Lithium to increase life expectancy?

In September, the New York Times published an article by Anna Fels, in which the author suggests adding lithium to drinking water, since trace amounts of this element are associated with a decrease in the likelihood of developing mental illness, the frequency of cruelty and, in particular, suicide. However, she did not mention that populations that consume water with a naturally high lithium content are also characterized by greater longevity. Despite insufficient evidence, there is a real mechanism acting by inhibiting a chemical signaling molecule known as glycogen synthase-kinase-3-beta (GSK-3-beta). The dosages in question are approximately 0.5-2 mg per day – no more than 0.1% of the dose of lithium, usually prescribed for the treatment of bipolar disorders.

Lithium is a chemical element located in the periodic table of Mendeleev above sodium. Theoretically, the body is not able to distinguish these two elements. Sodium is a vital electrolyte that performs a huge number of functions in the body. The movement of nerve impulses is carried out due to the exchange of sodium ions for potassium ions. There is a theory according to which lithium ions in residual amounts in the body can replace sodium ions and, due to their smaller weight and size, move a little faster through cell membranes.

The only study devoted to the study of the effect of lithium on mortality from all causes in humans and the effect of small concentrations of lithium on the lifespan of nematodes Caenorhabditis elegans was conducted in Japan – Zarse et al., Low-dose lithium uptake promotes longevity in humans and metazoan (European Journal of Nutrition, 2011). Within its framework, the composition of drinking water was analyzed and mortality rates were compared in 18 different cities, in which 1.2 million people lived in general.

Top picture: 18 Japanese cities. Bottom figure: C.elegans survival curve.

The upper diagram shows a 10% reduction in mortality in regions of Japan where drinking water is characterized by a naturally high lithium content. At a rough approximation, a 10% reduction in mortality roughly corresponds to one additional year of life. Larger circles correspond to regions with more numerous populations.

The lower graph shows the survival curve of nematodes contained in a lithium-enriched medium compared to control group nematodes contained in a conventional medium.

The most numerous and illustrative data on the number of suicides and brutal murders in cities with different natural lithium content in water. In a review by Mauer et al. Standard and trace-dose lithium: A systematic review of dementia prevention and other behavioral benefits (Australian and New Zealand Journal of Psychiatry, 2013) summarizes the results of 20 studies on this topic conducted in different parts of the world. It also presents the results of four studies in which lithium was used to treat Alzheimer's disease. In all four cases, a positive effect was demonstrated, manifested by an improvement in cognitive function.

Lithium in foodAccording to the well-established opinion, lithium does not accumulate in the body of herbivores and plants are the richest dietary source of this element.

What are the most useful plants? The answer to this question depends on the lithium content in the soil of the region in which the plants grow. A product can be called a "good source of lithium" only based on the region in which it is grown. Therefore, it is impractical to calculate the lithium content in the diet. A blood test can help with this, but when conducting it, it should be borne in mind that lithium is rapidly excreted from the body (along with sodium) and the results obtained will reflect only the food eaten within the last 24 hours.

How does it work?Of course, we do not know the mechanisms by which lithium exerts its effect.

However, all assumptions are circulating around a powerful and ubiquitous signaling molecule of glycogen synthase-kinase-3-beta (GSK-3-beta). Lithium suppresses the activity of this compound, the most detailed description of which (alpha and beta forms) is given in the article The Alpha and Beta of GSK-3s - first in the Strange but Powerful Molecules Series, published in 2014 in the blog of James Watson (James P Watson) - not to be confused with Watson, who received the Nobel Prize a prize for deciphering the structure of DNA!

Despite the similarity of nomenclature names, the alpha and beta forms of GSK-3 are not different forms of the same protein. They are two different compounds encoded by different genes. Moreover, their names reflect not so much the functions performed as the special circumstances of their identification (in 1980).

If "energy is the currency of the body", then phosphate groups can be considered as dollar bills. Kinases are enzymes that activate other compounds by attaching phosphate groups to them. GSK-3 are a kind of enhancers of kinase activity. They specialize in detecting molecules to which one phosphate residue is already attached, and attaching additional phosphate residues to them to fully activate the substrate.

GSK-3-beta has been implicated in the formation of amyloid plaques in brain tissue, which is considered the cause of the development of Alzheimer's disease. This stimulated the conduct of clinical studies of the effect of lithium on the condition of patients with this disease, which have already brought promising preliminary results.

