Low-dose lithium - a life-long partner in longevity journey

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Disclaimer - not medical advise

This article is based on my research of information from publicly available sources and my personal experience. The information, opinions, and references provided in this article are for informational purposes only. This article does not endorse any products. This article is not a medical advise and is not intended to treat, diagnose or prescribe for any illness or condition. Under no circumstances should you attempt self-diagnosis or treatment based on anything you have seen or read in this article.  Please consult your doctor or healthcare provider for your specific diagnosis and treatment.

Why should you be excited about lithium?

It is well documented that lithium can promote significant lifespan increase in different species, for example, a 46% median lifespan increase in worms, a 16% median lifespan increase in flies, and yeast. As a skeptic, you should rightly ask - will these results translate to humans?

Well, in the past 10 years, several important studies on lithium came out. For example, two studies looked at large cohorts of population (in Japan [2011] and Texas [2018]) and found that trace amounts of lithium in drinking water are associated with a lower all-cause mortality after adjustment for suicide mortality (which is decreased by lithium as shown by many studies across the world - more details below in this article) and socioeconomic status. Let me emphasize what’s most important here:

• Very low doses of lithium. Mean lithium levels in the Texas study ranged from 0.003 and 0.539 mg/L with a higher boundary showing statistically significant lowering of all-cause mortality. That would translate to 2 mg of lithium if you drink 4 liters of “lithium induced” water per day. For comparison, a typical lithium supplement will contain 1 to 5 mg of lithium per capsule.
• The studies were based on large cohorts of population in different part of the world (Japan, US, Greece, Austria) meaning that this effect is not specific to one population or its other living conditions.
• Life-long exposure to low dose lithium seems to be critical to experience a decrease all-cause mortality.

That all sounds great. Many longevity focused researchers, whom I know, take low-dose lithium and plan to take it for life for the reasons described above. However, in the general population there is still a fair amount of skepticism about lithium for several reasons, for example:

• It is used to treat bipolar disorder and is, thus, perceived as a powerful drug.
• It exhibits potential toxicity (mostly renal toxicity).
• In rat studies it has been associated with decreased sperm motility.

These concerns are not unfounded but they are all related to much higher doses (100-1000x) than what you need for longevity benefits.

In this article, I dive deeper into the science behind lithium and how it works to produce its benefits, namely:

• Improve mood by inhibiting activity of GSK3B enzyme

• Decrease risks of all-cause mortality
• Decrease risks of neurodegenerative diseases including dementia and Alzheimer’s
• Promote anti-aging by maintaining longer telomeres

What is lithium?

Lithium is one of the original earth elements (along with hydrogen and helium) and is a mineral abundantly present in nature in rocks, soil, and water.

Lithium salts, in the form of lithium carbonate, is a prescription medicine which have been used clinically to treat the symptoms of bipolar disorder for over 70 years and are sometimes used in a number of other conditions including major depression, schizophrenia, disorders of impulse control, and some psychiatric disorders in children. It is typically used in high doses. For example, a typical prescription for maintenance of bipolar disorder could be 900-1200 mg of lithium carbonate per day containing 170-225 mg of elemental lithium.  

At high doses lithium elicits potential toxic effects, mostly with renal function, thyroid function, and parathyroid function. That is why lithium has gained a somewhat cautionary reputation.

There is an alternative way to use lithium - in low doses in the form of lithium orotate. Lithium orotate is a dietary supplement which does not require a prescription. Animal studies show that it has a higher bioavailability compared to lithium carbonate.

How does lithium work?

While the specific biochemical mechanism of lithium action in improving mood, health, and lifespan is unknown, at least several mechanisms appear to be involved. The lithium ion Li+ competes with Sodium (Na+), Magnesium (Mg+2), and Calcium (Ca+2) thanks to its smaller diameter and, thus, has the ability to competitively act on several critical neuronal enzymes and neurotransmitter receptors. This is how most of the effects of lithium are modulated in the human body.

Lithium inhibits glycogen synthase kinase 3beta (GSK3B) which is involved in energy metabolism, neuronal cell development, and body pattern formation. Abnormal expression of GSK3B is associated with an increased risk of bipolar disorder. GSK3 has over 100 known substrates and about 500 probable substrates and lithium will to some extent influence all pathways where these substrates are involved.

