Mini-review: The anti-aging effects of lithium

Abstract

The medical use of lithium has grown since its initial introduction in the 1800s as a treatment for gout. Today, the divalent cation remains as the pharmacological gold standard in treatment of bipolar disorder (BD) with strong mood stabilizing effects. Lithium has demonstrated efficacy in the treatment of acute affective episodes, in the reduction of affective episode recurrence, and in significantly decreasing the risk of suicide in patients. BD has been consistently associated with clinical signs of accelerated aging, including increased rates of age-related diseases such as cardiovascular diseases, malignancies, and diabetes mellitus. This clinical scenario parallels accelerated aging mechanisms observed on a molecular basis, with studies reporting shortened telomeres, increased oxidative stress, and accelerated epigenetic aging in patients with BD compared to controls. Lithium has proved useful as a potential agent in slowing down this accelerated aging process in BD, potentially reversing effects induced by the disorder. This mini review summarizes findings of anti-aging mechanisms associated with lithium use and provides a discussion of the clinical implications and perspectives of this evolving field. Despite many promising results, more studies are warranted in order to elucidate the exact mechanism by which lithium may act as an anti-aging agent and the extent to which these mechanisms are relevant to its mood stabilizing properties in BD.

1. Introduction

Lithium is a commonly used mood stabilizer for bipolar disorder (BD) treatment, although its first medical utilization was to treat gout in the 1800s [1]. By the 1930s, most lithium-containing products treated renal calculi and hyperuricemia [2]. While lithium was used as an anticonvulsant and antidepressant throughout the 1890s, it was not until 1949 when lithium was first shown to be effective for treating mania [2]. At that time, John Cade theorized that uric acid might be responsible for “psychotic excitement” in his manic patients; interestingly, some of the patients responded remarkably well and were even discharged after years of hospitalization [3]. This small case series eventually led to the breakthrough of lithium treatment in 1952 when Mogens Schou conducted the first randomized clinical trial of lithium treatment for mania [2].

Even without considering medications’ side effects, BD is highly associated with increased cardiovascular risk score [4]. In addition, BD has been linked to increased rates of aging-related conditions such as hypertension, metabolic imbalances, dementia, and cancer [5]. Interestingly, lithium appears to have a protective effect against aging processes in BD [5]. For instance, BD patients treated with lithium have been shown to demonstrate longer telomere lengths than those who were not [6]. Preventing accelerated aging in BD may help treat and mitigate many age-related conditions and the overall premature health decline observed in patients. In this sense, a better understanding of lithium’s anti-aging mechanisms may aid in uncovering target molecules implicated in BD mood stabilization and aid in developing precision therapies and pharmacological interventions without adverse side effects. This mini-review aims to summarize findings of accelerated aging in BD, review relevant evidence of lithium’s anti-aging effects in BD, and discuss the clinical implications and future directions of this mood stabilizer as a promising anti-aging treatment.

2. Bipolar disorder as an accelerated aging disease

Conceptually, aging is a decline in various facets of life due to internal physiologic degeneration. Accordingly, BD has been repeatedly associated with age-related conditions and an overall accelerated aging process [7]. For instance, individuals with BD have demonstrated higher premature mortality rates in comparison to the general population [7], and a national cohort study of Swedish adults demonstrated that women and men with BD died 9 and 8.5 years earlier, respectively, in comparison to the national average [7]. This increased mortality and reduced lifespan has been largely explained by medical comorbidities associated with BD, including cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, influenza or pneumonia [7].

Similar to its effect on physiological aging, BD has been shown to demonstrate a great effect on cognitive aging, as well [8]. Specifically, BD has been linked to impairment across several areas in cognition, including attention, processing speed, executive function, learning and memory, and psychomotor speed [9]. This impairment has been shown to occur not only during active affective episodes, but during euthymia and remission, as well [10]. Euthymic BD patients demonstrated significant decline in executive function and stable cognitive impairment over the course of 9 years [11], which has been primarily attributed to illness progression. In contrast, a meta-analysis demonstrated no change in cognition in BD individuals compared to healthy controls in the short- (1.5 years) and long-term (5.5 years) [12]. This finding may also be in part due to differences in what authors dictated as “long-term disease”, such that cognition at 5.5 years would vastly differ from 26 years. Other factors associated with greater cognitive impairment in BD include earlier age of onset, features of psychosis, and an increased number of manic episodes [8].