Two forms of GSK-3 are involved in many different processes that activate and inactivate dozens of genes. The mechanisms of their action are very diverse and complex, so these compounds cannot be unambiguously characterized as useful or harmful. Watson views GSK-3-alpha as a "predominantly positive character", whereas GSK-3-beta as a "predominantly negative character". The expression of GSK-3-beta increases with age, which may contribute to aging. Moderate suppression of its activity (and lithium is one of its inhibitors) gives certain positive results. The expression level of GSK-3-alpha does not correlate with age. However, knockout of the GSK-3-alpha gene in mice not only does not deprive them of viability, but is also associated with less adipose tissue in the body and increased sensitivity of tissues to insulin. Both of these parameters are characteristic of increased life expectancy. However, GSK-3-alpha still remains a "predominantly positive character" due to its ability to suppress three targets of the aging process: mammalian rapamycin target protein (mTOR), a signaling mechanism mediated by the Wnt protein, and the p53 protein.

P53 performs the function of regulating apoptosis, or programmed cell death, the activation of which is greatly facilitated in old age. Indiscriminate suppression of apoptosis could preserve muscle and nerve cells, but it significantly increases the risk of cancer.

The mTOR protein is the target of the drug rapamycin, which became a sensation about three years ago. Experiments have demonstrated its ability to increase the lifespan of mice even at the beginning of use in the later stages of life. Rapamycin is a powerful immunosuppressor, which makes it too dangerous for widespread use, but other drugs that suppress the TOR-mediated signaling mechanism may well provide the desired results.

Assumptions for the futureApparently, both forms of GSK-3 are important components of the aging mechanism and other metabolic functions.

However, it is quite possible that they are not suitable targets for anti-aging interventions, since they simultaneously "advocate for both teams" (stimulate pro- and anti-aging mechanisms). The fact that they need "initiation" – preliminary phosphorylation by a more specific kinase – indicates that they do not lie at the origins of aging and that there are better targets.

In trace amounts, lithium may be useful for a moderate increase in life expectancy and preventing the development of Alzheimer's disease. I would like to see studies on mice and larger-scale epidemiological studies, which would subsequently allow for clinical studies. To date, only one epidemiological study has been conducted. It's probably not difficult to find a region where people rarely move and analyze the correlation between the concentration levels in drinking water and local variations in age at the time of death.

For those who can't waitIf you want to experiment with lithium, the author suggests that doses up to 1 mg per day are safe.

This is a very small amount. One ounce (28.3 grams) of lithium is enough for a lifetime. Higher doses are toxic to humans.

Lithium is not a standard ingredient in combined dietary supplements. Lithium carbonate is a prescription drug. It consists of tablets of 300 and 500 mg, which can be easily divided into doses of 1 mg (1000 mcg), dissolved in an appropriate amount of teaspoons of water, and taken one teaspoon at a time. Lithium salts can also be purchased in chemical reagent stores.

In addition, food additives containing low doses of organic lithium salts, such as arginate and lithium orotate, can be purchased online. They are no better and no more bioavailable than ordinary carbonate, but they are much more expensive.

From the editorial officeIn Russia, the normal concentration of lithium in the blood is 3.5-14 mg/ l (this is an outdated unit, long ago replaced by the SI 0.5-2 mmol/ l), which is almost 1000 times lower than used in medicine (in practice, it is not recommended to exceed the concentration of 1.2 mmol / l, the maximum permissible is 1.6 mmol / ll).

One of the serious problems when prescribing lithium preparations for the treatment of psychotic disorders is the need to observe a narrow therapeutic corridor of pharmacological doses in which the action of lithium is effective and safe (gradually increasing to 1.5-2.1 g per day) with regular monitoring of lithium concentration in the blood. But even at the same time, undesirable side effects may occur (first of all, tremor, nystagmus, coordination disorders, dysarthria, cardiac arrhythmias). In case of overdose, lithium acts primarily on the central nervous system and kidneys; overdose relatively often ends in death.

The author of the above article hints that it would be nice to take lithium daily in doses more than 3 times larger than the 100 micrograms that on average enter the body of an adult with water and food, although 4 orders of magnitude smaller than in psychiatric practice. If those who like to experiment on themselves will not be able to get a prescription in a district neuropsychiatric dispensary, lithium salts can be bought inexpensively in chemical reagent stores (although not less than a kilogram, and this in the dosages recommended by the author will be enough for a lifetime for 30 people). And lithium salts are very different there, except for carbonate.  You can, of course, replace it with orotate or citrate, but maybe it's better to wait for the results of experiments not on nematodes, but at least on rabbits first?

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Josh Mittendorf: Lithium for Life Extension?25.11.2014