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Low-dose lithium uptake promotes longevity in humans and metazoans

DOI:10.1007/s00394-011-0171-x
Authors:
Kim Zarse
Kim Zarse
Kim Zarse
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Takeshi Terao at Oita University
Takeshi Terao
Jing Tian at Huazhong Agricultural University
Jing Tian
Noboru Iwata at Kiryu University
Noboru Iwata
  • Kiryu University
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Abstract and Figures

Lithium is a nutritionally essential trace element predominantly contained in vegetables, plant-derived foods, and drinking water. Environmental lithium exposure and concurrent nutritional intake vary considerably in different regions. We here have analyzed the possibility that low-dose lithium exposure may affect mortality in both metazoans and mammals. Based on a large Japanese observational cohort, we have used weighted regression analysis to identify putative effects of tap water-derived lithium uptake on overall mortality. Independently, we have exposed Caenorhabditis elegans, a small roundworm commonly used for anti-aging studies, to comparable concentrations of lithium, and have quantified mortality during this intervention. In humans, we find here an inverse correlation between drinking water lithium concentrations and all-cause mortality in 18 neighboring Japanese municipalities with a total of 1,206,174 individuals (β = -0.661, p = 0.003). Consistently, we find that exposure to a comparably low concentration of lithium chloride extends life span of C. elegans (p = 0.047). Taken together, these findings indicate that long-term low-dose exposure to lithium may exert anti-aging capabilities and unambiguously decreases mortality in evolutionary distinct species.
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Low-dose lithium uptake promotes longevity in humans and metazoa
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... While lithium efficacy in relieving affective disorders long-term and preventing suicides is well established [7], recent studies both in animal models and in humans have uncovered that lithium may have life-extending properties. AGING Lithium increases longevity in the nematode Caenorhabditis elegans, both at clinical concentrations [8] and in trace amounts [9], in the fruit fly Drosophila melanogaster [10], as well as in yeast (Schizosaccharomyces pombe) [11]. In Drosophila, lithium increases lifespan by inhibiting glycogen synthase kinase-3 (GSK-3) and activating nuclear factor erythroid 2-related factor (NRF-2) [10], suggesting that lithium regulates metabolism and stress resistance. ...
... Nutritionally ingested lithium, as present in plantderived foods and drinking water, is readily bioavailable and evenly disseminated in every tissue, but its distribution in food and water is variable and regiondependent [14,15]. Using geographic differences in lithium concentration as a natural experiment, studies in independent populations worldwide have demonstrated a positive correlation between trace amounts of lithium in drinking water and longevity [9,16,17]. The protective effects of higher dose of lithium intake on all-cause mortality have indirectly been evaluated in prospective intervention studies aimed at comparing the clinical efficacy and suicide rates of lithium on patients suffering from bipolar and related disorders [18,19]. ...
... Our findings are in line with previous works demonstrating that trace amounts of lithium in drinking water are positively correlated with longer lifespan [9,17] and cognitive improvement [27], and support the idea that lithium could be used as a nutritional longevity supplement [16]. Lithium use in humans has been linked with molecular changes associated with longevity. ...
Lithium treatment extends human lifespan: findings from the UK Biobank
Article
Full-text available
  • Jan 2023
Lithium is a nutritional trace element that is also used pharmacologically for the management of bipolar and related psychiatric disorders. Recent studies have shown that lithium supplementation can extend health and lifespan in different animal models. Moreover, nutritional lithium uptake from drinking water was repeatedly found to be positively correlated with human longevity. By analyzing a large observational aging cohort (UK Biobank, n = 501,461 individuals) along with prescription data derived from the National Health Services (NHS), we here find therapeutic supplementation of lithium linked to decreased mortality (p = 0.0017) of individuals diagnosed with affective disorders. Subsequent multivariate survival analyses reveal lithium to be the strongest factor in regards to increased survival effects (hazard ratio = 0.274 [0.119-0.634 CI 95%, p = 0.0023]), corresponding to 3.641 times lower (95% CI 1.577-8.407) chances of dying at a given age for lithium users compared to users of other anti-psychotic drugs. While these results may further support the use of lithium as a geroprotective supplement, it should be noted that doses applied within the UK Biobank/NHS setting require close supervision by qualified medical professionals.
