The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No.
2 • March 2008
Activation of Autophagy for Neuroprotection:
Lithium Induces Autophagy, Delays
Amyotrophic Lateral Sclerosis
Autophagy (“self-eating”) is an important process in which defective organelles (such as mitochondria), aggregated proteins, and other undesirable cellular contents are “eaten” in autophagosomes and the constituents recycled. In fact, autophagy is not just important in the context of getting rid of “garbage.” Between meals, the liver and other organs routinely get some of the raw materials they need, such as amino acids and energy, via autophagy. As such, autophagy is important for survival during starvation.
As the authors of Reference 1 explain, “. . . the requirements for autophagy is [sic] even more evident under disease conditions. Recent studies reveal that degradation of disease-related mutant proteins is highly dependent on autophagy in addition to the ubiquitin-proteasome system.” Autophagy function is known to decline with aging and cancer has been genetically linked to autophagy malfunction. Moreover, loss of autophagy in the central nervous system has been shown to cause neurodegeneration in mice.
A very recent paper reports that lithium, at least in part by inducing autophagy, delayed the progression of amyotrophic lateral sclerosis (ALS) in 44 human patients affected by ALS. The patients received either riluzole (a standard drug treatment) or the same amount of riluzole plus two daily doses of 150 mg of lithium carbonate. Lithium delayed the development of ALS in the patients receiving it. “In fact, all subjects treated with lithium were alive at the end of the follow up (15 months) . . . By contrast, ~30% of the patients receiving [only] riluzole died during the study.” This survival difference was significant at 12 and 15 months. “When we compared the groups at the end of the follow up, the mean decrement in the normalized Norris score [a measure of disease progression] was 46.1% in patients receiving riluzole only and 10.6% in those receiving lithium.” The authors conclude that the patients receiving lithium had “very slow” progression in their disease as compared to those not receiving lithium.
In the same study, the researchers examined the effects of lithium treatment on the survival of motor neurons in a mouse model of ALS. They found preservation of the size of the motor neurons, preservation of motor neuron number and size in those areas that (in the ordinary course of the disease) degenerate later, and decreased aggregation of alpha-synuclein, ubiquitin, and SOD1. Moreover, the administration of lithium resulted in a marked increase in autophagy vacuoles, signifying induction of autophagy.
The dosage given the human patients, 150 mg of lithium carbonate twice daily, is far more than the low-dose lithium (1–4 mg per day) contained in a normal daily consumption of lithium-containing mineral waters. It is, in fact, within the therapeutic range of lithium taken by those with bipolar disorder for mania. Hence, we would not suggest that such a high dose be used only for the induction of autophagy in those without ALS, in light of potential side effects at therapeutic dosage levels. It is not clear whether low-dose lithium can induce autophagy; this would be a worthy subject for an aging research project, since even a small increase in autophagy could be a practical antiaging strategy.
1. Mizushima et al. Autophagy fights disease through cellular self-digestion. Nature 451:1069-75 (2008).
2. Komatsu et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880-4 (2006).
3. Hara et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885-9 (2006).
4. Fornai et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 105(6):2052-7 (2008).
5. Nielsen et al. Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc Natl Acad Sci USA 105(9):3634-9 (2008).
Sirt1 Inducers Such as Resveratrol May
Just as we were nearly finished writing this issue, we read an exciting, newly published paper that indicates that Sirt1 also induces autophagy. Autophagy is induced by starvation or chronic caloric restriction, and Sirt1 has been shown to be required for the beneficial changes of caloric restriction in mice. The new paper examined the role of Sirt1 in detail in a cell-culture study.
Sirt1 is a histone deacetylase, that is, it regulates whether a gene is turned on or off by modifying the acetylation of histones surrounding DNA to allow or not allow access to gene transcription molecules. The researchers of the new paper found that the absence of Sirt1 leads to markedly elevated acetylation of proteins known to be required for autophagy; the elevated acetylation deactivates them. They show that Sirt1 knockout mice embryonic fibroblasts do not fully activate autophagy under starved conditions. “Reconstitution with wild-type but not a deacetylase-inactive mutant of Sirt1 restores autophagy in these cells.”
The authors propose that Sirt1 can increase the manufacture of new mitochondria and, by inducing autophagy, stimulate the clearance of defective mitochondria. They and others have shown that “Sirt1 can interact and regulate the activity [of] the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor 1alpha (PGC-1alpha). Most evidence suggests that Sirt1 can augment PGC-1alpha activity and thereby increase the supply of new mitochondria. In this report, our data would suggest that by regulating autophagy, Sirt1 may also be important for the clearance of old and damaged mitochondria.”
There is evidence that resveratrol improves mitochondrial function by activating Sirt1 and PGC-1alpha. Thus, resveratrol very possibly enhances autophagy. We take resveratrol as a functional component in our MealMate™, a weight-control formulation. Another recent paper reports that NF-kappaB activation mediates the repression of autophagy in response to TNF-alpha (tumor necrosis factor-alpha) in three models of cancer cell lines. “In contrast,” the authors report, “in the absence of NF-kappaB activation, TNF-alpha induces macroautophagy (autophagy) . . .”
6. Lee et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105(9):3374-9 (2008).
7. Lagouge et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:
8. Djavaheri-Mergny et al. Regulation of autophagy by NFkappaB transcription factor and reactive oxygen species. Autophagy 3:4, 390-2 (July/Aug. 2007).