Alongside the clinical presentation of accelerated aging in BD, structural and functional neuroimaging methods have allowed insights into the physical changes that occur in parallel to cognitive dysfunction. Gross pathologic changes associated with BD include reduced whole-brain volume, increased lateral ventricular volume, reduced prefrontal lobe volume, increased globus pallidus volume, and ventricular enlargement [9]. In addition, there has been evidence of reduced temporal lobe volume in BD patients compared to controls, and white matter hyperintensities have also been preferentially seen in frontal lobes of euthymic BD patients. Finally, reduced callosal areas associated with decreased interhemispheric white matter tract quantity or integrity have been reported in BD patients [9]. All in all, these findings are supportive of age-related structural changes in BD and further support the hypothesis of accelerated aging in this disorder.

Accelerated aging in BD expands past clinical and structural evidence and impacts individuals on a molecular basis, as well. BD individuals have demonstrated greater biological accelerated aging as seen in many biomarker changes [5]. As reviewed elsewhere, premature biological aging may largely be explained by the following principle mechanisms: (1) telomere attrition, (2) genomic instability, (3) epigenetic alterations, (4) loss of proteostasis, (5) deregulated nutrient sensing, (6) mitochondrial dysfunction, (7) cellular senescence, (8) stem cell exhaustion, and (9) altered intercellular communication [13]. Accordingly, biomarkers derived from these processes reflect age estimations across tissues and can vary in concentration and location throughout life. BD's accelerated aging mechanisms have primarily been interrogated through monitoring of telomere length, reactive oxidative species (ROS), inflammatory markers, changes in DNA methylation, and changes in mitochondrial DNA (mtDNA) copy number [5]. Telomeres aid in maintenance and protection of eukaryotic DNA ends, but are often eroded through the ongoing process of DNA replication. Several studies have established significant associations between BD and telomere shortening such that individuals with BD show shorter telomere lengths than healthy controls [14]. Importantly, various comorbidities may underlie these findings, including obesity [15], smoking [16], and chronic stress [17]. In addition, BD has also been associated with significantly increased oxidative stress markers [18], which may exert accelerated shortening of telomeres in patients [19].

Inflammation has also been considered as a biomarker of aging primarily due to the association of inflammation and age-related illnesses and disease [20]. Inflammation largely occurs in conjunction with BD, as well, affecting both central and peripheral tissues in patients with BD [21]. Increased levels of various proinflammatory cytokines [22] and increased acute phase reactive C-reactive protein (CRP) have been found in BD individuals compared to healthy controls [23]. This proinflammatory state has also been linked to increased eosinophil levels and possible neuroprogression, an indirect measurement of accelerated aging [24]. Interestingly, there was no significant differences between euthymic BD individuals and controls in serum levels of Eotaxin-1/C-C Motif Chemokine Ligand 11 (CCL11), a cytokine greatly associated with aging; however, a negative correlation was found between eotaxin-1/CCL11 levels and left-hemisphere's superior-temporal volume found solely in BD patients [25]. In addition, growth differentiation factor 15 (GDF-15) levels, a biomarker of cardiovascular risk and aging [26] have been found to be not only much higher in patients with BD than controls, but also positively correlated with age and illness duration [27]. Lastly, human cytomegalovirus (CMV) serology has been implicated in accelerated immunosenescence, and individuals with BD were found to have higher levels of CMV IgG than controls [28]. CMV's role has been associated with expansion of cells involved in viral control (such as CD8+CD28 -- T cells and natural killer cells), suggesting immunosenescence involvement with BD type I [28].