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... with long-term outcomes in humans with susceptible kidneys, like those living with a transplanted kidney. While beneficial effects of higher dietary lithium intake have been reported for all-cause mortality and suicide rates (14,15) in the general population, no epidemiological studies have investigated whether variations in dietary lithium intake are associated with long-term outcomes in kidney transplant recipients. Classic dietary assessments have many limitations, including under-and overreporting, illiteracy and motivation requirements, changes in diet due to self-reflections, errors in portion size estimates, and socially desirable answers (16,17). ...
... The analyses of the current study demonstrate that a higher urinary lithium excretion in associated with a reduced risk of all-cause mortality, independent of the potential confounders included in this study. This finding is in alignment with previous cohort studies in the general population that have demonstrated an inverse association between lithium drinking water concentration and the risk of all-cause mortality (15). ...
Dietary lithium intake, graft failure and mortality in kidney transplant recipients
Article
Full-text available
Background & aims: Long-term high dose lithium therapy in bipolar disorder is known to adversely affect kidney function. However, recent animal studies revealed that low amounts of lithium are beneficial for the kidney when it is damaged by exposure to nephrotoxic compounds, inflammation, or oxidative stress. This study aimed to investigate whether urinary lithium excretion, reflecting dietary lithium intake, is associated with adverse long-term kidney graft outcomes and patient survival. Methods: Urinary lithium concentration was measured using inductively coupled plasma-mass-spectrometry in 642 stable kidney transplant recipients. Graft failure was defined as start of dialysis or re-transplantation, and kidney function decline was defined as doubling of serum creatinine. Results: Median [interquartile range] urinary lithium excretion was 3.03 [2.31-4.01] μmol/24 h. Urinary lithium excretion was associated with energy, plant protein and water intake. During a median follow-up of 5.3 [4.5-6.0] years, 79 (12%) KTR developed graft failure and 127 (20%) KTR developed kidney function decline. Higher urinary lithium excretion was associated with lower risk of graft failure (hazard ratio [95% confidence interval]: 0.54 [0.38-0.79] per log2 μmol/24 h) and kidney function decline (HR [95% CI]: 0.73 [0.54-0.99] per log2 μmol/24 h). These associations remained independent of adjustment for potential confounders and in sensitivity analyses. There was significant effect modification by use of proliferation inhibitors (P = 0.05) and baseline eGFR (P < 0.001), with higher urinary lithium excretion being more protective in KTR not using proliferation inhibitors and in KTR with lower baseline eGFR. Furthermore, higher urinary lithium excretion was associated with reduced risk of all-cause mortality (HR [95% CI]: 0.64 [0.49-0.83]; P = 0.001). Conclusion: Dietary lithium intake may be a potentially modifiable-yet rather overlooked-risk factor for adverse long-term kidney graft outcomes and patient survival.
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... [50][51][52][53][54][55] Remarkably, the outcomes of these studies are fairly similar to effects of lithium reported in mammalian models. 11,27,[56][57][58] The potential impact of lithium on female fruit fly fecundity, however, has not been in the center of attention to date. Accordingly, we chose to investigate a putative role of dietary lithium on egg production and quality in D. melanogaster, whereby monitoring possible impacts on feed intake, food choice and offspring development. ...
Dietary lithium stimulates female fecundity in Drosophila melanogaster
Article
Full-text available
  • Sep 2023
The trace element lithium exerts a versatile bioactivity in humans, to some extend overlapping with in vivo findings in the model organism Drosophila melanogaster . A potentially essential function of lithium in reproduction has been suggested since the 1980s and multiple studies have since been published postulating a regulatory role of lithium in female gametogenesis. However, the impact of lithium on fruit fly egg production has not been at the center of attention to date. In the present study, we report that dietary lithium (0.1–5.0 mM LiCl) substantially improved life time egg production in D. melanogaster w 1118 females, with a maximum increase of plus 45% when supplementing 1.0 mM LiCl. This phenomenon was not observed in the insulin receptor mutant InR E19 , indicating a potential involvement of insulin‐like signaling in the lithium‐mediated fecundity boost. Analysis of the whole‐body and ovarian transcriptome revealed that dietary lithium affects the mRNA levels of genes encoding proteins related to processes of follicular maturation. To the best of our knowledge, this is the first report on dietary lithium acting as an in vivo fecundity stimulant in D. melanogaster , further supporting the suggested benefit of the trace element in female reproduction.
