Background: Lithium is an established treatment for bipolar disorder and has been associated with favorable mortality outcomes in psychiatric populations. Environmental epidemiological studies and experimental investigations have also raised interest in its possible effects on neurodegeneration, biological aging, and longevity. These observations have stimulated research into low-dose and microdose lithium exposure, although their clinical significance remains uncertain.
Objective: To critically evaluate the evidence linking lithium exposure to mortality, cognitive aging, and longevity, with particular emphasis on the biological rationale, clinical evidence, and safety of microdose supplementation.
Methods: A critical narrative review was conducted using targeted searches of peer-reviewed biomedical literature, trial registries, and selected grey literature. Randomized trials, observational studies, ecological investigations, systematic reviews, and experimental reports were examined. Evidence was interpreted according to study design, exposure category, clinical outcomes, and methodological limitations.
Results: Conventional lithium treatment has been associated with lower all-cause mortality in patients with mood disorders, although these findings cannot establish a direct anti-aging effect. Environmental studies have reported inverse associations between trace lithium exposure and mortality or dementia-related outcomes, but results are inconsistent. Small clinical studies of low-dose lithium have suggested possible cognitive benefits, whereas more recent trials and meta-analyses have yielded inconclusive or negative findings. Experimental investigations implicate glycogen synthase kinase-3, autophagy, oxidative stress responses, and endogenous brain lithium homeostasis. A 2025 study identified reduced lithium availability in human brain tissue affected by cognitive impairment and demonstrated favorable effects of lithium replacement in mouse models. However, no randomized clinical trial has demonstrated that microdose lithium supplementation reduces all-cause mortality or extends human lifespan.
Conclusions: Lithium represents a biologically plausible candidate for further investigation in geroscience. Nevertheless, therapeutic mortality benefits, environmental associations, and experimental findings cannot be directly extrapolated to preventive microdose supplementation. Clinical efficacy, optimal exposure, and long-term safety remain unresolved.