Epigenetic alterations have also been used to study accelerated aging in BD. DNA methylation changes in multiple tissues have been shown to predict chronological and biological age and have allowed for the development of so-called "epigenetic clocks" [29]. In BD, DNA methylation (DNAm) aging was found to be more advanced than chronological age in older BD individuals compared to controls in peripheral blood [30] in postmortem hippocampal tissue [31], suggesting that accelerated epigenetic aging affects both central and peripheral cellular systems.

3. Anti-aging effects of lithium

Lithium has remained the pharmacological standard in acute and chronic treatment of BD with strong mood stabilizing effects demonstrated with treatment of acute affective episodes, reduction of affective episode recurrence, and significant decrease in risk of suicide [32]. Overall, lithium has demonstrated greater reduction in mortality than other mood stabilizers used in BD [33]. This clinical improvement parallels structural improvement seen on neuroimaging studies. Specifically, lithium treatment has been associated with increased gray matter volume in the anterior cingulate gyrus, amygdala, and hippocampus, regions notably responsible for cognitive control and emotional processing [34].

Lithium treatment has repeatedly demonstrated potential anti-aging effects in preclinical models [35] and in clinical studies [6,36] suggesting that lithium can be repurposed as an anti-aging drug. One method to depict lithium’s potential anti-aging mechanism is through close observation of its effect on telomere length in BD. Telomere shortening is a hallmark biomarker of cellular aging and has been seen to prematurely occur in the BD population, as previously discussed [5,37]. Lithium, however, has demonstrated potential reversal with one study that demonstrated longer peripheral blood leukocyte telomere lengths in lithium-treated BD individuals than healthy age- and sex-matched controls [6]. Moreover, BD individuals who clinically responded to lithium and those who did not respond to lithium revealed an interesting phenomena such that lithium-responders had longer telomere lengths than non-responders, with this finding later replicated [6,38]. In the same vein, in vitro studies with lymphoblastoid cell lines (LCLs) from BD individuals demonstrated cell rescue of telomere shortening with lithium treatment [36]. Duration of lithium treatment may also play a role in telomere length elongation. An increase in telomere length within the lithium-treated BD group was positively correlated with a treatment duration of more than 30 months [6], with similar findings of increased telomere length in BD patients with extended duration of treatment replicated in other samples [39,40].

Although still under investigation, lithium-induced increase in telomere length has been proposed to involve the upregulation of telomerase activity through the inhibition of glycogen synthase kinase-3β (GSK-3β) and increased retention of β-catenin [41]. Specifically, lithium was found to significantly increase β-catenin mRNA expression and protein levels in Flinders Sensitive Line (FSL) rats [35] with concomitant upregulation of telomerase reverse transcriptase (Tert) expression and subsequent telomerase activity in the hippocampus [35]. Another study using triple-transgenic mouse models also demonstrated longer telomere length in hippocampal tissue after a chronic 8-month lithium treatment [42].

Increased telomere lengths and potential upregulation of telomerase have also been reported in clinical trials, with lithium-treated BD type I patients exhibiting upregulated Tert expression in comparison to controls [43]. In addition, this Tert upregulation positively correlated with a duration of lithium treatment of more than 24 months [43], which has led the authors to propose that an increase in Tert expression contributes to lithium's neuroprotective properties by decreasing oxidative stress and improving mitochondrial function [43]. In this same vein, several authors have demonstrated upregulated mitochondrial activity with lithium treatment in animal models [44] and BD individuals [45], suggesting that lithium's protective effects may target mitochondrial energy metabolism.

Lithium treatment has been shown to increase activity of electron transport chain (ETC) complexes I, II, and III, important protein complexes in generating adenosine triphosphate (ATP), in postmortem frontal cortex of BD individuals [45]. Similar findings have been found in peripheral systems, as well, such that lithium treatment was associated with increased activity of ETC complex I in leukocytes [46]. In addition to increasing mitochondrial activity, lithium's role as an anti-aging tool may stem from its ability to prevent and reverse oxidative stress and lipid damage as demonstrated in animal studies [47]. Clinical studies also showed that manic BD patients under acute lithium treatment show a decrease of superoxide dismutase (SOD)/catalase ratio and thiobarbituric acid reactive substances (TBARS) concentrations, further suggesting a potential antioxidant activity of lithium [48]. Similar findings of decreased SOD and TBARS in BD patients have been replicated with interesting variance in lithium-responders and non-responders, as well, with lithium-responders showing significantly lower levels of TBARS than non-responders [49]. Of note, lithium's antioxidant activity may function independently of BD. Healthy volunteers undergoing therapeutic dosing of lithium treatment were found to have decreased levels of SOD as well, once again underlining lithium's potentially antioxidant effects [50]. Within the context of accelerated aging, reduction of oxidizing damage may assist in reversing the hastened accumulation of oxidants found in BD [51], as previously discussed.