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... al., 2015), хвороби Альцгеймера (Matsunaga et al., 2015), хвороби Паркінсона та Хантингтона (Lazzara & Kim, 2015), деяких видів раку (Berk et al., 2017), остеопорозу (Tang et al., 2015). Низькі дози літію знижують загальну смертність і сприяють продовженню життя людини (Zarse et al., 2011). ...
Accumulation lithium in the tissues and organs of goslings concerning of its level in the mixed feed
Article
Full-text available
  • Mar 2023
We studied the possibility of fortification of goslings’ products with lithium and peculiarities of its depositing in the organs and tissues of goslings concerning lithium level in the mixed feed. Experimental studies have been conducted on goose breed Legart. A total of 320 one-day-old goslings were divided on the principle of analogues into four groups and 80 heads each. The goslings of the first control group did not receive the lithium supplement with the feed mix. Experimental groups were fed with the feed mixed that additionally was supplemented with different doses of lithium by the scheme of the experiment. After 70 days of rearing, three birds were randomly selected from each group and their control slaughter. The lithium content in the representative samples of muscle tissue and organs of goslings was determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES). It was established that feeding the growing goslings with mixed feed containing lithium supplements in doses of 0.05, 0.1 and 0.15 mg/kg, contributed to the increase (P < 0.001) of the concentration of this trace element in the muscles of the thigh and drumstick accordingly 789.5, 1589.5 and at 3447.4 %, in the muscles of the breast 1096.8, 2080.6 and at 3948.4 %, liver are 455.4, 824.6 and at 1440.8 % are compared to goslings that did not receive lithium supplements. Significantly high values of lithium accumulation factors in organs and tissues of gosling (3.21–14.44) indicated that this element has a substantial accumulating capacity. The meat of goslings enriched with lithium can be considered as a natural product with bio-corrective action that can be used in human nutrition. These meat products can be particularly useful for people that are living in regions with a low environmental level of lithium.
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... Moreover, the same Li concentration extends the average lifespan of glp-1(q224) mutants by 10% [142]. Finally, 10 mM Li extends lifespan by ∼3.5% [143]. ...
Mitophagy-promoting agents and their ability to promote healthy-aging
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The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.
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... Li increases hippocampal and cortical size [31,32], slows cognitive deterioration [42], preserves cognition in responder patients [43], and its deficiency causes behavioral abnormalities in rats [45]. We found that Li increased CTRL and Li-R hCS size, and increased expression of MAP2 in CTRL hCS and SV2A in both CTRL and Li-N hCS, consistent with findings showing that Li increases MAP2 expression in neural stem cells [46], as well as neurogenesis in animal models [31]. Although most in vitro studies are conducted with cells from patients on Li medication, our results in CTRL hCS suggest that Li neuroprotective effects are independent of diagnosis, in line with findings that long-term lowdose dietary Li intake is associated with longevity in the general population [47,48]. ...
Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids
Article
Full-text available
  • Jan 2023
Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects of 1 mM Li treatment for 1 month in iPSC-derived human cortical spheroids (hCS) from 10 healthy controls (CTRL) and 11 BD patients (6 Li-responders, Li-R, and 5 Li non-treated, Li-N). At day 180 of differentiation, BD hCS showed smaller size, reduced proportion of neurons, decreased neuronal excitability and reduced neural network activity compared to CTRL hCS. Li rescued excitability of BD hCS neurons by exerting an opposite effect in the two diagnostic groups, increasing excitability in BD hCS and decreasing it in CTRL hCS. We identified 132 Li-associated differentially expressed genes (DEGs), which were overrepresented in sodium ion homeostasis and kidney-related pathways. Moreover, Li regulated secretion of pro-inflammatory cytokines and increased mitochondrial reserve capacity in BD hCS. Through long-term Li treatment of a human 3D brain model, this study partly elucidates the functional and transcriptional mechanisms underlying the clinical effects of Li, such as rescue of neuronal excitability and neuroprotection. Our results also underscore the substantial influence of treatment duration in Li studies. Lastly, this study illustrates the potential of patient iPSC-derived 3D brain models for precision medicine in psychiatry.