Mitochondrial function may be especially sensitive to lithium levels because mitochondria contain much higher levels of active GSK3B compared to the cytosol. Mitochondrial damage and dysfunction are associated with both mood disorders and neurodegenerative disorders. Lithium has been shown to upregulate complex I and II in mitochondria in brain tissue and this might be one of the reasons for lithium’s positive effects on both disorders. In addition, inhibition of GSK3 gene activates Nrf2 pathway, an antioxidant response mechanism, leading to mitochondrial biogenesis or simply growth of new mitochondria. I talked in detail about mitochondrial biogenesis in the longevity principle #4. One study on flies showed that low dose lithium led to a 16% median life extension via activation of Nrf2 pathway. Activation of Nrf2 pathway is typical for interventions demonstrating a hormetic response curve. This means that a low dose stimuli, in this case, a low dose lithium, creates a beneficial type of stress response by the organism, called hormesis, while a high dose stimuli becomes toxic.

Another major mechanism of lithium’s action is inhibition of inositol monophosphatase, a key enzyme involved in the regulation of second-messengers (molecules that transmit signals received at receptors on the cell surface). Lithium induces autophagy by inhibiting inositol monophosphatase and this might be beneficial for treating and preventing neurodegenerative diseases.

Why do I like lithium?

Lithium is considered an essential nutrient meaning that it is required for normal body functioning and cannot be synthesized by the body. It is naturally found throughout the body in very low (trace) amounts and is present in many foods. Interestingly, there is substantial evidence based on observational and pre-clinical studies in humans that low-dose lithium exposure has strong benefits for mood, health, and lifespan.

Lithium consumption has been associated with enhanced mood. Lithium inhibits GSK3B enzyme which is expected to increase the expression of brain-derived neurotrophic factors (BDNF). Reduced levels of BDNF have been associated with depression, bipolar disorder, and dementia. In fact, at least 6 independent studies based on populations from different parts of the world (Texas [1990, 2013], Japan [2009], Austria [2012, 2015], Greece [2013], based showed that a higher lithium concentration in the drinking water was positively correlated with the lower suicide rates.

Low-dose lithium consumption has also been associated with decreased all-cause mortality in at least 2 observational studies using data on Japan [2011] and Texas [2018] suggesting a positive effect of low dose lithium supplementation on health and lifespan.

Long-term lithium supplementation may also support longer telomeres, protective caps for chromosomes. Shortening of telomeres is one of the hallmarks of aging. Lithium has been shown to increase the expression of the telomerase gene in human neural progenitor cells, which support longer telomeres.

In addition, lithium possesses neuroprotective properties and, thus, may be effective in treating and preventing neurodegenerative disorders.

How to take and NOT to take lithium?

• Lithium comes in 2 major forms - lithium carbonate (pharmaceutical form) and lithium orotate (supplement). Some might think that lithium orotate is less effective because it’s a supplement but it’s not. In fact, it has been shown to have 3x higher bioavailability (in rats).
• Lithium likely requires a long-term supplementation to achieve the highest health and lifespan benefits based on its effectiveness in long-term observational studies.
• Lithium should be taken in low-doses (1 mg capsule per day is enough).
• Lithium should NOT be taken in high-doses because it increases renal toxicity risks and doesn’t make it any more effective to decrease all-cause mortality. The exception here would be when a doctor prescribes higher doses to treat specific symptoms such as depression (naturopathic doctors often use lithium to improve symptoms of depression and prescribe doses ranging from 1 to 20 mg).

How does lithium feel?

If you have normal mood, you could experience no changes in mood to slight improvement. In my case, my general life satisfaction increased from 6 to 9 out of 10. I became calmer and all around happier. To be fair, other factors could have been at play here since it wasn’t a perfect experiment.

If you have unstable or low mood, you could experience noticeable improvements in your mood. However, this could require higher doses and take time (4-8 weeks) to feel the effect.

If you read reddit reports, you’ll find that some people experience headache when they start taking lithium. I normally never have headache but started experiencing onsets of severe headache after 3 days of taking lithium. I continued for another 3 days, then stopped for a couple of weeks, and continued again. I’ve been on lithium for 6+ months with no symptoms of headache.

Contraindications

• While lithium is generally safe, especially, in some people it can cause nausea, diarrhea, dizziness, muscle weakness, fatigue, and a dazed feeling.
• It should not be used by someone with significant renal or cardiovascular disease, severe dehydration or sodium depletion.
• Lithium may interact with medications such as ACE inhibitors, anticonvulsants, antidepressants, calcium channel blockers, dextromethorphan, loop diuretics, meperidine, methyldopa, and monoamine oxidase inhibitors (MAOIs).

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