Changes in oxidant levels may potentially stem from changes in global DNA methylation from lithium treatment [52]. Accordingly, DNA methylation studies have yielded promising results, with studies having established an accelerated epigenetic aging in older BD patients [30,31]. Lithium's effect on modulating DNA methylation has been previously reported [53], but few studies emphasize the changes in DNA methylation as it relates to epigenetic aging. Okazaki and coworkers described a significant decrease in epigenetic aging via Horvath's clock in patients with BD taking mood stabilizers versus BD patients not taking medications or on monotherapy [54]. While these results emphasize a potential deceleration in epigenetic aging, lithium's exact role in this mechanism would prove difficult to elucidate due to patients taking a combination of carbamazepine and lithium or valproic acid [54]. In contrast, one study found no in vitro effect of lithium on epigenetic age via Horvath's clock nor on epigenetic aging acceleration in BD patients or controls [36], although the lack of detected effects may have been masked by the use of an inappropriate cell model for its investigation. Further studies are warranted to explore the potential role of lithium on DNA methylation, especially as it relates to biological aging.

4. Clinical implications and future directions

As previously mentioned, contrasting results have made it difficult to elucidate lithium's specific role on aging, although the vast majority of studies suggest interesting anti-aging properties with important clinical implications. Though lithium remains as a key first-line pharmacological therapy in treatment of BD, this treatment is not without adverse systemic side effects on the kidneys, thyroid gland, and parathyroid gland, thus requiring careful monitoring due to its narrow therapeutic index. In addition to better identifying its neuroprotective effects, uncovering lithium's potential anti-aging effects would yield prospective development of targeted therapies, diminishing adverse effects associated with lithium.

As discussed in the previous sections, differences in lithium's efficacy in treating BD has been brought about through the identification of lithium-responders and non-responders groups. Clinically, low rates of comorbidities is thought to be one of the strongest predictors of lithium response in patients [55]. In addition, although no difference has been found between responders and non-responders for alcohol and drug use [56], a lower body mass index (BMI) was associated with a better lithium response among patients [56]. A poor response to lithium has also been associated with insulin resistance [57] and an impaired glucose metabolism [58], suggesting many of these differences in somatic comorbidities to (at least partly) contribute to the shorter telomere lengths found in non-responders, albeit even excellent responders may present higher loads of comorbidities than the general population. The exact molecular causes of this response stratification remains unclear, yet studies propose that differences in genetic or epigenetic architecture may hold the answer (such as those conducted by the International Consortium on Lithium Genetics (ConLiGen) [59,60]). Specifically, studies have linked lithium response (or lack thereof) to a region containing two genes for long, non-coding RNAs [60] and also to polygenic risk scores for schizophrenia [59]. By further characterizing genes implicated in lithium effectiveness and its anti-aging properties, one may be able to predict whether an individual may benefit from lithium treatment for BD, as one in silico study suggests [61]. Further use and characterization of genes may hold potential for individualized treatment depending on one's genomic data and supplemental biological information.

In summary, from lithium's initial use as gout therapy to its effect in potentially reversing BD-induced accelerated aging, this therapy holds much promise. Though the exact mechanism of lithium's anti-aging effects remains unclear, the data procured from these studies show that more and more future development of therapies remain at hand.

Highlights.

• Bipolar disorder has been linked to accelerated aging mechanisms

• Lithium has been shown to counteract many aging mechanisms

• Lithium use can prevent telomere shortening in patients with bipolar disorder