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The concentration of Lithium in water resources: A systematic review, meta-analysis and health risk assessment
Article
The presence of trace elements such as lithium (Li) in water resources in the long term can endanger consumers' health. Several studies have been conducted on Li concentration in water sources; hence, this study attempted to retrieve studies using a systematic search. The search was conducted in Web of Sciences, Embase, PubMed, and Scopus databases from 1 January 2010 to 15 January 2023. Li concentration was meta-analyzed based on the type of water resources and countries subgroups in the random effects model (REM) statistical analysis. In addition, health risk assessment in different age groups was calculated using the target hazard quotient (THQ). This study included 76 papers with 157 data reports in our meta-analysis. The overall pooled concentration of Li was 5.374 (95 % CI: 5.261-5.487 μg/L). The pooled concentration of Li in groundwater (40.407 μg/L) was 14.53 times surface water (2.785 μg/L). The highest water Li content was attributed to Mexico (2,209.05 μg/L), Bolivia (1,444.05 μg/L), Iraq (1,350 μg/L), and Argentina (516.39 μg/L). At the same time, the lowest water Li content was associated with Morocco (1.20 μg/L), Spain (0.46 μg/L), and India (0.13 μg/L). THQ due to Li in water resources in consumers of Iraq, Mexico, South Africa, Afghanistan, Bolivia, Portugal, Malawi, South Korea, Nepal, South Korea, Argentina, and the USA was higher than 1 value. Therefore, continuous monitoring of Li concentration in water sources and reducing Li concentration, especially in groundwater water, using new water treatment processes in these countries are recommended.
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An investigation into the association between suicide mortality rate and lithium levels in potable water: a review study
Article
  • Jan 2023
This study aimed to investigate the association between lithium levels in potable water and suicide mortality rates in the total inhabitants. We systematically searched Embase, PubMed/MEDLINE, Scopus, PubMed Central (PMC), Google Scholar databases, as well as medRxiv using the following keywords: drinking water, lithium, standardized mortality ratio (SMR), tap water, suicide, and ground water. Pearson regression analysis was used to test an association between variables with 95% confidence interval (CI). A value of P < 0.05 was considered significant. A total of 16 eligible articles were identified. Lithium concentrations in drinking water range from 0.4 to 32.9 μg/l. Average rates of suicide mortality (per 100 000 capita) range between 0.790 (±0.198) and 123 (±50). About 16 original studies confirmed the inverse relationship between lithium concentrations in potable water and suicide mortality rates (R = -0.576; R2 = 0.3323; 95% CI, -0.820 to -0.325; β = -0.3.2; P = 0.019). High lithium concentrations in potable water were associated with decreased suicide rates. We concluded that lithium concentration in potable water was inversely associated with suicide mortality rates among a total population. However, further research is required to clarify the relationship between lithium concentrations in drinking water and suicide rate.
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Wasserstoff und Alkalimetalle: Elemente der ersten Hauptgruppe
Chapter
  • Jan 2023
Hier sind alle Elemente der ersten Hauptgruppe vereint, also Wasserstoff und sämtliche Alkalimetalle. Wasserstoff wurde vor 250 Jahren, die Metalle Lithium, Natrium und Kalium vor 200 Jahren entdeckt. Rubidium und Cäsium folgten 50 Jahre später, und Francium, dessen Isotope alle extrem kurzlebig sind, wurde 1939 erstmals beschrieben. Obwohl diese Elemente in vielen Publikationen genannt werden und daher ziemlich bekannt sind, haben wir auch hier eine interessante Elementenfamilie vor uns. Die Alkalimetalle sind chemisch sehr reaktiv und zeigen regelmäßige Abstufungen ihrer Eigenschaften. So nehmen vom Lithium zum Cäsium Dichte und Reaktivität zu, Schmelz- und Siedepunkte sowie Elektronegativitäten dagegen ab. Ebenso erfolgt heftige bis explosionsartige Reaktion mit Wasser und Mineralsäuren. In ihren Verbindungen sind sie fast durchweg immer der elektropositive Partner.
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Lithium in drinking water and risk of suicide
Article
Full-text available
Although lithium is known to prevent suicide in people with mood disorders, it is uncertain whether lithium in drinking water could also help lower the risk in the general population. To investigate this, we examined lithium levels in tap water in the 18 municipalities of Oita prefecture in Japan in relation to the suicide standardised mortality ratio (SMR) in each municipality. We found that lithium levels were significantly and negatively associated with SMR averages for 2002-2006. These findings suggest that even very low levels of lithium in drinking water may play a role in reducing suicide risk within the general population.
