In an epidemiological study published in Aging, scientists have shown that patients who take lithium have much lower all-cause mortality than patients on other psychotropic drugs [1].
Is lithium a longevity drug?
Lithium has long been prescribed for certain psychiatric conditions, mainly bipolar disorder. With time, evidence began to accumulate that lithium might have other benefits for health and longevity; this is similar to what happened with metformin, which is an anti-diabetes drug.
Lithium is thought to work by promoting autophagy and stress resistance via inhibition of glycogen synthase kinase-3 beta (GSK-3β). However, because GSK-3β has multiple functions related to many pathologies [2], scientists are just beginning to unravel lithium’s full potential.
Lithium has been shown to extend lifespan in simple animal models, such as drosophila, even when administered later in life [3]. Human epidemiological studies also showed a slight bump in life expectancy in regions with trace amounts of lithium in drinking water [4]. Of course, epidemiological studies cannot establish causation and are notoriously hard to interpret.
Lithium vs other psychotropic drugs
In this new study, epidemiological as well, the researchers used data from UK Biobank – a huge repository of medical information on almost half a million of British citizens – to see if taking lithium as a drug was associated with lower all-cause mortality. They analyzed a cohort of patients with F3X mood disorders, so called because they are in the International Classification of Diseases (ICD-10) as F30 to F39. According to the study, those diagnoses significantly shorten lifespan by increasing the risk of death from suicide, respiratory diseases, mental disorders, COVID-19, and other proximate causes..
Patients who took lithium were compared to patients who took psychotropic drugs for at least three consecutive months. While the two groups were largely similar, they differed from each other as well as from the general population. For instance, patients who were prescribed lithium normally took the drug longer than patients who were prescribed other antipsychotic medications and had more consecutive F3X episodes. Such heterogeneity makes analyzing the data somewhat harder.
To account for as many confounding variables as possible, the scientists used a tool called propensity score matching (PSM), which theoretically “allows to analyze an observational non-randomized study so that it mimics a randomized controlled trial in a post-hoc fashion”. The researchers controlled for several comorbidities, including diabetes and cancer, and traits, such as sleep quality, smoking, physical activity, alcohol intake, and body mass index (BMI).
A massive decrease in mortality
Despite UK Biobank’s huge size, the resulting cohorts were not that big – just 276 lithium users and 552 users of other psychotropic drugs. However, the trend was clear: lithium significantly extended lifespan. Lithium users had 3.6 times lower chances of dying at a given age compared to other antipsychotic drug users. Importantly, the effect was sex-independent, unlike with some known geroprotective drugs. The causes of death in lithium users and other drug users did not differ significantly, implying that lithium might affect underlying mechanisms of aging and not just mechanisms behind one or two specific diseases.
While the data looks very encouraging, it should be interpreted cautiously. First, the study was populational and had a small sample size. Second, patients on psychotropic drugs generally have more health problems and higher mortality than the rest of the population, so it is not clear how effective lithium would be in extending lifespan in otherwise healthy people. The researchers themselves note that “an alternative interpretation for these findings is that lithium in F3X-diagnosed patients has fewer lifespan-decreasing effects than other medications used to treat F3X diagnoses, and therefore it protects its users from side effects which may lead to premature death”. Finally, lithium treatment requires a lot of caution and supervision, since lithium levels must be kept inside a narrow range.
This study is the first to evaluate the effects of lithium on lifespan in a large aging observational cohort. We have employed a state-of-the-art statistical algorithm, namely propensity score matching, to take advantage of the large amount of observational data in the UK Biobank and simulate a randomized control trial setting to evaluate whether lithium is a geroprotective agent in humans. We have unveiled that lithium at therapeutic concentrations is not only effective in ameliorating mental health, but it is also able to decrease mortality in individuals affected by F3X diagnoses, a demographics that would normally be more fragile and shorter-lived compared to healthy individuals, as also shown in this study.
Conclusion
The results of this study (a 3.6-fold decrease in mortality) certainly look promising and will fuel the growing interest in lithium as a potential geroprotector. However, more research is needed. For instance, while there is data suggesting that metformin users, who are usually diabetic, have fewer chances of dying than even their healthy peers, we don’t have such data for lithium yet.
Literature
[1] Araldi, E., Jutzeler, C. R., & Ristow, M. (2023). Lithium treatment extends human lifespan: findings from the UK Biobank. Aging, 15.
[2] Mancinelli, R., Carpino, G., Petrungaro, S., Mammola, C. L., Tomaipitinca, L., Filippini, A., … & Giampietri, C. (2017). Multifaceted roles of GSK-3 in cancer and autophagy-related diseases. Oxidative medicine and cellular longevity, 2017.
[3] Castillo-Quan, J. I., Li, L., Kinghorn, K. J., Ivanov, D. K., Tain, L. S., Slack, C., … & Partridge, L. (2016). Lithium promotes longevity through GSK3/NRF2-dependent hormesis. Cell reports, 15(3), 638-650.
[4] Zarse, K., Terao, T., Tian, J., Iwata, N., Ishii, N., & Ristow, M. (2011). Low-dose lithium uptake promotes longevity in humans and metazoans. European journal of nutrition, 50, 387-389.
