6 , Gavin S Dawe  2   3   7 , Cathryn M Lewis  5   8
Affiliations
Observational Study

The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality

Julian Mutz et al. Geroscience. 2024 Dec.

Abstract

Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (β = - 0.022, 95% CI - 0.081 to 0.037, p = 0.47), the total duration of use (β = - 0.005, 95% CI - 0.023 to 0.013, p = 0.57) or the duration of the first prescription period (β = - 0.018, 95% CI - 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use.

Keywords: Biological ageing; Frailty; Lithium; Metabolomic age; Mortality; Telomere.

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Conflict of interest statement

AHY declares the following: paid lectures and advisory boards for companies with drugs used in affective and related disorders (Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema pharma, Compass, Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage and Neurocentrx); principal investigator in the Restore-Life VNS registry study funded by LivaNova; principal investigator on “ESKETINTRD3004: An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression”; principal investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants”; principal investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)”; principal investigator on “A Double-Blind, Randomized, Parallel-Group Study with Quetiapine Extended Release as Comparator to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy” (Janssen); principal investigator on “An Open-label, Long-term, Safety and Efficacy Study of Aticaprant as Adjunctive Therapy in Adult and Elderly Participants with Major Depressive Disorder (MDD)” (Janssen); principal investigator on “A Randomized, Double-blind, Multicentre, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants with Major Depressive Disorder (MDD) with Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy”; principal investigator on “A Study of Disease Characteristics and Real-life Standard of Care Effectiveness in Patients with Major Depressive Disorder (MDD) With Anhedonia and Inadequate Response to Current Antidepressant Therapy Including an SSRI or SNR” (Janssen); UK chief investigator for Compass COMP006 & COMP007 studies; UK chief investigator for Novartis MDD study MIJ821A12201; grant funding (past and present) from NIMH (USA), CIHR (Canada), NARSAD (USA), Stanley Medical Research Institute (USA), MRC (UK), Wellcome Trust (UK), Royal College of Physicians (Edin), BMA (UK), UBC-VGH Foundation (Canada), WEDC (Canada), CCS Depression Research Fund (Canada), MSFHR (Canada), NIHR (UK), Janssen (UK) and EU Horizon 2020. No shareholdings in pharmaceutical companies. CML sits on the scientific advisory board for Myriad Neuroscience and has received speaker fees from SYNLAB and consultancy fees from UCB. JM, WLEW, TRP and GSD declare no financial conflict of interest.

Figures

Fig. 1
Fig. 1
Scatter plots of telomere length (T/S ratio loge transformed and Z-standardised) by lithium prescription count, total duration of use and duration of the first prescription period. The lines were estimated using ordinary least squares regression, and the shaded areas correspond to 95% confidence intervals. Lithium use (yes/no) at the time of the baseline assessment when telomere length was measured is shown in different colours. Individuals without baseline data on current lithium use are not shown. Tx = treatment; Rx = prescription
Fig. 2
Fig. 2
Scatter plots of telomere length (T/S ratio loge transformed and Z-standardised), the frailty Index and metabolomic age (MileAge) delta by total duration of lithium use. The lines were estimated using ordinary least squares regression, and the shaded areas correspond to 95% confidence intervals. tx = treatment
Fig. 3
Fig. 3
Hazard ratios (HR) and 95% confidence intervals from Cox proportional hazards models for all-cause mortality. Age (in years) was used as the underlying time axis. The model was adjusted for age and sex. Reference group: individuals in the lowest quintile of the distribution of the duration of lithium use (prescription count, total duration and duration of the first prescription period). Tx = treatment; Rx = prescription
Fig. 4
Fig. 4
Log hazard ratios and 95% confidence intervals from Cox proportional hazards models for all-cause mortality. Age (in years) was used as the underlying time axis. The model was adjusted for age and sex. Vertical lines indicate the median of the distribution. Tx = treatment; Rx = prescription
See this image and copyright information in PMC

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