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Thermotolerance and Extended Life-Span Conferred by Single-Gene Mutations and Induced by Thermal Stress
Article
Full-text available
  • Sep 1995
We have discovered that three longevity mutants of the nematode Caenorhabditis elegans also exhibit increased intrinsic thermotolerance (Itt) as young adults. Mutation of the age-1 gene causes not only 65% longer life expectancy but also Itt. The Itt phenotype cosegregates with age-1. Long-lived spe-26 and daf-2 mutants also exhibit Itt. We investigated the relationship between increased thermotolerance and increased life-span by developing conditions for environmental induction of thermotolerance. Such pretreatments at sublethal temperatures induce significant increases in thermotolerance and small but statistically highly significant increases in life expectancy, consistent with a causal connection between these two traits. Thus, when an animal's resistance to stress is increased, by either genetic or environmental manipulation, we also observe an increase in life expectancy. These results suggest that ability to respond to stress limits the life expectancy of C. elegans and might do so in other metazoa as well.
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Lithium in the Prevention of Suicidal Behavior and All-Cause Mortality in Patients With Mood Disorders: A Systematic Review of Randomized Trials
Article
Full-text available
  • Nov 2005
Observational studies suggest that long-term lithium treatment has a strong antisuicidal effect in mood disorders, but it is uncertain whether this association is a genuine therapeutic effect or is due to confounding factors in nonrandomized studies. The authors conducted a systematic review and meta-analysis of randomized trials to investigate the effect of lithium, compared to placebo and other active treatments, on the risk of suicide, deliberate self-harm, and all-cause mortality in patients with mood disorder. The data source was the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE (1966-June 2002), EMBASE (1980-June 2002), CINAHL (1982-March 2001), PsycLIT (1974-June 2002), PSYNDEX (1977-October 1999), and LILACS (1982-March 2001). The Cochrane Central Register of Controlled Trials (CENTRAL) was searched with the term "lithium" for new records entered into the database from 1999 to 2003. Studies selected included randomized, controlled trials comparing lithium with placebo or all other compounds used in long-term treatment for mood disorders (unipolar depression, bipolar disorder, schizoaffective disorder, dysthymia, and rapid cycling, diagnosed according to DSM or ICD criteria). Of 727 references identified in the search, 52 articles were marked as possibly relevant on the basis of the abstract, and 32 randomized, controlled trials were eligible for inclusion in the review. Two independent reviewers extracted the data, and disagreements were resolved by consensus with a third reviewer. Methodological quality was assessed according to the criteria of the Cochrane Collaboration. When the outcomes of interest were not reported, an attempt was made to obtain the required data from the original authors. In 32 trials, 1,389 patients were randomly assigned to receive lithium and 2,069 to receive other compounds. Patients who received lithium were less likely to die by suicide (data from seven trials; two versus 11 suicides; odds ratio=0.26; 95% confidence interval [CI]=0.09-0.77). The composite measure of suicide plus deliberate self-harm was also lower in patients who received lithium (odds ratio=0.21; 95% CI=0.08-0.50). There were fewer deaths overall in patients who received lithium (data from 11 trials; nine versus 22 deaths; odds ratio=0.42, 95% CI=0.21-0.87). Lithium is effective in the prevention of suicide, deliberate self-harm, and death from all causes in patients with mood disorders.
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Bipolar disorder and mechanisms of action of mood stabilizers
Article
  • Jul 2009
Bipolar disorder (BD) is a major medical and social burden, whose cause, pathophysiology and treatment are not agreed on. It is characterized by recurrent periods of mania and depression (Bipolar I) or of hypomania and depression (Bipolar II). Its inheritance is polygenic, with evidence of a neurotransmission imbalance and disease progression. Patients often take multiple agents concurrently, with incomplete therapeutic success, particularly with regard to depression. Suicide is common. Of the hypotheses regarding the action of mood stabilizers in BD, the "arachidonic acid (AA) cascade" hypothesis is presented in detail in this review. It is based on evidence that chronic administration of lithium, carbamazepine, sodium valproate, or lamotrigine to rats downregulated AA turnover in brain phospholipids, formation of prostaglandin E(2), and/or expression of AA cascade enzymes, including cytosolic phospholipase A(2), cyclooxygenase-2 and/or acyl-CoA synthetase. The changes were selective for AA, since brain docosahexaenoic or palmitic acid metabolism, when measured, was unaffected, and topiramate, ineffective in BD, did not modify the rat brain AA cascade. Downregulation of the cascade by the mood stabilizers corresponded to inhibition of AA neurotransmission via dopaminergic D(2)-like and glutamatergic NMDA receptors. Unlike the mood stabilizers, antidepressants that increase switching of bipolar depression to mania upregulated the rat brain AA cascade. These observations suggest that the brain AA cascade is a common target of mood stabilizers, and that bipolar symptoms, particularly mania, are associated with an upregulated cascade and excess AA signaling via D(2)-like and NMDA receptors. This review presents ways to test these suggestions.
