As research has continued to unfold around our understanding of lithium, some fairly interesting effects are starting to be revealed. While benefits for bipolar disorder, reducing aggression and risks of suicide are well established (Mueller-Oeringhausen 2010), other potential benefits of the mineral, including potential effects on aging itself, have started to emerge. Some of the latest studies show effects from lithium that may help hold back the turning of the cellular clock though interactions with telomeres.
Telomeres
There is currently a lot of hype around telomeres, so it’s worth establishing what telomeres are and what they do. Humans have linear chromosomes with each strand of DNA having a beginning and an end. Due to the functioning of DNA polymerase, the enzyme that copies DNA for cell division, the tail end of a DNA strand can not be copied and is lost with each replication (Levy 1992). Telomeres are a non-coding section of DNA filled with repeats of a specific sequence that effectively cap the end of each DNA strand. With every cellular DNA replication, a portion of this telomere cap is lost, shortening the strand. This protects the coding section of the DNA from degradation as cells reproduce.
When telomeres become too short, a cell can no longer divide and enters replicative senescence. The majority of cells in the human body appear to go through this process and have a “Hayflick limit,” the limit on the number of possible cell divisions before telomeres are exhausted (Mohamad 2020). Replicative senescence appears to be strongly tied to the overall aging process with cells from short-lived animals having a significantly lower Hayflick limit than cells from animals with a longer life span (Haines 2013). As telomeres become short, tissue dysfunction and organ failure can result.
On the flip side, processes that add telomere length or circumvent telomere shortening appear to allow cells to become immortal. Cancer cells that replicate endlessly are a significant example. Cancer that runs in families is sometimes associated with lengthened telomeres (McNally 2019).
Lithium, Telomeres and Telomerase
Interest in methods for extending cell life and thereby extending human lifespan have to address telomere length. Stress appears to shorten telomeres and research suggests an interplay between mental health and telomere shortening (Kapczinksky 2008).
A rat model of depression showed shorter telomeres and less telomerase activity in depressed animals. In cells, telomerase is an enzyme that can lengthen telomeres. In depressed rats treated with lithium, telomerase levels were increased and telomeres lengthened, although in the study, telomere lengthening didn’t reach full statistical significance (Wei 2015).
A recent analysis of bipolar patients suggests benefits for telomeres in humans as well. Bipolar patients both with a history of lithium treatment and without were compared to controls. Bipolar patients without a history of lithium treatment had shorter telomeres than bipolar patients treated with lithium. The treated patients had telomeres that were similar to control patients without bipolar disorder showing potential telomere protecting properties (Pisanu 2020). Other studies have documented increased enzymatic activity of telomerase with lithium, although failing to show telomere lengthening or preservation (Lundberg 2020).
Perhaps relatedly, lithium itself has been shown to have some potential benefits for a number of conditions associated with aging, including heart disease and Alzheimer’s dementia (Ahrens 1995, Velosa 2020). Research even suggests that the use of lithium decreases the risk of death in bipolar patients from all causes (Cipriani 2005, Smith 2015).
Telomeres, Mitochondria and Lithium
Putting all the pieces together, evidence is starting to suggest that lithium has neuroprotective properties due to effects on telomerase enzymes and mitochondrial function (Lundberg 2020). Mitochondria are often a source of free radical production in the body (Raha 2000). This free radical production has also been associated with aging and can play a part in damaging telomeres (Qian 2019).
Lithium has been shown to increase the activity of mitochondrial enzymes involved with energy production (Maurer 2009). It’s also been shown to protect mitochondria from damage from chemical agents (Valvassori 2010, Kim 2016). Lithium has even been shown to upregulate several genes involved with mitochondrial function (McQuillin 2007). While some studies have found lithium can damage mitochondria (Salami 2017), the concentration of lithium appears relevant, with therapeutic levels displaying more protective and supportive effects (Pietruczuk 2009). It appears plausible that lithium may also have indirect telomere protecting properties through improved mitochondrial function.
Conclusion
Lithium, as a treatment, displays a wide degree of biochemical effects that add to the complexity of its potential benefits. Research in bipolar patients is strongly suggestive of benefits for Alzheimer’s, heart disease and all cause mortality.
Telomeres and free radical production are intimately connected with diseases of aging and the aging process itself. The latest research is starting to suggest that some of lithium’s complex effects may involve telomere protection, increased telomerase activity and decreased damage to telomeres through reduced free radical production from improved mitochondrial function. With the challenges and costs associated with diseases of aging, it’s worth further exploration to elucidate and explore the potential anti-aging benefits of lithium.
