LAUSR

Lithium—a light metal named after the Greek word “lithos,” meaning “stone”—has been extensively used, in various salt forms, in the treatment of mood disorders for over half a century. During this stretch of time, a large body of evidence has demonstrated its efficacy and effectiveness, most notably when used as prophylactic treatment for bipolar disorder and as augmentation agent for treatment-refractory unipolar depression. The powerful mood-stabilizing properties of the drug have sustained its front-line use for the management of affective disorders, despite the emergence of newer mood stabilizers with favorable side effect profiles. While the benefits of lithium on mood stabilization have been long documented, studies more recently identified a notable property of the drug: its ability to extend survival. This was initially ascribed to lithium’s role in preventing affective recurrences and decreasing suicide risk. However, several observations suggest that it may influence mortality through additional mechanisms. First, the pro-survival effect of lithium has been observed independent of its impact on mood stabilization or recurrence prevention [1]. Second, lithium more strongly reduces mortality than other mood stabilizers [2, 3], suggesting that certain of its beneficial effects are not shared by other compounds. Third, lithium has been shown to reduce not only suicide mortality but also non-suicide, cardiovascular, and all-cause mortality [2–5]. The mechanisms underlying these intriguing observations are poorly understood. Bringing these observations to new light, emerging evidence from studies in humans, but also cellular and animal models, suggests that lithium can exert multifaceted effects on the aging process. In the nematode Caenorhabditis elegans, exposure to a range of lithium concentrations was shown to extend median lifespan up to 46%, and this effect was accompanied by changes in the expression of chromatin regulators [6]. In Drosophila fruit flies, lithium exposure at different time points extended lifespan up to 18%, an effect mimicked by downregulation of glycogen synthase kinase-3 [7], the enzyme that is targeted and inhibited by lithium treatment. In an in vitro model of human replicative senescence, lithium decreased the levels of senescence-associated markers, leading to reversible arrest of cell proliferation [8]. More recently, the in vivo relevance of lithium for human aging was supported by studies showing that patients with bipolar disorder receiving lithium have longer telomeres, with the duration of lithium treatment further correlating with telomere length [9]. Taken together, these findings suggest that lithium may beneficially influence several processes and hallmarks of aging. The potential of lithium to modulate aging-related processes could explain some of its pro-survival properties; however, the underlying molecular events, their causal direction, and the extent to which they are universal or only occur in selective populations remain to be determined. Although lithium can exert effects on mortality independent of mood stabilization or suicide prevention, some of these effects may nonetheless depend on disease status; for example, lithium may reduce the excess cardiovascular mortality associated with affective disorders, yet it is unclear whether the same benefit is generalizable to populations without affective dysregulation. At the molecular level, disease-specific effects could result from the reversal of aberrations induced by affective states, but they could also stem from the drug’s ability to modulate alterations in molecular pathways that predispose to both affective disorders and accelerated aging. Such a disease-related effect has been suggested in rat models of depression, where lithium was shown to rescue the depression-related decrease in hippocampal expression and activity of telomerase [10], the enzyme that maintains telomere length. Another possibility is that the impact on aging-related processes could itself contribute to lithium’s mood-stabilizing properties. * Anthony S. Zannas [email protected]