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Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions
Article
  • Jun 1990
Using data for 27 Texas counties from 1978-1987, it is shown that the incidence rates of suicide, homicide, and rape are significantly higher in counties whose drinking water supplies contain little or no lithium than in counties with water lithium levels ranging from 70-170 micrograms/L; the differences remain statistically significant (p less than 0.01) after corrections for population density. The corresponding associations with the incidence rates of robbery, burglary, and theft were statistically significant with p less than 0.05. These results suggest that lithium has moderating effects on suicidal and violent criminal behavior at levels that may be encountered in municipal water supplies. Comparisons of drinking water lithium levels, in the respective Texas counties, with the incidences of arrests for possession of opium, cocaine, and their derivatives (morphine, heroin, and codeine) from 1981-1986 also produced statistically significant inverse associations, whereas no significant or consistent associations were observed with the reported arrest rates for possession of marijuana, driving under the influence of alcohol, and drunkenness. These results suggest that lithium at low dosage levels has a generally beneficial effect on human behavior, which may be associated with the functions of lithium as a nutritionally-essential trace element. Subject to confirmation by controlled experiments with high-risk populations, increasing the human lithium intakes by supplementation, or the lithiation of drinking water is suggested as a possible means of crime, suicide, and drug-dependency reduction at the individual and community level.
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Lithium Salts in the Treatment of Psychotic Excitement
Article
Dr John Cade, one of the most distinguished Australian psychiatrists, died in November, 1980. We republish his seminal paper and acknowledge our debt to The Medical Journal of Australia for allowing us to reprint the article from their September 1949 issue.
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Lithium: Occurrence, Dietary Intakes, Nutritional Essentiality
Article
  • Mar 2002
Lithium is found in variable amounts in foods; primary food sources are grains and vegetables; in some areas, the drinking water also provides significant amounts of the element. Human dietary lithium intakes depend on location and the type of foods consumed and vary over a wide range. Traces of lithium were detected in human organs and fetal tissues already in the late 19th century, leading to early suggestions as to possible specific functions in the organism. However, it took another century until evidence for the essentiality of lithium became available. In studies conducted from the 1970s to the 1990s, rats and goats maintained on low-lithium rations were shown to exhibit higher mortalities as well as reproductive and behavioral abnormalities. In humans defined lithium deficiency diseases have not been characterized, but low lithium intakes from water supplies were associated with increased rates of suicides, homicides and the arrest rates for drug use and other crimes. Lithium appears to play an especially important role during the early fetal development as evidenced by the high lithium contents of the embryo during the early gestational period. The biochemical mechanisms of action of lithium appear to be multifactorial and are intercorrelated with the functions of several enzymes, hormones and vitamins, as well as with growth and transforming factors. The available experimental evidence now appears to be sufficient to accept lithium as essential; a provisional RDA for a 70 kg adult of 1,000 microg/day is suggested.
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Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress
Article
Increasing cellular glucose uptake is a fundamental concept in treatment of type 2 diabetes, whereas nutritive calorie restriction increases life expectancy. We show here that increased glucose availability decreases Caenorhabditis elegans life span, while impaired glucose metabolism extends life expectancy by inducing mitochondrial respiration. The histone deacetylase Sir2.1 is found here to be dispensable for this phenotype, whereas disruption of aak-2, a homolog of AMP-dependent kinase (AMPK), abolishes extension of life span due to impaired glycolysis. Reduced glucose availability promotes formation of reactive oxygen species (ROS), induces catalase activity, and increases oxidative stress resistance and survival rates, altogether providing direct evidence for a hitherto hypothetical concept named mitochondrial hormesis or "mitohormesis." Accordingly, treatment of nematodes with different antioxidants and vitamins prevents extension of life span. In summary, these data indicate that glucose restriction promotes mitochondrial metabolism, causing increased ROS formation and cumulating in hormetic extension of life span, questioning current treatments of type 2 diabetes as well as the widespread use of antioxidant supplements.
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