References
Müller-Oerlinghausen B, Lewitzka U. Lithium reduces pathological aggression and suicidality: a mini-review. Neuropsychobiology. 2010;62(1):43-49. doi:10.1159/000314309
Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J Mol Biol. 1992;225(4):951-960. doi:10.1016/0022-2836(92)90096-3
Mohamad Kamal NS, Safuan S, Shamsuddin S, Foroozandeh P. Aging of the cells: Insight into cellular senescence and detection Methods. Eur J Cell Biol. 2020;99(6):151108. doi:10.1016/j.ejcb.2020.151108
Haines DD, Juhasz B, Tosaki A. Management of multicellular senescence and oxidative stress. J Cell Mol Med. 2013;17(8):936-957. doi:10.1111/jcmm.12074
McNally EJ, Luncsford PJ, Armanios M. Long telomeres and cancer risk: the price of cellular immortality. J Clin Invest. 2019;129(9):3474-3481. Published 2019 Aug 5. doi:10.1172/JCI120851
Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev. 2008;32(4):675-692. doi:10.1016/j.neubiorev.2007.10.005
Wei YB, Backlund L, Wegener G, Mathé AA, Lavebratt C. Telomerase dysregulation in the hippocampus of a rat model of depression: normalization by lithium. Int J Neuropsychopharmacol. 2015;18(7):pyv002. Published 2015 Jan 24. doi:10.1093/ijnp/pyv002
Pisanu C, Congiu D, Manchia M, et al. Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment. Pharmacogenomics. 2020;21(8):533-540. doi:10.2217/pgs-2020-0028
Lundberg M, Biernacka JM, Lavebratt C, et al. Expression of telomerase reverse transcriptase positively correlates with duration of lithium treatment in bipolar disorder. Psychiatry Res. 2020;286:112865. doi:10.1016/j.psychres.2020.112865
Ahrens B, Müller-Oerlinghausen B, Schou M, et al. Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium prophylaxis. J Affect Disord. 1995;33(2):67-75. doi:10.1016/0165-0327(94)00074-j
Velosa J, Delgado A, Finger E, Berk M, Kapczinski F, de Azevedo Cardoso T. Risk of dementia in bipolar disorder and the interplay of lithium: a systematic review and meta-analyses. Acta Psychiatr Scand. 2020;141(6):510-521. doi:10.1111/acps.13153
Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162(10):1805-1819. doi:10.1176/appi.ajp.162.10.1805
Smith EG, Austin KL, Kim HM, et al. Mortality associated with lithium and valproate treatment of US Veterans Health Administration patients with mental disorders. Br J Psychiatry. 2015;207(1):55-63. doi:10.1192/bjp.bp.113.138685
Lundberg M, Millischer V, Backlund L, et al. Lithium and the Interplay Between Telomeres and Mitochondria in Bipolar Disorder. Front Psychiatry. 2020;11:586083. Published 2020 Sep 29. doi:10.3389/fpsyt.2020.586083
Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci. 2000;25(10):502-508. doi:10.1016/s0968-0004(00)01674-1
Qian W, Kumar N, Roginskaya V, et al. Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction. Proc Natl Acad Sci U S A. 2019;116(37):18435-18444. doi:10.1073/pnas.1910574116
Maurer IC, Schippel P, Volz HP. Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord. 2009;11(5):515-522. doi:10.1111/j.1399-5618.2009.00729.x
Valvassori SS, Rezin GT, Ferreira CL, et al. Effects of mood stabilizers on mitochondrial respiratory chain activity in brain of rats treated with d-amphetamine. J Psychiatr Res. 2010;44(14):903-909. doi:10.1016/j.jpsychires.2010.02.009
Kim HK, Isaacs-Trepanier C, Elmi N, Rapoport SI, Andreazza AC. Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment. J Psychiatr Res. 2016;76:59-65. doi:10.1016/j.jpsychires.2016.02.001
McQuillin A, Rizig M, Gurling HM. A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder. Pharmacogenet Genomics. 2007;17(8):605-617. doi:10.1097/FPC.0b013e328011b5b2
Salimi A, Gholamifar E, Naserzadeh P, Hosseini MJ, Pourahmad J. Toxicity of lithium on isolated heart mitochondria and cardiomyocyte: A justification for its cardiotoxic adverse effect. J Biochem Mol Toxicol. 2017;31(2):10.1002/jbt.21836. doi:10.1002/jbt.21836
Pietruczuk K, Jóźwik A, Ruckemann-Dziurdzińska K, Bryl E, Witkowski JM. Cytoprotective effect of lithium against spontaneous and induced apoptosis of lymphoid cell line MOLT-4. Folia Histochem Cytobiol. 2009;47(4):639-646. doi:10.2478/v10042-009-0118-8
