The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No.
3 • July 2005
More on Glycogen Synthase Kinase-3, Inhibited by Lithium:
Alzheimer’s, Neurotoxicity, and Cellular Senescence
Glycogen synthase kinase-3beta is a central figure in many intracellular signaling pathways and is inhibited by lithium. We wrote earlier about this in our discussion of our brain-maintenance formulation that includes low-dose lithium for the purpose of partially inhibiting glycogen synthase kinase-3beta.*
As glycogen synthase kinase-3 is importantly involved in cell survival and proliferation, many new findings are being reported on its effects. Here we report on four of the latest papers we’ve found: inhibition of glycogen synthase kinase-3 as a potential protectant against the development of Alzheimer’s disease, how the inactivation of glycogen synthase kinase-3beta protects against kainic acid-induced excitotoxicity in brain cells, and how glycogen synthase kinase-3 accumulates in the nuclei of replicatively senescent human fibroblasts.
Alzheimer’s: A new paper reports that inhibition of glycogen synthase kinase-3 by lithium correlates with reduced levels of aggregated, insoluble tau. Tau is a normal protein found in the brain, but its abnormal aggregated and insoluble form is found in neurofibrillary tangles, such as are found in aging and in larger quantities in Alzheimer’s disease. This study found that levels of aggregated tau correlated strongly with the degree of axonal degeneration, while lithium-treated mice showed less degeneration when begun during the early stages of tangle development.
In the next paper, researchers found that glycogen synthase kinase-3 protein was increased in white blood cells in both Alzheimer’s patients and those with mild cognitive impairment relative to elderly controls. The authors explain, “These data are in line with previous studies suggesting an altered response to insulin in AD [Alzheimer’s disease]. Glucose regulation is aberrant in AD, and fasting plasma insulin levels are higher; features of insulin resistance indicative of a failure of the normal inhibitory effects of insulin on GSK-3 [glycogen synthase kinase-3]. They are also in line with neuroimaging studies pointing to altered glucose utilization in brain in AD.” [citations omitted] The authors suggest, therefore, that “… inhibition of GSK-3 might be a useful therapeutic strategy.” Moreover, “Our findings raise the possibility that measures of GSK-3 in circulating white cells might be useful in the diagnosis of AD.”
Excitotoxicity: In another paper, scientists found that lithium was protective against kainic acid-induced excitotoxicity in hippocampal slice cultures.
Cellular Senescence: In the final paper, an interesting interaction of glycogen synthase kinase-3 with p53 (an important tumor-suppressor protein) in which the activity of p53 was enhanced was reported. When cells are damaged, p53 is induced; p53 suppresses cell division and hence permits damage repair (or apoptosis if the damage is too great to repair) to take place. Senescent cells do not divide; hence, having a large percentage of senescent cells can promote aging by limiting repair by cell division to replace damaged and defective cells. The researchers found that, compared with young and middle-aged human WI-38 fibroblasts, senescent cells contained increased levels of glycogen synthase kinase-3beta in the nucleus (and also tended to contain increased levels of the other isoform, glycogen synthase kinase-3alpha). Upon inhibition of glycogen synthase kinase-3beta with lithium, the senescence-associated accumulation of p53 was reduced. The treated cells exhibited changes (lithium blocked the increases in beta-glucosidase, p53, and p21 normally associated with senescence) suggesting a reversal of senescence into a reversible state of quiescence. These effects were seen for lithium at a dose of 10mM, but not at 1 mM or 3 mM. It is not clear from this study, as it is a cell-culture study, what would be an appropriate and effective, yet nontoxic, dose of lithium in a whole organism, let alone a human, for the purpose of “treating” cell senescence. Nevertheless, we consider safe low-dose lithium supplementation possibly to have a beneficial effect on such senescence, since even small doses may inhibit glycogen synthase kinase-3beta to some extent. It is certainly worth studying further.
- Jope and Bijur. Mood stabilizers, glycogen synthase kinase-3beta, and cell survival. Molec Psychiatry 7:S35-45 (2002).
- Noble et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102(19):6990-5 (2005).
- Hye et al. Glycogen synthase kinase-3 is increased in white cells early in Alzheimer’s disease. Neurosci Lett 373:1-4 (2005).
- Goodenough et al. Inactivation of glycogen synthase kinase-3beta protects against kainic acid-induced neurotoxicity in vivo. Brain Res 1026:116-25 (2004).
- Zmijewski and Jope. Nuclear accumulation of glycogen synthase kinase-3 during replicative senescence of human fibroblasts. Aging Cell 3:309-17 (2004).